JP4986411B2 - Patch - Google Patents

Description

  The present invention relates to a patch having an adhesive layer containing a mixed adhesive base containing a hydrocarbon rubber and a silicon-containing polymer and a drug.

  As a drug administration method, an oral administration method using tablets, capsules, syrups and the like is conventionally known, but in recent years, a method of administering a drug using a patch has been studied. The method using a patch can solve various problems caused by the oral administration method, and has advantages such as reduction in the number of administrations, improvement in compliance, ease of administration and discontinuation, etc., so the patient is an elderly person or a child. It has been expected as a useful drug administration method.

  However, when a conventional patch is used, the stratum corneum has extremely high lipid solubility, so that the skin permeability of drugs is generally extremely low, and the stratum corneum of normal skin prevents foreign substances from entering the body. In many cases, the compounded drug is not sufficiently absorbed through the skin because it has a barrier function to prevent it.

  Therefore, in order to enhance the transdermal absorbability of the drug in the transdermal administration method using a patch, various studies on the composition of the adhesive used in the patch have been advanced, and as part of this, acrylic polymers and rubbers have been promoted. Patches using a polymer material such as a polymer as an adhesive base have been proposed (see Patent Documents 1 to 6). However, even with these attempts, the transdermal absorbability of the drug compounded in the patch is not sufficient, and further development of a preparation having excellent transdermal absorbability has been desired. In addition, preparations using conventional adhesive bases may have problems with irritation to the skin and stability over time of the drug compounded in the patch, and further improvement in preparation is desired. It was.

  On the other hand, ambroxol, particularly ambroxol hydrochloride, is known as an excellent expectorant and is widely used in respiratory diseases with a lot of epilepsy in clinical settings. Conventionally, oral administration methods using tablets, liquids, syrups, dry syrups, capsules and the like have been widely adopted, but this did not prevent degradation and metabolism associated with oral administration. In addition, it is known that acupuncture is difficult when waking up early in the morning, and as an expectorant, it is more important than in the daytime how effective it is in the morning, but ambroxol is Because of its short half-life, even with the conventional oral administration methods (tablets, syrups, etc.), even after administration, sufficient blood concentration cannot be obtained early in the morning, and the drug effect can be fully exerted. There wasn't.

  In order to solve such problems, sustained-release capsules have been developed, which makes it possible to maintain a high blood concentration continuously and to show a higher therapeutic effect than tablets and the like. However, in preparations other than sustained release capsules, it is still difficult to perform effective treatment, and even when sustained release capsules are used, there is a difficulty in administration. In other words, the age group of patients who are prescribed expectorants account for 70% of children and the elderly, so taking into account the difficulty of swallowing the elderly and the child's body shape, These patients were difficult to take. In addition, in the recent aging society, the number of elderly patients with reduced swallowing power is increasing, and therefore, a formulation of a dosage form that is easier to take is clinically desired.

  Patent Documents 7 to 9 disclose tape preparations, pressure-sensitive adhesives, and pressure-sensitive adhesive tapes that are used for medical purposes. Although ambroxol hydrochloride is described as a drug that can be used in the tape preparations, Only the name of the sole is mentioned, and since no specific prescription is disclosed, it is not recognized that it is fully disclosed from a practical point of view, and it is actually used for patient treatment It has not been clarified whether or not a patch containing ambroxol hydrochloride can be prepared as an effective preparation having sufficient transdermal absorbability to the extent possible.

Furthermore, as a topical preparation for expectorants, a transdermal absorption preparation containing bromohexine as an active ingredient has been disclosed (Patent Document 10), but no transdermal absorption preparation containing ambroxol has existed so far. It was.
Japanese Patent Laid-Open No. 4-266721 JP-A-9-301854 WO2002 / 069942 WO2004 / 019930 WO2004 / 019987 WO2004 / 019988 Japanese Patent No. 3132737 Japanese Patent No. 3192765 Japanese Patent No. 3233732 JP-A-11-12167

  Therefore, the subject of the present invention is a patch with extremely good transdermal absorbability of the drug in the preparation, low skin irritation, and excellent stability over time of the drug in the preparation, It is an object of the present invention to provide a patch capable of achieving a simplified method of taking and improving compliance. Furthermore, an object of the present invention is to provide an ambroxol-containing patch having sufficient transdermal absorbability that can be actually used for treatment of a patient.

  In order to solve the above-mentioned problems, the present inventors are diligently studying the present invention by blending a mixed adhesive base containing a hydrocarbon-based rubber and a silicon-containing polymer together with a drug into the adhesive layer in the patch. In addition, it has been found that it is possible to obtain a preparation having excellent drug transdermal absorbability and physical properties of the patch, low skin irritation, and good stability over time of the drug in the preparation. It has been found that the sustainability of the medicinal effect is remarkably superior to that of the oral preparation, and that it is found that simplification of the administration method and improvement of compliance are achieved, and the patch of the present invention has been completed. As a result of further research, the present inventors have realized that an ambroxol-containing patch can be realized by adding ambroxol to the patch of the present invention, and that ambroxol has undergone extremely good treatment. The inventors have found for the first time that it can be a skin-absorbing patch and have completed the present invention.

  That is, the present invention is a patch comprising a support layer and an adhesive layer containing a drug, wherein the adhesive layer contains a mixed adhesive base containing a hydrocarbon rubber and a silicon-containing polymer. It relates to the patch.

  The present invention also relates to the patch, wherein the hydrocarbon rubber is an ABA block copolymer.

  The present invention further relates to the patch, wherein the ABA block copolymer is a styrene-isoprene-styrene block copolymer and / or a styrene-butadiene-styrene block copolymer.

  The present invention further relates to the patch, wherein the ABA block copolymer is a styrene-isoprene-styrene block copolymer.

  The present invention also relates to the patch, wherein the silicon-containing polymer is a silicone partially endcapped with trimethylsilyl groups.

Furthermore, the present invention relates to the patch, wherein the silicon-containing polymer is polydimethylsiloxane.

  Moreover, this invention relates to the said patch whose compounding ratio of hydrocarbon-type rubber and a silicon-containing polymer is 10: 1-120.

  Furthermore, the present invention relates to the patch, wherein the drug is ambroxol and / or a pharmaceutically acceptable salt thereof.

  The patch of the present invention is a patch using a conventionally used adhesive base by blending a mixed adhesive base containing a hydrocarbon-based rubber and a silicon-containing polymer together with a drug into the adhesive layer of the patch. Compared to the above, the permeability of the drug contained in the patch to the skin is dramatically improved and it can be made into a preparation having extremely excellent transdermal absorbability. The effect of can be fully demonstrated.

  In addition, the patch of the present invention has excellent physical properties, low skin irritation, and good temporal stability of the drug in the preparation. Therefore, a highly safe drug-containing patch according to the present invention is provided. Can be provided. Furthermore, by administering a drug that has been administered as a conventional oral preparation as a patch of the present invention, it is remarkably excellent in sustained drug efficacy without being degraded in the digestive tract or being metabolized in the liver or the like. Since it can be administered as a preparation, the patch of the present invention enables simplification of conventional administration methods and improvement of compliance.

  Furthermore, the ambroxol containing patch which has the said effect can be provided by mix | blending ambroxol as a medicine with the patch of this invention. That is, the ambroxol-containing expectorant preparation of the present invention has excellent skin permeability and is extremely excellent in percutaneous absorption, and can improve the conventional administration method and compliance. Containing formulations can be provided.

  That is, the patch of the present invention is capable of sufficiently transdermally absorbing the drug compounded in the patch, exhibiting the effect of the drug sufficiently, having excellent physical properties and low skin irritation, The drug blended in is excellent in stability over time, and further, by blending with ambroxol, an ambroxol-containing patch having the above-described effects can be obtained. In addition, the patch having such an effect is realized for the first time in the present invention.

  Hereinafter, embodiments of the present invention will be described in detail.

  The patch of the present invention is a patch in which a support layer, a pressure-sensitive adhesive layer, and a release liner layer are sequentially laminated, and the pressure-sensitive adhesive layer includes at least one drug, a hydrocarbon rubber, and a silicon-containing layer. A mixed adhesive base containing a polymer is blended as an essential component.

The hydrocarbon rubber used in the patch of the present invention may be a polymer whose composition formula is C _n H _m (n and m are each independently n = 20 to 10,000, m = 20 to 10,000). There is no particular limitation. Examples of the hydrocarbon rubber used in the present invention include a styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS), isoprene rubber, polyisobutylene (hereinafter abbreviated as PIB), and styrene-butadiene-. Examples thereof include styrene block copolymer (hereinafter abbreviated as SBS), styrene-butadiene rubber (hereinafter abbreviated as SBR), and among them, ABA block copolymers are preferable, and SIS and PIB are more preferable. Preferably, SIS is most preferred. Such hydrocarbon rubber may be used alone or in combination of two or more.

  The blending amount of the hydrocarbon rubber in the patch of the present invention is not particularly limited, but it is 5 to 90% by weight based on the total amount of the preparation from the viewpoint of formation of the pressure-sensitive adhesive layer and permeability to the skin. Preferably, it is 10 to 70% by weight, more preferably 10 to 50% by weight.

  The silicon-containing polymer used in the patch of the present invention is not particularly limited as long as it has a favorable influence on the transdermal absorbability of the drug by using a mixed adhesive base with a hydrocarbon rubber. That is, a general medical grade silicone-based pressure-sensitive adhesive can be used. Among them, a silicone partially endcapped with a trimethylsilyl group is preferable, and a polydimethylsiloxane is particularly preferable. This is because an increase in drug release from the preparation is expected by reducing the content of residual silanol groups in the silicone and weakening the interaction with the drug. In the present invention, “partially endcapped with a trimethylsilyl group” means that at least one silanol group in silicone is endcapped with a trimethylsilyl group.

  Examples of polydimethylsiloxanes, silicones that are partially end-capped with trimethylsilyl groups, include Dow Corning pressure sensitive adhesives, BIO-BSA X7-4201, BIO-BSA X7-2960, BIO-BSA X7-3027, BIO-BSA X7-2910, BIO-BSA X7-4820, BIO-BSA X7-2892, BIO-BSA X7-2994, BIO-BSA X7-3019, BIO-BSA Q7-2920, etc. Among them, particularly preferred is pressure sensitive adhesive BIO-BSA X7-4201 manufactured by Dow Corning. Such silicon-containing polymers may be used alone or in a combination of two or more.

  The blending amount of the silicon-containing polymer in the patch of the present invention is not particularly limited, but is preferably 3 to 90% by weight based on the total amount of the preparation from the viewpoint of formation of the pressure-sensitive adhesive layer and permeability to the skin. 5 to 60% by weight, more preferably 10 to 30% by weight.

  In the patch of the present invention, the mixing ratio of the hydrocarbon rubber and the silicon-containing polymer in the pressure-sensitive adhesive layer is not particularly limited, but it is 10: 1 to 120 from the viewpoint of pharmaceutical properties and drug skin permeability. It is preferably 10: 1 to 20, more preferably 3: 4.

  Moreover, you may mix | blend an acrylic polymer other than said essential component as a base of the adhesive layer in the patch of this invention. The acrylic polymer may be a copolymer containing at least one (meth) acrylic acid derivative typified by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like. For example, acrylic acid / octyl acrylate ester copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer, listed as adhesives in Pharmaceutical Additives Encyclopedia 2000 (edited by Japan Pharmaceutical Additives Association) Combined solution, acrylate ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion Adhesives such as an acrylic polymer containing an acrylic resin alkanolamine solution, Duro-Tak acrylic adhesive series (manufactured by National Starch and Chemical Company) can be used Eudragit series (Higuchi Shokai) and the like.

  The drug used in the patch of the present invention is not particularly limited as long as the percutaneous absorbability can be improved by using the mixed adhesive base containing the hydrocarbon rubber and the silicon-containing polymer. However, ambroxol and / or pharmaceutically acceptable salts thereof are particularly preferred. The pharmaceutically acceptable salt is not particularly limited and may be an inorganic salt or an organic salt. Among them, ambroxol hydrochloride is a typical salt of ambroxol and is particularly preferable.

  Ambroxol and / or a pharmaceutically acceptable salt thereof is preferably blended in an amount of 0.5 to 50% by weight based on the total amount of the preparation from the viewpoint of physical properties and transdermal absorbability.

  Further, the adhesive layer in the patch of the present invention may contain a plasticizer. Plasticizers that can be used include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil), silicon oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, sebacine) Diethyl acetate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton, etc. , In particular liquid paraffins Among them, liquid polybutene, isopropyl myristate, diethyl sebacate, hexyl laurate is preferred.

  These plasticizers may be used alone or in combination of two or more. In consideration of sufficient permeability of the drug to the skin and maintenance of sufficient cohesive strength as a patch preparation, such a plasticizer is preferably 5 to 70% by weight in total based on the total composition of the pressure-sensitive adhesive layer, preferably Can be blended in an amount of 5 to 60% by weight, more preferably 10 to 50% by weight.

  In the pressure-sensitive adhesive layer in the patch of the present invention, when the adhesive strength is insufficient, it is desirable to further add a tackifier resin. Examples of tackifying resins that can be used include rosin derivatives (eg, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythritol ester of rosin), alicyclic saturated hydrocarbon resins (eg, alkone). P100, Arakawa Chemical Industries), aliphatic hydrocarbon resins (for example, Quinton B170, Nippon Zeon), terpene resins (for example, Clearon P-125, Yasuhara Chemical), maleic resin and the like. Among them, particularly preferred tackifying resins are hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin.

  Such tackifying resin is 5 to 70% by weight, preferably 5 to 70% by weight based on the total composition of the pressure-sensitive adhesive layer in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. It can be blended in an amount of 60% by weight, more preferably 10 to 50% by weight.

  The pressure-sensitive adhesive layer in the patch of the present invention may contain an absorption enhancer, and any absorption enhancer that can be used is any known compound that is recognized to promote absorption in the skin. For example, fatty acids having 6 to 20 carbon chains, fatty alcohols, fatty acid esters, amides, or ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers (above saturated, unsaturated Any of saturated, cyclic, linear or branched), and also lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, azone, azone derivatives , Pyrothiodecane, glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters (Span series), poly Rubeto system (Tween type), polyethylene glycol fatty acid esters, polyoxyethylene hardened castor oils (HCO type), polyoxyethylene alkyl ethers, sucrose fatty acid esters, vegetable oils and the like.

  Specific examples of absorption enhancers include caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol , Isostearyl alcohol, cetyl alcohol, methyl laurate, hexyl laurate, diethanolamide laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid , Methyl cinnamate, cresol, cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate, geraniol, thymol, eugenol, terpineol, l-menthol, bom Renoleol, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, glycerol monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20 , Propylene glycol, propylene glycol monolaurate, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyoxyethylene lauryl ether, HCO-60, pyrothiodecane, olive oil, lauryl alcohol, isostearyl alcohol, lauric acid diethanolamide, Glycerol monocaprylate, glycerol monocaprate, glycerol monooleate, sorbitan monolaurate, Particularly preferred are propylene glycol monolaurate, polyoxyethylene lauryl ether, and pyrothiodecane.

  Such absorption promoters may be used alone or in combination of two or more. In addition, the content of the absorption accelerator is 0.01 to 20 based on the total composition of the pressure-sensitive adhesive layer in consideration of sufficient skin permeability as a patch and irritation to the skin such as redness and edema. It is preferably wt%, more preferably 0.05 to 10 wt%, particularly preferably 0.1 to 5 wt%.

  In the present invention, when the drug form is a pharmaceutically acceptable acid addition salt, it is desirable to further include an organic acid in the adhesive layer. Organic acids that can be used include aliphatic (mono, di, tri) carboxylic acids (eg acetic acid, propionic acid, isobutyric acid, caproic acid, caprylic acid, lactic acid, maleic acid, pyruvic acid, oxalic acid, succinic acid, Tartaric acid etc.), aromatic carboxylic acid (eg phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid etc.), alkyl sulfonic acid (eg methane sulfonic acid, ethane sulfonic acid, propyl sulfonic acid, butane sulfonic acid, polyoxyethylene alkyl) Ether sulfonic acid, etc.), alkyl sulfonic acid derivatives (eg, N-2-hydroxyethylpiperidine-N′-2-ethanesulfonic acid (hereinafter abbreviated as “HEPES”), etc.), cholic acid derivatives (eg, dehydrocol) Acid), among which acetic acid, propionic acid, lactic acid, salicyl Preferably, acetic acid is particularly preferred. These organic acids may be used in the form of a salt or a mixture thereof.

  The content of these organic acids is preferably 0.01 to 20% by weight based on the total composition of the pressure-sensitive adhesive layer from the viewpoint of sufficient skin permeability as a patch and irritation to the skin. More preferably, it is 0.1 to 15% by weight, and particularly preferably 0.1 to 10% by weight.

  In addition, the patch of the present invention can contain an antioxidant, a filler, a cross-linking agent, an antiseptic and an ultraviolet absorber as necessary. As the antioxidant, tocopherols and ester derivatives thereof can be used. , Ascorbic acid, ascorbic acid stearate, nordihuman log ayretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like are desirable, and as fillers, calcium carbonate, magnesium carbonate, silicate (for example, silicic acid) Aluminum, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, etc. are desirable, and as the crosslinking agent, amino resin, phenol resin, epoxy resin, alkyd resin, unsaturated polyester Thermosetting resins such as isocyanate compounds, bromine Inorganic crosslinkers such as polyisocyanate compounds, organic crosslinkers, metals or metal compounds are desirable, and as preservatives, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc. are desirable, and UV absorbers are , P-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like are desirable.

  Such antioxidants, fillers, crosslinking agents, preservatives and ultraviolet absorbers are preferably 10% by weight or less, more preferably 5% by weight, based on the total composition of the adhesive layer of the patch. In the following, it can be blended particularly preferably in an amount of 2% by weight or less.

  The patch of the present invention containing the adhesive layer having the above-mentioned composition containing a drug can be produced as appropriate.For example, the adhesive base component containing the drug is dissolved in a solvent such as toluene, hexane, ethyl acetate, It can be obtained by stretching on a release liner or support and drying and removing the solvent, followed by bonding to the support or release liner. However, the patch of the present invention cannot be produced by the hot melt method.

  The support layer in the patch of the present invention is not particularly limited as long as it is suitable for supporting the pressure-sensitive adhesive layer, but a stretchable or non-stretchable one can be used. For example, cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, aluminum sheet, or a composite material thereof can be used.

  As the release liner layer in the patch of the present invention, specifically, a polyester film such as polyethylene terephthalate, a film such as polyvinyl chloride or polyvinylidene chloride, a laminate film of fine paper and polyolefin, or the like can be used. In these release liner layers, it is preferable to perform fluorine treatment on the side of the release liner layer that comes into contact with the pressure-sensitive adhesive layer in order to enhance the workability when the release liner is peeled off from the sticking side.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples of the present invention. However, the present invention is not limited to these examples, and the blending order of each component is not particularly limited. Various modifications can be made without departing from the technical idea of the present invention. In the examples, “%” means all percentages by weight.

Example 1
SIS 15.4%
Silicon-containing polymer (BIO-BSA X7-4201, Dow Corning) 20.5%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 46.1%
Isopropyl myristate (IPM) 5.0%
Pirothiodecane 3.0%
Ambroxol 10.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate (IPM) are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and it was bonded to a support to obtain the patch of the present invention.

Example 2
SIS 13.5%
Silicon-containing polymer (BIO-BSA X7-4201, Dow Corning) 18.0%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 40.5%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 20.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and it was bonded to a support to obtain the patch of the present invention.

Example 3
SIS 11.6%
Silicon-containing polymer (BIO-BSA X7-4201, Dow Corning) 15.5%
Alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical 34.9%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 30.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and it was bonded to a support to obtain the patch of the present invention.

Example 4
SIS 9.75%
Silicon-containing polymer (BIO-BSA X7-4201, Dow Corning) 13.0%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 29.25%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 40.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and it was bonded to a support to obtain the patch of the present invention.

Comparative Example 1
Silicon-containing polymer (BIO-BSA X7-4201, Dow Corning) 72.0%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 20.0%
Total amount 100.0%

In advance, ambroxol, pyrothiodecane and isopropyl myristate are mixed well and then mixed with the silicon-containing polymer. After coating on the release liner, the solvent was removed by drying, and the mixture was bonded to a support to obtain a patch of a comparative example.

Comparative Example 2
SIS 20.5%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 61.5%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 10.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and the mixture was bonded to a support to obtain a patch of a comparative example.

Comparative Example 3
SIS 18%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 54%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 20.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and the mixture was bonded to a support to obtain a patch of a comparative example.

Comparative Example 4
SIS 15.5%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 46.5%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 30.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and the mixture was bonded to a support to obtain a patch of a comparative example.

Comparative Example 5
SIS 13.0%
Alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industries) 39.0%
Isopropyl myristate 5.0%
Pirothiodecane 3.0%
Ambroxol 40.0%
Total amount 100.0%

Ambroxol, pyrothiodecane and isopropyl myristate are mixed well in advance, and then mixed with the remaining components dissolved in toluene. After coating on the release liner, the solvent was removed by drying, and the mixture was bonded to a support to obtain a patch of a comparative example.

Comparative Example 6

Acrylic polymer (SK Dyne MAS811, Soken Chemical) 80.0%
Ambroxol 20.0%
Total amount 100.0%

In advance, ambroxol and acrylic polymer are mixed and stirred. After coating on the release liner, the solvent was removed by drying, and the mixture was bonded to a support to obtain a patch of a comparative example.

Test Example: Skin Permeability Test Using Hairless Mice The back skin of hairless mice was peeled off, the dermis side was the receptor layer side, and a flow-through cell (5 cm ² ) in which 37 ° C. warm water was circulated around the outer periphery was attached. The preparations obtained in Examples 1 to 4 and Comparative Examples 1 to 6 were affixed to the stratum corneum side, physiological saline was used for the receptor layer, and the rate was 5 ml / hour (hr) every 2 hours up to 24 hours. Sampling was performed. The receptor solution obtained at each time accurately measures the flow rate, measures the drug concentration by high-performance liquid chromatography, calculates the drug permeation rate per hour, and permeates the drug skin per unit area in the steady state. The speed was determined. A larger skin permeation rate value is recognized as having better transdermal absorbability. The results are shown in Table 1.

注 この製剤は凝集破壊のために皮膚透過性試験を行うことができなかった。

NOTE This formulation could not be tested for skin permeability due to cohesive failure.

  As is clear from the results shown in Table 1, when each example of the present invention was compared with a comparative example containing an equal amount of drug to the preparation obtained in each example of the present invention, The preparations obtained in each Example have a drug skin permeability that is about 1.5 times better than the preparations of Comparative Examples, and the patch of the present invention has extremely excellent transdermal absorbability. It became clear that it was a new formulation. Moreover, since Comparative Example 1 caused cohesive failure and had problems with physical properties, it was also clarified that the patch of the present invention was a preparation with extremely excellent physical properties.

  Therefore, the patch of the present invention has a dramatic improvement in the transdermal absorbability of the drug compounded in the patch, compared with a patch using a conventional adhesive base, and has good physical properties, It is understood that the patch is excellent in the temporal stability of the drug in the preparation. Further, it was shown that the patch containing ambroxol was a preparation having a very excellent percutaneous absorbability and sufficiently exhibiting the medicinal effect.

  As described above, according to the present invention, the percutaneous absorbability of the drug in the preparation is very good, the physical properties are excellent, the skin irritation is low, and the stability of the drug in the preparation over time is excellent. Therefore, the patch of the present invention is expected to be applied as a pharmaceutical product that can achieve a simplified dosage method and an improved compliance. Furthermore, according to the present invention, an ambroxol-containing patch having excellent transdermal absorbability that can be used for treatment of patients can be provided.

It is sectional drawing which shows the structure of the patch of this invention.

Explanation of symbols

1: Support layer 2: Adhesive layer containing drug 3: Release liner layer

Claims (8)

A patch comprising a support layer and an adhesive layer containing ambroxol and / or a pharmaceutically acceptable salt thereof, wherein the adhesive layer comprises 10 to 50% by weight of hydrocarbon-based rubber and The adhesive patch comprising a mixed adhesive base containing 5 to 60% by weight of a silicon-containing polymer. The patch according to claim 1, wherein the hydrocarbon rubber is an ABA block copolymer. The patch according to claim 2, wherein the ABA block copolymer is a styrene-isoprene-styrene block copolymer and / or a styrene-butadiene-styrene block copolymer. The patch according to claim 2, wherein the ABA block copolymer is a styrene-isoprene-styrene block copolymer. The patch according to any one of claims 1 to 4 , wherein the silicon-containing polymer is silicone partially endcapped with a trimethylsilyl group. The patch according to any one of claims 1 to 4, wherein the silicon-containing polymer is polydimethylsiloxane. The patch according to any one of claims 1 to 6, wherein the blending ratio of the hydrocarbon rubber and the silicon-containing polymer is 10: 1 to 120. The patch according to any one of claims 1 to 7, further comprising isopropyl myristate and / or pyrothiodecane.

Images