JPH04297415A - Tacky agent for administering medicine - Google Patents

Abstract

PURPOSE:To obtain a tacky agent for administering medicines capable of sticking to the skin by moderate tackiness together with various medicines without causing contact dermatitis due to low skin irritancy and capable of maintaining the absorption of the medicines in the skin moderate, a skin application type tacky pharmaceutical and a sustained release tacky material containing the above-mentioned tacky agent. CONSTITUTION:A tacky agent for administering medicines containing a higher alpha-olefinic (co)polymer composed of a 6-12C straight-chain higher alpha-olefin ingredient, preferably polyhexene, polyoctene, polydecene, hexene-1.ethylene copolymer, octene-1.ethylene copolymer, decene-1.ethylene copolymer, etc., especially at least one of the polyhexene, polyoctene and polydecene as a principal ingredient in an amount of normally 5-100mol%, preferably 60-100mol%. A skin application type tacky pharmaceutical containing the aforementioned tacky agent as a tacky ingredient and preferably further a percutaneous absorbefacient or a sustained release tacky material, containing the above-mentioned tacky agent as the tacky ingredient and capable of releasing moderate amounts of various medicines is obtained.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to adhesives for drug administration, and in particular, they contain various drugs, adhere to the skin with appropriate adhesive strength, are less irritating to the skin, do not cause rashes, and do not cause rashes. Adhesive materials for drug administration that can maintain appropriate levels of absorption into the skin, adhesive formulations that stick on the skin containing the same, and sustained release properties that can sustainably release various drugs in appropriate amounts. Regarding a release adhesive material.

0002

[Prior Art] Conventionally, although the medicinal effects are high, when administered at high concentrations through oral administration, which is the usual form of drug administration,
There were times when it caused harm. For example, indomethacin,
When administered orally, analgesic anti-inflammatory drugs such as perisoxal citrate and flurbiprofen, and angina drugs such as nitroglycerin and isosorbide nitrate, can put a burden on the liver and cause gastrointestinal disorders. Therefore, it is desirable to improve the route of drug administration and to make the dosage form more sustained. By absorbing the drug directly from the vicinity of the affected area without going through the liver, the burden on the liver is eliminated, and the detoxification effect in the liver is avoided to effectively exert the medicinal effect. Efforts are being made to prolong the efficacy of medicines. Furthermore, the skin-applying adhesive preparation can eliminate the inconvenience of oral administration, which requires frequent administration in small doses.

[0003] Conventionally, the adhesive used in the skin adhesive preparation is made of natural rubber, olefin rubber, or olefin polymer.

0004

[Problems to be Solved by the Invention] However, the adhesives used in the conventional skin-patch type adhesive preparations have weak adhesion to the skin, or conversely, are too strong and may leave residue on the skin. There were times when I did something like that. In addition, some of them caused rashes because they were highly irritating to the skin.

Furthermore, insect repellents, plant growth promoters, disinfectants,
In order to exert the effectiveness of chemicals such as rust preventives, preservatives, fragrances, and deodorants over a long period of time, it is preferable to retain the chemicals and release them slowly at an appropriate rate. . Therefore, there is a need for an adhesive material that can be blended with a drug and adhered to a location where the drug needs to be administered, and that has excellent sustained release properties for the drug.

[0006]The first object of the present invention is to adhere to the skin with various drugs with a moderate adhesive force, have little skin irritation and therefore do not cause a rash, and have excellent sustained release properties so that the drug can be applied to the skin. An object of the present invention is to provide an adhesive material for drug administration that can maintain appropriate absorption of the drug, and a skin-applied adhesive preparation containing the same.

[0007] A second object of the present invention is to provide a sustained-release adhesive material that has excellent sustained-release properties and can gradually release appropriate amounts of various drugs blended therein.

[0008]

[Means for Solving the Problems] In order to solve the above problems, the present invention mainly uses a higher α-olefin type (co)polymer consisting of a linear higher α-olefin component having 6 to 12 carbon atoms. The present invention provides an adhesive for drug administration as a component.

It is preferable that the higher α-olefin (co)polymer is at least one selected from polyhexene, polyoctene and polydecene.

[0010] The present invention also provides a skin-applying adhesive preparation containing the above-mentioned drug administration adhesive as an adhesive component.

[0011] It is preferable that the skin-applying adhesive preparation contains a transdermal absorption enhancer.

Furthermore, the present invention provides a sustained release adhesive material containing the above-mentioned drug administration adhesive as an adhesive component.

[0013] Below, the adhesive for drug administration of the present invention, the skin-applied adhesive preparation containing the same, and the sustained-release adhesive material are as follows:
Explain in detail.

The higher α-olefin type (co)polymer consisting of a linear higher α-olefin component having 6 to 12 carbon atoms, which is the main component of the adhesive for drug administration of the present invention, has 6 to 1 carbon atoms.
Contains at least one linear higher α-olefin of 2 (
co)polymer, for example, at least one carbon number 6
A (co)polymer consisting of ~12 linear higher α-olefins, or a copolymer of at least one linear higher α-olefin having 6 to 12 carbon atoms and at least one other α-olefin Examples include merging.

[0015] Examples of the linear higher α-olefin having 6 to 12 carbon atoms include hexene-1, heptene-1
, octene-1, nonene-1, decene-1, undecene-1, dodecene-1, and the like. Examples of other α-olefins include ethylene, propylene, butene-1, pentene-1, and 4-methylpentene-1.

Specific examples of the above-mentioned (co)polymer comprising at least one linear higher α-olefin having 6 to 12 carbon atoms include hexene-1 polymer, heptene-1 polymer, octene-1 polymer, polymer, nonene-1 polymer, decene-1
polymer, undecene-1 polymer, dodecene-1 polymer,
Hexene-1/octene-1 copolymer, hexene-1/
Examples include decene-1 copolymer, octene-1/decene-1 copolymer, and the like.

[0017] Furthermore, at least one of the above-mentioned species has a carbon number of 6 to
Specific examples of copolymers of 12 linear higher α-olefins and at least one other α-olefin include hexene-1/ethylene copolymer, heptene-1/ethylene copolymer, octene-1/ethylene copolymer, 1. Ethylene copolymer, nonene
1・ethylene copolymer, decene-1・ethylene copolymer, undecene-1・ethylene copolymer, dodecene-1・
Ethylene copolymer, hexene-1/propylene copolymer, heptene-1/propylene copolymer, octene-1/
Propylene copolymer, decene-1/propylene copolymer, dodecene-1/propylene copolymer, hexene-1/
Butene-1 copolymer, octene-1/butene-1 copolymer, decene-1/butene-1 copolymer, dodecene-1/
Butene-1 copolymer, hexene-1/pentene-1 copolymer, octene-1/pentene-1 copolymer, decene-1
1.pentene-1 copolymer, dodecene-1.pentene-
1 copolymer, octene-1,4-methylpentene-1 copolymer, decene-1,4-methylpentene-1 copolymer, dodecene-1,4-methylpentene-1 copolymer, etc. .

Among these, hexene-1 polymer, octene-1 polymer, decene-1 polymer, hexene/ethylene copolymer, octene-1/ethylene copolymer, decene-1/ethylene copolymer, Octene-1/Butene-1
Copolymers, decene-1/butene-1 copolymers are preferred, and hexene-1 polymers, octene-1 polymers, and decene-1 polymers are particularly preferred.

The content of the linear higher α-olefin component having 6 to 12 carbon atoms in this higher α-olefin type (co)polymer is determined in such a way that an adhesive for drug administration having sufficient adhesiveness can be obtained. , usually 50 to 100 mol%, preferably 60 to 100 mol%, particularly preferably 70 to 10 mol%
It is 0 mol%.

In addition, gel permeation chromatography (GP) of this higher α-olefin (co)polymer
C) The weight average molecular weight (polystyrene equivalent value) measured by the measurement method is usually in the range of 100,000 to 1,000,000, preferably in the range of 300,000 to 800,000, since it has excellent shape retention as an adhesive and is easy to process. It is something that is in .

This higher α-olefin (co)polymer can be produced according to known methods. For example, at least one linear higher α-olefin having 6 to 12 carbon atoms is (co)polymerized in the presence of a transition metal catalyst consisting of a transition metal compound such as titanium, vanadium, or zirconium and an organoaluminium catalyst. Alternatively, it can be produced by a method of copolymerizing at least one linear higher α-olefin having 6 to 12 carbon atoms and another α-olefin. The transition metal catalyst used is preferably a highly active titanium catalyst containing magnesium, titanium, halogen, and an electron donor as essential components. At this time, alcohols, phenols, ketones, aldehydes, carnebonic acid, esters, ethers,
It is preferable to use an electron donor catalyst such as an acid amide, an acid anhydride, or an alkoxysilane in combination.

[0022] The highly active titanium catalyst can be prepared by, for example,
JP 50-108385, JP 50-12659
Publication No. 0, Publication No. 51-20297, Publication No. 51-281
No. 89, No. 51-64586, No. 51-92
No. 885, No. 51-136625, No. 52-
No. 87489, No. 52-100596, No. 5
No. 2-147688, No. 52-104593, No. 53-2580, No. 53-40093, No. 53-40094, No. 53-43094, No. 55-135102, No. 55 -13510
Publication No. 3, Publication No. 55-152710, Publication No. 56-81
Publication No. 1, Publication No. 56-11908, Publication No. 56-186
Publication No. 06, Publication No. 58-83006, Publication No. 58-13
No. 8705, No. 58-138706, No. 58
-138707 publication, 58-138708 publication,
No. 58-138709, No. 58-138710, No. 58-138715, No. 60-2340
Publication No. 4, Publication No. 61-21109, Publication No. 61-378
This can be carried out by the methods disclosed in Publication No. 02, Publication No. 61-37803, and the like.

The catalyst components, (co)polymerization conditions, and other (co)polymer production conditions in the production of the higher α-olefin (co)polymer are not particularly limited, and the linear higher α-olefin The olefin content and weight average molecular weight can be selected appropriately, but usually the (co)polymerization temperature is 30 to 100°C and the pressure is normal pressure to
It is about 50 kg/cm2. Furthermore, the (co)polymerization can be carried out in any of the batch, semi-continuous, and continuous formats. It is preferable to use hydrogen during this (co)polymerization because the molecular weight of the resulting (co)polymer can be adjusted.

The adhesive for drug administration of the present invention is mainly composed of a higher α-olefin (co)polymer composed of the linear higher α-olefin component having 6 to 12 carbon atoms. Furthermore, various additives that are blended into this type of adhesive can be blended as needed. For example, inorganic or organic fillers, lubricants, softeners, heat stabilizers, surfactants, pigments, dyes, etc. may be added. Among these, it is preferable to incorporate a filler in that the release of the drug from the adhesive increases.

[0025] The content of the higher α-olefin (co)polymer in the adhesive for drug administration of the present invention is usually
It is about 10 to 95% by weight, preferably about 30 to 90% by weight.

[0026] The adhesive for drug administration of the present invention is produced by mixing the above-mentioned higher α-olefin (co)polymer and various additives as necessary in the required amounts, kneading, and then using it in the form of a rolled sheet. It will be done. As this method, after kneading by roll kneading, it can be manufactured by molding according to a low temperature compression molding method, a normal extrusion molding method such as T-die molding, or the like.

[0027] The present invention also provides a skin-applying adhesive preparation containing the above-described adhesive for drug administration.

[0028] This skin-patch type adhesive preparation is made by blending a predetermined amount of a predetermined drug with the above-mentioned drug administration adhesive.

Drugs that can be incorporated into the skin adhesive preparation of the present invention are not particularly limited, and include, for example, analgesic and anti-inflammatory agents such as indomethacin, flurbiprofen, morphine, perisoxal citrate, and aspirin, and pitolterol nosylate. Bronchodilators, antitussives such as theopherine, dextromethorphan hydrobromide, allergy drugs such as ketotifen fumarate, tranilast, sodium cromoglycate, antiarrhythmia drugs such as pindolol, gout drugs such as colchicine, anti-itch drugs, antibiotics. Examples include drugs that are absorbed into the skin from the surface of the skin and administered to treat affected areas.

[0030] Furthermore, by incorporating a transdermal absorption enhancer into this skin-applying adhesive preparation, the release rate of the drug from the adhesive preparation can be increased, and the skin permeability of the drug can be promoted. So, it's preferable. This transdermal absorption enhancer is a substance that promotes skin permeability of drugs, and is required to be non-irritating to the skin. Furthermore, skin permeability cannot be achieved without release from the adhesive formulation. Therefore, as a transdermal absorption enhancer, at the skin surface temperature,
It is preferable to use a drug that dissolves at least a portion of the solid drug, has an affinity for the hydrophobic adhesive, promotes the diffusion of the drug into the adhesive, and has an excellent effect of promoting absorption into the skin of living things.

The transdermal absorption enhancer is not particularly limited as long as it becomes liquid at the skin surface temperature, dissolves at least a small portion of the drug, and has an affinity for the adhesive. For example, octyl alcohol , higher alcohols having 8 to 20 carbon atoms such as nonyl alcohol, decyl alcohol, dodecyl alcohol, tridecyl alcohol, myristyl alcohol, 1-pentadecanol, cetyl alcohol, stearyl alcohol, oleyl alcohol, 1-nonadecanol, 1-eicosanol, etc. can be mentioned. These may be used alone or in combination of two or more.

Among these, higher alcohols having 8 to 20 carbon atoms and mixtures thereof;
20 higher alcohols, lower alcohols, polyhydric alcohols such as glycerin, diglycerin, propylene glycol, polyvinyl alcohol, higher fatty acid esters, m
-cresol, isosorbitol, amyl alcohol,
A mixture with hexyl alcohol or the like, which becomes liquid at the skin surface temperature, is preferable because it allows the drug to diffuse into the adhesive quickly and has an excellent effect of promoting absorption of the drug into the skin.

Furthermore, the skin adhesive preparation of the present invention may contain inorganic fillers such as calcium carbonate, talc, silica, synthetic hydrotalcite, inorganic fillers, etc., as necessary, to the extent that the object of the present invention is not impaired. Organic fillers such as organic fillers, paraffin, wax, vaseline, beeswax, and lanolin, stabilizers such as antioxidants, heat stabilizers, and surfactants, tackifiers such as rubber copolymers, thickeners, and softeners. , plasticizers, pigments such as titanium white, dyes, colorants, and other various additives can be blended.

[0034] In the form of the skin patch type adhesive preparation of the present invention, the method for forming a thin layered skin patch is to mix the drug with an adhesive, a transdermal absorption enhancer, and, if necessary, other additives. is plasticized by using the solvent of the adhesive or by heating, kneaded using a two-roll, screw extruder, etc., and then spread on one side of a thin film-like support, A protective film is formed by overlapping the release surface of release paper or release film that has been provided with release properties using silicone or the like on the other drug-containing surface. When applied to the skin,
This protective film is peeled off before use. As the membrane-like support, an elastic membrane having flexibility that can follow the expansion and contraction of the skin,
For example, polyethylene, polypropylene, ethylene/vinyl acetate copolymer, ethylene/ethyl acrylate copolymer, ethylene/propylene copolymer, ethylene/propylene/α-olefin copolymer, thermoplastic elastomer, silicone rubber, soft polyurethane. Membranes such as, porous membranes, or thin membranes such as woven fabrics, nonwoven fabrics, and flexible paper are preferred. Further, it is preferable that the protective film is made of a material or has a shape that is more rigid than the support because operability during peeling is improved.

The skin adhesive preparation of the present invention obtained as described above is usually formed into a thin layer having a thickness of about 20 to 300 μm before use.

The blending ratio of the adhesive for drug administration and the drug in the skin adhesive preparation of the present invention is appropriately selected according to the effective concentration of the drug used, the thickness of the layer to be formed, etc., and is not particularly limited. When the thickness of the layer used is about 50 to 150 μm, the drug is usually added at 5 parts by weight to 30 to 90 parts by weight of the adhesive for drug administration in order to obtain sufficient adhesion to the skin.
Preferably, the proportion is 50 parts by weight. In addition, when incorporating a transdermal absorption enhancer, the drug is released into the skin faster, the transdermal absorption rate increases, and the transdermal absorption enhancer does not bleed out and has sufficient adhesive strength. The proportion is 5 to 30 parts by weight based on the above proportion.

The present invention also provides a sustained release adhesive material containing the above-mentioned drug administration adhesive as an adhesive component.

[0038] This sustained release adhesive material is made by blending a predetermined amount of a predetermined drug with the above-mentioned drug administration adhesive.

Drugs that can be incorporated into the sustained release adhesive of the present invention are not particularly limited, and include, for example, insect repellents such as naphthalene, dichlorobenzene, and butopyronoxyl, plant growth promoters such as auxin, shikonin, carbolic acid, and formalin. Examples include disinfectants, disinfectants, fragrances, and deodorizers.

The amount of the drug administration adhesive used in the sustained release adhesive of the present invention is usually about 10 to 95% by weight, preferably about 50 to 95% by weight.

[0041] The sustained release adhesive material of the present invention can be produced by mixing the above-mentioned drug administration adhesive and a predetermined amount of a drug by a method such as roll mixing or extrusion molding.

[0042]

[Examples] Examples and comparative examples of the present invention are listed below.
Although the present invention will be specifically explained, the present invention is not limited to these Examples in any way.

(Examples 1 to 3) In each example, high α-
Octene-1 polymer, which is an olefinic (co)polymer (
Weight average molecular weight (polystyrene equivalent value) determined by GPC measurement method: 695,000), 30 parts by weight of indomethacin (IM: manufactured by Wako Pure Chemical Industries, Ltd.), an analgesic and anti-inflammatory agent, and synthetic hydrotalcite (SHT: Kyowa) as a filler. 10 parts by weight (manufactured by Kagaku Co., Ltd.) and the transdermal absorption enhancers shown in Table 1 in the amounts shown in Table 1 to prepare a mixture.

[0044]

The obtained mixture was roll-kneaded at 50°C for 3 minutes, and then kneaded at 50°C using release paper on both sides.
A sample for an elution test was prepared by pressure molding at a pressure of cm2. This sample was subjected to a dissolution test according to the following method.

[Elution test of indomethacin] A sample for the elution test was cut into a circular shape with a diameter of 26 mm, and Shuragard (microporous polypropylene film) was pasted on one side as a backing material, and a molting snake was applied to the other side as an elution film. A membrane (Yamakagashi: product 4 to 5 days after shedding) was pasted and attached to a glass vertical diffusion cell to obtain an elution test piece. Next, a dissolution test was conducted using a dissolution test apparatus schematically shown in FIG. In this dissolution test device, a dissolution test piece 2 to which a shedding snake membrane 3 and a backing material 1 are attached is fixed to a lower receptor 4 by a cylindrical upper receptor 8, and the top of the upper receptor 8 is open. Further, a stirrer 6 is disposed inside the lower receptor 4 to stir the eluate 9 and to flow constant temperature water to the outer side 5 of the lower receptor to keep the temperature in the system constant. In this elution test device, the eluate 9 was added to the lower receptor 4 side at 37°C.
0.1M phosphate buffer (pH: 7.22) kept warm at
) is injected in a specified amount from the outlet 7 of the diffusion cell to remove the skin from the molting snake membrane 3.
The temperature of the water circulating around the outside 5 of the lower receptor is set to 37°C, and the temperature of the entire device is set to 2.
It was placed in a constant temperature and humidity chamber at 3°C and 50% humidity. After stirring for 5 minutes using the stirrer 6, 10 ml of the eluate was collected from the outlet 7, and the amount (ppm) of indomethacin eluted into the eluate was determined. Similarly, the amount of indomethacin eluted into the eluate was quantified over time. The cumulative elution amount (mg) of indomethacin was calculated, the area of the scales of the shedding snake membrane 3 was measured using an image analysis device (manufactured by Pierce Co., Ltd.), and from the area of the shedding snake membrane excluding the scales, Elution amount of indomethacin per elapsed time (mg/cm
2) was calculated. The results are shown in Figure 2.

(Comparative Example 1) Commercially available Inteban ointment (1%
26 mmφ, 1
Apply to a thickness of mm and follow the same method as in Example 1.
A dissolution test was conducted to determine the amount of indomethacin eluted at each elapsed time (mg/cm2). The results are shown in Figure 2.

(Examples 4 to 7) In each example, 30 parts by weight of pindolol as an antiarrhythmia agent and 20 parts by weight of dodecyl alcohol as a transdermal absorption enhancer were added to the higher α-olefin (co)polymer shown in Table 2. were mixed in the same manner as in Example 1 to prepare a mixture.

[0049]

[0050] Each of the obtained mixtures was pressure-molded to prepare test pieces for the dissolution test in the same manner as in Example 1.
An elution test was conducted in the same manner as in Example 1, and the elution amount (mg/cm2) of pindolol was measured at each elapsed time. In addition, the skin of a striped snake was used as the shedding snake membrane. The results are shown in Figure 3.

(Examples 8 to 11) In each example, high-grade α
- Polyoctene (weight average molecular weight: 695,000), which is an olefin (co)polymer, is blended with 20 parts by weight of dodecyl alcohol as a transdermal absorption enhancer and 30% by weight of the drug with synthetic hydrotalcite as a filler, and further 5 parts by weight (Example 8), 10 parts by weight (Example 9), 20 parts by weight (Example 10), or 30 parts by weight (Example 11) of dextromethorphan hydrobromide, which is an antitussive, was blended. Four types of mixtures were prepared. Each of the four obtained mixtures was pressure-molded in the same manner as in Example 1 to prepare a test piece for the dissolution test. The elution amount (mg/cm2) of dextromethorphan hydrobromide was measured. In addition, as the shedding snake membrane, that of Yamakagashi was used. The results are shown in Figure 4.

[0052]

[Effects of the Invention] The adhesive for drug administration of the present invention is formulated with various drugs and adheres to the skin with appropriate adhesive strength, and has little skin irritation, so it does not cause rash, and the drug does not affect the skin. Absorption can be maintained at a moderate level.

[0053] Furthermore, the skin-patch type adhesive preparation of the present invention containing this adhesive material for drug administration allows the drug to be released in a sustained manner through the skin, thereby eliminating the shortcomings of conventional oral preparations. This eliminates the inconvenience of having to administer the drug, and by applying it to the skin near the affected area, the detoxification effect in the liver can be avoided, increasing the utilization efficiency of the drug. It has the advantage of avoiding unnecessary side effects associated with administration and reducing the burden on patients.

[0054] Furthermore, the sustained release adhesive of the present invention can be formulated with various drugs and gradually release the drugs in appropriate amounts, and has excellent sustained release properties. Therefore, the sustained release adhesive material of the present invention is suitable for applications such as insect repellents, plant growth promoters, deodorants, and fragrances.

[Brief explanation of drawings]

FIG. 1 is a schematic cross-sectional view of a dissolution test device used in Examples and Comparative Examples.

FIG. 2 is a diagram showing the results of indomethacin elution tests conducted in Examples 1 to 3 and Comparative Example 1.

FIG. 3 is a diagram showing the results of pindolol elution tests conducted in Examples 4 to 7.

FIG. 4 is a diagram showing the results of elution tests for dextromethorphan hydrobromide conducted in Examples 8 to 11.

[Explanation of symbols]

1. Lining material 2 Sample 3 Shedding snake membrane 4 Lower receptor 5 Lower receptor outer side 6 Stirrer 7 Outlet part 8 Upper receptor 9 Eluate

Claims (5)

[Claims] 1. An adhesive for drug administration, the main component of which is a higher α-olefin (co)polymer composed of a linear higher α-olefin component having 6 to 12 carbon atoms. 2. The adhesive for drug administration according to claim 1, wherein the higher α-olefin (co)polymer is at least one selected from polyhexene, polyoctene, and polydecene. 3. A skin-applicable adhesive preparation comprising the drug administration adhesive according to claim 1 or 2 as an adhesive component. Claim 4: Claim 3 further comprising a transdermal absorption enhancer.
The skin adhesive preparation described in . 5. A sustained release adhesive material comprising the adhesive for drug administration according to claim 1 or 2 as an adhesive component.