JP2000063267A - Percutaneous absorption patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a percutaneous absorption patch excellent in transdermal absorption of estradiol by employing an ester of estradiol. SOLUTION: When percutaneous absorption patch has a medicament-including layer, where medicament and percutaneous absorbefacient are uniformly included in base matrix, on one surface of a support, the medicament is estradiol-17 β-valeric acid ester and percutaneous absorbefacient is isopropyl myristate in a content of 5-40 w/w% based on the weight of the medicament-including layer. The medicament-including layer virtually include neither 1-8C aliphatic alcohol nor polyethylene glycol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a transdermal patch containing a prodrug of estradiol, and more particularly to a transdermal patch containing estradiol-17β-valeric acid ester.

[0002]

BACKGROUND OF THE INVENTION Estradiol is a kind of estrogen, and the physiologically active 17β type has the strongest activity among natural estrogen. Estradiol is effective for the treatment of menopausal disorders, osteoporosis, menstrual abnormalities, etc., but when administered orally, it has a high liver metabolism rate, resulting in a significant decrease in bioavailability. For this reason, it is possible to administer by injection, but since the blood concentration of estradiol cannot be maintained for a long period of time by injection, long-term repetitive injection is used for the intended treatment of menopausal disorders, osteoporosis, menstrual disorders, etc. It is unavoidable and puts an undue burden on the patient. Therefore, in order to maintain the blood concentration of estradiol for a long time without placing a burden on the patient, a patch-type transdermal absorption preparation (herein,
It is called a "transdermal patch." ) Was devised and has already been used clinically (Estraderm TTS (registered trademark):
Novartis Pharma). Clinically used estradiol percutaneous absorption patch slowly feeds estradiol into the blood through the skin by applying a film patch on the abdomen or waist, but since it contains ethanol as a percutaneous absorption enhancer. It is irritating to the skin and may cause contact dermatitis. For this reason, it is necessary to be careful not to continuously apply the same area. It is also known that alcohols such as ethanol adversely affect the metabolism of the skin, and it is not desirable to include ethanol in the preparation to be applied to the skin for an extremely long period from that point as well.

Further, since the transfer rate of estradiol from the unit area of the currently used clinically used estradiol patch is low, the amount of estradiol required to be transferred into the living body per unit time is reduced. In order to make it correspond, it is required to attach a preparation having an area which is sufficiently commensurate with it. Therefore, if the transfer rate of estradiol from the preparation to the blood is low, a larger preparation area is required, but since it is a preparation that covers the skin for a long time, comfort for patients and unexpected effects on the skin are also considered. However, it is preferable that the size is as small as possible. Therefore, a preparation having excellent skin permeability has been desired.

In addition to the above Estraderm TTS (registered trademark), transdermal preparations of estradiol have been proposed (JP-A-2-196714 and JP-A-2-233617).
No. 3-17018, and 3-44326.
JP-A-3-44327, JP-A-4-342531
No. 7, JP-A-7-247217 and JP-A-8-27003.
No. 9-59148). Although the use of an ester of estradiol is also proposed in these publications, in each of the examples, only a transdermal preparation using estradiol itself is specifically disclosed. There is no specific formulation example.

Various substances have already been known as percutaneous absorption enhancers. Which transdermal absorption enhancer or a combination thereof is suitable depends on the molecular weight of the drug to be percutaneously absorbed, Since it depends largely on physical and chemical properties, metabolism in the skin, required dose, etc., a percutaneous absorption enhancer suitable for one drug is similar to other drugs for the same pharmacological action. Not suitable for. If the molecular weight and the hydrophilic / lipophilic balance differ between the two drugs, it is difficult to predict the difference. To date, when a drug is indicated, there is no practical guideline for predicting a suitable percutaneous absorption enhancer for that drug. Under the current circumstances, there is no choice but to seek out from a very large number of compounds by trial and error.

Prodrugs have drawbacks by chemically modifying drug molecules (parent drugs) which have therapeutically useful but pharmaceutical or biopharmaceutical disadvantages to control their physical properties. Is a drug that has improved. The prodrug itself does not exhibit a pharmacological effect, but exhibits a pharmacological effect after being chemically or enzymatically converted into the parent drug in the body after administration. By using a prodrug instead of the parent drug, it is possible to try to formulate with a drug having a hydrophilic / lipophilic balance different from that of the parent drug. The absorption characteristics can be adjusted. Therefore, there is a possibility that percutaneous absorption can be greatly improved by selecting an appropriate percutaneous absorption enhancer.

In the case of designing a percutaneous absorption preparation for the purpose of systemic administration of a drug using a prodrug, not only the percutaneous absorption of the prodrug in the preparation is promoted, but also the prodrug is parented in the skin when passing through the skin. It needs to be converted into a drug. Therefore, it is preferable that the formulation does not contain a substance that may prevent the conversion of the prodrug to the parent drug in the skin. In particular, alcohols such as ethanol and octanol, and polyethylene glycols are listed as components that may inhibit skin metabolism when applied to the skin for a long period of time.

[0008]

The present invention uses an ester of estradiol as a prodrug of estradiol and combines it with a suitable transdermal absorption enhancer to dramatically increase the transdermal absorption rate of a drug. It is intended to increase the transfer rate of estradiol into the body per unit area of a transdermal patch.

[0009]

[Means for Solving the Problems] As an ester of estradiol, 17β-valeric acid ester was used, and the transdermal absorption-promoting effect of various compounds was examined. As a result, isopropyl myristate was found to be particularly preferable. Was issued.

That is, the present invention provides a percutaneous absorption patch comprising a support and a drug-containing layer obtained by homogeneously containing a drug and a percutaneous absorption promoter in a base matrix, the layer comprising: The drug is estradiol-17β-valeric acid ester, and 5 to 4 in the drug-containing layer as a transdermal absorption enhancer
Isopropyl myristate in an amount of 0 W / W% is contained, and the drug-containing layer contains substantially no aliphatic alcohol having up to 8 carbon atoms or polyethylene glycol. A skin absorption patch is provided.

Further, for estradiol-17β-valeric acid ester, not only isopropyl myristate but also a predetermined concentration of limonene and a predetermined concentration of lauryl laurate, oleyl laurate, myristyl laurate,
It has been found that when lauryl oleate or lauryl myristate is used in combination, excellent transdermal absorption can be maintained even when the concentration of isopropyl myristate is relatively low.

That is, the present invention further provides a percutaneous absorption patch having a drug-containing layer in which a drug and a percutaneous absorption enhancer are homogeneously contained in a base matrix and held on one side of a support. The drug is estradiol-17β-valerate, and the drug-containing layer contains isopropyl myristate in an amount of 5 to 20 W / W% as a transdermal absorption promoter, and the transdermal absorption promoter As a further
(A) 1-10 W / W% of limonene, and (b) 1-10
A percutaneous absorption patch according to claim 1, characterized in that it also contains W / W% of lauryl laurate, oleyl laurate, myristyl laurate, lauryl oleate or lauryl myristate.

These percutaneous absorption patches of the present invention bring about good transfer of estradiol into the blood and make it possible to reduce the size of the estradiol patch compared to the conventional ones. In addition, it is not necessary to contain an aliphatic alcohol or polyethylene glycol having up to 8 carbon atoms in an amount that affects the skin metabolism, and does not adversely affect skin irritation.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the base matrix of the transdermal patch is not particularly limited, but a base matrix composed of a silicone elastomer, an acrylic adhesive or the like can be used as appropriate. Comparing the two, a silicon-based matrix is more preferable. When using a silicon-based matrix, as the base component,
It is preferable to contain about 2 to 8 W / W% of silicone oil. As will be shown later in the data, the inclusion of silicone oil has the effect of increasing the skin permeability of estradiol ester. The "support" is a tape formulation,
It may be one that is usually used for preparations to be applied to the skin, such as patches and poultices, and any material that is compatible with the skin and convenient for use in the present invention may be used. Good.

Although the silicone base matrix itself does not have adhesiveness to the skin, an adhesive layer may be provided on the surface of the drug-containing layer that comes into contact with the skin, or a support larger than the drug-containing layer may be used. An adhesive layer may be provided on the surface of the support, which extends beyond the periphery of the drug-containing layer, so that the surface of the support on the drug-containing layer side adheres to the skin. Various kinds of pressure-sensitive adhesives that are used for sticking a tape or a preparation to the skin are known and can be appropriately selected and used from them.

The concentration of estradiol-17β-valeric acid ester contained in the base matrix can be appropriately set depending on the kind and degree of the target disease, and the like.
If it is 2 to 20 W / W%, more preferably 2 to 10 W / W%, for example, about 5 W / W% of the drug-containing layer, that is, the layer consisting of the base material and the drug added thereto, the transdermal absorption enhancer, etc. Good. It should be noted that the present invention does not prohibit containing an aliphatic alcohol having up to 8 carbon atoms or polyethylene glycol in a small amount that does not affect skin metabolism.

The test methods and results of the transdermal patch used in the present invention are listed below.

<General method for producing percutaneous absorption patch using silicone base matrix> When a silicone base is used, the percutaneous absorption patch can be produced according to the following procedure. That is, according to the following formulation, a percutaneous absorption enhancer is added to a disposable cup (for example, made of polypropylene) containing a drug, and they are mixed sufficiently. Then about 2.0
After adding mL of toluene or ethyl acetate and ultrasonically treating for about 30 seconds to dissolve the drug, silicone oil, silicone elastomer and curing agent are sequentially added thereto and mixed sufficiently. After degassing the mixture, spread it on a backing liner (Cerafeel # 25) using a doctor knife or a baker applicator (Nippon Applied Technology). This is left at room temperature for about 1 hour and then cured at 40 ° C. to prepare a silicone film preparation. For transdermal absorption experiments,
This is punched out into a circle having a diameter of about 1.5 cm and used (thickness containing about 1 mg of drug).

(Prescription) Drug: Percutaneous absorption enhancer ... Predetermined amount Silicone elastomer (Note 1)・ ・ ・ 4.5 g Silicone oil (Note 2) ・ ・ ・ ・ ・ ・ 0.25 g Curing agent (Note 3) ・・ ・ ・ ・ ・ ・ ・ ・・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ 2.0 ~ 3.0 mL Note 1: For example, SLASTIC (registered trademark) MDX4-4210 medical grade (Dow Corning Asia) is used. Note 2: For example, use 360 medical fliud, 20cs (Dow Corning Asia). Note 3: For example, SLASTIC (registered trademark) MDX4-4210: (Dow Corning Asia) is used.

In the above formulation, the concentration of the drug is determined by using the weight of each component used, drug / (drug + transdermal absorption promoter + silicone elastomer + silicone oil + curing agent) ×
It is calculated as 100. Toluene and ethyl acetate will not be included in the calculation because they volatilize.

<General Method for Producing Transdermal Absorption Patch Using Acrylic Base Matrix> When an acrylic base matrix is used, a transdermal absorption patch can be produced according to the following procedure. That is, according to the following formulation, a percutaneous absorption enhancer is added to a disposable cup (for example, made of polypropylene) containing a drug, and they are mixed sufficiently. Then add about 1.0 mL of ethyl acetate or toluene to about 30
After ultrasonic treatment for 2 seconds to dissolve the drug, 5.0 g of an acrylic pressure-sensitive adhesive as a dispersion base is added and mixed. Further, 0.15 g of a coagulation accelerator is added and mixed well. After degassing, the mixture is spread on a packing liner (Cerafeel # 25) using a doctor knife or a baker applicator (Nippon Applied Technology) and dried at room temperature.
In the percutaneous absorption experiment, this is punched out into a circle having a diameter of about 1.5 cm (a thickness containing about 1 mg of the drug).

(Prescription) Drug: Percutaneous absorption enhancer: Predetermined amount: Acrylic adhesive (Note 4) ) ・ ・ ・ ・ 5.0 g Aggregation accelerator (Note 5) ・ ・ ・ ・ 0.15 g Toluene or ethyl acetate ・ ・ ・ ・ 1.0 to 2.0 mL Note 4: For example, acrylic copolymer Resin, PE-300 (Nippon Carbide Industry), solid content / solvent = 40: 60 are used. Note 5: For example, CK-401 (Nippon Carbide Industry) is used.

In the above formulation, the drug concentration is calculated as drug / (drug + transdermal absorption accelerator + acrylic adhesive + aggregation accelerator) × 100, using the weight of each component used. Toluene and ethyl acetate volatilize,
Not included in the calculation.

<Adhesive Layer> When the adhesive layer is provided on the surface of the drug-containing layer made of a silicon-based matrix, the adhesive may be appropriately selected from commercially available ones. For example, the following adhesive can be used. (A) Silicone adhesive: BIO-PSA Q7-4501, BIO-PSA X
7-4201 (Dow Corning Asia): Solid content / solvent = 40:
60) (b) Polymethylphenylsiloxane copolymer (Lintec) (c) Acrylic acid-dimethylsiloxane copolymer: BPK-
1, BPK-2 (Wako Pure Chemical Industries)

<Method of skin permeation experiment of drug from percutaneous absorption patch> (1) Skin permeation experiment device For skin permeation experiment, a side by side permeation experiment device is used.
A side-by-side cell Permcell HK-5P (Ogura Glass Industry) was used. FIG. 1 shows a cell 1 on one side of a symmetrical pair of devices. The effective area of the opening 2 of the cell 1 is 0.
Is 64cm ^2, the effective volume of the cell 1 is 5.0 mL. The water jacket part of the device is connected to a circulating constant temperature water tank with a silicon tube, and the solution temperature in the cell is maintained at 37 ° C.
Also, the inside of the cell is constantly stirred by a magnetic stirrer (rotation speed 1200 rpm).

(2) Preparation of skin sample The intact skin of the abdomen of 8 to 11-week-old hairless mice (Hr / Kud strain) was cut off, and the adhered fat was removed with dissecting scissors.

(3) Skin permeation experiment procedure of drug from transdermal patch See FIG. The hairless mouse skin 3 collected above is attached to cover one side 1 of the side-by-side diffusion cell 1 (referred to as the receptor side cell) with the opening 2 (0.64 cm ² ) covered, and then transdermally. The absorbent patch 5 is applied, covered with a support net 7 to fix it, covered with an aluminum sheet 9, and the other cell is overlaid so that the openings are aligned with each other. Fix both cell comrades. 40W / W% PEG4 in the cell on the receptor side
00 Fill the solution and keep the temperature at 37 ℃
A 100 μL sample was taken, and estradiol hydrolyzed in the skin and transferred to the receptor side and estradiol-17β-valeric acid ester that had permeated the skin and transferred to the receptor side without being decomposed were treated with H under the following conditions.
Measured by PLC. In order to maintain the liquid volume in the receptor cell, the same amount of 40 W / W% PEG400 aqueous solution is replenished to the cell after the sample is collected. Under these conditions, the permeability to estradiol-17β-valerate and the ability of the ester to hydrolyze in the skin remain substantially constant for at least 48 hours.

(4) Skin permeation experiment procedure of estradiol from Estraderm TTS (registered trademark) In the case of Estraderm TTS (registered trademark), it is difficult to use a side-by-side type diffusion cell because of its structure. Fr for skin permeation studies of estradiol from formulations
An anz type diffusion cell (see FIG. 2) is used. The fact that there is no substantial difference in the measured values between the side-by-side type diffusion cell and the Franz type cell is that skin permeation experiments were performed using both types of cells using a typical transdermal patch. Confirmed by performing and comparing.

(5) Estradiol-1 in the sample
HPLC was used for the quantitative analysis of undegraded estradiol-17β-valerate in the quantitative sample of 7β-valerate, and the conditions were as follows. Column: Waters μ-Bondapak C18 125Å 10 μm (3.9
Pre-column: μ-Bondapak C18 pre-column Column temperature: 40 ° C Measurement wavelength: 205 nm Mobile phase: Acetonitrile / distilled water (Raise the acetonitrile concentration from 45% to 90% over 32 minutes) Flow rate: 1.0 mL / min Retention time: 8.8 minutes (estradiol-17β-valerate), 26.5 minutes (estradiol)

(6) Quantitative analysis of estradiol in the sample HPL was used for quantitative analysis of estradiol in the sample.
C was used and the conditions were as follows. Column: Shimadzu L-column ODS (4.6 x 250 mm) Guard column: TOSOH TSKgel ODS-80TM (15 x 3.2 m
m) Column temperature: 40 ° C Measurement wavelength: 205 nm Mobile phase: Acetonitrile / distilled water (45/55) Flow rate: 1.0 mL / min Retention time: 8.4 min

<Results of permeation experiment> (1) Skin permeation of estradiol from Estraderm TTS (registered trademark) Accumulation of estradiol from Estraderm TTS (registered trademark) (estradiol content: 5 W / W%) attached to the skin of hairless mice The measurement results of the amount of skin permeation are shown in FIG. The vertical axis represents the cumulative amount of permeation of estradiol (μg) per cm ^{2 of} skin, and the horizontal axis represents the elapsed time from the start of the test. In addition, the following table shows the cumulative skin permeation amount of estradiol at 24, 48 and 72 hours after the start of the test in μg / cm ² . Values are mean ± S.E. D. Represents (n = 3).

[0032]

[Table 1]

(2) Skin permeation of estradiol from a silicone-based patch using one percutaneous absorption-accelerating agent, as described in the above-mentioned "General method for producing a transdermal-absorption patch using a silicon-based matrix". Cumulative permeation of the drug per 1 cm ^{2 of} skin in the patch prepared as above, containing 5 W / W% of estradiol-17β-valerate and containing no transdermal absorption enhancer Amount and 5 W / W% of estradiol-17β-valerate and one of cineole, terpineol, L-lactic acid, isopropyl myristate, lauryl laurate and myristyl laurate as a candidate substance for promoting percutaneous absorption The accumulated permeation amount of the drug per 1 cm ² of the skin was measured at 24 hours from the start of the test for each of the various applied patches. . The results are shown in the table below. In the table, "EV" represents estradiol-17β-valerate, "E" represents estradiol produced by hydrolysis of EV in the skin during permeation, and "IMP" represents isopropyl myristate ( same as below). Values are mean ± S.E. D. (N = 3).

[0034]

[Table 2]

As can be seen from the table, it was the parent drug, estradiol, which was mostly reconstituted by hydrolysis after transfer to the receptor side, and the undecomposed ester remained in a very small amount. That is, it can be seen that the skin has sufficient metabolic activity to hydrolyze permeating estradiol-17β-valerate to estradiol.

Cyclic monoterpenes such as terpineol and cineole are known to exhibit a transdermal absorption promoting effect on indomethacin, 5-FU and the like. However, as shown in the table, estradiol-17β-
No effect was observed with 5% cineol on valerate. Also, with 5% terpineol, the amount of estradiol permeation increased nearly twice that of the control,
No effect was seen with the formulation in which the terpineol concentration was increased to 10%. That is, with terpineol, at most, a permeation enhancement about twice that of the control was obtained, which is extremely insufficient for the purpose of the present invention. L-lactic acid, which is attracting attention as a component that promotes metabolism of the stratum corneum, is used at 3 W / W.
Almost no effect was observed even with the patch contained at a concentration of%.

On the other hand, the patch containing 10%, 20%, 30% and 40% isopropyl myristate (IPM) had a large amount of 2.9 times, 8.3 times, 12.4 times and 11.9 times that of the control, respectively. Estradiol moved to the receptor side. This promoting effect of isopropyl myristate is
Dose-dependent, isopropyl myristate concentration 30
It reaches maximum at ~ 40% and is saturated. Table 2 and Estrader
Comparing with Table 1 for m TTS (registered trademark), 30
The amount of drug permeation per unit area of skin for 24 hours using the patch containing% isopropyl myristate is the above Estraderm TTS.
It is about 9 times the cumulative permeation amount of the drug per unit area of skin for 24 hours obtained in the skin permeation experiment of estradiol from (registered trademark). This means that the silicone patch containing 30% isopropyl myristate can have the same effect with an area of 1/9 of Estraderm TTS (registered trademark), that is, with a diameter of 1/3 in the case of a circle. To do.

Further, 10% lauryl laurate, 20% lauryl laurate, and 5% myristyl laurate also showed excellent effects of 4.7 times, 9.9 times, and 3.1 times that of the control, respectively.

As can be seen from the above table, in the patch containing any of isopropyl myristate, lauryl laurate and myristyl laurate, despite the increase in the amount of estradiol that migrates to the receptor side, it remains unchanged. The transmission of some EVs remains negligible. This is because these transdermal absorption enhancers
It shows that it does not adversely affect the skin metabolism (ester hydrolysis) of 17β-valerate.

(3) Skin permeation of estradiol from an acrylic patch using one percutaneous absorption enhancer (a) Section of the above-mentioned "general production method of a transdermal patch using an acrylic base" As described above, regarding an acrylic patch containing 5 W / W% estradiol-17β-valerate (EV) containing no transdermal absorption enhancer,
A skin permeation experiment was performed. Results are shown in FIG. In addition, various patches containing one of lauric acid, lauryl laurate, IPM, oleic acid and 1-menthol as a candidate substance for promoting percutaneous absorption in the skin for 24 hours after the start of the test. The cumulative permeation amount of the drug per 1 cm ² is shown in the following table. "Control" indicates a patch containing no transdermal absorption enhancer. Values are mean ± S.E. D. (N = 3).

[0041]

[Table 3]

As can be seen from the comparison with the silicone-based patch, the same concentration (5 W / W%) of estradiol-1 was used.
Regarding 7β-valerate, the skin permeation of the acrylic patch was generally smaller than that of the silicone patch, but the effect of IPM addition was still remarkably confirmed in the acrylic patch. That is, 30% or 40% of IP
In the formulation using M as a percutaneous absorption enhancer, about 7.
The skin permeation was 5 times higher, and the skin permeation was about 3.6 times higher than that of Estraderm TTS (registered trademark). Therefore, 30
% To 40% isopropyl myristate-containing acrylic patch can have an equivalent effect with 1 / 3.6 or 0.28 times the area of Estraderm TTS (registered trademark), and in the case of a circle,
A diameter of 0.53 times is sufficient, and the formulation can be miniaturized.

(4) Skin permeation of estradiol from a silicone patch using a combination of two types of percutaneous absorption enhancers. Next, a silicone patch using a combination of two types of percutaneous absorption enhancers. The skin permeation of estradiol ester and estradiol from the drug was investigated. The combination of percutaneous absorption enhancers used is IPM + geraniol, IPM
+ Vitamin E, IPM + Limonene, IPM + Cineol and IPM + Octanol.

The results are shown in FIGS. For convenience of comparison, each figure shows a control containing no transdermal absorption enhancer, Estrader.
Graphs have been added for silicone based patches containing m TTS® or IPM at various concentrations. In addition, the following table summarizes the cumulative skin penetration of the drug at 24 hours after the start of the test. In the table, "Control" column and 10-40% I
For convenience of comparison, the values in the above table are described in the column of the silicone patch when PM alone is used as the transdermal absorption enhancer.

[0045]

[Table 4]

For a 5% estradiol-17β-valeric acid ester (EV) -containing silicone patch, 5% limonene as a transdermal absorption enhancer was used in combination with 10% IPM to give a 4.7-fold increase compared with the control. About 1.6 times as much drug permeation was obtained as compared with the case where only 10% IPM was used as the transdermal absorption enhancer. Vitamin E is known to promote the skin permeation of prednisolone ester bodies accompanied by skin metabolism, but even when used in combination with 10% IPM, 10% IPM alone has been found to enhance the transdermal absorption promotion effect. There wasn't. When 3% L-lactic acid is used in combination with IPM, 10% IPM
Higher drug permeation was observed than the stimulating effect by itself, but
The effect of the combined use of 10% IPM and limonene was not reached. Also, the use of L-sodium lactate, which is more suitable for formulation stability than L-lactic acid, conversely decreased drug penetration. Also, by using lauryl laurate in combination with 10% IPM, drug penetration is increased, and its effect is 5% IPM and 10%.
It was especially remarkable in combination with lauryl laurate.

(5) Skin permeation of estradiol from a silicone patch by a combination of three types of percutaneous absorption enhancers With reference to the above results, a combination of three types of transdermal absorption enhancers with silicone Skin permeation of estradiol ester and estradiol from the system patches was tested. The transdermal absorption enhancer combination used was IPM + Limonene + Lauryl laurate.

FIG. 10 shows a control containing no transdermal absorption enhancer, and 10% IPM, 10% IPM + 5% lauryl laurate,
The cumulative skin permeation amount of the drug in a 5% estradiol-17β-valeric acid ester (EV) -containing silicone patch using 10% IPM + 5% lauryl laurate + 5% limonene as a transdermal absorption enhancer is shown. It can be seen that the addition of limonene significantly increased the skin permeability of the drug.

Further, as a percutaneous absorption promoter, 10% IPM
+ 5% Limonene (L) + 5% Lauryl laurate (L
L), 10% IPM + 5% limonene (L) + 5% myristyl laurate (ML), and 10% IPM + 5% limonene (L) + 5% oleyl laurate, 5% IPM + 5% limonene (L) + 5% lauryl laurate (LL). ),as well as
The effect of each combination consisting of 10% IPM + 10% limonene (L) + 5% lauryl laurate (LL) was comparatively examined. The results are shown in the table below. The values in the table show the cumulative skin permeation amount of the drug from the start of the test to 24 hours later.

[0050]

[Table 5]

As is clear from the figure and table, the combination of these three types of percutaneous absorption enhancers all exhibited excellent effects. Especially, isopropyl myristate + limonene +
A particularly excellent effect was observed for the combination of lauryl laurate. That is, when compared to the control formulation shown in Table 2: (a) 11.5 for 10% IPM + 5% L + 5% LL
Double (b) 9.4 times for 10% IPM + 5% L + 5% ML (c) 8.0 times for 10% IPM + 5% L + 5% OL (d) 12.3 for 5% IPM + 5% L + 5% LL
A double (e) 10% IPM + 10% L + 5% LL resulted in a cumulative transmission of 9.7 times. These are Estraderm TTS
When compared with the 24-hour values in Table 1 for (registered trademark), the values are 8.3 times, 6.8 times, 5.8 times, 8.9 times and 7.0 times, respectively.

Then, as a transdermal absorption enhancer, 10% IP
M + 5% limonene + 5% lauryl myristate, and 10
The effect of the combination consisting of% IPM + 5% limonene + 5% lauryl oleate was investigated. The results are shown in FIG.
In addition, in FIG. 11, the above 10% IPM + 5% limonene +
The results of a preparation containing 5% lauryl laurate as a percutaneous absorption enhancer are added for comparison.

As shown in FIG. 11, 10% IPM + 5
% Limonene + 5% lauryl myristate, and 10% IP
The combination of M + 5% limonene + 5% lauryl oleate also showed the same effect as 10% IPM + 5% limonene + 5% lauryl laurate.

[0054]

EXAMPLES The present invention will be further described below with reference to representative examples, but it is not intended that the present invention be limited to the details of these examples. Example 1: 5 W / W% of estradiol-based on the entire silicon-containing patch drug-containing layer
17β-valeric acid ester and 5 as a transdermal absorption promoter
A silicone patch containing W / W% isopropyl myristate is produced according to the following composition. That is, estradiol-17β-valeric acid ester (E
Add isopropyl myristate to a disposable cup (made of polypropylene) containing V) and mix thoroughly. Then, toluene or ethyl acetate is added and ultrasonically treated for about 30 seconds to dissolve the drug, and then silicone oil, silicone elastomer, and curing agent are sequentially added thereto and mixed sufficiently. After degassing the mixture, spread it on a backing liner (Cerafeel # 25) using a doctor knife or a baker applicator (Nippon Applied Technology). This is left at room temperature for about 1 hour and then cured at 40 ° C. to prepare a silicone film preparation. At the time of preparation, the thickness is adjusted so as to contain about 1 mg of the drug when punched out into a circle with a diameter of about 1.5 cm.

(Prescription) EV: 0.28 g Isopropyl myristate: 0.28 g Silicone elastomer (Note 1): 4.5 g Silicone oil (Note 2): 0.25 g Curing agent (Note 3): 0.25 g Toluene or ethyl acetate : 2.5 mL Note 1: SLASTIC (registered Trademark) MDX4-4210 Medical grade (Dow Corning Asia) Note 2: 360 medical fliud, 20cs (Dow Corning Asia) Note 3: SLASTIC (registered trademark) MDX4-4210 (Dow Corning Asia)

Is the obtained silicone adhesive patch capable of being covered with an adhesive sheet so that it can be applied to the skin by applying it to a sheet having a skin-compatible adhesive layer on one surface and having a size larger than that of the adhesive patch? Or, by applying the following adhesive to the surface of the silicone patch, it can be attached to the skin. Silicone adhesive: BIO-PSA Q7-4501, BIO-PSA X7-42
01 (Dow Corning Asia): Solid content / solvent = 40:60)

Example 2: 5 W / W% of estradiol-based on the entire silicon-containing patch drug-containing layer
10 as 17β-valerate and transdermal absorption enhancer
A silicone patch containing W / W% isopropyl myristate is produced according to the following composition in the same manner as in Example 1.

(Prescription) EV: 0.29 g Isopropyl myristate: 0.59 g Silicone elastomer: 4.5 g Silicone oil・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ 2.5 mL

The resulting silicone-based patch is attached to a pressure-sensitive adhesive sheet having a skin-compatible pressure-sensitive adhesive layer on one side and larger than the patch, so that it can be covered with the pressure-sensitive adhesive sheet and applied to the skin. Alternatively, the following adhesive is applied to the surface of the silicone patch so that it can be attached to the skin. Adhesive: Acrylic acid-dimethyl siloxane copolymer: B
PK-1, BPK-2 (Wako Pure Chemical Industries)

Example 3: 5 W / W% of estradiol-based on the entire silicon-containing patch drug-containing layer
20 as 17β-valerate and percutaneous absorption enhancer
A silicone patch containing W / W% isopropyl myristate is produced in the same procedure as in Example 1 according to the following composition. For percutaneous absorption experiments, punch out a circle with a diameter of about 1.5 cm (containing about 1 mg of drug).

(Prescription) EV: 0.33 g Isopropyl myristate: 1.33 g Silicone elastomer: 4.5 g Silicone oil・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ 2.5 mL

The obtained silicon-based patch is attached to a pressure-sensitive adhesive sheet having a skin-compatible pressure-sensitive adhesive layer on one side and larger than the patch, so that it can be covered with the pressure-sensitive adhesive sheet and applied to the skin. .

Example 4: 5 W / W% of estradiol-based on the entire silicon-containing patch drug-containing layer
30 as 17β-valerate and transdermal absorption enhancer
A silicone patch containing W / W% isopropyl myristate is produced in the same procedure as in Example 1 according to the following composition.

(Prescription) EV: 0.38 g Isopropyl myristate: 2.31 g Silicone elastomer: 4.5 g Silicone oil・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is attached to a pressure-sensitive adhesive sheet having a skin-compatible pressure-sensitive adhesive layer on one side and larger than the patch, so that it can be covered with the pressure-sensitive adhesive sheet and applied to the skin. .

Example 5: 5 W / W% of estradiol with respect to the entire silicon-containing patch drug-containing layer
40 as 17β-valerate and transdermal absorption promoter
A silicone patch containing W / W% isopropyl myristate is produced in the same procedure as in Example 1 according to the following composition.

(Prescription) EV: 0.45 g Isopropyl myristate: 3.64 g Silicone elastomer: 4.5 g Silicone oil・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is attached to a pressure-sensitive adhesive sheet having a skin-compatible pressure-sensitive adhesive layer on one side and larger than the patch, so that it can be covered with the pressure-sensitive adhesive sheet and applied to the skin. .

Example 6: 5 W / W% of estradiol-based on the entire silicone patch drug-containing layer
10 as 17β-valerate and transdermal absorption enhancer
A silicone-based patch containing W / W% isopropyl myristate, 5 W / W% limonene and 5 W / W% lauryl laurate is prepared according to the following composition. That is, isopropyl myristate, limonene, and lauryl laurate are added to a disposable cup (made of polypropylene) containing estradiol-17β-valerate (EV) and mixed sufficiently. Next, after adding about toluene or ethyl acetate and ultrasonically treating for about 30 seconds to dissolve the drug, silicone oil, silicone elastomer, and curing agent are sequentially added thereto and mixed sufficiently. After degassing the mixture, spread it on a backing liner (Cerafeel # 25) using a doctor knife or a baker applicator (Nippon Applied Technology). About 1
After leaving it at room temperature for 40 hours, it is cured at 40 ° C to prepare a silicone film preparation.

(Prescription) EV: 0.33 g Isopropyl myristate: 0.67 g Limonene: ...・ 0.33 g Lauryl laurate ・ ・ ・ ・ ・ ・ 0.33 g Silicone elastomer ・ ・ ・ ・ ・ ・ 4.5 g Silicone oil ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is applied to the skin by covering it with a sheet having a skin-compatible pressure-sensitive adhesive layer on one side and having a size larger than that of the patch. Alternatively, the following adhesive is applied to the surface of the silicone patch so that it can be attached to the skin. Adhesive: Acrylic acid-dimethyl siloxane copolymer: B
PK-1, BPK-2 (Wako Pure Chemical Industries)

Example 7: 5 W / W% of estradiol-based on the entire silicone-based patch drug-containing layer
10 as 17β-valerate and transdermal absorption enhancer
A silicone patch containing W / W% isopropyl myristate, 5 W / W% limonene and 5 W / W% oleyl laurate is prepared according to the following composition and in the same procedure as in Example 6.

(Prescription) EV: 0.33 g Isopropyl myristate: 0.67 g Limonene: ...・ 0.33 g oleyl laurate ・ ・ ・ ・ ・ ・ ・ 0.33 g Silicone elastomer ・ ・ ・ ・ ・ ・ 4.5 g Silicone oil ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is attached to a sheet having a skin-compatible pressure-sensitive adhesive layer on one surface and larger than the patch, so that it can be covered with the pressure-sensitive adhesive sheet to be applied to the skin. Alternatively, the following adhesive is applied to the surface of the silicone patch so that it can be attached to the skin. Silicone adhesive: BIO-PSA Q7-4501, BIO-PSA X7-42
01 (Dow Corning Asia): Solid content / solvent = 40:60)

Example 8: 5 W / W% of estradiol-based on the whole agent-containing layer of the silicone patch
10 as 17β-valerate and transdermal absorption enhancer
A silicone patch containing W / W% isopropyl myristate, 5 W / W% limonene and 5 W / W% myristyl laurate is prepared according to the following composition and in the same procedure as in Example 6.

(Prescription) EV: 0.33 g Isopropyl myristate: 0.67 g Limonene ::・ 0.33 g Myristyl laurate ・ ・ ・ ・ ・ ・ 0.33 g Silicone elastomer ・ ・ ・ ・ ・ ・ 4.5 g Silicone oil ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・ ・・ ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is attached to a sheet having a skin-compatible pressure-sensitive adhesive layer on one surface and larger than the patch, so that it can be covered with the pressure-sensitive adhesive sheet and attached to the skin. Alternatively, the following adhesive is applied to the surface of the silicone patch so that it can be attached to the skin. Adhesive: Acrylic acid-dimethyl siloxane copolymer: B
PK-1, BPK-2 (Wako Pure Chemical Industries)

Example 9: 5 W / W% of estradiol-based on the entire silicon-containing patch drug-containing layer
10 as 17β-valerate and transdermal absorption enhancer
A silicone patch containing W / W% isopropyl myristate, 10 W / W% limonene and 5 W / W% lauryl laurate is produced according to the following composition and in the same procedure as in Example 6.

(Prescription) EV: 0.36 g Isopropyl myristate: 0.72 g Limonene ::・ 0.72 g Lauryl laurate ・ ・ ・ ・ ・ ・ 0.36 g Silicone elastomer ・ ・ ・ ・ ・ ・ 4.5 g Silicone oil ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is attached to a sheet having a skin-compatible pressure-sensitive adhesive layer on one side and larger than the patch so that it can be covered with the pressure-sensitive adhesive sheet to be applied to the skin. Or, by applying the following adhesive to the surface of the silicone patch, it can be attached to the skin. Adhesive: Acrylic acid-dimethyl siloxane copolymer: B
PK-1, BPK-2 (Wako Pure Chemical Industries)

Example 10: 5 W / W% of estradiol-based on the entire acrylic patch drug-containing layer
30W as 17β-valerate and transdermal absorption enhancer
An acrylic patch containing / W% isopropyl myristate is produced according to the following formulation. That is,
Add isopropyl myristate to a disposable cup (eg polypropylene) containing the drug and mix well. Then add about 1.0 mL of ethyl acetate or toluene and sonicate for about 30 seconds to dissolve the drug,
Add 5.0 g of acrylic adhesive, which is a dispersion base, and mix. Further, 0.15 g of a coagulation accelerator is added and mixed well. After degassing, the mixture is spread on a packing liner (Cerafeel # 25) using a doctor knife or a baker applicator (Nippon Applied Technology) and dried at room temperature. In the percutaneous absorption experiment, this is punched out into a circle having a diameter of about 1.5 cm (a thickness containing about 1 mg of the drug).

(Prescription) Drug: 0.4 g Isopropyl myristate: 2.38 g Acrylic adhesive (Note 4) 5.0 g Aggregation accelerator (* 5) ........ 0.15 g Toluene or ethyl acetate ... 1.0 to 2.0 mL * 4: For example, acrylic copolymer resin, PE-300 (Japan Carbide Industry), solid content / solvent = 40:60. Note 5: For example, CK-401 (Nippon Carbide Industry) is used.

Example 11: 5 W / W% of estradiol-based on the whole drug-containing layer of the acrylic patch
40 as 17β-valerate and transdermal absorption promoter
An acrylic patch containing W / W% isopropyl myristate is produced in the same procedure as in Example 9 according to the following formulation.

(Prescription) Drug: 0.47 g Isopropyl myristate: 3.75 g Acrylic adhesive: 5.0 g Aggregation accelerator: 0.15 g Toluene or ethyl acetate: 1.0 to 2.0 mL

Example 12: 5 W / W% of estradiol-based on the whole silicon-containing patch drug-containing layer
5W as 17β-valerate and percutaneous absorption enhancer
A silicone patch containing / W% isopropyl myristate, 5 W / W% limonene and 5 W / W% myristyl laurate is prepared by the same procedure as in Example 6 according to the following composition.

(Prescription) EV: 0.31 g Isopropyl myristate: 0.31 g Limonene ::・ 0.31 g Myristyl laurate ・ ・ ・ ・ ・ ・ 0.31 g Silicone elastomer ・ ・ ・ ・ ・ ・ 4.5 g Silicone oil ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Curing agent ・ ・ ・ ・・ ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ 2.5 mL

The obtained silicone patch can be applied to the skin by covering it with a sheet having a skin-compatible adhesive layer on one surface and having a size larger than that of the patch,
Alternatively, the following adhesive is applied to the surface of the silicone patch so that it can be attached to the skin. Silicone adhesive: BIO-PSA Q7-4501, BIO-PSA X7-42
01 (Dow Corning Asia): Solid content / solvent = 40:60)

Example 13: 5 W / W% of estradiol-based on the entire silicon-containing patch drug-containing layer
5W as 17β-valerate and percutaneous absorption enhancer
A silicone patch containing / W% isopropyl myristate, 5 W / W% limonene and 5 W / W% lauryl laurate is produced according to the following composition and in the same procedure as in Example 6.

(Prescription) EV: 0.31 g Isopropyl myristate: 0.31 g Limonene ::・ 0.31 g lauryl laurate ・ ・ ・ ・ ・ ・ ・ 0.31 g Silicone elastomer (Note 1) ・ ・ ・ ・ 4.5 g Silicone oil (Note 2) ・ ・ ・ ・ ・ ・ 0.25 g Curing agent (Note 3) ・・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 0.25 g Toluene or ethyl acetate ・ ・ ・ ・ ・ ・ ・ ・ 2.5 mL

The obtained silicone patch is applied to the skin by covering it with a sheet having a skin-compatible pressure-sensitive adhesive layer on one surface and having a size larger than that of the patch. Alternatively, the following adhesive is applied to the surface of the silicone patch so that it can be attached to the skin. Silicone adhesive: BIO-PSA Q7-4501, BIO-PSA X7-42
01 (Dow Corning Asia): Solid content / solvent = 40:60)

[0091]

INDUSTRIAL APPLICABILITY The present invention can greatly improve the efficiency of migration of estradiol from the patch to the living body compared with the conventional method, and thus makes it possible to reduce the surface area of the formulation required for treatment and to miniaturize the formulation. .

[Brief description of drawings]

FIG. 1 is a conceptual side view illustrating the attachment of skin and formulation to one cell of a side-by-side permeation experiment device.

FIG. 2 is a conceptual side view illustrating the attachment of skin and formulation to a Franz diffusion cell.

FIG. 3 is a graph showing cumulative skin permeation amount of a drug from Estraderm TTS (registered trademark) over time.

FIG. 4 is a graph showing the effect of the combined use of isopropyl myristate and limonene on the cumulative skin permeation amount of estradiol from a silicon-based agent.

FIG. 5 is a graph showing the effect of the combined use of isopropyl myristate and vitamin E or cineol on the cumulative skin permeation amount of estradiol from a silicone base.

FIG. 6 is a graph showing the effect of the combined use of isopropyl myristate and geraniol on the cumulative skin permeation amount of estradiol from a silicon-based agent.

FIG. 7: Isopropyl myristate and L versus cumulative skin permeation of estradiol from a silicone-based base
-A graph showing the effect of combined use with lactic acid.

FIG. 8 is a graph showing the effect of the combined use of isopropyl myristate and lauryl laurate on the cumulative skin permeation amount of estradiol from a silicon-based agent.

FIG. 9 is a graph showing the effect of the combined use of isopropyl myristate and octanol or sodium L-lactate on the cumulative skin permeation amount of estradiol from a silicon-based agent.

FIG. 10: Isopropyl myristate, based on cumulative skin permeation of estradiol from a silicone-based agent,
The graph which shows the effect of the combined use of lauryl laurate and limonene.

FIG. 11 is a graph showing the effect of the combined use of lauryl myristate and limonene with lauryl oleate or lauryl myristate on the cumulative skin permeation amount of estradiol from a silicon-based agent.

[Explanation of symbols]

1 = side-by-side diffusion cell, 3 = skin, 5 =
Transdermal patch, 7 = support net, 9 = aluminum sheet, 10 = Franz diffusion cell, 11 = cell cap, 1
2 = receptor, 13 = cell cap holder, 15
= Sampling port

Continued front page    F term (reference) 4C076 AA72 BB31 CC30 CC42 DD34                       DD45N EE10A EE27A FF34                 4C086 AA01 AA02 DA08 MA01 MA05                       MA32 MA63 NA11 NA15 ZA89                       ZC11

Claims (7)

[Claims] 1. A percutaneous absorption patch comprising a support and a drug-containing layer in which a drug and a percutaneous absorption promoter are homogeneously contained in a base matrix, the support being provided on one side of the support, wherein the drug is estradiol. -17β-valeric acid ester, which contains isopropyl myristate in an amount of 5 to 40 W / W% in the drug-containing layer as a percutaneous absorption enhancer, and the drug-containing layer has up to 8 carbon atoms. A transdermal patch, characterized in that it substantially contains neither the aliphatic alcohol nor polyethylene glycol. 2. A percutaneous absorption patch comprising a support, on one side of which a drug-containing layer obtained by homogeneously containing a drug and a transdermal absorption promoter in a base matrix, wherein the drug is estradiol. -17β-valeric acid ester, which contains isopropyl myristate in an amount of 5 to 20 W / W% in the drug-containing layer as a percutaneous absorption enhancer, and further as a percutaneous absorption enhancer (a ) 1-10 W / W% limonene and (b) 1-10 W / W% lauryl laurate, oleyl laurate, myristyl laurate, lauryl oleate or lauryl myristate. , Transdermal patch. 3. The percutaneous absorption patch according to claim 1, wherein the base comprises a silicone elastomer or an acrylic adhesive. 4. The base is made of a silicone elastomer,
The percutaneous absorption patch according to claim 3, wherein the base contains 2 to 8% of silicone oil. 5. The transdermal patch according to any one of claims 1 to 4, further comprising an adhesive layer provided on the surface of the drug-containing layer that comes into contact with the skin surface. 6. A support holding the drug-containing layer has a portion extending beyond the periphery of the drug-containing layer, and an adhesive layer is provided on the surface of the drug-containing layer side of the portion. The percutaneous absorption patch according to any one of claims 1 to 5, further characterized by: 7. The drug-containing layer comprises 2 to 20 W / W of estradiol-17β-valerate in the drug-containing layer.
The percutaneous absorption patch according to any one of claims 1 to 6, characterized in that it is contained in an amount of%.