WO2004089347A1 - Transdermal absorption preparation containing tulobuterol and patch using the same - Google Patents

Abstract

A transdermal absorption preparation characterized in that tulobuterol is loaded in the form of fine solid matters in voids in a fibrous or porous structure, within small pores thereof and/or the surface of the structure. Although this tulobuterol-containing transdermal absorption preparation contains no filler causative of skin irritation, it shows favorable transdermal absorption characteristics. Thus, a transdermal absorption preparation containing tulobuterol with less skin irritation can be provided while simplifying the production process and cutting costs.

Description

 Description Percutaneous absorption preparation containing allobuterol and dermal patch using the same

 The present invention relates to a transdermal absorption preparation containing rlobbuterol, and more particularly, to a transdermal absorption preparation containing rlobbuterol in a fine solid state without an excipient, and a patch using the same. Background art

 Allobuterol has the following formula (I)

Since it has a sympathetic nerve stimulating action, it has been used as a bronchodilator for the treatment of respiratory distress due to airway obstruction such as bronchial asthma and emphysema. This rolobuterol is used as an acid addition salt of rolobuterol hydrochloride as an oral preparation, but has been used as a percutaneous absorption agent in the form of a basic form of rolobuterol.

However, conventional percutaneous absorption preparations containing allobuterol require dissolving allobuterol in a plaster layer mainly composed of an adhesive in order to make a dosage form such as a patch or a tape. Also contained various excipients (see Patent No. 2753800, Patent No. 3260765, and Japanese Patent Publication No. 07-025669). In addition, in the manufacture of the plaster, a process of kneading the excipient and rolobuterol so as to be uniform is required, which requires complicated labor and causes a large cost. I was wearing it. For this reason, it was necessary to omit these steps as much as possible.

 In addition, the above-mentioned excipients may include those that cause rash.To solve this problem, the contact area between the adhesive layer containing the excipients and the skin was reduced. (3) We had to deal with it by reducing the number of times of peeling and sticking.

 Furthermore, the reason that excipients have been used in the past is not only to form a dosage form as a patch or tape, but also to allow the absorption of allobuterol from the skin. It was thought that it was necessary to be in contact with the skin. The active ingredient dissolving layer is a layer containing a substance capable of dissolving or dispersing the active ingredient, and usually contains a good solvent for the active ingredient.

 In other words, it was thought that lolopterol would be absorbed from the skin only after dispersing or dissolving in the active ingredient dissolution layer.Therefore, there is no formulation method other than using an excipient to form the active ingredient dissolution layer. Was thought not to.

 Therefore, there has been a demand for a transdermal preparation having a lower irritating effect on skin while at the same time simplifying the manufacturing process and reducing the cost of absorbing rolobuterol from the skin. Disclosure of the invention

 The present inventors have conducted intensive studies in view of the above circumstances, and as a result, even without using an excipient that has been considered to be necessary for dissolving allobutterol, that is, The inventors have found that allobuterol can be absorbed transdermally without the presence of an active ingredient dissolving layer between the skin and the skin, and completed the present invention.

That is, the present invention provides a percutaneous absorption preparation in which allobuterol is carried in a fine solid state on the inside of the void or micropore formed by the fibrous or porous structure and / or on the surface of the structure. The present invention also provides the above-mentioned percutaneous absorption preparation further containing a basic substance.

 Further, the present invention provides a patch comprising a substrate layer, an adhesive layer, and the above-mentioned transdermal absorption agent layer having an area smaller than that of the adhesive layer, which are laminated in this order. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a drawing schematically showing an example of the configuration of a patch using the transdermal preparation of the present invention. The reference numerals in FIG. 1 are as follows.

 1 ■ · ·

 2 ■ · ·

 3 ■ · · · Drug impermeable layer

 4 ■ · ■

 5 · · · Protective film

 FIG. 2 is a graph showing the concentration of ropopterol in plasma of the product of the present invention and the comparative product. BEST MODE FOR CARRYING OUT THE INVENTION

 The fibrous structure used for the transdermal absorption preparation containing rlobbuterol of the present invention is not particularly limited, but has a form in which a woven fabric, a nonwoven fabric, a knitted fabric, fibers are simply shaped into a layer, or a paper form. Can be used. Preferred forms are woven, nonwoven or paper, and particularly preferred forms are nonwovens.

 The material constituting the fibrous structure is not particularly limited, and various known materials can be used. Specifically, cellulose or its derivatives such as paper; fiber materials derived from plants such as cotton and hemp; fiber materials derived from animals such as silk and wool; inorganic materials such as glass fibers and metal fibers. Materials: Organic materials such as polyester, polyethylene, and polyamide are exemplified.

Of these fiber materials, preferred is cellulose or a derivative thereof. Examples thereof include body, cotton, polyester, polyethylene, and polyamide, and particularly preferably, polyester. On the other hand, the porous structure used in the transdermal absorption preparation of the present invention is not particularly limited, but preferably has a form in which the pores are not isolated but continuous. In other words, there are two types of foaming resin, open-cell type and non-open-cell type. Both types can be used in the present invention, but the open-cell type with good air permeability should be used in terms of skin irritation. Is desirable.

 The material of the porous structure is not particularly limited, and various known materials can be used. Specific examples include polyurethane, polystyrene, polyethylene, silicone resin, polyvinyl chloride, polypropylene, polyester, polyamide, foamable metal, charcoal, cork, leather, natural rubber, and the like. Examples include polystyrene and polyethylene. Particularly preferred is polyurethane, and in combination with the above-mentioned form, continuous reading cell type foamable resin is particularly preferred. In the present invention, ropterol needs to be supported inside the voids or micropores formed by the fibrous or porous structure (hereinafter referred to as “structure”) and / or on the surface of the structure. This support may be held simply by frictional force, or may be held by intermolecular force. Further, it may be directly attached to the material surface of the structure, or may be attached via an adhesive component.

As a method for supporting allobuterol, for example, a method of dissolving allobuterol in an appropriate solvent, applying this solution to the structure, and then drying, or a method of attaching finer allobuterol crystal powder to the structure And the like. At this time, if the adhesive force is insufficient, an adhesive component such as polyacrylic acid, polyvinyl alcohol, carboxyvinyl polymer, gelatin, gum arabic, methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L · s), a solution containing methacrylic acid-ethyl acrylate copolymer (trade name: Eudragit L30D), etc., is impregnated into the structure, which is then dried to make the material surface of the structure an adhesive component. After performing the process of covering with, butterol may be supported.

 The solvent used for dissolving rlobbuterol is not particularly limited as long as it can dissolve the required amount of rlobbuterol in the formulation. Methanol, ethanol, n-pentane, n-hexane, getyl ether , Ethyl acetate, n-propanol, isopropanol, acetone, cyclopentane, cyclohexane, benzene, toluene, petroleum ether and the like. Of these, methanol, ethanol, isopropanol, acetone, and ethyl acetate are preferred from the viewpoint of worker safety and cost, and it is particularly desirable to use methanol, ethanol, and isopropanol. Further, the percutaneous absorption preparation of the present invention can contain a basic substance in order to increase the percutaneous absorption of ropopterol. Such a basic substance can be used without particular limitation as long as it does not irritate the skin, regardless of whether it is an inorganic substance or an organic substance. Specifically, disodium hydrogen phosphate, sodium acetate, sodium hydrogen carbonate and the like can be used. Lithium and the like are particularly preferred.

 The solvent for dissolving the above basic substance is not particularly limited, but water, methanol, ethanol, n-pentane, n-hexane, dimethyl ether, ethyl acetate, n-propanol, A substance in which the basic substance is soluble can be selected from isopropanol, acetone, cyclopentane, cyclohexane, benzene, toluene, petroleum ether and the like. Above all, water is preferred from the viewpoint of cost and safety.

In addition, in the case where allobuterol and a basic substance are supported on the structure at the same time, a common one of the above-mentioned solvents is used, or both solvents are mixed at an appropriate ratio. A solvent may be used. According to the above method, the average particle size of allobuterol supported on the structure is usually 5 Otm or less, and preferably 10 m or less in a fine solid state. If the average particle size of lobbuterol is larger than this, the holding power on the carrier may be insufficient, and lobbuterol may spill out of the structure to reduce the effect. Further, allobuterol may be attached to the structural material as a crystal or as an amorphous material.

 In the transdermal absorption preparation of the present invention, the degree of persistence can also be controlled. In this case, a method of adjusting the concentration of allobuterol to be carried on the structure, a method of selecting a material of the structure, a method of selecting a fiber diameter or a pore diameter of the structure material, and the like are exemplified.

 The percutaneous absorption preparation of the present invention thus obtained is not particularly limited as long as the structure supporting ropopterol can be brought into contact with the skin, and can be used as a dosage form such as a patch or a tape. Alternatively, the transdermal absorption preparation of the present invention may be simply fixed with an adhesive tape or the like so as to be in contact with the skin. Hereinafter, a patch is taken as an example of a dosage form using the percutaneous absorption preparation of the present invention, and the configuration of the patch will be described with reference to the drawings.

FIG. 1 schematically shows the constitution of the patch of the present invention, wherein 1 is a substrate layer, 2 is an adhesive layer, 3 is a drug impermeable layer, 4 is a transdermal absorption preparation layer, and 5 is a protective film. Is shown. In the patch of the embodiment shown in FIG. 1, a base layer 1, an adhesive layer 2, a drug-impermeable layer 3, and a transdermal absorption preparation layer 4 are laminated in this order. Of these, the drug-impermeable layer 3 and the percutaneous absorption preparation layer 4 each have an area smaller than the pressure-sensitive adhesive layer 2, and the pressure-sensitive adhesive layer 2 is adhered to the skin or the like so as to enclose these layers. The protective film 5 is sealed so as to cover the pressure-sensitive adhesive layer 2 and the transdermal absorption preparation layer 4. Among the above, the base material layer 1 is not particularly limited as long as it is a sheet-like material that can hold the pressure-sensitive adhesive layer 2 and the transdermal absorption preparation layer 4, and is used as a base material layer of a general pressure-sensitive adhesive tape. Can be used if they are available. For example, non-woven fabric, knit, polyester, etc. can be advantageously used.

 The adhesive layer 2 is a layer for fixing the percutaneous absorption preparation layer 4 to the skin by its adhesive strength, and the type of the adhesive used is not limited as long as it has appropriate adhesiveness to the skin. Although not preferred, adhesives such as acrylic adhesives, rubber adhesives, and silicone adhesives are exemplified.

 Among the preferred pressure-sensitive adhesives, acrylic pressure-sensitive adhesives include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, vinyl acetate, methyl acetate, and methyl acetate. (B) or (meth) acrylic acid (co) polymers or block copolymers thereof.

 Examples of the rubber-based adhesive include natural rubber, synthetic isoprene rubber, polyisobutylene rubber (PIB), polyvinyl ether, polyethylene, polyisoprene, polybutadiene, styrene-butadiene-styrene block copolymer (SBS). Styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer (SIS), and the like. In particular, a styrene-isoprene-styrene block copolymer is preferable.

 Further, examples of the silicone-based pressure-sensitive adhesive include those containing a polyorganosiloxane such as polydimethylsiloxane as a main component.

The pressure-sensitive adhesive layer may contain a known tackifier or softener in addition to the above-mentioned pressure-sensitive adhesive. For example, as a tackifier, rosin-based rosin or rosin derivative hydrogenated, disproportionated, polymerized, or esterified; terpene resin such as 0! -Binene, β-pinene; terpene-phenol resin An aliphatic, aromatic, alicyclic, or copolymeric petroleum resin; alkyl-phenyl resin; xylene tree Fats and the like are used. Examples of the softener include higher fatty acid esters such as polybutene, liquid paraffin, liquid isoprene rubber, polyisobutylene, and isopropyl myristylate; silicon oil; almond oil, leabe oil, camellia oil, persic oil, or laccase oil. Vegetable oils, such as oils, are used, especially liquid barffins.

 In addition, the drug-impermeable layer 3 is formed of the adhesive layer 2 and the percutaneously absorbable preparation layer 4 in order to prevent allobuterol from migrating to the adhesive layer 2 and reducing the concentration of allobuterol in the transdermal absorbent layer 4. Placed between.

 As the drug-impermeable layer 3, a known material which does not allow permeation of rlobbuterol and has a certain flexibility can be used. Specific examples include various plastic films, aluminum foils, and silicon resin films.

 The area of the drug-impermeable layer 3 needs to be smaller than that of the adhesive layer 2 because it is necessary to attach the adhesive layer 2 to the skin. Also, because of the function of preventing contact between the percutaneously absorbable preparation layer 4 and the adhesive layer 2, the size of the percutaneously absorbable agent layer 4 is such that the area around the percutaneously absorbable agent layer 4 projects outside within a range of about 5 mm or less. It is preferable that From the viewpoint of manufacturability, it is particularly preferable that the size is the same as that of the transdermal absorption preparation.

 The drug-impermeable layer 3 is omitted when the transfer of rolobuterol to the adhesive layer 2 is not so important or when an aqueous pressure-sensitive adhesive having low affinity with rolobuterol is used as the adhesive layer. Is also possible.

 As described above, the percutaneous absorption preparation layer 4 is a layer in which allobuterol is retained, and is composed of the above-described embodiment and material.

The thickness of the percutaneous absorption preparation layer 4 is not particularly limited, but if it is too thin, the volume of the space for holding the drug is insufficient, so that it is not possible to hold a sufficient amount of the drug. 2 has wrinkles and inferior usability. Therefore, in a state where the structure is not compressed, the thickness is usually about 0.05 mm to 1 Omm, preferably 0.1 mm to 5 mm, and particularly preferably about 0.2 mm to 2 mm. It is desirable to have a thickness No.

 In addition, a product in which a drug-impermeable layer and a drug-retaining layer are integrated in advance is commercially available (LMV-9004 / # 6A, manufactured by Japan Vilene Co., Ltd.). It can also be a patch.

The protective film 5 protects the preparation until use, and is peeled off during use. As the protective film 5, various known materials can be used. Specific examples include films of polyethylene, polypropylene, polyester, polyvinyl acetate, polyvinyl chloride, polyurethane, and paper coated with silicon. The mechanism of absorption of rlobbuterol in the present invention is not clear, but in the portion where rlobbuterol directly comes into contact with the skin, migration and absorption occur to the skin, and the drug holding layer is formed in such a manner as to compensate for the lack of concentration of rlobopterol near the skin. It is presumed that the mouthwater in the part of the skin that does not directly contact the skin moves to the vicinity of the skin at the molecular level. In addition, in the formulation, coexistence of basic substance with rlobbuterol increases transdermal absorption of ropopterol _θ The mechanism of this action is unknown, but by adding a basic substance, It is presumed that Η Ρ can be kept more basic, and that the percutaneous absorption ability of ロ orbute can be enhanced. In the past, it has been known that, in a wound treatment patch such as a bandage, a non-woven fabric, a gauze or the like holds a drug such as a bactericide and is used for local treatment (for example, see JP-A-54-〗). (See No. 2 217 17). However, if the target drug is absorbed through undamaged skin, acts non-locally, and the drug is absorbed over time, such drug-retained drugs are known. I didn't. Example

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. There is no restriction on these. Example 1

Dissolve 10 Omg of rlobbuterol in 1 OmL of methanol and cut 0.2 mL of this solution into a 3.2 cm X 3.2 cm non-woven fabric with a drug impermeable layer (Japan Vilene LMW-9004 / # 6A The weight was uniformly dropped to 50 g / m ² ) and air-dried.

 On the other hand, a commercially available adhesive tape (trade name: Registered trademark: TapeTape Scotch No. 8453 M) was cut into 5 cm x 5 cm, and the above-mentioned nonwoven fabric with the drug impermeable layer was cut thereon. The patch was adhered and arranged on the surface of the drug-impermeable layer, and further covered with a protective film to obtain a patch of the present invention. Example 2

Mix 7 mL of a solution of 43 g of allobuterol in methanol to make 1 OmL and 3 mL of a solution of 42.6 mg of sodium hydrogen phosphate in water to make 1 OmL. The resulting solution was uniformly dropped on a nonwoven fabric with a drug impermeable layer (LMW—9004 / # 6A, manufactured by Nippon Vileen Co., Ltd., 50 g / m ² ) cut to a size of cm × 3.2 cm and air-dried. Thereafter, the patch of the present invention was prepared in the same manner as in Example 1. Example 3

Mix 7 mL of a solution of 43 mg of rolobuterol in methanol to make 1 OmL and 3 mL of a solution of 42.6 mg of sodium acetate in water to make 10 mL, and add 0.2 mL of this solution to 3.2 cm X 3.2 cm. Was uniformly dropped on a nonwoven fabric with a drug-impermeable layer (LMW_9004 / # 6A, weight: 50 g Zm ² , manufactured by Nippon Vilene Co., Ltd.) cut to the dimensions described above, followed by air drying. Then, in the same manner as in Example 1, The patch was used as the patch of the present invention. Example 4

Dissolve 100 mg of rolobuterol in methanol and mix with 10 mL of solution (7 | 71), and 32.6 mL of a solution of 42.6 mg of sodium hydrogen carbonate in water to make 1 mL. 2 mL was uniformly dropped on a nonwoven fabric with a drug impermeable layer (LMW—9004 / # 6A, 50 g / m ² per unit weight, manufactured by Nippon Vilene Co., Ltd.) cut to a size of 3.2 cm x 3.2 cm, and air-dried. Thereafter, the patch of the present invention was prepared in the same manner as in Example 1. Example 5

 Dissolve 0 mg of ropopterol in methanol to make 1 OmL, and apply 0.2 mL of this solution to a polyurethane porous resin (UC 0050 made by Kuraray) cut to 3.2 cm x 3.2 cm. And then air-dried. The polyurethane porous resin holding the cellulose butter was placed on a drug-impermeable layer (MR-125, manufactured by Mitsubishi Chemical Polyester Corporation) of a silicone-treated polyethylene terephthalate film. Furthermore, they are cut onto a commercially available adhesive tape (trade name: Registered Trademark BokTape Scotch No. 8453M), which is cut to a size of 5 cm x 5 cm, with the drug impermeable layer facing down. , And then covered with a protective film from the top to obtain a patch of the present invention. Test example

The patches obtained in Examples 1 to 5 were subjected to a plasma concentration measurement test and a skin primary irritation test by the following methods. As a comparison, a commercially available transdermal absorption-type allobuterol formulation (trade name: registered trademark Hocnarin (r) Tape 2 mg) in which allobuterol was dissolved in an excipient was used. <Plasma concentration measurement test>

A 7-week-old male hair resrat was preliminarily reared for one week and used in the experiment with a non-fasted body weight of around 260 _g . After completely shaving the rat's hair, wiping the belly and back with 70% ethanol, drying the body, and applying three transdermal preparations (paste) of Examples 1 to 5 and Comparative to the belly Then, I wrapped an adhesive bandage from above and pressed down the tape. Eight hours after application, fasting and water deprivation were performed, and blood was collected from the jugular vein at a predetermined time, and plasma was separated. The plasma concentration of plasma was adjusted to pH 9.5 with borate buffer, extracted with ethyl acetate ethyl acetate (3/1), concentrated, and measured by HPLC (n = 4 to 6). . The results are shown in Table 1 and FIG.

 table 1

From Table 1 and FIG. 2, the concentration of rlobbuterol in the plasma of Examples 1 to 4 was equal to or higher than that of the comparison, and the transdermal absorption preparation of the present invention has sufficient practicality. It turned out that. In addition, in Examples 2 to 4 in which the basic substance was blended, compared to Example 1 in which the basic substance was not blended, the value of the plasma oral buterol concentration was higher in the time zone of 4 to 6 hr. As shown, it was possible to increase the absorption rate by adding a basic substance. <Skin primary irritation test>

 Japanese white heron males were used in the experiment under a non-fasting condition and weighing around 2.0 kg. One day before the test, the back of the egret was shaved with a clipper. On the day of the test, the back of the heron was completely shaved with a hair clipper, and then the transdermal absorption preparation (patch) of Example 2 and the comparative example was applied to the back of the heron, and three adhesive bands were applied from above. Holding down the winding tape. Twenty-four hours after application, the tape was peeled off, and the skin reaction was evaluated according to the Draise standard (n = 4). Table 2 shows the results.

 Table 2

 From Table 2, it was found that a lot of inflammation was observed at the location where the comparative preparation was applied, but no inflammation was observed at the location where Example 2 was applied. From the above, it was found that the transdermal absorption preparation of the present invention had lower skin irritation than the comparative example using an excipient.

In Example 5, although the amount of absorption was small, a certain amount of absorption was observed. It can be assumed that a sufficient amount of the drug can be absorbed by adjusting the concentration of rolobuterol per unit area, and that the skin irritation is excellent as in Example 2. It is better than the comparative example. Industrial applicability

 According to the present invention, it is possible to provide a percutaneous absorption preparation having a completely new absorption mechanism by adhering allobuterol to the space (voids or micropores) or the surface inside the fibrous or porous structure. is there. As a result, it is possible to provide a transcutaneous absorption preparation containing no excipients, which simplifies the production process, reduces cost, and reduces skin irritation.

Claims

The scope of the claims  1. A transdermal absorption preparation characterized in that llobuterol is carried in a fine solid state in the inside of the voids or micropores formed by the fibrous or porous structure and / or on the surface of the structure. 2. The percutaneous absorption preparation according to claim 1, wherein the allobuterol is supported on the fibrous or porous structure directly or via an adhesive component. 3. The percutaneous absorption preparation according to claim 1 or 2, wherein the fibrous structure is a woven fabric, a nonwoven fabric, or a paper. 4. The transdermal preparation according to any one of claims 1 to 3, wherein the material of the fibrous structure is cellulose or a derivative thereof, cotton, polyester, polyethylene or polyamide. 5. The percutaneous absorption preparation according to claim 1, wherein the material of the porous structure is polyurethane, polystyrene or polyethylene. 6. The transdermal preparation according to any one of claims 1 to 5, further comprising a basic substance. 7. The transdermal absorption preparation according to claim 6, wherein the basic substance is disodium hydrogen phosphate, sodium acetate, or sodium hydrogen carbonate. 8. The base material layer, the adhesive layer, and an area smaller than the adhesive layer. A patch comprising the rlobbuterol-containing transdermal absorption preparation layer according to any one of the above, which is laminated in this order.  9. The patch according to claim 8, further comprising a drug-impermeable layer between the adhesive layer and the layer of transdermal preparation containing rlobuterol.  10. The patch according to claim 8 or 9, further comprising a protective film for protecting the adhesive layer and the layer of transdermal preparation containing rlobbuterol.