JP4641394B2 - Method for producing transdermal preparation - Google Patents

Description

  The present invention relates to a method for producing a transdermally absorbable preparation. More specifically, the present invention relates to a method for effectively producing a percutaneously absorbable preparation in which a pressure-sensitive adhesive layer containing a transdermally absorbable drug in a dissolved and crystalline state in a uniform and stable state is provided on the support surface. Is.

As a general method for administering a drug into the body, oral administration and injection are known. However, in these administration methods, the blood drug concentration is short in the therapeutic area and the blood concentration is toxic. It often leads to an unfavorable situation of reaching the zone.
For this reason, various methods for controlling the sustained release of drugs have been studied, and one of them is a transdermal administration method. This transdermal administration method is a method in which the drug is transdermally absorbed, for example, by pasting a polymer polymer containing the transdermal drug on the skin or mucosal surface. A general patch-type preparation is prepared by blending a transdermal drug with an acrylic or rubber-based adhesive and forming it on a support according to the purpose.
In such a patch-type transdermal preparation, the drug is usually kept in a dissolved state in consideration of transdermal absorbability. In this case, the drug concentration in the preparation decreases with the permeation of the drug, and as a result, the permeation rate decreases due to the decrease in the concentration gradient. In order to prevent this, a method of allowing a crystallized drug to coexist has been proposed (for example, see Patent Documents 1 to 7).
All of the above prior arts basically use a drug-soluble solvent, mix and dissolve the drug solution and the adhesive solution, and then change the drug solubility in the adhesive substrate in the process of removing the solvent The drug is recrystallized to produce a preparation. However, in this method, the drug can be dissolved, and when mixed with the adhesive solution, there is often no solvent that does not cause aggregation of the adhesive, and there are cases where it cannot be handled.
JP 60-185713 A Japanese Patent Laid-Open No. 62-273913 JP-A-62-273914 JP-A-63-93714 Japanese Patent No. 2587365 Japanese Patent No. 2681365 Japanese Patent No. 3260765

  Under such circumstances, the present invention is suitable for a transdermal absorption preparation in which a pressure-sensitive adhesive layer containing a transdermal absorbable drug uniformly and stably in both dissolved and crystalline states is provided on the support surface. The object of the present invention is to provide a method for producing an effective drug even in the case of a drug that does not contain any solvent.

As a result of intensive research to achieve the above object, the present inventors have found that it is hardly soluble or insoluble in certain solvents and is soluble at room temperature that is soluble in the solid content of the pressure-sensitive adhesive layer forming material. The drug is dispersed in the pressure-sensitive adhesive layer-forming material without using a solvent for dissolving it, applied to the surface of the support, heat-treated at a temperature equal to or higher than the melting point of the drug, and then cooled. The present inventors have found that the object can be achieved, and have completed the present invention based on this finding.
That is, the present invention
(1) on the support surface, ketoprofen, upon producing the percutaneous absorption preparation provided a pressure-sensitive adhesive layer containing both a state of drug dissolution and crystallization which is selected from indomethacin and ceramides, the drug is dissolved it Without using a solvent, prepare a coating agent by mixing and dispersing in the pressure-sensitive adhesive layer-forming material in an amount exceeding the saturation solubility at room temperature, and then using this to provide a coating layer on the support surface or release sheet surface The drug is dissolved in the pressure-sensitive adhesive layer forming material by heating at a temperature equal to or higher than the melting point of the drug, and then cooled to form a drug-containing pressure-sensitive adhesive layer. When the coating layer is provided, the release sheet is used. When the coating layer is provided on the release sheet surface, the support is attached, and then the supersaturated portion of the drug in the pressure-sensitive adhesive layer is recrystallized. Characteristic of transdermal drug delivery Manufacturing method,
(2) The method for producing a percutaneously absorbable preparation according to (1), wherein the pressure-sensitive adhesive layer-forming material is an acrylic pressure-sensitive adhesive or a rubber-based pressure-sensitive adhesive.
(3) The method for producing a transdermal preparation according to (1) or (2) above, wherein the pressure-sensitive adhesive layer forming material is an organic solvent-type pressure-sensitive adhesive, and ( 4 ) the pressure-sensitive adhesive layer forming material is none. A method for producing a percutaneous absorption-type preparation according to the above (1) or (2), which is a solvent-type adhesive;
Is to provide.

  According to the present invention, a transdermal preparation having a pressure-sensitive adhesive layer containing a transdermally absorbable drug uniformly and stably in both a dissolved state and a crystalline state on the surface of a support is obtained. Even in such a case, it is possible to provide a method for effectively producing.

In the method for producing a transdermally absorbable preparation of the present invention, a transdermally absorbable preparation is produced by providing a pressure-sensitive adhesive layer containing a transdermally absorbable drug in both dissolved and crystalline states on the surface of a support.
There is no restriction | limiting in particular about the said support body, From the well-known thing used as a support body of the conventional sticking type | formula percutaneous absorption type | mold, arbitrary things can be selected suitably and can be used. As this support, for example, a sheet or film made of a synthetic resin such as polyester, polyvinyl chloride, polypropylene, polyethylene, or polyurethane, a synthetic paper, or a cellulose sheet or film, and a nonwoven fabric or woven cloth made of various materials, Examples include knitted fabrics. The thickness of the support is usually 500 μm or less, preferably 10 to 150 μm.
In the present invention, a percutaneously absorbable drug is used which is hardly soluble or insoluble in toluene or ethyl acetate and is soluble at room temperature and soluble in the solid content of the pressure-sensitive adhesive layer forming material. Here, “slightly soluble or insoluble in toluene or ethyl acetate” means that the drug powder is placed in toluene or ethyl acetate solvent and shaken vigorously at 20 ± 5 ° C. every 5 minutes for 30 seconds. This refers to the case where the amount of solvent required to dissolve 1 g of drug powder is 1000 mL or more. Further, “soluble in the solid content of the pressure-sensitive adhesive layer-forming material” means that when the drug is dissolved in the pressure-sensitive adhesive at a temperature equal to or lower than the saturation solubility at room temperature, the drug crystals do not precipitate even when left at room temperature. .
As such a transdermal drug, it is desirable to use a powdery substance having a melting point of preferably 50 to 150 ° C, more preferably 60 to 130 ° C. The type of the drug is not particularly limited as long as it satisfies the above-mentioned conditions, and for example, ceramide and various pharmacologically active substances can be used.
The ceramide is known to be an important substance as a moisture retention component of the epidermal stratum corneum. It is known that keratinocyte lipids are important for the retention of water in the epidermal stratum corneum, and ceramide, cholesterol, cholesterol ester, and free fatty acids are approximately 50%, 15%, 10%, respectively, in this keratinocyte lipid. % And 20%. Among them, ceramide is deeply involved in the ability to form lamellae between cells, and it is said that moisture is retained between the formed lamellae and exhibits a moisturizing function. There are various types of ceramides having such functions, and both natural products and synthetic products have been put into practical use, and are being used for skin care products and hair care products.
These ceramides are hardly soluble or insoluble in various solvents, but are soluble in the solid content of acrylic adhesives and rubber adhesives. Moreover, although melting | fusing point is based also on a type, generally it is about 60-130 degreeC.
Such ceramide can impart moisturizing ability to the skin when applied to the skin as a transdermal absorption preparation.
On the other hand, pharmacologically active substances include, for example, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antihistamines, central nervous system agents, hormone agents, antihypertensive agents, cardiotonic agents, antiarrhythmic agents, coronary vasodilators, topical agents. Anesthetics, hypnotics / sedatives, analgesics, antibiotics, antifungals, antineoplastic agents, anti-pressure diuretics, parasympatholytic agents, antiepileptics, anti-Parkinson's disease agents, sulfa drugs, and vitamins, Of the prostaglandins, anticonvulsants and the like, those satisfying the above-mentioned requirements required in the present invention can be appropriately selected and used. These pharmacologically active substances may be used alone or in combination of two or more.
Specific examples of the pharmacologically active substance that can be used in the present invention include ketoprofen, which is a non-steroidal anti-inflammatory agent.

In the present invention, the pressure-sensitive adhesive layer forming material is not particularly limited, and a material conventionally used for forming a pressure-sensitive adhesive layer in a patch type transdermal preparation can be used. Examples of such a pressure-sensitive adhesive layer forming material include acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives, and silicone-based pressure-sensitive adhesives.
Examples of the acrylic pressure-sensitive adhesive include, as a main component, an acrylic ester homopolymer, a copolymer containing two or more acrylic ester units, and a copolymer of an acrylic ester and another functional monomer. What contains at least 1 sort (s) chosen from the inside is used. Examples of the acrylic ester include (meth) acrylic acid methyl ester, (meth) acrylic acid ethyl ester, (meth) acrylic acid butyl ester, (meth) acrylic acid pentyl ester, (meth) acrylic acid hexyl ester, (meth) ) Acrylic heptyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid decyl ester, and the like. Examples of the functional monomer include hydroxyl group-containing monomers such as (meth) acrylic acid hydroxyethyl ester and (meth) acrylic acid hydroxypropyl ester, and amides such as (meth) acrylamide and dimethyl (meth) acrylamide. Examples thereof include a group-containing monomer and a carboxyl group-containing monomer such as (meth) acrylic acid, itaconic acid and maleic acid.
In addition, examples of the monomer copolymerizable with the above monomer include N-vinyl-2-pyrrolidone and vinyl acetate.
A crosslinking agent, a tackifier, a filler, etc. can be mix | blended with this acrylic adhesive as needed.
The rubber-based pressure-sensitive adhesive is selected from, for example, natural rubber, polyisoprene rubber, polyisobutylene, polybutadiene rubber, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer as a main component. Those containing at least one selected from the above are used. This rubber-based pressure-sensitive adhesive can be mixed with a tackifier, a softener, an antioxidant, a filler and the like as desired.
Furthermore, as the silicone-based pressure-sensitive adhesive, for example, polydimethylsiloxane, polymethylphenylsiloxane, or polydiphenylsiloxane is contained as a main component, and a tackifier, a softener, a filler, or the like is further contained as desired. Is preferably used.
These adhesives, as the tackifier to be blended as desired, for example, rosin resins, natural resins such as polyterpene resins, C ₅ based, C ₉ type, DCPD petroleum resins, coumarone-indene resin, Examples thereof include synthetic resins such as xylene resin.
In the present invention, among these pressure-sensitive adhesives, acrylic pressure-sensitive adhesives and rubber-based pressure-sensitive adhesives are preferably used.
The adhesive may be either an organic solvent type or a solventless type (hot melt type). In the case of an organic solvent type, the solvent contained in the adhesive as a transdermally absorbable drug. It is preferable to use a drug that is hardly soluble or insoluble.
When using a solvent-free pressure-sensitive adhesive, for example, among the rubber-based pressure-sensitive adhesives, an ABA type thermoplasticity such as a styrene-butadiene-styrene block copolymer, a styrene-isoprene-styrene block copolymer, etc. An adhesive comprising 20 to 50% by mass of a rubber elastic body, 10 to 70% by mass of a softening agent such as liquid paraffin and olive oil, and 20 to 60% by mass of a tackifier such as a polyterpene resin, a terpene phenol resin, and a petroleum resin. preferable.

（式中Ｒ¹は水素原子、炭素数１〜２０のアシル基又は炭素数１〜２０の炭化水素基、Ｒ²は水素原子又は炭素数１〜２０の炭化水素基を示す。）
で表されるアントラニル酸誘導体などを挙げることができる。
これらの吸収促進剤は、１種を単独で用いてもよく、２種以上組み合わせて用いてもよい。その使用量に特に制限はないが、塗工剤の固形分量に基づき、通常５０質量％以下である。 In the present invention, a predetermined transdermally absorbable drug is added to the pressure-sensitive adhesive layer forming material such as the acrylic or rubber pressure-sensitive adhesive in an amount exceeding the saturation solubility at room temperature without using a solvent for dissolving the drug. Then, a coating agent is prepared by mixing and dispersing. At this time, the pressure-sensitive adhesive layer forming material may be either an organic solvent type or a solventless type. In the case of the solventless type, the pressure-sensitive adhesive layer forming material is heated to add the drug in a liquid state, and mixed and dispersed to prepare a coating agent. The drug is preferably added in powder form.
The amount of the transdermally absorbable drug is usually about 0.01 to 50% by mass, preferably 0.05 to 30% by mass, based on the solid content of the coating agent.
In the present invention, the coating agent can contain an absorption enhancer for a transdermal drug, if necessary. Examples of the absorption accelerator include glycols such as diethylene glycol, propylene glycol, and polyethylene glycol; oils and fats such as olive oil, squalene, and lanolin; urea derivatives such as urea and allantoin; isopropyl myristate, isopropyl palmitate, and sebacic acid diester Higher fatty acid ester, higher fatty acid triglyceride; fatty acid (mono) diethanolamide; salicylic acid; salicylic acid ester; combined use system of ethanol and d-limonene; nonionic such as polyoxyethylene hydrogenated castor oil, isostearyl glyceryl ether, sorbitan fatty acid ester Surfactant and further the general formula [1]

(In the formula, R ¹ represents a hydrogen atom, an acyl group having 1 to 20 carbon atoms or a hydrocarbon group having 1 to 20 carbon atoms, and R ² represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms.)
Anthranilic acid derivatives represented by
One of these absorption promoters may be used alone, or two or more thereof may be used in combination. Although there is no restriction | limiting in particular in the usage-amount, Based on the solid content of a coating agent, it is 50 mass% or less normally.

Using the coating agent thus prepared, a coating layer is provided on the surface of the support or the release sheet. Next, the coating layer is heated at a temperature equal to or higher than the melting point of the transdermal drug contained therein, for example, at a melting point +5 to 40 ° C. for about 1 to 10 minutes to melt the drug and then cooled. To do. Thereby, an adhesive layer containing the drug in both dissolved and crystalline states is formed.
Thereafter, when the coating layer is provided on the surface of the support on the pressure-sensitive adhesive layer, the release sheet is adhered. When the coating layer is provided on the surface of the release sheet, the support is adhered, and a desired process is performed. A skin-absorbing preparation is obtained.
Although there is no restriction | limiting in particular in the thickness of the drug-containing adhesive layer formed in this way, Usually, 5-500 micrometers, Preferably it selects in the range of 10-300 micrometers.
Examples of the release sheet include paper substrates such as glassine paper, coated paper, cast coated paper, laminated paper obtained by laminating a thermoplastic resin such as polyethylene on these paper substrates, or polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate. Examples thereof include a polyester film such as phthalate or a plastic film such as a polyolefin film such as polypropylene or polyethylene and a release agent such as a silicone resin applied thereto. Although there is no restriction | limiting in particular about the thickness of this peeling sheet, Usually, it is about 20-150 micrometers.
Thus, in the case of a drug for which a suitable solvent is not present, a transdermal preparation having a pressure-sensitive adhesive layer that uniformly and stably contains a transdermal drug on the support surface in both dissolved and crystalline states. But it can be manufactured effectively.
When used, the release sheet is peeled off, and the exposed drug-containing pressure-sensitive adhesive layer side may be applied to a predetermined portion of the skin.

EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited at all by these examples.
Example 1
Acrylic adhesive solution [“O204” manufactured by Lintec Corporation, solid content 50% by mass, solvent: ethyl acetate], 100 g of synthetic ceramide [“Soft Care SL-E” manufactured by Kao Corporation, melting point 70-75 ° C., Hereinafter, it may be referred to as “SL-E”. 2 g were mixed and dispersed (SL-E did not dissolve in this state). On a 38 μm-thick polyethylene terephthalate (PET) film [“SP-PET3811” manufactured by Lintec Co., Ltd.] obtained by peeling this with a silicone compound, the coating amount after drying becomes 30 g / m ² (thickness 32 μm). And dried for 2 minutes at 95 ° C., which is higher than the melting point of SL-E. After drying, a PET film having a thickness of 25 μm [“Lumirror” manufactured by Toray Industries, Inc.] was bonded to prepare a preparation.
The state of crystallization immediately after the preparation of this preparation and after 1 day was visually confirmed.
Next, the forearm inner side part was wiped 50 times with the absorbent cotton in which a small amount of toluene was added to the three test subjects, and degreased. The preparation (sheet) was affixed to the same site for 24 hours, and after 2 hours of peeling, the dehydration fraction of the attachment site was measured with a skin moisture meter ["DM-R1-A" manufactured by Matsushita Electric Industrial Co., Ltd.] did. Moreover, the measurement of the non-degreasing part and the non-sticking part after degreasing was implemented.
These results are shown in Tables 5 and 1.
Example 2
1 g of ketoprofen (melting point: 94 ° C.) was mixed and dispersed in 100 g of acrylic pressure-sensitive adhesive solution “O204” (described above) (in this state, ketoprofen did not dissolve). A preparation was prepared in the same manner as in Example 1 except that the drying temperature was set to 100 ° C. higher than the melting point of ketoprofen. The state of crystallization immediately after the preparation of this preparation and after 1 day was visually confirmed. The results are shown in Table 5.
Next, in order to confirm the skin permeability of the drug in the above sample, the amount of permeation over time was measured according to the following method using the following Franz type permeation cell and rat abdominal excised skin. The results are shown in Table 2 and graphically in FIG.
<Skin permeability test>
(1) The upper part of the Frantz-type transmission cell (see FIG. 4, transmission part diameter 15 mm) covered with a PET film (188 μm) from the samples of Examples and Comparative Examples attached to the abdominal excised skin of Wistar rats. And the upper and lower parts were clamped on the top and bottom.
(2) 18 mL of a pH 7.4 phosphate buffer solution was used as a receiver phase, immersed in a thermostatic bath set at 37 ° C., and sampled over time.
The internal standard solution was added to this solution, and after stirring sufficiently, the cumulative amount of drug permeated through the skin was measured by HPLC.
Comparative Example 1
A preparation was prepared in the same manner as in Example 1 except that the drying temperature was 65 ° C. below the melting point of SL-E, and the state of crystallization was confirmed. In this preparation, the moisture content was measured by three subjects in the same manner as in Example 1. The results are shown in Tables 5 and 1.
Comparative Example 2
A preparation was prepared in the same manner as in Example 2 except that the drying temperature was 80 ° C. below the melting point of ketoprofen, and the state of crystallization was observed. The results are shown in Table 5. In this preparation, the permeation amount after 24 hours was measured in the same manner as in Example 2. The results are shown in Table 2 and graphically in FIG.

Example 3
100 parts by mass of a styrene-isoprene-styrene block copolymer [manufactured by Kraton Polymer Co., Ltd., “Clayton D-1107”], tackifier [polyterpene resin, Yashara Chemical Co., Ltd., “YS Resin PX1150”] 60 parts by mass, liquid paraffin [ 120 parts by mass of “liquid paraffin 350-S” manufactured by Sanko Chemical Industry Co., Ltd. was dissolved in toluene so as to have a solid content of 50% by mass to obtain an adhesive solution. In the subsequent methods, preparations were prepared in the same manner as in Example 2, and permeation measurement was performed. These results are shown in Table 3 and graphically in FIG.
Comparative Example 3
A preparation was prepared in the same manner as in Example 3 except that the drying temperature was set to 80 ° C. below the melting point of ketoprofen, and permeation measurement was performed. These results are shown in Table 3 and graphically in FIG.

Example 4
100 parts by mass of a styrene-isoprene-styrene block copolymer [manufactured by Kraton Polymer, “Clayton D-1107”], 100 parts by mass of a tackifier [polyterpene resin, Yashara Chemical Co., Ltd., “YS Resin PX1150”], liquid paraffin [ 3.14 parts by weight of indomethacin (melting point: 155 to 162 ° C.) was added to 150 parts by weight of Sanko Chemical Co., Ltd., “liquid paraffin 350-S”], and melted and mixed at 130 ° C. using a kneader.
The coating amount is 50 g / m ² (thickness 55 μm) at 130 ° C. on a 75 μm-thick PET film [Lintec Co., Ltd., “SP-PET7501”] which has been peeled off by a hot melt method. The film was heat-treated at 170 ° C. for 3 minutes, and then a 25 μm-thick PET film [manufactured by Toray Industries, Inc., “Lumirror”] was bonded to prepare a preparation.
The preparation was confirmed for crystal state and measured for permeation in the same manner as in Example 2, and the results are shown in Tables 5 and 4 and graphically shown in FIG.
Comparative Example 4
In Example 4, the preparation was prepared and evaluated in the same manner except that the heat treatment was not performed at 170 ° C. for 3 minutes. The results are shown in Tables 5 and 4 and FIG.

From the results of Example 1, in the preparation in which the drug was once dissolved and the supersaturated portion was recrystallized in the preparation, recovery of the skin moisture content was confirmed, and it is considered that ceramide was transferred to the skin. On the other hand, in the preparation in which the crystals of Comparative Example 1 were only dispersed once without being dissolved, recovery of the skin moisture content was not confirmed, and therefore it is considered that there was almost no migration of ceramide.
Moreover, the difference of the permeation | transmission amount was confirmed from the result of Example 2, Comparative Example 2, Example 3, Comparative Example 3, Example 4, and Comparative Example 4, and it combined with the result of Example 1 and Comparative Example 1, and this manufacturing was carried out. It is considered that the method can provide a preparation capable of efficiently transferring a drug (active ingredient) to the skin.

  The method for producing the percutaneously absorbable preparation of the present invention is suitable for a percutaneously absorbable preparation provided with a pressure-sensitive adhesive layer containing a transdermally absorbable drug uniformly and stably in both a dissolved state and a crystal state on the support surface. Even in the case of a drug in which no solvent exists, it can be produced effectively.

3 is a permeation curve of a drug in the preparations obtained in Example 2 and Comparative Example 2. 2 is a permeation curve of a drug in the preparations obtained in Example 3 and Comparative Example 3. 4 is a permeation curve of a drug in the preparations obtained in Example 4 and Comparative Example 4. It is explanatory drawing of the skin-permeation test apparatus used by the Example and the comparative example.

Claims (4)

When producing a transdermal preparation by providing a pressure-sensitive adhesive layer containing a drug selected from ketoprofen, indomethacin and ceramide in both dissolved and crystalline states on the support surface, a solvent that dissolves the drug is used. Without preparing a coating agent by mixing and dispersing in the pressure-sensitive adhesive layer-forming material in an amount exceeding the saturation solubility at room temperature, and using this to provide a coating layer on the support surface or release sheet surface, the drug After the heat treatment at a temperature equal to or higher than the melting point, the drug is dissolved in the pressure-sensitive adhesive layer forming material, and then cooled to form a drug-containing pressure-sensitive adhesive layer, and then a coating layer on the surface of the support is formed on the pressure-sensitive adhesive layer. In the case of providing a release sheet, when a coating layer is provided on the surface of the release sheet, a support is attached, and then the supersaturated content of the drug in the pressure-sensitive adhesive layer is recrystallized. Manufacturing method for transdermal drug delivery .   The method for producing a transdermal preparation according to claim 1, wherein the pressure-sensitive adhesive layer-forming material is an acrylic pressure-sensitive adhesive or a rubber pressure-sensitive adhesive.   The method for producing a transdermal preparation according to claim 1 or 2, wherein the pressure-sensitive adhesive layer-forming material is an organic solvent-type pressure-sensitive adhesive. The method for producing a transdermal absorption preparation according to claim 1 or 2, wherein the adhesive layer forming material is a solventless adhesive.

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