JP3020630B2 - Adhesive for drug administration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pressure-sensitive adhesive for drug administration, and more particularly to a method for admixing various drugs, which adheres to the skin with an appropriate level of adhesiveness and has little irritation to the skin. Adhesive for drug administration capable of keeping absorption to the skin at an appropriate level, a skin-adhesive adhesive preparation containing the same, and a sustained release with excellent sustained release properties capable of sustained release of various formulated drugs in appropriate amounts It relates to a release adhesive.

[0002]

2. Description of the Related Art Conventionally, the drug efficacy is high, but when administered at a high concentration by oral administration, which is a usual drug administration form,
In some cases, adverse effects were caused. For example, indomethacin,
Oral administration of an analgesic and anti-inflammatory drug such as perisoxal citrate and flurbiprofen, and nitroglycerin and isosorbide dinitrate, which are drugs for angina, cause a burden on the liver and cause digestive disorders. Therefore, it is desired to improve the administration route of the drug or to provide a sustained release of the dosage form, and the skin-adhesive preparation obtained by mixing the drug with an adhesive is applied to the skin in the vicinity of the affected area, whereby the drug is administered. Is absorbed directly from the affected area without passing through the liver, etc., eliminating the burden on the liver, avoiding the detoxification effect in the liver and effectively exerting the medicinal effect, and at the same time, by sustained release administration of the drug, Attempts are being made to maintain drug efficacy. In addition, according to the adhesive preparation to be applied to the skin, the inconvenience of oral administration, which requires frequent administration in small amounts, can also be solved.

[0003] As the adhesive used in the adhesive preparation to be adhered to the skin, those comprising natural rubber, olefin rubber or olefin polymer have been used.

[0004]

However, the pressure-sensitive adhesive used in the above-mentioned conventional pressure-sensitive adhesive preparations for skin application has a weak adhesive force to the skin or, conversely, an excessively strong adhesive force, resulting in peeling off from the skin. Or something. Some skin irritation caused irritation.

Further, insect repellents, plant growth promoters, disinfectants,
In order to exert the effect of a drug such as a rust inhibitor, a preservative, a fragrance, and a deodorant over a long period of time, it is preferable that the drug is retained and is gradually released at an appropriate rate. . Therefore, there is a need for an adhesive material that mixes a drug and adheres to a site where the drug needs to be administered, and that is excellent in sustained release of the drug.

[0006] Therefore, a first object of the present invention is to adhere to the skin with an appropriate amount of adhesiveness together with various drugs, and to prevent skin irritation due to low skin irritation, and to provide excellent sustained-release properties to the skin of the drug. It is an object of the present invention to provide a drug-applied pressure-sensitive adhesive material capable of appropriately maintaining absorption of a drug and a skin-adhesive pressure-sensitive adhesive preparation containing the same.

A second object of the present invention is to provide a sustained-release pressure-sensitive adhesive excellent in sustained-release property, which can gradually release various kinds of formulated drugs in an appropriate amount.

[0008]

In order to solve the above-mentioned problems, the present invention mainly comprises a higher α-olefin (co) polymer comprising a linear higher α-olefin component having 6 to 12 carbon atoms. It is intended to provide an adhesive for drug administration as a component.

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

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

It is preferable that the above-mentioned skin-adhesive preparation contains a transdermal absorption enhancer.

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

Hereinafter, the pressure-sensitive adhesive for drug administration of the present invention, a skin-applied pressure-sensitive adhesive preparation containing the same, and a sustained-release pressure-sensitive adhesive will be described.
This will be described in detail.

The higher α-olefin (co) polymer comprising a linear higher α-olefin component having 6 to 12 carbon atoms, which is a main component of the adhesive for drug administration of the present invention, has 6 to 1 carbon atoms.
A (co) polymer containing at least one linear higher α-olefin of 2, for example, a (co) polymer consisting of at least one linear higher α-olefin having 6 to 12 carbon atoms, or Copolymers of at least one straight-chain higher α-olefin having 6 to 12 carbon atoms and at least one other α-olefin are exemplified.

The straight-chain higher α-olefins having 6 to 12 carbon atoms include, for example, hexene-1, heptene-
1, octene-1, nonene-1, decene-1, undecene-1, dodecene-1 and the like. In addition, other α-
Examples of the olefin include ethylene, propylene,
Butene-1, pentene-1, 4-methylpentene-1 and the like.

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

Further, the at least one kind of carbon having 6 to 6 carbon atoms.
Specific examples of the copolymer of 12 straight-chain higher α-olefins and at least one other α-olefin include hexene-1 · ethylene copolymer, heptene-1 · ethylene copolymer, octene- 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 pentene-1 copolymer, dodecene-1 pentene-1 copolymer Coupling, octene-1.4-methylpentene-1
And copolymers of decene-1,4-methylpentene-1 and dodecene-1,4-methylpentene-1.

Among them, 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 and 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 the higher α-olefin (co) polymer is determined so that a pressure-sensitive adhesive for drug administration having sufficient tackiness can be obtained. , Usually 50 to 100 mol%, preferably 60 to 100 mol%, particularly preferably 70 to 10 mol%.
0 mol%.

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

The production of the higher α-olefin (co) polymer can be carried out according to a known method. For example, in the presence of a transition metal catalyst comprising a transition metal compound such as titanium, vanadium, zirconium and the like, and an organoaluminum catalyst, at least one linear higher α-olefin having 6 to 12 carbon atoms is (co) polymerized. Alternatively, it can be produced by a method of copolymerizing at least one linear higher α-olefin having 6 to 12 carbon atoms with another α-olefin. As the transition metal catalyst to be used, a highly active titanium catalyst containing magnesium, titanium, halogen and an electron donor as essential components is preferable. At this time, it is preferable to use an electron donor catalyst such as alcohols, phenols, ketones, aldehydes, carnebonic acid, esters, ethers, acid amides, acid anhydrides and alkoxysilanes in combination.

The preparation of the highly active titanium catalyst is carried out by, for example,
JP-A-50-108385, 50-12659
Nos. 0, 51-20297, 51-281
No. 89, 51-64586, 51-92
No. 885, No. 51-136625, No. 52-
No. 87489, No. 52-1000059, No. 5
Nos. 2-147688, 52-104593, 53-2580, 53-40093, 53-40094, 53-43094, 55-135102, 55-55 −1351
No. 03, No. 55-152710, No. 56-8
No. 11, No. 56-11908, No. 56-18
Nos. 606, 58-83006 and 58-1
38705, 58-138706 and 5
JP-A-8-138707, JP-A-58-138708, JP-A-58-138709, and JP-A-58-13871
Nos. 0, 58-138715 and 60-23
Nos. 404, 61-21109, 61-3
It can be carried out by the method disclosed in, for example, JP-A-7802 and JP-A-61-37803.

The catalyst component, (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 (co) polymer is not particularly limited. The olefin content and the weight-average molecular weight can be appropriately selected so as to obtain the one having the weight average molecular weight. Usually, the (co) polymerization temperature is 30 to 100 ° C., and the pressure is about normal pressure to about 50 kg / cm ² . is there. The (co) polymerization can be performed in any of a batch system, a semi-continuous system, and a continuous system. It is preferable to use hydrogen during the (co) polymerization because the molecular weight of the obtained (co) polymer can be adjusted.

The pressure-sensitive adhesive for drug administration of the present invention comprises, as a main component, a higher α-olefin (co) polymer comprising the above-mentioned linear higher α-olefin component having 6 to 12 carbon atoms. Further, if necessary, various additives to be mixed with this kind of pressure-sensitive adhesive can be mixed. For example, inorganic or organic fillers, lubricants, softeners, heat stabilizers, surfactants, pigments, dyes, and the like may be added. Above all, it is preferable to add a filler, since the release property of the drug from the adhesive becomes high.

The content of the higher α-olefin (co) polymer in the pressure-sensitive 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.

In the production of the pressure-sensitive adhesive for drug administration of the present invention, the above-mentioned higher α-olefin (co) polymer and various additives as required are mixed in required amounts, kneaded and used as a rolled sheet. Can be As this method, after kneading by roll kneading, it can be manufactured by molding according to a method of low-temperature compression molding, a method of ordinary extrusion molding such as T-die molding or the like.

The present invention also provides a skin-adhesive adhesive preparation containing the above-mentioned adhesive for drug administration.

This adhesive preparation to be adhered to the skin is obtained by mixing a predetermined amount of a predetermined drug with the above-mentioned pressure-sensitive adhesive for drug administration.

The drug which can be incorporated into the adhesive preparation of the present invention is not particularly limited, and examples thereof include analgesic and anti-inflammatory agents such as indomethacin, flurbiprofen, morphine, perisoxal citrate and aspirin, and pitolterol nosylate. Bronchodilators, theophylline, antitussives such as dextromethorphan hydrobromide, ketotifen fumarate,
Allergic drugs such as tranilast and sodium cromoglycate, arrhythmic drugs such as pindolol, gout drugs such as colchicine, itching, antibiotics, etc. are absorbed into the skin from the surface of the skin and administered to treat the affected area. Drugs.

Further, when a percutaneous absorption enhancer is added to this skin-adhesive preparation, the rate of release of the drug from the adhesive preparation can be increased, and the skin permeability of the drug can be promoted. Is preferred. This transdermal absorption enhancer is a substance that promotes skin permeability of the drug, and is required to have no skin irritation. Further, skin release cannot be achieved without release from the adhesive preparation. Therefore, as a transdermal absorption enhancer, at the surface temperature of the skin,
It is preferable to dissolve at least partially a solid drug and have an affinity for a hydrophobic adhesive to promote the diffusion of the drug into the adhesive, and furthermore, to excel in the action of promoting absorption into the skin of living organisms.

The percutaneous absorption enhancer is not particularly limited as long as it becomes liquid at the surface temperature of the skin, dissolves at least a part of the drug, and has an affinity for the adhesive. And 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, and 1-eicosanol. Is mentioned. These may be used alone or in combination of two or more.

Among them, higher alcohols having 8 to 20 carbon atoms and mixtures thereof;
20 higher alcohols, lower alcohols, glycerin, diglycerin, polyhydric alcohols such as propylene glycol, polyvinyl alcohol, higher fatty acid esters,
A mixture with m-cresol, isosorbitol, amyl alcohol, hexyl alcohol, etc., which becomes a liquid at the surface temperature of the skin, rapidly diffuses the drug into the adhesive and promotes absorption of the drug into the skin It is preferable in that the effect is excellent.

Further, the skin-adhesive pressure-sensitive adhesive preparation of the present invention may contain, if necessary, inorganic fillers such as calcium carbonate, talc, silica, synthetic hydrotalcite, inorganic filler, etc. within a range not to impair the object of the present invention. Organic fillers, organic fillers such as paraffin, wax, vaseline, beeswax, and lanolin; antioxidants, heat stabilizers, stabilizers such as surfactants, tackifiers such as rubber copolymers, thickeners, and softeners And various additives such as a plasticizer, a pigment such as titanium white, a dye, and a colorant.

As a method of forming a thin layered skin patch as a form of the skin patch type adhesive preparation of the present invention, a drug is prepared by using an adhesive, a transdermal absorption enhancer and, if necessary, other additives. Using a solvent for the pressure-sensitive adhesive or plasticized by heating, kneaded using a two-roll, screw-type extruder and the like, and then spread on one surface of a thin film-like support, A protective film is formed by superimposing a release surface of a release paper or a release film provided with release properties using silicone or the like on the other surface of the drug content. When attaching to the skin, the protective film is peeled off before use. As the film-like support, an elastic film having flexibility capable of following the expansion and contraction of the skin, for example, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, ethylene-propylene copolymer And a film of ethylene / propylene / α-olefin copolymer, thermoplastic elastomer, silicone rubber, soft polyurethane, or the like, or a porous film, or a thin film of woven fabric, nonwoven fabric, flexible paper, or the like. Further, it is preferable that the protective film be made of a material or a shape having a higher rigidity than the support, since the operability at the time of peeling becomes good.

The skin adhesive preparation of the present invention obtained as described above is usually used in the form of a thin layer having a thickness of about 20 to 300 μm.

The mixing ratio of the pressure-sensitive adhesive for drug administration and the drug in the pressure-sensitive adhesive preparation for skin application of the present invention is appropriately selected according to the drug concentration of the drug to be used, the thickness of the layer to be formed, and the like, and is not particularly limited. When the thickness of the layer to be used is about 50 to 150 μm, a sufficient amount of adhesive force to the skin is obtained.
It is preferred that the proportion is 50 parts by weight. In addition, when a percutaneous absorption enhancer is blended, the rate of release of the drug into the skin is increased, the percutaneous absorption rate is increased, and the transdermal absorption enhancer has sufficient adhesive strength without bleeding out. Is a ratio of 5 to 30 parts by weight with respect to the above ratio.

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

The sustained-release pressure-sensitive adhesive is obtained by mixing a predetermined amount of a predetermined drug with the pressure-sensitive adhesive for drug administration.

The drug which can be blended with the sustained-release adhesive of the present invention is not particularly limited. For example, insect repellents such as naphthalene, dichlorobenzene, butopyronoxyl, plant growth promoters such as auxin, shikonin, phenolic acid, formalin And the like, disinfectants, germicides, fragrances, deodorants and the like.

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

The sustained-release adhesive of the present invention can be produced by mixing the above-mentioned adhesive for drug administration 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 will be described below.
The present invention will be described specifically, but the present invention is not limited by these examples.

(Embodiments 1 to 3)
Octene-1 polymer (weight average molecular weight by GPC measurement (polystyrene conversion value: 695,000)) which is an olefin (co) polymer, and indomethacin (IM: manufactured by Wako Pure Chemical Industries, Ltd.) 30 which is an analgesic and anti-inflammatory agent Parts by weight, and 10 parts by weight of synthetic hydrotalcite (SHT: manufactured by Kyowa Chemical Co., Ltd.) as a filler, and a percutaneous absorption enhancer shown in Table 1 in a blending amount shown in Table 1 to obtain a mixture. Prepared.

[0044]

After the obtained mixture was roll-kneaded at 50 ° C. for 3 minutes, 50 kg / 50 kg / m.
Pressure molding was performed at a pressure of cm ² to prepare a sample for a dissolution test. This sample was subjected to a dissolution test according to the following method.

[Dissolution test of indomethacin] A sample for dissolution test was cut into a circular shape having a diameter of 26 mmφ, a slagard (microporous polypropylene film) was adhered to one side as a backing material, and a moulting snake was used as an elution film on the other side. Paste the membrane (Yamakagashi: 4-5 days after molting)
The sample was attached to a vertical diffusion cell made of glass to obtain a dissolution test piece. Next, a dissolution test was performed using a dissolution test apparatus schematically shown in FIG. In this dissolution test apparatus, a dissolution test piece 2 in which a denuded serpentine membrane 3 and a backing material 1 are adhered to a lower receptor 4 is fixed by a columnar upper receptor 8, and the top of the upper receptor 8 is open. In addition, a stirrer 6 is disposed in the lower receptor 4 to stir the eluate 9 and to flow constant temperature water to the outer side 5 of the lower receptor, so that the temperature in the system is kept constant. In this dissolution test apparatus, 37 was used as the dissolution liquid 9 on the lower receptor 4 side.
0.1 M phosphate buffer (pH: 7.2)
2) is injected in a prescribed amount from the outlet 7 of the diffusion cell and filled so as to be in contact with the molting membrane 3, the temperature of the water circulating outside the lower receptor 5 is set to 37 ° C. The sample was placed in a thermo-hygrostat at 50 ° C. and a humidity of 50%. After stirring for 5 minutes with the stirrer 6, 10 ml of the eluate was collected from the outlet 7 and the amount of indomethacin eluted (ppm) in the eluate was determined. Similarly, the amount of indomethacin eluted into the eluate was determined over time. The cumulative elution amount (mg) of indomethacin was calculated, and the area of the scale of the molting serpentine 3 was measured using an image analyzer (manufactured by Pierce Co., Ltd.). Eluted amount of indomethacin per elapsed time (mg / c
m ² ) was determined. The results are shown in FIG.

Comparative Example 1 Commercially available inteban ointment (1%
Indomethacin) on a molted serpentine membrane at 26 mmφ, 1
mm thick and applied in the same manner as in Example 1.
The sample was subjected to a dissolution test to determine the amount of dissolution of indomethacin (mg / cm ² ) at each elapsed time. The results are shown in FIG.

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

[0049]

Each of the obtained mixtures was pressure-molded in the same manner as in Example 1 to prepare a test piece for a dissolution test.
A dissolution test was performed in the same manner as in Example 1 to measure the dissolution amount (mg / cm ² ) of pindolol at each elapsed time. The snake skin was used as a molting serpentine membrane. The results are shown in FIG.

(Embodiments 8 to 11)
-Polyoctene (weight average molecular weight: 695,000), which is an olefin (co) polymer, is mixed with 20 parts by weight of dodecyl alcohol as a transdermal absorption enhancer and 30% by weight of a synthetic hydrotalcite as a filler, and 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 is blended. Thus, four mixtures were prepared. Each of the obtained four kinds of mixtures was subjected to pressure molding in the same manner as in Example 1 to prepare a test piece for a dissolution test, and subjected to a dissolution test in the same manner as in Example 1, and subjected to a dissolution test. Of dextromethorphan hydrobromide (mg / cm ² ) was measured. In addition, as a moulting serpentine membrane, one of Yamakagashi was used. FIG. 4 shows the results.

[0052]

The pressure-sensitive adhesive for drug administration of the present invention contains various drugs and adheres to the skin with an appropriate level of adhesiveness. The skin is less irritating and does not cause irritation. The absorption can be kept moderate.

Further, the skin-adhesive adhesive preparation of the present invention containing the adhesive for administration of a drug can be frequently released in small amounts, which is a disadvantage of the conventional oral administration preparation, by releasing the drug through the skin. By eliminating the inconvenience of having to administer, and by applying it to the skin in the vicinity of the affected area, detoxification in the liver can be avoided. It has the advantage of avoiding unnecessary side effects associated with taking and reducing the burden on the patient.

The sustained-release pressure-sensitive adhesive of the present invention is capable of blending various drugs and gradually releasing the drugs in an appropriate amount, and has excellent sustained-release properties. Therefore, the sustained-release adhesive of the present invention is suitable for applications such as insect repellents, plant growth promoters, deodorants, and fragrances.

[Brief description of the drawings]

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

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

FIG. 3 shows the results of a pindolol dissolution test performed in Examples 4 to 7.

FIG. 4 is a graph showing the results of a dissolution test of dextromethorphan hydrobromide performed in Examples 8 to 11.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Backing material 2 Sample 3 Molting serrated membrane 4 Lower receptor 5 Lower receptor outer side 6 Stirrer 7 Outlet 8 Upper receptor 9 Eluate

Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) A61K 9/70 A61K 47/32 C08L 23/20 C08L 23/24 C09J 123/18 CA (STN)

Claims (5)

(57) [Claims] 1. An adhesive for drug administration comprising a higher α-olefin (co) polymer as a main component comprising 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. An adhesive preparation to be adhered to the skin, comprising the adhesive for drug administration according to claim 1 or 2 as an adhesive component. 4. The adhesive preparation according to claim 3, further comprising a transdermal absorption enhancer. 5. A sustained-release adhesive comprising the adhesive for drug administration according to claim 1 or 2 as an adhesive component.