JPS6248643B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a patch with improved drug release properties. Ointments conventionally used as external skin preparations,
Liquid liniments and sprays allow for easy adjustment of the drug content and are excellent in fast-acting properties, but there is a large loss of drug due to the drug adhering to clothing.
Therefore, a patch has been proposed in which a pressure-sensitive adhesive layer carrying a drug is provided on a support. This type of patch includes one in which a drug is mixed into the adhesive layer, and one in which the drug is coated on the surface of an adhesive layer. However, in the former case, it is difficult for the drug to be efficiently released from the surface of the adhesive layer, resulting in poor drug utilization or rapid action.On the other hand, when a large amount of the drug or a release auxiliary substance that promotes the release of the drug is added, the adhesive properties deteriorate. It will be damaged. In addition, in the latter case, since the drug is applied to the surface of the adhesive layer, its adhesive properties are impaired, and it also has drawbacks such as the inability to adhere a large amount of the drug and the durability of the drug's efficacy. This invention aims to provide a more effective adhesive patch that does not have the above-mentioned drawbacks, and one embodiment of this invention will be described below with reference to the drawings. FIG. 1 is a cross-sectional view showing an example of the adhesive patch of the present invention, in which 1 is a support made of a synthetic resin film such as polyethylene, paper, nonwoven fabric, or other generally flexible material; 2 is the support described above. This is an adhesive layer provided on a support 1 with a thermoplastic resin film 3 interposed therebetween. 4 is a drug-containing component embedded in a large number of small holes 5 penetrating the adhesive layer 2 and the thermoplastic resin film 3; 6 is a partition wall for preventing contact between the component 4 and the adhesive layer 2; The partition wall 6 is formed by extending the base portion 3a of the thermoplastic resin film 3 to the inner wall surface of the small hole 5. Next, the manufacturing method of this patch will be explained with reference to the process diagram in Figure 2. For example, in step (A), a thermoplastic resin film 3 made of polyethylene, nylon, etc. is coated with natural rubber, synthetic rubber, or styrene. - Applying an adhesive composition containing various adhesive polymers such as isoprene-styrene block polymer, polyacrylic acid ester, and polyisobutylene, and tackifiers and other additives as necessary. An adhesive layer 2 is formed. Next, in step (B), after bonding the heat-resistant release film 7 to the adhesive layer 2, a perforator M as shown in the figure is heated and pressed at appropriate intervals from the thermoplastic resin film 3 side. The pressed portion of the film 3 is softened and stretched toward the heat-resistant release film 7 so that the pressure-sensitive adhesive layer 2 in that portion is wrapped therein, and then cut. By this cutting, a large number of small holes 5 penetrating the thermoplastic resin film 3 and the adhesive layer 2 are formed, and at the same time, the small holes 5
A partition wall 6 from which a base portion 3a of a thermoplastic resin film 3 extends is formed on the inner wall surface. Next, in the step (C), the support 1 is laminated on the base 3a of the thermoplastic resin film 3, and then the heat-resistant release film 7 is peeled off in the step (D). Fill in 4. After this embedding, a separator is attached to the two sides of the adhesive layer as needed to obtain a patch having the above structure. The drug-containing component 4 to be implanted in step (D) above is generally a mixture of a drug and a release auxiliary substance that usually promotes the release of the drug in a solidifying agent (drug retention agent) such as various polymers and greases. It is. In some cases, it is also possible to use the drug or the release aid alone. The drugs used here are those that can be transferred or absorbed into the body, such as corticosteroids, anesthetics, antihistamines, antibacterial substances, antifungals, analgesics and anti-inflammatory agents, keratin emollients,
There are vitamins, anticonvulsants, etc., and systemic drugs such as antihypertensive agents, antibiotics, central nervous system agents, vasodilators, antispasmodics, sedatives, sex hormones, and antidiabetic agents. An appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug. Corticosteroids include prezonisolone acetate, presonisolone, hydrocortide acetate,
Examples include hydrocortide, dexamethasone, fluocinolone acetonide, betamethasone, beclomethasone propionate, fludroxycortide, fluocinonide, and the like. Anesthetics include benzocaine, lidocaine, and ethyl aminobenzoate, antihistamines include diphenhydramine hydrochloride, isocypenzyl hydrochloride, and diphenylimidazole, and antibacterial agents include benzalkonium chloride and nitrofurazone. Examples of the agents include nystatin and undecylenic acid, and examples of analgesic and anti-inflammatory agents include indomethacin, methyl salicylate, glycol salicylate, salicylic acid amide, and sodium salicylate. In addition, salicylic acid, vitamin A, atropine,
Examples include methscopolamine bromide. In addition, systemic drugs such as antihypertensive agents such as reserpine and clonidine, antibiotics such as erythromycin, chloramphenicol, cephalexin, tetracycline, neomycin sulfate, oxytetracycline, and penicillin, and central nervous system agents such as barbiturates, diazepam, nitrazepam, and chlorpromazine and vasodilators such as nitroglycerin and isosorbide dinitrate. In addition, release aid substances that can be used with the above drugs can be simply defined as those that promote the release of drugs to the body surface, but this includes improving the solubility and diffusivity of the drug within the adhesive layer. Transdermal absorbability, such as the ability to retain water in the stratum corneum, soften the stratum corneum, permeate the stratum corneum (loosening it), act as a penetration aid or pore opener, and change the surface condition of the skin. This includes a wide range of drugs, including those that have the function of improving the drug's efficacy, and those that have both of the above-mentioned functions, or in addition to these functions, also have the function of promoting drug efficacy to make the drug more effective. Specific examples of these release aids include glycols (mainly drug-soluble) such as diethylene glycol, propylene glycol, and polyethylene glycol; oils and fats (mainly drug-diffusing) such as olive oil, squalene, and lanolin; urea;
Urea derivatives such as allantoin (mainly for the water retention capacity of stratum corneum), dimethyldecyl phosphooxide, methyloctyl sulfoxide, dimethyl laurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetamide, dimethyl sulfoxide,
Polar solvents such as dimethylformamide (mainly keratin permeability), salicylic acid (mainly keratin softening), amino acids (mainly penetration aid), benzyl nicotinate (mainly pore opening agent), sodium lauryl sulfate (mainly (function that changes the skin interface condition), Sarokol (used in combination with drugs that have good transdermal absorption), etc. Others diisopropyl adipate, phthalate ester,
Examples include plasticizers such as diethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers, ethoxylated stearyl alcohol, higher ester ethers of glycerin, isopropyl myristate, and ethyl laurate. In this way, in the above structure, the drug-containing component 4 is embedded in a large number of small holes 5 penetrating the adhesive layer 2 and the thermoplastic resin film 3, and the partition wall formed on the inner wall surface of the small holes 5 is used. Since the adhesive and the drug are completely separated by preventing contact between the drug-containing component 4 embedded in the adhesive layer 2 and the adhesive layer 2, there is no need to worry about damaging the adhesiveness of the adhesive layer 2. It is possible to apply the drug to the body surface by utilizing its adhesiveness, and the release properties of the drug are improved. Since the release rate can be freely set, very good results can be achieved in terms of effective use of the drug, fast-acting properties, and long-lasting drug effects. Furthermore, by separating the adhesive and drug as described above, it is possible to use an adhesive made of a hydrophilic polymer in combination with a lipophilic drug, or to use an adhesive made of a lipophilic polymer in combination with a hydrophilic drug. Benefits such as: Further, according to the above structure, it is possible to adopt a modification such as dividing the large number of small holes 5 into two or more groups and filling each group with drug-containing components 4 having different drug release rates. According to this embodiment, the durability of the medicinal effect can be further improved. As detailed above, the adhesive patch of the present invention has an adhesive layer provided on a support via a thermoplastic resin film, and a large number of small holes penetrating the adhesive layer and the film. A drug-containing component is embedded in the small hole, and the film is extended to the inner wall surface of the small hole to form a partition wall that prevents contact between the drug-containing component and the adhesive layer. According to this, it is possible to provide an extremely useful patch that eliminates the drawbacks of conventional patches. Examples of the present invention will be described below to explain it more specifically. Note that in the following, parts and % mean parts by weight and % by weight. Example 1 A natural rubber-based pressure-sensitive adhesive was applied to a 300μ thick polyethylene film to a thickness of 200μ by a conventional method, and a 4mm thick polyester film that had been subjected to a release treatment was laminated to this coated surface. This composite film was introduced between a perforated roll heated to 145°C and a Tatsuchi roll with cooling water circulated so that the polyethylene film surface was on the heated perforated roll side, and the polyethylene film and adhesive layer were penetrated. 49 pores/cm ² with an average pore diameter of 500 μm were provided. Next, this perforated film was introduced into a laminating machine, and a polyethylene support having a thickness of 50 μm was laminated on the polyethylene film side. After cooling, the peel-treated polyester film was removed, and the following drug-containing component (A) was filled and coated into the holes using a knife doctor, and a release paper was attached to obtain the adhesive patch of the present invention. <Drug-containing ingredients (A)> Methyl salicylate 79 parts d-camphor 16 parts - Menthol 73 parts Glycol salicylate 12 parts Tocopherol acetate 1.5 parts Thymol 10 parts Natural rubber 70 parts Hydrophilic ointment (Japanese Pharmacopoeia) 30 parts The above-mentioned patch of this invention The results of investigating the performance of
The results were as shown in Table 1 below. Adhesion, time to start working, duration of effect, and strength of effect are all average evaluations of practical test results by 42 paranays, and adhesion is indicated as good (〇) or poor (x). In addition, the effect strength was indicated as very good (◎), good (○), and poor (×). In addition, the amount of remaining drug was measured by the following method. Furthermore, Comparative Example 1 in Table 1 refers to the test results of a commercially available poultice containing a natural rubber-based polymer as a base and containing the same amount of the drug of the same composition per unit area as that used in Example 1. It is. <Residual drug amount> Two test pieces of Example 1 and Comparative Example 1 were applied to the backs of each of the three panelists, and one test piece each was removed after 5 hours and 10 hours of application to determine the amount remaining in the sample. The amount of drug contained in the product was quantified and expressed as a percentage by weight relative to the amount of drug contained in the unused product. Note that methyl salicylate, -menthol, d-camphor, and thymol were determined by gas chromatography, and glycol salicylate was determined by high-performance liquid chromatography.

[Table] Example 2 A patch of the present invention was prepared in exactly the same manner as in Example 1, except that the following drug-containing component (B) was used in place of the drug-containing component (A). <Drug containing ingredients (B)> Sodium polyacrylate (food additive standard) 1 part triethanolamine 1 part Tween 80 (emulsifier) 70 parts propylene glycol 5 parts water 13 parts indomethacin 10 parts The performance of the above patch is as follows. The results of investigating the effect of carrageenan in suppressing foot edema were as shown in Table 2. Note that the reference examples in Table 2 are test results for samples in which the drug-containing component (B) was not filled and applied to the pores at all. <Carrageenin paw edema suppression test> A group of 6 male Wistar rats weighing approximately 200 g was treated with 0.05 ml of 1% carrageenan in the right hind foot pad.
Immediately after subcutaneous injection, a 2 cm ² test piece was applied to the site. After 3 hours, remove the test piece,
The weight of paw edema was measured one hour after removal. The suppression rate in the table is the weight reduction achieved by Example 2 expressed as a percentage of the weight of the foot edema of the reference example.

[Table] Example 3 After applying an acrylic pressure-sensitive adhesive to a thickness of 100μ on a 200μ thick polyethylene sheet, 49 pores/cm ² with an average pore diameter of 300μ were formed in the same manner as in Example 1.
Except for using the following drug-containing ingredient (C),
A patch of the present invention was obtained in exactly the same manner as in Example 1. <Drug Ingredients (C)> White petrolatum 25 parts Stearyl alcohol 22 parts Ethanol 20 parts Propylene glycol 12 parts Sodium lauryl sulfate 1.5 parts Ethyl paraoxybenzoate 0.04 parts Water 19.075 parts Fludroxycortide 0.385 parts How to test the efficacy of the above patch As, Mckenzie &
Stoughton [Arch.Derm., 86608 (1962)] and the recent FDA guidelines for clinical testing of topical corticosteroids show that vasoconstriction is highly correlated with the clinical effects of steroids. The accompanying pallor phenomenon was investigated. The test method was as follows, and the test results are shown in Table 3 below. Comparative Example 2 in Table 3 refers to a commercially available adhesive tape in which the same proportion (4 mcg/cm ² ) of fludroxycortide as in Example 3 is uniformly mixed into an acrylic pressure-sensitive adhesive layer. These are the test results. <Test method> Christie & Moore-Robinson [Br.J.Derm.,
82, 93 (1970)], a 10 mm x 10 mm sample was pasted on the flexor side of the forearm of a panel (30 healthy people who had not received steroid therapy within the past 4 weeks) and removed after 6 hours. After that, judgment was made at predetermined time intervals according to the following criteria. 0 points: Same as untreated area 1 point: Slight whitish appearance 2 points: Two corners can be distinguished relatively clearly. 3 points: All corners can be clearly distinguished. In addition, those who were determined to have a score of 2 or more based on the above criteria were considered to be positive, and the positive rate for each hour was calculated according to the following formula. Positive rate = number of positive people / number of panelists x 100 (%)

[Table] Example 4 In place of drug-containing ingredient (A), use the following drug-containing ingredient (D)
After filling each hole with this component (D), apply electrons of 0, 2, 4, and 6 Mrad stepwise (with a width of 1 cm) from one side edge of the coated surface to the other side edge. The above ingredients (D) applied to each hole by irradiation with a line
A patch of the present invention was obtained in exactly the same manner as in Example 1, except that a crosslinking treatment was performed to vary the degree of crosslinking in the above direction. <Drug-containing ingredients (D)> Polyvinyl alcohol (average degree of polymerization 2000; degree of saponification 98-99%) 8 parts Ethyl alcohol 25 parts Tween 20 (emulsifier) 5 parts Water 42 parts Isosorbide dinitrate 20 parts Paste above The drug was cut into a size of 8 cm x 8 cm, and this was pasted on the chest area of a cynomolgus monkey, and the blood concentration of the drug was examined at predetermined intervals using the following method. <Method for measuring drug blood concentration> 2 ml of plasma obtained by directly centrifuging the collected blood
Nitroglycerin 8ng (0.8μ
10 g/ml n-hexane nitroglycerin solution
Add μ) and shake for a few seconds. This n-
Add 5.5 ml heptane and shake for 40 seconds. Immediately after shaking, transfer the organic solvent layer to a Spitz tube and evaporate the solvent with a rinse of inert gas. After adding 100μ of n-hexane to the residue and shaking, the sample is separated using a gas chromatograph equipped with an electron capture detector. The setting conditions of the gas chromatograph are as follows. Radiation source: 10 mCi of ⁶³ Ni Chiarior gas: Nitrogen gas 20 ml/mm (flow rate) Column temperature: 130°C Injection temperature: 15°C Tedector temperature: 180°C Column: Glass column with inner diameter of 2.4 mm and length of 1.2 m (silanized) ) Filler: 3% silicon OV-101 (80 to 100 mesh) The above measurement results were as shown in Table 4 below. Comparative Example 3 in the table refers to commercially available ointment 1 with an isosorbide dinitrate content of 10%.
This figure shows the change over time in the blood concentration of the drug when it was applied to the area of chest hair removal in an area approximately 20 cm x 20 cm using G.

[Table] FIG. 3 qualitatively shows the change over time in the drug blood concentration of the patch of the present invention according to Example 4. In the figure, the curve M is the result of Example ₄ , and the dotted line
X ₁ , X ₂ , and X ₃ are 2 Mrad, 4 Mrad, and 4 Mrad, respectively, on the entire coated surface after applying the drug-containing component (D).
These are the results when uniformly irradiated with a 6 Mrad electron beam. As can be understood from this figure, in this invention, when the degree of crosslinking of the drug-containing component applied to each hole is varied, the drug release rate can be obtained in accordance with the degree of crosslinking, so that the drug can be effective in a short period of time after application. It appears that this medicinal effect lasts for a longer period of time.

[Brief explanation of the drawing]

FIG. 1 is a cross-sectional view showing an example of the patch of the present invention, FIGS. 2 A to D are process diagrams for explaining the manufacturing method of the patch, and FIG. 3 is a diagram illustrating the performance of the patch of the present invention. FIG. DESCRIPTION OF SYMBOLS 1... Support, 2... Adhesive layer, 3... Thermoplastic resin film, 4... Drug-containing component, 5... Small hole, 6... Partition wall.

Claims (1)

[Claims] 1. An adhesive layer is provided on a support via a thermoplastic resin film, and a large number of small holes are provided that penetrate through this adhesive layer and the film, and a drug-containing component is embedded in the small holes. On the other hand, a patch characterized in that the film is extended to the inner wall surface of the small hole to form a partition wall that prevents contact between the drug-containing component and the adhesive layer.