JPH0367044B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel poultice that has excellent water retention, adhesive properties, and cooling sensation, and significantly reduces side effects such as dermatitis. More specifically, an aqueous solution of a hydrophilic polymer is dispersed in a base polymer consisting of a thermoplastic elastomer and a necessary softener without the use of an emulsifier (surfactant) as its base component, and then the medicinal properties are added to the base polymer. The present invention relates to a poultice characterized by containing the following ingredients. Now, conventional poultices have methyl salicylate and menthol as the main ingredients, water as a dispersion medium, and excipients such as zinc oxide kaolin and bentonite, and as necessary, polyethylene glycol, gelatin, gum arabic, polyvinyl alcohol, and carboxyvinyl polymer. , cellulose derivatives, etc. were commonly used. However, this conventional product had drawbacks in stability during storage, drug release, adhesive strength, release of medicinal odor, etc., and was not necessarily satisfactory. Therefore, in recent years, various studies have been conducted to compensate for the above-mentioned drawbacks, one of which is a teleblock copolymer elastomer of the A-B-A type (definitions of A and B will be described later), which is a thermoplastic elastomer. A water-containing gel is obtained by emulsifying and dispersing water particles using an emulsifier (surfactant) in an oily continuous phase consisting of oil and oil components. Poultices containing medicinal ingredients such as medicinal ingredients are being considered. However, it is clear that emulsifiers (surfactants) are added as an essential component to the plasters using the known A-B-A type teleblock copolymer elastomer. The reasons for this need not be stated, but are common knowledge in terms of physical chemistry. I can't stand it. (2) Solubility and release of drugs added to poultices;
It has a negative effect on diffusion in the base material. All of these are related to the basic properties of poultices, and the inclusion of emulsifiers (surfactants) is considered to be necessary. However, poultices containing emulsifiers (surfactants) (1) promote side effects such as dermatitis (rash, itching, redness, etc.); (2) The mixed water and drug remain trapped and are poorly released from the plaster, resulting in a cooling sensation on the affected area and a lack of medicinal efficacy. Although various studies have been made to address these serious drawbacks, they have not yet been resolved. Therefore, the inventors of the present application have conducted various studies in search of developing a cataplasm that overcomes the drawbacks of the above-mentioned emulsifiers (surfactants).As a result, in a cataplasm using an A-B-A teleblock copolymer elastomer, They discovered a new composition that is completely contrary to the physical and chemical common sense of blending water without using an emulsifier (surfactant), and completed the present invention as detailed below. The present invention uses a thermoplastic elastomer and a necessary softening agent such as oil or higher fatty acid as a base polymer, and disperses a specific hydrophilic polymer aqueous solution described below without using an emulsifier (surfactant).
This invention relates to a pad made by blending various medicinal ingredients into the base obtained thereby. Each component will be explained one by one below. The thermoplastic elastomer has the following general formula (A-B)n-A [where A is substantially a monovinyl-substituted aromatic compound polymer block, B is substantially a conjugated diolefin polymer block, n represents an integer from 3 to 7]
It means a copolymer represented by and a mixture thereof. Examples of the monovinyl-substituted aromatic compound include styrene, o- or p-vinyltoluene, methylstyrene, ethylstyrene, and the like. In addition, conjugated diolefins include 1,3-butadiene,
Examples include 1,3-pentadiene and isoprene. A particularly preferred combination is styrene and 1,3-
Butadiene, styrene and isoprene. Block A, which is a polymer of styrene, is an inelastic thermoplastic hard polymer with a glass transition temperature of 25°C or higher, and Block B, which is a copolymer of isoprene or butadiene, is an elastic polymer with a glass transition temperature of lower than room temperature. It is a copolymer. The terminal block A of the block copolymer comprises approximately 10-15% of the total weight. Specific examples of the thermoplastic elastomer used in the present invention include, for example, CALIFLEX TR-1101 (styrene-butadiene-styrene block copolymer) manufactured by Ciel Chemical Co., Ltd., which is easily available as a commercial product; Califrex TR-
1102 (styrene-butadiene-styrene teleblock copolymer), CALIFLEX TR-1107 (styrene-isoprene-styrene block copolymer), CALIFLEX 1107 (styrene-isoprene-styrene teleblock copolymer), CALIFLEX 1102 (styrene-butadiene-styrene block copolymer), manufactured by Asahi Kasei Corporation, product name: Solprene T-431 (styrene-butadiene-
Styrene radial teleblock copolymer), manufactured by Philippe Petroleum Company, product name: Soprene
418 (styrene-isoprene-styrene radial block copolymer) and the like. However, it goes without saying that the present invention is not limited to the above-mentioned examples. In addition, the amount of the thermoplastic elastic body used in the present invention is at least 1 to 30% by weight, preferably 2 to 20% by weight, and more preferably 3 to 10% by weight based on the total plaster.
% by weight. Next, the oil or higher fatty acid to be used as a softening agent is selected from liquid paraffin, olive oil, camellia oil, almond oil, berth oil, peanut oil, oleic acid, and the like. In addition, the amount thereof to be blended is 1 to 50% by weight, preferably 2 to 40% by weight, and more preferably 5 to 30% by weight based on the total mass of the paste. Next, the hydrophilic polymer aqueous solution (hereinafter simply referred to as the present aqueous solution), which is the most significant feature of the present invention, will be described. The specification of this aqueous solution allows water to be blended into the thermoplastic elastomer without using an emulsifier (surfactant) in the present invention. Now, this aqueous solution is composed of a specific hydrophilic polymer, a specific polyhydric alcohol, and water, and this structure itself has significant characteristics. First, the hydrophilic polymers used in this aqueous solution include polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid or their salts or esters, crosslinked polyacrylic acid or salts or esters, sodium carboxymethyl cellulose, polyvinyl methyl ether, arabic rubber,
It means one selected from hydroxyethyl cellulose, methyl cellulose, sodium alginate, pectin, carboxyvinyl polymer, gelatin, polyethylene oxide, etc., or a mixture thereof. Among them, particularly preferable hydrophilic polymers are polyvinyl alcohol, polyvinylpyrrolidone, polyacrylates, or esters [e.g., trade name, LUBARAJEL
)], crosslinked polyacrylates or esters,
Carboxymethylcellulose sodium, etc. The amount of the hydrophilic polymer in the aqueous solution is 1 to 30% by weight, preferably 1 to 20% by weight, and more preferably 1 to 15% by weight. Next, as the polyhydric alcohol used in the aqueous solution, one of glycerin, sorbitol, maltitol, polyethylene glycol, polypropylene glycol, etc. or a mixture thereof is used. In addition, the amount blended in this aqueous solution is 2
It is used in a range of 60% by weight, preferably 5% to 50% by weight, more preferably 7% to 40% by weight. Next, water is added to the aqueous solution in an amount of 2 to 80% by weight, preferably 2 to 70% by weight, and more preferably 3 to 60% by weight. As detailed above, this aqueous solution is composed of the above-mentioned hydrophilic polymer, polyhydric alcohol, and water, and the amount of this aqueous solution added to the total paste is 30 to 90% by weight, preferably By blending 50 to 85% by weight, the desired effects of the present invention can be obtained. Next, the medicinal ingredients contained in the poultice of the present invention will be described. Medicinal ingredients include ketoprofen, indomethacin, ibuprofen, alcrofenac,
flurbiprofen, diclofenac, fuenoprofen, pirprofen, naproxen, sulindac, benoxaprofen, indobufuen, pranoprofen, indanal, fentiazac, diflunisal, miloprofen, amfenac, zomepirac, sprofen and their ester derivatives, oxyphenbutazone, Non-steroidal analgesic and anti-inflammatory agents such as pentazocine, fenazole, mepirizole, piroxicam, bufuexamac, acemethacin, etofenamate, zontar, fenbufuen, bendazac, ibuprofen piconol, salicylic acid, methyl salicylate, salokol and platonin;
This refers to anti-rheumatic drugs such as lobenzaritu (CCA) used alone or in combination of two or more. The above medicinal ingredients are used by dissolving the drug in a solubilizer such as benzyl alcohol butyl benzoate, isopropyl myristate, isopropyl palmitate, polypropylene glycol, crotamiton, ethylene glycol, butylene glycol, diethyl sebacate, diisopropyl adipate, etc., as necessary. It will be done. Furthermore, peppermint oil, l
-Skin irritants such as menthol, camphor, nonylic acid vanylamide, capsaicin, and conventionally known transdermal absorption enhancers, stabilizers, anti-aging agents, ultraviolet absorbers, antioxidants, kaolin, titanium oxide,
Inorganic fillers such as zinc oxide and talc, polybutene,
Additives such as polyisobutylene, rosin, and ester gum can also be blended as necessary. or,
There is no problem in adjusting the pH by adding various acids (for example, citric acid, tartaric acid, oxalic acid, phosphoric acid, sorbic acid, succinic acid, and ascorbic acid) to improve drug stability. The amount of the medicinal ingredient to be added to the total paste is 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight. Next, a method for manufacturing the poultice of the present invention will be explained. The poultice of the present invention can be easily produced by conventionally used known methods, known techniques known from literature, and simple application techniques thereof. An example of the manufacturing method will be shown below, but it goes without saying that it can be manufactured by other similar methods. Adding 1 to 30% by weight of a thermoplastic elastomer to 1 to 50% by weight of oil or higher fatty acid as a softening agent,
A base polymer is obtained by heating and melting at ~200°C for 5 to 60 minutes. Next, the mixture is heated to 50 to 180°C, and a 30 to 90% by weight aqueous solution of a hydrophilic polymer consisting of a hydrophilic polymer, a polyhydric alcohol, and water is added, and the mixture is stirred and mixed for 1 to 60 minutes to obtain a uniform melt. Then 20
At ~150°C, 0.01~5.0% by weight of the medicinal ingredient is dissolved in a dissolving agent, added to the dissolved solution with stirring, and mixed and dispersed until a uniform state is obtained to obtain a paste. The obtained paste is spread and coated on a support selected from fabric, nonwoven fabric, paper, synthetic resin film, etc. using a spreading machine such as a doctor roll, reverse roll, or knife coater, and then a release coating is applied thereon. Paste things together. The release coating is appropriately selected from release-treated release paper, cellophane, polyethylene, polypropylene, silicone, or silicone-treated paper. Finally, it is cut into the desired shape to make a usable poultice. The above are manufacturing examples of the present invention. As detailed above, the present invention provides: (1) (A-B) nX or (A-B) n-A [A,
The definitions of B, The present invention relates to a poultice comprising an aqueous polymer solution; (4) a medicinal ingredient; and the amount of each ingredient is the specified amount. As is clear from the above structure, the present invention does not use any emulsifier (surfactant) when adding water. Therefore, the poultice obtained from the present invention includes:
It has the following superior effects compared to conventional poultices using emulsifiers (surfactants). That is, when applied to human skin, (1) drug release is good and long-lasting (2) drug absorption is good through the skin (3) water release stability (water retention) is good (4) ) It has a good cool feeling and is long-lasting. (5) It has moderate adhesiveness and elasticity, and there is no plaster left behind when it is peeled off. (6) It is extremely stable against changes over time under high temperature and high humidity conditions. (7) It has remarkable effects such as significantly reducing side effects such as skin disorders (dermatitis), and it is believed that the completion of the present invention will make a significant contribution to industry as a very useful pharmaceutical product. . Next, conventional technology related to the present invention will be explained. Publicly known materials regarding topical patches using thermoplastic elastic materials include Japanese Patent Publication No. 56-34567;
There are patent publications such as JP-A-56-12613, JP-A-56-18916, JP-A-56-20515, and JP-A-55-92314. However, in all of the above-mentioned publicly known materials, emulsifiers (surfactants) are clearly described as essential components, and there is no mention at all of poultices that do not contain emulsifiers (surfactants). Of course, there is no description that suggests this. In other words, the present invention forms a poultice without using an emulsifier (surfactant) when a thermoplastic elastomer and a softener are used as a base polymer, and an aqueous hydrophilic polymer solution and a medicinal ingredient are blended therein. This is the first thing a person could have done. The excellent effects of the present invention are as described above, but in order to further explain this, test examples will be shown below. In addition, in the test examples, the poultices of examples, commercially available poultices A, and poultices of reference examples refer to the poultices obtained in the examples and reference examples described later in the specification of the present application, and the poultices described later. This shows a commercially available poultice with the same composition. Test Example 1 Usability Comparison Test Examples 1 and 2 of the present specification were administered to 30 subjects.
The poultice described in Reference Example 3 and the commercially available poultice A as a comparative example (a poultice based on a thermoplastic elastomer, the composition of which is as described below), and the poultice described in Reference Example 3 (composition The compositions are described below as reference examples.) were applied to the surface of the forearm and peeled off after 6 hours. The following items were tested and judged. The results are shown in Table 1. The judgment method was to have the subjects report the corresponding test results for each test item using the following scores. [Test items, distribution of test results, and scores] (a) Cold sensation Strong cold sensation...3 Mild cold sensation...2 No cold sensation...1 (B) Duration of cold sensation 3 hours More than 3 hours...2 None...1 (c) Fast-acting (time to start feeling irritation) Within 5 minutes...3 Within 5-10 minutes...2 10 minutes or more...1 (d) Stimulation Duration (time until irritation disappears) More than 5 hours ...3 2 to 5 hours ...2 Less than 2 hours ...1 (e) Adhesion Good adhesion throughout application ...3 Edges peel off Items that have more than half peeled off...1 (F) Strength of irritation Very strong...3 Strong...2 Weak...1 (G) Pain when peeling Easily peeled off...3 Feeling pain ...2 I feel strong pain ...1 Table 1 below shows the total of the scores answered by each subject regarding the above seven items, and the average values for each of the 30 people for each item.

[Table] As is clear from the above results, the patch of the present invention has a better cooling sensation, quick-acting, durability, adhesion, strength of irritation, and time of peeling compared to commercially available poultices and reference poultices. Remarkable good results were obtained regarding pain. Test example 2 Adhesive force test Tatsuku tester (product name: Pikma tatsuku tester
PICMA TACK TESTE (manufactured by Toyo Seiki Co., Ltd.)
The adhesive strength was compared using The results are shown in Table 2 below.
Shown below. The definition of commercially available poultices is as described above.

[Table] From the above results, it is clear that the poultice of the present invention has superior adhesive strength compared to commercially available poultices. Test Example 3 Stability Test Each patch was covered with a release film, placed in a sealed bag, and left for 2 hours at a temperature of 70°C and a humidity of 90%, and then observed for sagging of the plaster and seepage of the base fabric. The results are shown in Table 3 below. Incidentally, the evaluation was made as ○ if no sag or seepage was observed, and × if observed. The definitions of commercially available poultices and reference examples are as described above.

[Table] From the above results, it is clear that the poultice of the present invention is stable at high temperatures and high humidity. Test Example 4 Human Skin Irritation Test Twenty healthy male volunteers were administered the poultices described in Example 1, Example 2, and Reference Example 3 of the present specification as well as commercially available poultice A (as defined above). ) were applied to the back for 24 hours. The degree of skin irritation was determined by observing the degree of skin change 1 hour and 24 hours after peeling. The results are shown in Table 4. In Table 4, Examples 1, 2, and Reference Example 3 refer to poultices having the compositions described in the Examples and Reference Examples. In addition, the criteria for determining skin irritation are as follows. No change: - is displayed. Slight redness: ± 〃 Clear redness: ＋ 〃 Severe feeling: 〃

【table】

[Table] As is clear from the above results, the poultice of the present invention causes much less skin irritation than the poultice of the reference example and the commercially available poultice. Test Example 5 Moisture release test Poultice described in Example 1, commercially available poultice A
(the definition is as above), and three types of poultices described in Reference Example 3, [20g each (10×
14cm)], the release paper was peeled off, it was pasted on aluminum foil, and it was left in a constant temperature room at 32°C. The weight was measured every hour to measure the amount of water volatilization. The results are shown in Figure 1. (A) shows the poultice described in Example 1 of the present invention, (B) shows the commercially available poultice A, and (C) shows the poultice described in Reference Example 3. As is clear from FIG. 1, compared to the other two types, the poultice of the present invention can stably release a sufficient amount of water to provide a sustained cooling sensation. Test Example 6 Percutaneous Absorption Test Fifteen male Wistar rats (weighing around 110 g) were divided into three groups, and the animals' back coats were removed the day before the experiment. The poultice described in Example 1 of the present invention, which had been cut to a size of 2 x 2 cm, was applied to the back skin and covered and fixed with adhesive tape. Reference example 3 for the other group
The poultice described in 1. was fixed in the same manner in a size of 2 x 2 cm. In another group, 28.6 mg of 3% caprofen ointment was evenly applied to the back skin in an area of 2 x 2 cm. After applying the patch for 6 hours, blood was collected by cutting the femoral artery and vein, and after coagulation, centrifugation was performed at 2800 rpm for 15 minutes to collect serum. Transfer 0.5ml of serum to a test tube with a screw cap, add 0.5ml of distilled water and 0.1ml of perchloric acid (60%).
ml, then 6 ml of ether was added, followed by shaking and extraction for 15 minutes. After centrifugation, 5 ml of the ether layer was transferred to another test tube and washed with 2 ml of 1N hydrochloric acid and then with 2 ml of distilled water. After dehydrating the ether layer with anhydrous sodium sulfate, 3 ml of the ether layer was collected, and the solvent was distilled off at 40 to 50°C under a nitrogen stream. The residue was dissolved in 0.5 ml of methanol, filtered through a Millipore filter (size 0.5 μm), and 10 μm of the solution was injected into a high performance liquid chromatograph under the following conditions for quantitative determination. At the same time, add ketoprofen to 0.5 ml of control serum at 0.1, 0.2,
A recovery calibration curve was created by adding 0.5, 1.0, 2.0, 4.0 and 10.0 μg and performing an extraction operation. Measurement conditions Equipment: Waters ALC/GPC M-244 Column: Radial pack cartridge C ₁₈ inner diameter 4
mm, length 10cm Solvent: Acetate buffer (PH3.2) Acetonitrile (3:7) Flow rate: 1.5ml/min Injection size: 10μ Detector: UV 254nm x 0.02 AUFS The test results are shown in Table 5.

[Composition of commercially available poultice A]

Califrex TR-1107 6.7% by weight Liquid paraffin 66.9〃 Sorbitan monoaliphatic ester 3.3 〃 Methyl salicylate 1.7〃 l-menthol 0.7 〃 dl−camphor 0.7 〃 Wednesday 20.0 〃 100.0% by weight

[Brief explanation of drawings]

(1) Figure 1 shows the amount of water volatilized per hour after leaving the poultice at 30°C with the base fabric side up. (2) In FIG. 1, A represents the poultice described in Example 1, B represents the commercially available poultice A, and C represents the poultice described in Reference Example 3.

Claims (1)

[Scope of Claims] 1. A hydrophilic polymer aqueous solution consisting of a hydrophilic polymer, a polyhydric alcohol, and water is added to a base polymer consisting of a thermoplastic elastomer and a softener as base components in an amount of 30 to 90% by weight of the total amount. % and contains medicinal ingredients. 2 The thermoplastic elastomer of the base component is (A-B)n-
A-type elastic copolymer [wherein A is substantially a monovinyl-substituted aromatic compound polymer block, B is substantially a conjugated diolefin polymer block, and n represents an integer from 3 to 7]; The blending amount is 1 to 30
A hydrophilic polymer aqueous solution consisting of a hydrophilic polymer, a polyhydric alcohol, and water is added to a base polymer whose blending amount is 1 to 50% by weight, and the softener is oil or higher fatty acid.
~90% by weight, dispersed, and further add 0.01~90% of analgesic and anti-inflammatory agent or anti-rheumatic agent as a medicinal ingredient.
The poultice according to claim 1, characterized in that it contains 5.0% by weight. 3 The hydrophilic polymer aqueous solution contains 1 to 30% by weight of the hydrophilic polymer based on the total amount of the hydrophilic polymer aqueous solution,
Claim 1, characterized in that it consists of 5 to 60% by weight of polyhydric alcohol and 1 to 80% by weight of water.
The poultice according to item 1 or 2.