JPH0137375B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to transdermally administered tape-shaped pharmaceuticals, particularly,
Concerning tape-shaped pharmaceutical products containing ISDN as a medicinal ingredient in an adhesive base. (Prior Art) ISDN, along with nitroglycene (NG), is known as an effective drug for angina pectoris. but,
Since ISDN and NG have a short duration of efficacy in the body, they may not be able to suppress or prevent nocturnal seizures, so it is strongly desired that they be made into sustained-release preparations. To solve this problem, for example, US Pat. No. 4,420,470 discloses making ISDN or pentaerythritol tetranitrate into a tape-shaped transdermal preparation. According to it, as adhesive base, at least 50wt
Contains % alkyl (meth)acrylates, up to
Polymerizations with 20 wt% functional monomers or up to 40 wt% vinyl ester monomers are used.
Although such tape-shaped transdermal preparations generally have many advantages such as reducing the burden on the liver, they have the following three problems: The first problem is that such preparations However, because drugs are administered through the skin, which is a tissue that originally has the function of preventing foreign substances from entering the body, it is difficult to administer the amount of drug necessary for the drug to be effective. Usually, measures are taken such as increasing the area of application or adding an absorption enhancer to the base material. A second problem is that tape-like preparations with an adhesive base layer have the side effect of irritating the skin. During the period when the preparation is applied to the skin, the base layer is in contact with the skin surface, which impedes normal secretion, metabolism, and expansion and contraction of the skin in that area, and the edges of the tape or the base layer itself I wake up because I am constantly stimulated by this. As a result, erythema develops, accompanied by crusting and edema formation in severe cases, and can persist for several days after tape removal. Measures to reduce such side effects are not yet known. Japanese Patent Publication No. 58-23846, Japanese Patent Application Publication No. 57-14527, and Japanese Patent Application Publication No. 58-134020 disclose the use of polymers containing polar monomers as a base for the preparation of drugs. A tape-like preparation that promotes diffusion into the skin has been disclosed, but the polar monomer component may increase irritation to the skin. The third problem is that when the tape is removed, it is unavoidable that a portion of the base layer remains on the skin surface during development. Another problem is that a part of the drug contained in the base permeates the support and leaches to the outside, or crystallizes at the interface with the support and does not function as a drug. (Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional problems, and its purpose is to effectively transdermally deliver ISDN, which is contained as a medicinal ingredient in an adhesive base layer. An object of the present invention is to provide a transdermally administered tape-shaped pharmaceutical product that can be absorbed. Another object of the present invention is to provide a transdermally administered tape-shaped pharmaceutical product that causes almost no skin irritation and does not leave a portion of the base on the skin surface when the tape is peeled off. Still another object of the present invention is to provide a percutaneously administered tape in which a part of the drug contained in the base does not pass through the support and flow out to the outside, or crystallize at the interface with the support. The goal is to provide medicines. (Means for Solving the Problems) The present invention provides that the base material with high ISDN release properties is
be selected from bases that can dissolve in high concentration;
To reduce skin irritation, the base must have high hydrophilicity; to reduce skin irritation, it is inappropriate to use polar monomers such as acrylic acid or methacrylic acid in the base; and N- This invention was completed based on the inventor's knowledge that it is suitable to use a base containing a monomer called vinyl-2-pyrrolidone. Therefore, in the transdermal drug of the present invention, an adhesive base layer containing a drug in a compatible state in an adhesive base is formed on a support that is flexible and impermeable to drugs; Base is 45 mol% 2-ethylhexyl acrylate (EHA)
Above, N-vinyl-2-pyrrolidone (VP) 20~
55 mol%, 35 mol% or less of (meth)acrylic acid ester with a carbon number of 3 to 12 in the ester moiety and a homopolymer Tg of -40°C or less, and a polyfunctional monomer of 0.005 to 0.5 weight of the total monomer weight. % of monomers, and the drug is isosorbide dinitrate (ISDN).
and its concentration in the adhesive base layer is at least 10
% by weight, thereby achieving the above objective. N-vinyl-2-pyrrolidone (VP) is a compound with the following structure and a molecular weight of 111. The homopolymer of VP is water-soluble and is listed in the Non-Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients. The present inventors have confirmed through experiments that this monomer can be copolymerized with various acrylates and methacrylates, and have found that the copolymer is promising as a base material. After examining various copolymer compositions, we found that a copolymer composition containing 2-ethylhexyl acrylate (EHA) and VP as main components had good adhesive properties,
Favorable results were obtained for each quality requirement of ISDN dissolution/release and low skin irritation. Its composition is EHA 45 mol% or more and VP 20 to 55 mol%, more preferably EHA 55 mol% or more.
The VP ranged from 30 to 45 mol%. VP is 20 mol%
If the amount is smaller, the advantage of being able to dissolve ISDN at a high concentration will be reduced. Moreover, if it exceeds 55 mol%, the adhesive properties of the base will decrease. The base material further includes a polyfunctional monomer copolymerized with other monomer components. The addition of polyfunctional monomers results in very slight crosslinking between the resulting polymers, thereby increasing the internal cohesive strength of the base. Therefore, the so-called adhesive residue phenomenon when the tape is removed is eliminated almost regardless of the properties of the skin to which it is applied or the amount of perspiration. Moreover, it does not have any effect on drug release properties or low skin irritation. Examples of such polyfunctional monomers include di(meth)acrylate, tri(meth)acrylate,
Examples include, but are not limited to, tetra(meth)acrylate. More specifically, di(meth)acrylates obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth)acrylic acid; polyalkylene glycols such as polyethylene glycol and polypropylene glycol ( Di(meth)acrylate obtained by combining with meth)acrylic acid; trimethylolpropane tri(meth)acrylate and glycerin tri(meth)acrylate
Tri(meth)acrylates such as acrylates;
and tetra(meth)acrylates such as pentaerythritol tetra(meth)acrylate. Two or more of these polyfunctional monomers may be used in combination. Among all the monomers used in the polymerization of the base, the polyfunctional monomer is
It is contained in a proportion of 0.005 to 0.5 wt%. usage amount
When it is less than 0.005 wt%, the effect of improving internal cohesive force due to crosslinking is small, and when it is more than 0.5 wt%, the adhesive obtained by polymerization tends to gel. The diffusion and emission of ISDN will also be affected. In addition, EHA 45 mol% or more, VP 20 mol% or more (more preferably EHA 55 mol% or more,
Even if one or more other (meth)acrylate monomers are copolymerized in a range of 35 mol% or less (more preferably 15 mol% or less) with 30 mol% or more of VP), the performance as a base material will change. I stopped talking. Regarding the other (meth)acrylate monomers mentioned herein, from the viewpoint of maintaining good adhesiveness, those having an ester moiety of 3 to 12 carbon atoms and a homopolymer Tg of -40°C or less are used.
Examples of such (meth)acrylates include butyl acrylate, hexyl acrylate, 2-
These include ethyl butyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl methacrylate, and lauryl methacrylate. In the base of such a composition, at least 10% by weight of ISDN (based on the base plus the weight of ISDN),
Preferably, the content is 10 to 30% by weight, and in the above composition range described as more preferable, it is possible to make them compatible at a high content of 13 to 25% by weight. For comparison, if we look at the prior art example in US Pat. No. 4,420,470, the concentration is 8 parts (7.4 wt%), so it is clear that the concentration of 10 to 30 wt% in the present application is extremely high. be. In general, the diffusion rate of a substance dispersed in a matrix is better when the substance exists in a compatible state in the matrix, whether it is diffusing within the matrix or outward from the matrix. It is known that this is overwhelmingly higher than when it exists as a. Therefore, it is possible to overcome the traditional problem of low ISDN emissions and to
In order to increase the release of ISDN, it is essential that ISDN be present in a compatible state in the base at a concentration as close as possible to saturation solubility. Here, the saturated solubility refers to the upper limit concentration at which ISDN crystal precipitation does not occur even after being left at room temperature for a long period of time. Also,
The state that exists below this concentration is called compatible. In the present invention, the saturation solubility of ISDN in the base material varies slightly depending on its monomer composition. Therefore, it is necessary to make ISDN compatible with each base so that the concentration is slightly lower than its saturation solubility. From the composition range of the base material of the present application, such ISDN concentration is at least 10 wt% or more, preferably 10 to 30 wt%, as described above.
In the composition range described as more preferable, 13
~25wt%. Generally, the amount of ISDN added to the base is preferably 80% or more of the ISDN saturation solubility concentration of the base from the viewpoint of ISDN release. As there are still unresolved issues regarding the measurement of the distribution coefficient between the base material and the skin surface and the analysis of the phenomenon in which the situation of the entire system changes due to sweating of the skin after applying the tape, Naturally, not all bases that can dissolve ISDN at high concentrations are desirable bases that release a large amount into the skin.
In the course of research, the present inventor found that the base of the present application is the most excellent in terms of transferability to the skin. Any support that is flexible and drug-impermeable can be used in the present invention. In this sense, single-layer films of polyethylene (PE) and ethylene-vinyl acetate copolymer (EVA) are not preferred. As an ISDN opaque film,
Polyesters such as polyethylene terephthalate (PET); polyamides such as nylon 6; and polyurethanes; and laminated films thereof;
A laminated film of these and PE or EVA is preferably used. In particular, PET-EVA and polyamide-EVA laminated films are preferably used from the viewpoint of strength, flexibility, and ease of adhesion to the skin surface. When an EVA film is laminated with another film and used as a support, the EVA film is usually prepared so as to be in contact with an adhesive base layer. In this case, in order to improve the adhesion between the base layer and the EVA film, it is preferable to subject the EVA film to a surface treatment such as corona treatment or plasma discharge treatment. Generally, crystallization of a compound tends to occur at the interface of the matrix in which it is dissolved. In a structure like the present formulation, the interface between the base layer and the support is considered to be the part where crystallization is most likely to occur. however,
In the case of this application, it seems that this is due to the properties of the base composition, but if ISDN is dissolved in the range of 80% or more and less than 100% of the saturated solution concentration, no matter which support is used, it will not last for a long time. No crystal formation was observed throughout. The tape-shaped transdermal drug of the present invention is prepared, for example, by solution polymerization as follows: Add acetic acid to predetermined amounts of each of EHA, VP, a polyfunctional monomer, and optionally a (meth)acrylate monomer. Ethyl and other common polymerization solvents are placed in a reactor equipped with a stirring device and a cooling reflux device for the vaporized solvent, and heated at a temperature of about 60°C for 8 to 40 hours under an atmosphere of _N2 gas. It is then subjected to a radical polymerization reaction. Polymerization temperature is 60℃~ in the latter half of the reaction
The temperature may be 70°C. EHA, VP, (meth)acrylate monomer, and solvent are used for the reaction all at once or divided as appropriate. The polyfunctional monomer, which is a crosslinking agent, is added during the polymerization reaction of the above-mentioned copolymerization components. The catalyst (polymerization initiator) is suitably divided and used for the reaction depending on the progress of the reaction. As the polymerization initiator, azobis type, peroxide type, etc. can be used, but the initiator is not limited thereto. Examples of azobis-based compounds include 2,2'-azobis isobutyronitrile (AIBN); 1,1'-azobis(cyclohexane-1-carbonitrile);2,2'-azobis-
(2,4-dimethylvaleronitrile), etc. Examples of peroxides include benzoyl peroxide (BPO); lauroyl peroxide (LPO); and ditertiary butyl peroxide. The resulting polymer contains solids in a proportion of 15 to 40 wt%.
The viscosity is 1000 to 100000 cps when the solid content is 25wt%,
and molecular weight (Gel Permeation
The weight average molecular weight (based on styrene equivalent) determined by chromatography is 100,000 to 1,000,000. Residual monomers for EHA and VP are each less than 4 wt% based on the total solid weight. The drug (ISDN) is added to the adhesive base solution thus obtained either directly or as a solution dissolved in a solvent such as ethyl acetate. When ISDN is added to the adhesive base solution in solution form, it is easy to mix uniformly. The amount of ISDN to be blended is appropriately determined by measuring the solid content concentration of the adhesive base of the solution. The ISDN solution is appropriately mixed with the adhesive base solution using a dissolver, homomixer, etc. under air, N ₂ atmosphere, or reduced pressure. The obtained coating solution is applied to a release paper or a support to a predetermined thickness using a coating machine such as a direct coater or a reverse coater. It is dried at a temperature below 70°C to form an adhesive base layer. Contains if the drying temperature is too high
ISDN may be scattered. A support or release paper is then laminated on the surface of the base layer. The concentration of ISDN in this adhesive base layer is 10-30 wt%, and the solvent concentration is 100 ppm or less. The remaining monomer is at a trace level (less than 0.1 wt%). Ball tack value is 15 or higher. Example 1 EHA45 mol% (215.2g), VP45 mol% (129.7
g), decyl methacrylate 10 mol% (55.1 g)
and trimethylolpropane triacrylate
0.01 wt% (40.0 mg) was placed in a separable flask, and 70.6 g of ethyl acetate was added so that the monomer concentration at the initial stage of polymerization was 85 wt%. This solution was heated to 60° C. under a nitrogen atmosphere, lauroyl peroxide and ethyl acetate as polymerization initiators were successively added little by little, and polymerization was carried out for 32 hours. After removing the polymer,
The solid content (polymer and
In addition, so that the total weight of ISDN is 25wt%,
4 with ISDN solid concentration of 22, 24, 26, 28wt%
Added as seeds. Thicken these solutions
35 μm PET was coated on silicone-treated release paper to a thickness of 60 μm after drying, and dried.
A 9 μm thick PET support was bonded together to prepare a formulation. Example 2 EHA65 mol% (302.0g), VP35 mol% (98.0
Four types of formulations were prepared in the same manner as in Example 1 using 0.02wt% (80.0mg) of hexamethylene glycol dimethacrylate and 0.02wt% (80.0mg) of hexamethylene glycol dimethacrylate. However, the solid concentration of ISDN was 14, 16, 18, and 20 wt%. Example 3 EHA55 mol% (261.9g), VP25 mol% (71.8
g), butyl acrylate 20 mol% (66.3 g) and polypropylene glycol diacrylate
4 from 0.01wt% (40.0mg) in the same manner as in Example 1.
Seed preparations were obtained. However, the solid concentration of ISDN was 10, 12, 14, and 16 wt%. Comparative example 1 EHA70 mol% (317.2g) and VP30 mol%
(82.1 g), four types of preparations were obtained in the same manner as in Example 1. However, the solid concentration of ISDN is 12,
The content was set to 14, 16, and 18wt%. Comparative Example 2 Three types of formulations were obtained in the same manner as in Example 1 from 100 mol % (400.0 g) of EHA. However, the solid concentration of ISDN was 6, 8, and 10 wt%. Comparative example 3 EHA35 mol% (188.7g) and VP65 mol%
(211.3g) in the same manner as in Example 1 to obtain four types of preparations. However, the solid concentration of ISDN is 24,
28, 32, and 36wt%. Comparative example 4 EHA 93 mol% (372.0g) and acrylic acid 7wt%
(28.0 g), three types of preparations were obtained in the same manner as in Example 1. However, the solid concentration of ISDN is
6, 8, and 10 wt%. Experiment 1 Using the above formulations, first, the saturation solubility was measured and the adhesive properties were evaluated. To measure the saturation solubility, remove a part of the release paper, place several ISDN needle crystals on the adhesive surface, attach the release paper again, encapsulate it in an aluminum laminate film, and store it at room temperature. After several months, judgment was made based on the presence or absence of crystal growth. In addition, the tackiness was evaluated by ball tack measurement at room temperature immediately after the preparation of each preparation. Table 1 below shows the measurement results of saturation solubility and the evaluation results of adhesive properties.

【table】

[Table] From the crystal growth results in Table 1, the saturation solubility of each composition is the concentration shown in parentheses in the same frame. It can be seen that the composition of Comparative Example 3 is unfavorable in terms of adhesive properties. Therefore, we next used the six types of adhesive bases mentioned above except for Comparative Example 3, and each of them had a saturated solubility shown in Table 1.
Eighteen formulations with ISDN concentrations corresponding to 90% were prepared. The method is similar to Example 1, but in each example 3
It was used as a street sample. One is a square cut out of each base layer with a thickness of 60 μm and an area of 10 ^cm2 , and the other is a square cut out of a base layer with a thickness of 60 μm so that the ISDN content per sheet is 10 mg. is calculated and cut out to make a square. In the third case, the thickness of the base layer was adjusted so that the ISDN content was 10 mg when cut out to 10 cm ² . The numbers and contents of these 18 samples are shown in Table 2 below.

[Table] As is clear from this table, according to the present invention, when the same 10 mg content and the same base layer thickness are used, the area is very small, and when the same 10 cm ² and the same base layer thickness are used. It can be seen that the dose of Four experiments described below were conducted using these preparations. Experiment 2 Formulation 6 with base layer thickness of 60 μm and ISDN content of 10 mg
Seeds (1-2, 2-2, 3-2, 4-2, 5-2,
6-2) was applied to the depilated back of a rabbit (Japanese white breed). Blood was collected 1, 4, 8, and 24 hours later.
The blood concentration of ISDN was measured. The number of repetitions is 3 in each case. The results are shown in Figure 1. Due to the small number of repetitions, the difference between the six preparations is not clear, but Examples 1 to 4, which have a small area, show at least the same blood concentration level as Comparative Examples 2 and 4, which have a large area. The formulation of the present invention may require a smaller area of about 1/2 to 1/3 to achieve the same blood concentration than the formulation of the comparative example, and therefore is easier to handle, reduces the area of skin application, etc. was realized. Experiment 3 Five formulations (1) with an area of 10 ^cm2 and an ISDN content of 10 mg
-3, 2-3, 3-3, 4-3, 5-3) were applied to the depilated dorsal and ventral sides of one rabbit (Japanese white breed). ,
The amount of ISDN transferred to the skin was measured 2, 8, and 24 hours after applying the preparation. The number of repetitions was 3 in all measurements. Peel off each formulation after a predetermined time,
After ISDN was extracted with methanol, it was quantified by liquid chromatography. The obtained value was subtracted from the initial content of 10 mg, and the value was taken as the amount transferred to the skin.
The results are shown in Figure 2. From this result, the amount of skin transfer is approximately inversely proportional to the base layer thickness, and Examples 1 to 3 with a thin base layer
It can be seen that the bioavailability is excellent. Experiment 4 Five preparations (1-1, 2-1, 3-1, 4-1, 6-1) with a base layer thickness of 60 μm and an area of 10 cm ² and Blenderm surgical tape cut into 10 cm ² pieces were used. No. 1525 (manufactured by 3M) was applied to one rabbit in the same manner as in Experiment 3 to evaluate skin irritation and adhesive residue. The number of repetitions was 4. To evaluate skin irritation, all tapes were removed after 24 hours of application, and the intensity of erythema was determined at two points: immediately after removal and 48 hours after removal. The evaluation and scores are as follows. 0...No erythema 1...Very mild erythema that can be barely discerned 2...Obvious erythema 3...Moderate erythema 4...Intense deep red erythema It was used as a skin irritation index. The results are shown in Table 3. Note that no edema or crust formation was observed in this experiment.

[Table] As is clear from Table 3, the skin irritation of the tape formulation of the present invention was at a lower level than that of Comparative Example 4, and almost the same as that of the surgical tape used as a control.
Extremely hypoallergenic. In addition, the adhesive residue was evaluated immediately after peeling off 24 hours after application, and the evaluation and rating were as follows. 0... No adhesive residue 1... Adhesive residue observed in a small area 2... Adhesive residue found on corners and edges of the tape 3... Adhesive residue in an area that is more than half of the tape area Average value (sum of ratings) The value divided by 4) was taken as the adhesive residue index. The results are shown in Table 4.

[Table] As is clear from Table 4, since the tape formulation of the present invention was crosslinked using a polyfunctional monomer, there was no adhesive residue at all. Experiment 5 The same four formulations used in Experiment 4 (1-1,
2-1, 3-1, 6-1) (the base layer thickness and area are the same, but the ISDN dose is different) was applied to the depilated back of a rabbit, and the blood concentration was determined 1, 6, and 24 hours later. Measurements were made. There were 3 repetitions.
The results are shown in Figure 3. From this result, it is clear that according to the present invention, a significant increase in blood concentration can be achieved with the same thickness and the same area. (Effects of the Invention) The transdermal tape-shaped pharmaceutical of the present invention has the adhesive base capable of dissolving ISDN at a high concentration, and
And its ISDN emission properties are excellent. Therefore, the effective dose from the same patch area for formulations containing the same amount of ISDN is greater. After application, high blood concentrations are obtained for at least several hours. Because the adhesive base has excellent drug release properties and transferability to the skin, the onset of drug efficacy is quick, and therefore it is particularly effective in treating angina pectoris and the like when administered after a seizure.
Regarding ISDN, the blood concentration per area of application can be maintained at a higher level compared to conventional products. In order to show excellent medicinal efficacy with a small area of application, the area of application is small. As a result, erythema that can occur in people who are sensitive to the skin irritation of the base is minimized. Furthermore, since the desired medicinal effect can be achieved even if the area of application is small, the discomfort felt through the skin during use is reduced. In conventional tape-shaped pharmaceuticals, if the adhesive base layer is thin, the duration of the drug's efficacy is short; if it is too thick, the transfer rate of ISDN to the skin becomes poor, reducing the effective utilization rate of the drug. However, since the tape-shaped pharmaceutical product of the present invention uses a specific base, it is possible to increase the dosage of ISDN by increasing the thickness of the base layer. The bases used inherently have very low skin irritation. Furthermore, since the internal cohesive force of the base is high, no part of the base remains on the skin surface when the tape is removed. Because the base material can dissolve ISDN in high concentration, even if the tape is stored for a long period of time, ISDN will not crystallize and its functionality as a drug will deteriorate.

[Brief explanation of drawings]

FIG. 1 is a graph showing changes in ISDN blood concentration over time when preparations having an adhesive base layer of a constant thickness, containing a constant amount of ISDN in the base layer, and having different areas are applied; Figure 2 shows a certain amount of water in a certain area.
A graph showing changes in ISDN blood concentration over time when preparations containing ISDN and having adhesive base layers of different thicknesses are applied, and Figure 3 shows a graph showing changes in ISDN blood concentration over time when preparations containing ISDN and having adhesive base layers of a constant thickness in a constant area are applied. 2 is a graph showing changes in ISDN blood concentration over time when preparations containing different amounts of ISDN are applied.

Claims (1)

[Scope of Claims] 1. An adhesive base layer consisting of an adhesive base containing a drug in a compatible state is formed on a flexible support that does not allow penetration of the drug, and the adhesive base contains 2-ethylhexyl. 45 mol% or more of acrylate (EHA), N-vinyl-2-
Pyrrolidone (VP) 20 to 55 mol%, the number of carbon atoms in the ester moiety is 3 to 12, and the Tg of the homopolymer is -40℃
35 mol% or less of the following (meth)acrylic esters and polyfunctional monomers based on the total monomer weight:
0.005 to 0.5% by weight of monomers, and the drug is isosorbide dinitrate (ISDN), the concentration of which in the adhesive base layer is at least 10% by weight. Administrative tape-shaped pharmaceutical products. 2 The adhesive base contains 55 mol% or more of EHA and VP
and the (meth)acrylic acid ester in an amount of 15 mol% or less, and the polyfunctional monomer in a proportion of 0.005 to 0.5 mol% of the total monomer weight. The tape-shaped pharmaceutical products listed. 3. The tape-shaped pharmaceutical according to claim 1, wherein the polyfunctional monomer is at least one selected from the group consisting of (meth)acrylate, tri(meth)acrylate, and tetra(meth)acrylate. 4 Claims in which the (meth)acrylic acid ester is at least one selected from the group consisting of butyl acrylate, hexyl acrylate, 2-ethylbutyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl methacrylate, and lauryl methacrylate. The tape-shaped pharmaceutical product described in paragraph 1. 5. The support according to claim 1, wherein the support is a laminated film of a polyethylene terephthalate film and an ethylene-vinyl acetate copolymer film, or a laminated film of a polyamide film and an ethylene-vinyl acetate copolymer film. Pharmaceutical tape. 6. The tape-shaped pharmaceutical product according to claim 4, wherein the surface of the ethylene-vinyl acetate copolymer film located on the adhesive base layer side of the laminated film is surface-treated by corona discharge or plasma jet.