JPS607966B2 - patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a patch that is applied directly or indirectly to the body for treating diseased areas of the body or administering medicine to the circulatory system.

Conventionally, as shown in FIG. 5, a patch of this type is known in which a polymer layer 52 in which a drug is dissolved is provided on the entire surface of a support 51 such as a plastic film.

In such a patch, if the polymer layer 52 has adhesiveness, it can be applied directly to the body surface by utilizing its adhesiveness, or if it does not have adhesiveness, it can be applied by other means such as adhesive tape. After pasting it on the body surface,
By transferring or absorbing the drug in the polymer layer 52 to the body surface by diffusion and movement over time, a diseased part of the body can be treated or the drug can be administered to the circulatory system. However, conventional patches with such a structure generally have poor sustained drug release properties, and have the disadvantage that their medicinal efficacy disappears in a short period of time. In other words, the curves ~ in Fig. 6 show the time changes in drug blood concentration when the above-mentioned conventional patch is applied to the body surface, and here, the drug efficacy time is the minimum effective concentration ( In the figure, from the time point (t,) when the concentration (represented by the dashed-dotted line a) is reached, to the time point (t,) when the concentration deviates from the concentration castle
2), and in conventional systems, this time was inevitably short. This tendency is almost the same even when the polymer layer 52 contains a very large amount of drug (until it becomes dispersed at a concentration higher than the dissolved concentration of the polymer), and in this case, for example, as shown by curve This only increases the amount of drug released, and if the activity of the drug is too strong, there is a concern that the toxic concentration (the concentration represented by the dashed line b in the figure) will be exceeded. In the course of many years of research into such adhesive patches, the inventors found that when the base polymer and other components of the polymer layer containing the drug were variously changed, the point at which the minimum effective concentration required for the expression of drug efficacy was reached (t) , ) changes, that is, there is a difference in the release rate curve of the drug, so we focused on this difference and decided to separately form the drug-containing polymer layer from two or more materials with different drug release rates. This invention was completed after learning that very good results could be obtained in terms of the persistence of medicinal efficacy.

This invention will be explained below with reference to the drawings. 1 and 2 show an example of the adhesive patch of the present invention, in which 1 is a support such as a plastic film, a laminated film of plastic and metal, or a discontinuous foam sheet; The drug-containing polymer layer is divided into three strips formed on this support 1, and each of the divided sections 2A, 2B, and 2C is made of a material with a different drug release rate. In this example, the divided section 2A is fast; 2B is medium and 2C is slow. Such a polymer layer 2 is generally prepared by preparing three types of polymer compositions in which the drug release rate is varied depending on the type or proportion of the base polymer, a release aid that promotes the release of the drug, and other ingredients. A solution prepared by dissolving or partially dispersing a prescribed drug in the substrate 1 is directly coated in streaks as shown in the figure and dried, or once coated on a release liner and then transferred as shown in the figure, if necessary. After that, it is formed by crosslinking treatment such as uniform irradiation with ionizing radiation.

The base polymer of the polymer composition used above may be one that exhibits tackiness when a polymer layer is formed, or it may be one that does not substantially show tackiness.

In short, it can be widely applied as long as the drug contained therein can diffuse and move inside the layer 2 and be transferred to or absorbed by the body surface. Polymers that exhibit adhesiveness include various polymers such as natural rubber, synthetic rubber, styrene-isoprene-styrene block polymer, polyacrylic acid ester, and polyisobutylene. Examples of polymers not shown above include sensitive polyamide resins, polyvinyl alcohol, polyolefin resins, and polyacrylic resins. The drug release rate of the polymer layer 2 varies depending on the type of base polymer as mentioned above, the number of functional groups, the number of carbon atoms, etc. even if the polymer is of the same type, but the drug release rate of the polymer layer 2 varies depending on the number of functional groups and the number of carbon atoms, etc., as described above. It can also be easily changed by changing the type and amount of auxiliary substances.

The above-mentioned release assisting substances can be simply defined as substances that promote the release of drugs to the body surface, but include substances that have the function of improving the solubility and diffusivity of drugs within the polymer layer; It also has functions to improve transdermal absorption, such as the water retention capacity of the stratum corneum, keratin softening properties, and stratum permeability (loosening), acting as a penetration aid and pore barrier agent, and changing the skin interface condition. It also includes a wide range of drugs, including those that have both of the above functions or, in addition to these functions, also have a function of promoting drug efficacy to make the drug more effective.

Specific examples of these release aids include glycols (mainly drug-soluble) such as diethyresoglycol, propylene glycol, and polyethylene glycol, olive oil, squalene, oils and fats such as funoline (mainly drug-diffusing), Urea, urea derivatives such as allantoin (
(mainly the water-retaining capacity of stratum corneum), dimethyldecyl phosphooxide,
Methyl octyl sulfoxide, dimethyl laurylamide, dodecyl pyrrolidone, polar solvents such as heisosorbitol, dimethylacetamide, dimethyl sulfoxide, and dimethyl formamide (mainly permeable to the stratum corneum), salicylic acid (mainly permeable to the stratum corneum), amino acids ( Penzyl nicotinate (mainly a pore opening agent), sodium lauryl sulfate (mainly functions to change the skin interface condition), Salocol (used in combination with drugs with good transdermal absorption), etc. .

Others diisopropyl adibate, phthalate,
Plasticizers such as ethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers include ethoxylated stearyl alcohol, higher ester ethers of glycerin, isopropyl myristate, and ethyl laurate. The drugs added to such polymer compositions are those that can be transferred to or absorbed into the body, such as corticosteroids, anesthetics, antihistamines, antibacterial agents, antifungal agents, analgesic and antiinflammatory agents, etc. Keratin softeners, vitamins, antispasmodics, etc., as well as systemic drugs such as antihypertensive agents, antibiotics, central nervous system agents, and vasodilators.
These include anti-inflammatory drugs, sedatives, sex hormones, and anti-diabetic 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, prezonisolone,
Examples include hydrocortide acetate, hydrocortide, dexamethasone, fluocinolone acetonide, betamethasone, beclomethasone propionate, fludroxycortide, fluocinonide, and the like.

Anesthetics include penzocaine, lidocaine, and ethyl aminobenzoate; antihistamines include diphenhydramine hydrochloride, isocybenzyl hydrochloride, and diphenylimidazole; antibacterial agents include penzalkonium chloride and nitrofurazone; antifungal agents include nystatin and undecylene. Examples of analgesic and anti-inflammatory agents include indomethamine, methyl salicylate, glycol salicylate, salicylic acid amide, and sodium salicylate.In addition, keratin softeners, vitamins, and antispasmodics include salicylic acid, vitamin A, atropine, and methscopol. Examples include amine furomide.

In addition, systemic drugs such as antihypertensive drugs such as reserpine and clonidine, antibiotics such as ylithromycin, chloramphenicol, cephalexin, 7tracycline, neomycin sulfate, oxytetracycline, and penicillin, barbiturates, diazenogum, and nitraxenogum , central nervous system agents such as chlorpromazine, and vasodilators such as nitroglycerin and isosorbide dinitrate. According to the patch having the above configuration,
When the two polymer layers of this adhesive patch are applied directly or indirectly (using adhesive tape, etc.) to the body surface, the time change in drug blood concentration is represented by curve M in Figure 3. Effective time (ra-
t,) becomes significantly longer.

In other words, in a polymer layer consisting of a single divided portion 2A with a high drug release rate, the concentration changes as shown by the curve x, and in a polymer layer consisting of a single divided portion 2B with a medium drug release rate, the concentration changes as shown in a curve Y, and furthermore, the drug release rate changes as shown by the curve Y. In a polymer layer consisting of only the slow splitting portion 2C, the concentration changes as shown by curve Z, and when these alone are used, there is only a difference in the time at which the medicinal effect starts to be exerted, and the effective time of the medicinal effect is short in all cases.

On the other hand, each of these parts 2A, 2B, 2C is
In the patch with the above structure formed together with the above, the concentration changes x, Y, and Z are combined into a concentration change as shown in the curve M, which significantly improves the durability of the drug effect. Become something. In the above example, the polymer layer 2 is divided into three parts, but the same effect as described above can also be obtained by dividing the polymer layer 2 into two or four or more parts and changing the drug release rate of the constituent material of each divided part.

Further, in Fig. 4, the divided parts 2A, 2B, 2C are further divided into 2A, 2~, 2, 2B, 2B2, 2B3, 2C, respectively.
, 2C2, and 2C3, however, it is also possible to explore an embodiment in which the polymer layer 2 is formed into a pattern as in this example, and the drug release rate of each drug is varied. As described above, the adhesive patch of the present invention is characterized in that the drug-containing polymer layer formed on the support is divided into two or more parts, and each divided part is made of a material with a different drug release rate. According to this study, the effect of greatly improving the sustainability of drug efficacy can be obtained.

Next, examples of the present invention will be described in more detail. In the following, parts shall mean parts by weight. Example 1 Fluocinolone acetonide was used as a drug, and 0.3 parts of this was added to each of the following three types of polymer compositions per 10 pieces of solid content.

Each formulation was applied to a polyethylene film with a dry thickness of 5.
The adhesive patch of the present invention was prepared by applying stripes in three stripes so as to have a thickness of 0.0 and drying. <Polymer Composition A> In a four-neck round bottom flask, 7 parts of 2 ethylhexyl acrylate, 28 parts of vinyl acetate, 2 parts of hydroxybutyl methacrylate, and 42 parts of ethyl acetate were added. After charging $1000 and replacing with nitrogen gas, azobisisobutyronitrile 0
．． Added 1 part.

Further, while 107.1 parts of ethyl acetate was added dropwise, the polymerization temperature was controlled at 60 to 6300°C, and polymerization was carried out for about 8 hours. Solid content thus obtained: 39. $wt%, viscosity (300
0) Polymer composition A was a 395 poise polymer solution.

<Polymer composition B> 7 anchor parts of polyisobutyl vinyl ether with a glass transition temperature of -190C and a specific gravity of 0.92 and hydrogenated wood chloride (glycerin ester of hydrogenated chloride; softening point 7 by ring and ball method)
Polymer composition B was a mixture of 1°C, acid value 3) and 200 parts of ethyl acetate.

<Polymer composition C> Average molecular weight 125,000, polystyrene content 14% by weight
, specific gravity 0.92, melt index 9, tensile strength 2
Styrene Soft with 18k9/s, elongation 1300%, solution viscosity at 770F of 25% by weight toluene solution 160 ps.

Ren-styrene block polymer 5, soft liquid paraffin 3, and alicyclic petroleum resin (average molecular weight 700,
A mixture of hydrogenated petroleum resin) 4 (hydrogenated petroleum resin) having a softening point of 100 oo, an acid value of 0, and a specific gravity of 1.532 was designated as polymer composition C. The following pallor test was conducted to examine the performance of the adhesive patch of Example 1, and the results were as shown in Table 1 below.

Note that in Table 1, No. 1 of Comparative Example 1. 1.No. 2.No.
3 shows the test results of patches formed from polymer compositions A, B, and C alone, respectively. .

<Pallarity test> Christie and Moore-R
20x2 from each patch according to obinson's method.
A test piece of 0c was prepared, pasted on the flexor side of the forearm, peeled off after a predetermined period of time, and examined for pallor on the pasted surface 2 hours after peeling, and evaluated as follows.

0 points: Same as unprocessed case.

1 point...The pasting surface is slightly whitish.

2 points: Two corners of the pasting surface have relatively clear white discoloration.

3 points... All corners of the pasting surface are very clearly whitened.

Table 1 Example 2 Isosorbide dinitrate was used as a drug, and 3 parts of it was added to each of the following four types of polymer compositions based on 10 parts of solid content.

Each formulation was coated in four strips on an 80mm thick film made of ethylene-vinyl acetate copolymer (vinyl acetate content: 2% by weight) so that the dry thickness was 50mm thick, and dried. Created an invented patch. <Polymer Composition A> Polyoctyl acrylate was dissolved in ethyl acetate to a solids concentration of about 30% by weight.

<Polymer Composition B> Polybutyl acrylate was dissolved in ethyl acetate for about 3
The solid content concentration was set as % by weight.

<Polymer composition C> Dissolve polyethyl acrylate in ethyl acetate and prepare about 3
The solid content concentration was set as % by weight.

<Polymer composition D> Polymethyl acrylate was dissolved in ethyl acetate for about 30 minutes.
The solid content concentration was set as % by weight.

As for the performance of the patch of Example 2, the following drug residual rate was investigated, and the results were as shown in Table 2 below.

In Table 2, No. 2 of Comparative Example 2. 1.No. 2.No.
3 and no. 4 are polymer compositions A, B, and C, respectively.
, D alone.

<Drug Survival Rate> A 4×4 arc test piece was prepared from each patch, and the hair on the rabbit's back was shaved. After 24 hours, the above test piece was applied to the hair loss area, and then the hair was shaved at predetermined intervals. The residual rate (%) of the drug (isosorbide dinitrate) was examined.

The drug was quantitatively determined by extracting it three times with a mixed solution of methanol:water = 8:2, removing the solution under reduced pressure, and then preparing a fixed amount of hexane solution for measurement using a gas chromatography device. Table 2 As is clear from Tables 1 and 2 above, the patch of the present invention exhibits a medicinal effect within a short time after application, and this medicinal effect lasts for a long time. I understand.

[Brief explanation of drawings]

FIG. 1 is a perspective view showing an example of the patch of the present invention, FIG. 2 is a sectional view taken along the □--RO line in FIG. 1, FIG. 3 is a characteristic diagram showing the performance of the patch, and FIG. 4 is a FIG. 5 is a perspective view showing another example of the patch of the present invention, FIG. 5 is a sectional view showing a conventional patch, and FIG.
The figure is a characteristic diagram showing the performance of the above-mentioned secondary patch. 1... Support, 2 (2A, 2A,, 2A2, 2, 2B
,2B,2B2,2&,2C,2C,,2C2,2C3
)...Polymer layer containing drug. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Claims (1)

[Claims] 1. A patch having a drug-containing polymer layer divided into two or more parts formed on a support, and each divided part of the polymer layer is made of a material having a different drug release rate.