JPH0229652B2 - - Google Patents

Description

[Detailed description of the invention]

In this invention, the adhesive polymer layer containing a drug is made thinner, and the drug-containing polymer layer is disposed on the side that comes into contact with the skin, making it possible to achieve a high therapeutic effect and effective use of the drug with a small amount of drug. The therapeutic device is comprised of a flexible buffer layer between the carrier and the drug-containing polymer layer in order to maintain its adhesive properties to keep up with the movement of the drug. Conventionally, as adhesive tape formulations containing drugs,
Plasters, poultices, and steroid adhesive tape preparations that have appeared in recent years, such as those in which corticosteroids are uniformly dissolved or dispersed in the adhesive layer, have a poor utilization rate of the drug contained therein, and are particularly difficult to use in the adhesive layer. Drugs that move at a low speed in the substrate have problems such as low therapeutic efficacy and lack of rapid drug efficacy. On the other hand, as a proposal to solve this problem, there is a method of coating a pressure-sensitive adhesive onto a carrier and then applying a drug-containing solution to this surface. On the other hand, the concentration of the drug near the surface of the adhesive changes, resulting in a difference in pharmacological efficacy between the time of preparation and after the passage of time, resulting in the problem that stable therapeutic effects cannot be obtained. Further, two adhesive layers made of the same polymer constituting the intermediate layer and the surface layer are formed on the carrier,
Adhesive tape formulations have also been proposed in which the surface layer contains a drug, but since they are made of the same polymer, the two layers behave in the same way, and the intermediate layer helps ensure that the surface layer adheres to the surface to which it is applied. Not only does it not,
There is a problem in that the drug in the surface layer migrates to the intermediate layer, making it impossible to achieve the initial objective of retaining the drug at a high concentration in the surface layer. In view of these prior art situations, the present inventors have developed an adhesive polymer layer containing a high concentration of drug only on the application side, providing a large effective adhesive area to the application surface, and furthermore, the drug is not applied. After intensive research aimed at developing a structure that decreases only when absorbed onto a surface, we found that this purpose could be achieved by freely combining a flexible carrier and a thin sticky polymer layer containing the drug. Providing a flexible buffer layer that deforms to increase the effective adhesive area between the polymer layer and the applied surface, does not restore against the adhesive force of the polymer layer, and satisfies the following requirements a) to e). This is something that has been successfully achieved through. B. Solubility index value is 10 or less. B. Difference in solubility index value from drug is 0.5 or more. C. Non-migration of drug. D. 10 seconds shear creep compliance is 0.1 to
30×10 ^-6 cm ² /dyne E Flexible non-porous polymeric material The "solubility index value" used in the present invention is a value generally called "Solubility Parameter (SP)", and is a value based on the molar cohesive energy density. The square root of (δ
= (E/V) ^1/2 (E: molar cohesive energy, V: molecule volume), and indicates the magnitude of intermolecular force; when the values are close, they dissolve easily, and when the values are far apart. This value indicates the degree of solubility that makes it difficult to dissolve. (Reference: Polymer Handbook 2nd
Ed., J. Brandrup, EHImmergut, Editors.
John Wiley & Sons, New York, 1975) According to the therapeutic device of the present invention, the drug concentration per unit volume is increased even with a small amount of drug by using a thin polymer layer, so that the drug concentration per unit volume is increased due to the concentration gradient. It is characterized in that the drug that is absorbed through the skin is absorbed without wastage, thus providing extremely high absorption efficiency. The combination of a carrier, a flexible specific buffer layer that does not transfer drugs, a drug, and an adhesive polymer layer that contains and retains the drug, which constitutes this invention, is as follows:
It is determined by the properties of each compound used. Further, the properties of the compounds constituting each compound have a certain range, and therefore, the selection of mutually adjacent compounds is made based on the purpose of the present invention. The flexible carrier used in this invention forms one surface of the therapeutic component according to the invention, ie the surface opposite the application surface, and also supports the component. Therefore, the material used as the carrier can be a film or sheet of polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, etc., and porous bodies made of these films or sheets, It can be a breathable sheet-like material such as foam, paper, cloth, or nonwoven fabric. The buffer layer interposed between the carrier and the polymer layer has several functions. One of them is the function of increasing the adhesive area between the application surface and the polymer layer, and the other is the function of not inducing peeling at the adhesive interface. And another feature is
This function is to prevent the drug contained in the polymer layer from migrating to the layer and carrier. These functions can be reliably obtained by using a polymer material that satisfies at least one of the following properties. One property is that the 10 second shear creep compliance is in the range of 0.1 to 30 x 10 ^-6 cm ² /dyne. Creep compliance is the "ease of slippage" of a polymer material measured under specific conditions.
Specifically, in a parallel plate shear creep plast instrument, a smooth film (e.g. polytetrafluoroethylene film) is
Place the sample body formed to a thickness of 500μ into the container.
By applying a weight, the deformation deviation (d), sample body area (A), sample thickness (h), and gravitational acceleration (F) of the weight are determined and measured using the following formula. Formula J(t)=AAd/hF Here, when d and h are expressed in cm and F is expressed in dyne, J(t) is given in cm ² /dyne. When J(10) is 0.1 to 30×10 ⁻⁶ cm ² /dyne, the adhesion area of the polymer layer to the application surface is increased and interfacial peeling is not induced. Another property is that the solubility index value (hereinafter referred to as SP value) is 10 or less, and the SP value difference with the drug described later is
By having a ratio of 0.5 or more, migration of the drug from the drug-retaining polymer layer can be reliably prevented. Note that the difference in solubility index values only needs to be 0.5 or more, and the effects of the present invention are not affected no matter which of the solubility index values of the buffer layer or the drug is larger. More preferably, the glass transition point (Tg) is 30°C or lower. These SP values and Tg are determined from the viewpoint of affinity with the polymer layer described later and flexibility of the buffer layer. A flexible buffer layer having these two properties can be made of, for example, a homopolymer of (meth)acrylic acid alkyl ester, an acrylic copolymer such as (meth)acrylic acid ester-vinyl acetate copolymer, polyvinyl alkyl ether, or styrene-based copolymer. Selected from flexible and non-porous polymeric materials such as isoprene (or butadiene)-styrene copolymers, natural rubber, polyvinyl acetate, ethylene-based copolymers such as ethylene-vinyl acetate copolymers, and polysiloxanes. Furthermore, if necessary, a low molecular weight or low Tg resin, softener, etc. can be added to these. The polymer layer is sticky at room temperature and has the function of holding the drug. Preferably, the material has a distribution coefficient of 10 or more with respect to the flexible buffer layer. In this invention, the distribution coefficient means the relationship between the concentration of drug in the polymer layer/concentration of drug in the buffer layer. Even though the polymer layer is formed thin, it is necessary that it has sufficient adhesion to commonly used surfaces. The thickness of the layer is preferably about 0.1 to 30 μm, and although it is possible to form the layer with a thickness greater than this, it is undesirable because the drug-containing concentration per unit area using the same amount of drug becomes low. Therefore, the present invention provides a polymer layer with a high drug-containing concentration per unit area on the application surface, and the drug in the polymer layer does not decrease other than being absorbed from the application surface, and also adheres to the application surface for a desired period of time. It will be appreciated that this provides a treatment element that can be fixed. As the polymer layer, it is possible to use many adhesive substances that are sticky at room temperature, and the polymer layer formed on the flexible buffer layer helps the buffer layer to function as described above. Borrow it to maximize its adhesive fixing ability. The adhesive substance used has a C number of 4 to 10.
Acrylic copolymers of acrylic acid esters and vinyl monomers such as (meth)acrylic acid, acrylamide, vinylpyrrolidone, maleic acid or their esters, vinyl acetate, high molecular weight polyvinyl alkyl ethers and low molecular weight polyvinyl alkyl ethers. ether and, if necessary, a copolymer of the above-mentioned acrylic ester and vinyl monomer, or a tackifying resin such as tenpene resin, coumaron indene resin, α- or β-pinene resin, or ester gum. polyvinyl alkyl ether mixtures, natural rubbers, synthetic rubbers, copolymer rubbers, and other rubbers with tackifying resins and softeners added, or silicone polymers containing polyorganosiloxane as the main component. Examples include things. The combination of the polymer layer and the flexible buffer layer satisfies the various conditions mentioned above, and in addition, for example, the adhesive material that makes up the polymer layer and the material that makes up the buffer layer have the same or similar polarity. It is also possible to create a combination in which one or each layer contains an appropriate amount of the following to improve the anchoring properties (adhesive properties) of both layers. The polymer layer contains the following transdermally absorbable drugs, but if necessary, auxiliary agents may be added to help the drug in the polymer layer move to the application surface, such as the skin, which is the application surface. Appropriate amounts of absorption aids, etc., which swell the surface and create a state in which the drug is easily absorbed through the skin, can be added. Examples of the drugs that can be used include the following, and two or more of these can also be used. 1 Steroid anti-inflammatory analgesics, such as betamethasone valerate, betamethasone dipropionate, fluocinonide, clobetasol propionate, triamcinolone, triamcinolone acetonide, dexamethasone, flurandrenolone, etc. 2 Non-steroidal anti-inflammatory analgesics, such as diphehydramine, acetamino Fuene, mefenamic acid, flunamic acid, indomethacin, diclofenac, oxyphenbutazone, ibufenac, flurbiprofen, methyl salicylate, etc. 3. Hypnotic analgesics, such as phenobarbital, amobaltal, etc. 4. Tranquilizers, such as flufenazine, thioridazine , diazepam, chlorpromazine, etc. 5 Hypertensive agents, such as clonidine, cyclopenthiazide, bentroflumethiazide, reserpine, etc. 6 Antibiotics, such as erythromycin, chloramphenicol, cephalosporin, fradiomycin, etc. 7 Local anesthetics, e.g. lidocaine, cocaine,
8 Antibacterial agents, such as acetosulfacin, clotrimazole, etc. 9 Antifungal agents, such as pentamycin, amphotericin B, pyrrolnitrine, 10 Antiepileptic agents, such as nitrazepam, meprobamate, Depagen, etc. 11 Coronary vascular tensile agents, such as dipyridamole, nitroglycerin, isosorbide nitrate, etc.12 Antitumor agents, such as bleomycin, 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, etc., polymers of these drugs The content in the layer depends on the absorption and effective therapeutic concentration of the drug, but is generally about
The range is 0.01 to 30% by weight, practically 0.05 to 20% by weight. The auxiliaries mentioned above include alcohols such as ethyl alcohol, isopropyl alcohol, 1,4-butanediol, 1,3-butanediol, propylene glycol, and glycerin, propyl stearate, ethyl laurate, diisopropyladipate, and ethyl alcohol. C-class alkyl carboxylic acids such as sebacate, butyl sebacate, dibutyl diglycol adipate, etc. and C1-8
esters consisting of alkyl alcohols, cellosolves such as ethyl cellosolve and hexyl cellosolve, polyoxyethylene alkyl ethers such as polyoxyethylene (15) stearyl ether, polyoxyethylene alkyl esters such as polyoxyethylene lauryl ester, Other examples include block copolymers of polyoxyethylene and polyoxypropylene, alkylamides, alkyl sulfoxides, and alkyl phosphines. As explained above, the therapeutic device of the present invention is composed of a carrier, a buffer layer, and a polymer layer, and a release member for protecting the polymer layer is temporarily attached to the polymer layer. The therapeutic device of the present invention can be used to treat a localized disease site or a disease site remote from the application site, and the device provides a therapeutically effective amount of drug to the blood. Examples of the present invention will be shown below, but the present invention is not limited to the following examples. The words "part of the text" indicate parts by weight. Example 1 A corona discharge treated polyethylene film (thickness 50 μm) was coated with a K value (1
% tetrahydrofuran solution at 20°C, and indicates the polymer properties calculated from the viscosity according to the West German standard (DIN 53726-A). )but
20 parts of polyvinyl isobutyl ether of 20-28 and K
Value (value at 20℃ of 0.5% isooctane solution)
A buffer layer (thickness: 30 μm) is formed of a mixture with 80 parts of polyvinyl isobutyl ether having 123 to 127. The 10 second shear creep compliance of the layer is 5.4 x 10 ^-6 cm ² /dyne and the SP value is 7.7. On the other hand, a copolymer (3.5% solution) of 60 parts of 2-ethylhexyl acrylate and 40 parts of vinyl acetate was polymerized in ethyl acetate using 0.2 parts of azobisisobutyronitrile (AIBN) as a polymerization initiator. 20 parts of dibutyl sebacate per 100 parts of the mold,
A mixture containing 0.6 parts of betamethasone valerate (SP value 8.7) is prepared. Next, the mixture is formed on the surface of the buffer layer so as to have a thickness of 5 μm after drying to obtain a treatment member of the present invention. Note that the distribution coefficient between the buffer layer and the polymer layer is 15. Example 2 Example 1 except that betamethasone dipropionate (SP value 8.8) was used instead of betamedasone valerate in Example 1, and spunbond nylon nonwoven fabric (basis weight 35 g/m ² , thickness 310 μm) was used as the carrier. It is the same as 1. Note that the distribution coefficient is 13. Example 3 A buffer layer (thickness: 30 μm) made of a mixture of 100 parts of polybutadiene rubber, 30 parts of polybutene (average molecular weight: 1200), and 30 parts of hydrogenated rosin was applied to the surface of a rayon nonwoven fabric (basis weight: 30 g, thickness: 300 μm). Form.
The 10 second shear creep compliance of the layer is 2.5
×10 ^-6 cm ² /dyne, and the SP value is 7.05. Next, a mixture is prepared by adding 20 parts of diethyl sebacate and 0.6 parts of clobetasol propionate (SP value 7.6) to the acrylic copolymer used in Example 1. Next, this mixture is formed on the surface of the buffer layer so as to have a thickness of 5 μm after drying to obtain a treatment member of the present invention. Note that the distribution coefficient is 12. Example 4 Styrene-isobrene-styrene block copolymer rubber (styrene:isoprene = 14:86 (weight ratio)) on polyvinyl chloride film (thickness 50 μm)
A buffer layer (thickness: 30 μm) is formed from a mixture of 100 parts of polybutene and 200 parts of polybutene having an average molecular weight of 1260. The 10 second shear creep compliance of the layer is 2.3 x 10 ^-6 cm ² /dyne and the SP value is 7.4. On the other hand, 70 parts of methoxyethyl acrylate and 30 parts of acrylic acid were polymerized in ethyl acetate using 0.2 parts of AIBN, and water containing 50 parts of polyethylene glycol and 1.4 parts of NaOH and isopropyl based on 100 parts of solid content of the polymer. Blend 100 parts of a mixture with alcohol (1:1), and further blend 20 parts of polyethylene glycol (average molecular weight 400), 10 parts of diisopropyl adipate, and 0.2 parts of triepoxypropyl isocyanurate as a crosslinking agent, and dissolve and mix. do. Next, add this to indomethacin (SP value
9.0) to obtain a mixture. The mixture is formed on the buffer layer surface of the film so as to have a thickness of 10 μm after drying to obtain the treatment member of the present invention. Note that the distribution coefficient is 22. Example 5 The same as Example 4 except that diclofenac (SP value 8.5) was used instead of indomethacin. Note that the distribution coefficient is 21. Example 6 Same as Example 4 except that the number of parts of polyethylene glycol in Example 4 was changed from 20 parts to 30 parts, diisopropyl adipate was replaced with polyoxyethylene sorbitan monooleate, and indomethacin was replaced with isosorbide nitrate (SP value 6.63). The same is true. Note that the distribution coefficient is 13. Example 7 Example 4 except that diisopropyl adipate in Example 4 was replaced with dimethylformamide and indomethacin was replaced with clonidine (SP value 8.4).
It is similar to Note that the distribution coefficient is 17. Example 8 A mixture consisting of polyvinyl chloride film (thickness 50 μm), 100 parts of styrene-isoprene-styrene block copolymer rubber (same as in Example 4), and 300 parts of a polyterpene resin with an average molecular weight of 450. A buffer layer (thickness: 30 μm) is formed. of the layer
10 seconds shear creep compliance is 8.3×10 ^-6
cm ² /dyen, and the SP value is 7.7. On the other hand, (CH ₃ ) _{3 SiO 0.5 units} and SiO ₂ units (in molar ratio
siloxane copolymer resin solution (xylene 40% by weight) consisting of
A block of polypropylene glycol and polyethylene glycol is added to 100 parts solids of a silicone composition prepared by mixing 1:1 (weight ratio) of 40% by weight and 1.2 parts of organic peroxide. Add 10 parts of copolymer and 10 parts of diisopropyladipate, and then add flurbiprofen (SP value 9.0)
1 part to obtain a mixture. This mixture is applied and dried on the buffer layer surface of the film to a thickness of 15 μm after drying to obtain the treatment member of the present invention. Note that the distribution coefficient is 35. Example 9 This is the same as in Example 4 except that indomethacin was replaced with scopolamine (SP value 9.3) and the copolymer of polypropylene glycol and polyethylene glycol was replaced with mineral oil. Note that the distribution coefficient is 34. Example 10 The same procedure as in Example 4 was repeated except that erythromycin (SP value 8.4) was used instead of indomethacin, and dimethylformamide was used instead of the copolymer of polypropylene glycol and polyethylene glycol. Note that the distribution coefficient is 14. Reference Example Example 1 was added to the nylon nonwoven fabric used in Example 2.
form a buffer layer. On the other hand, 70 parts of acrylic acid and 30 parts of butyl acrylate were used as a polymerization initiator, and 0.2 parts of ammonium persulfate was used as a polymerization initiator.
Polymerize in hot water (60℃) and add
An aqueous solution of 30 parts of NaOH dissolved in 100 parts of water is mixed. Next, 0.2 parts of triepoxypropyl isocyanurate, 10 parts of diazepam (SP value 8.0), 5 parts of N,N'-dimethyllaurylamide, and 10 parts of glycerin are each added to 100 parts of the solid content of this mixture. Next, this mixture is applied and dried on the buffer layer surface of the non-woven fabric to a thickness of 10 μm after drying to obtain the treatment member of the present invention. Note that the distribution coefficient is 17. Comparative Examples 1 to 11 Comparative Examples 1 to 11 correspond to Examples 1 to 11, respectively, and in each example, a drug-containing polymer layer (40 μm thick) was provided directly on the support without forming a buffer layer. It is something. However, the drug content per unit area is the same as in each example. Table 1 shows the test results of Examples 1 to 3 and Comparative Examples 1 to 3, and Table 2 shows the test results of Examples 4 to 6 and Comparative Examples 4 to 6.

[Table] The histamine edema suppression rate in Table 1 is measured by the following method. Prepare a 2 cm square sample A and a sample B that does not contain any drug as a control. Samples A and B were pasted in pairs on the hair-free area of the back of a Wistar rat (male weighing 200 g) across the midline of the spine, and peeled off after 2 hours. Next, 0.2 ml/100 g (body weight) of 1% Pontamine Sky Blue saline was injected through the tail vein, and immediately thereafter, 2 μg/μm histamine saline was injected intradermally into the 50 μm peeling scar, and 30 minutes later, intradermal dye was added. Measure the leakage circle area,
The suppression rate is calculated using the following formula. Suppression rate (%) = So - S / So × 100 where So is the dye leakage area of the control sample S is the dye leakage area of the sample application site

[Table] The carrageenan edema suppression rate in Table 2 is measured by the following method. Using a Wistar rat (male) weighing approximately 150 g, the volume of the rat's right hind paw was measured, and a 2 cm ² sample was attached to the right hind foot pad. After 2 hours, it was removed and 0.5% carrageenan saline was applied to the same area. The water
Inject 0.05ml subcutaneously, measure the volume of the right hind paw 3 hours later, take the difference between before and after mounting the sample as the paw edema volume, and calculate the inhibition rate using the following formula. Inhibition rate (%) = Vc - Vt / Vc x 100, where Vc and Vt represent the average foot edema volumes of the control group and sample attachment group, respectively. Next, the test results of Examples 6, 9 to 10, Reference Examples, and Comparative Examples 6 and 9 to 11 will be shown. Figures 1 and 2 show Example 6 (and Comparative Example 6)
and the test results of Example 7 (and Comparative Example 7). Note that the dashed line in the figure is the normal value. The graphs shown in Figures 1 and 2 are based on samples (4 cm x 4 cm square) taken from Wistar rats (body weight: 200 cm).
(~250g) abdomen was removed and pasted, and the caudal artery was measured. The test results of Example 9 (and Comparative Example 9) are shown.
Scopolamine has a blocking effect on the peripheral accessory sympathetic nerve innervated tract and also has a central depressing effect, so the eye blink reflex was used to evaluate efficacy. One group consisted of 10 dd mice (weight 18-20 g (male)),
Hair was removed from the abdomen, and a sample (2 x 2 cm square) was pasted there (Group A), and a drug-free sample was similarly pasted on the other group (Group B). Twenty minutes after application, 80% of the drug administration group (group A) had no blink reflex, and from 1 to 4 hours, blink reflex was absent in all animals. . On the other hand, in the control group B, the blink reflex was remarkable, and a clear difference was seen compared to the drug-administered group. On the other hand, comparative example 9
When the test was conducted in the same manner as above, 30% (3 animals) no longer showed the blink reflex at the 1st hour, and all showed the blink reflex at the 3rd hour.
There was no difference from the group. The test results of Example 10 (and Comparative Example 10) are shown.
A sample punched to a diameter of 10 mm was placed on top of B. Subtilis sown in an agar nutrient medium, and the bacterial growth inhibition zone was observed after 24 hours.
The values shown in the table were obtained.

[Table] Shows the test results of Reference Example (and Comparative Example 11).
Using 10 DD mice (male, weight 18-20 g) in each group, their abdomens were hair-removed, a 2 x 2 cm square sample was pasted thereon, and the number of animals with a blink reflex was observed over time. The results are shown in Table 4.

【table】 [Brief explanation of drawings]

Embodiment 6 of the present invention is shown in FIGS. 1 and 2.
and 7 are graphs showing the test results.

Claims (1)

[Scope of Claims] 1. A thin adhesive polymer layer containing a drug is provided between a flexible carrier and a thin adhesive polymer layer that can be freely deformed to increase the effective adhesion area between the polymer layer and the application surface. A treatment member characterized by being provided with a flexible buffer layer that does not restore its shape against the adhesive force and satisfies the following requirements (a) to (e). B. Solubility index value is 10 or less. B. Difference in solubility index value from drug is 0.5 or more. C. Non-migration of drug. D. 10 seconds shear creep compliance is 0.1 to
30×10 ^-6 cm ² /dyne E Flexible non-porous polymer material.