WO2000025792A1

WO2000025792A1 - Estradiol-containing adhesive preparation

Info

Publication number: WO2000025792A1
Application number: PCT/JP1999/005920
Authority: WO
Inventors: Miyuki Shinmura; Yasuhiro Ikeura
Original assignee: Hisamitsu Pharmaceutical Co., Inc.
Priority date: 1998-10-29
Filing date: 1999-10-26
Publication date: 2000-05-11
Also published as: JP2000136128A; AU6230799A

Abstract

An estradiol-containing adhesive preparation characterized in that 10 to 32% of the estradiol is released in 3 hours upon immersion in water at a temperature of 32±0.5 °C. The preparation preferably contains a thermoplastic elastomer, a tackifier, and a softener and/or an absorption accelerator. The elastomer preferably comprises a styrene/isoprene/styrene block copolymer and polyisobutylene. The preparation preferably comprises 0.5 to 3 wt.% estradiol, 15 to 24 wt.% styrene/isoprene/styrene block copolymer, 5.1 to 25 wt.% polyisobutylene, 26 to 40 wt.% tackifier, and 15 to 30 wt.% softener and/or 0.5 to 8 wt.% absorption accelerator.

Description

Specification

Patch containing estradiol

Technical field

TECHNICAL FIELD The present invention relates to an estradiol-containing patch having excellent drug release rate and adhesiveness to human skin, which is useful for treatment of menopause or ovarian deficiency.

Background art

Estrogen replacement therapy, Kampo therapy, psychotropic medication, coping therapy, etc. are being used as treatments for women's menopause or menstrual disorders, but recently estrogen replacement therapy has been actively used . This estrogen replacement therapy is a treatment that aims to correct the physical and psychological fluctuations specific to menopause by regulating sudden changes in the hormonal environment during menopause due to estrogen decline. .

Estrogen replacement therapy can improve menopausal symptoms based on estrogen deficiency in the short term, and coronary artery disease and osteoporosis due to its effects on lipid metabolism and bone metabolism in the long term. The preventive effect is obtained. As a result, estrogen replacement therapy has become a popular disease treatment. Among the estrogens produced and secreted from the ovaries, the most bioactive is estradiol (17-estradiol), but the first pass through the liver after oral administration of natural estrogen In effect, most are metabolized to estrone and its conjugates. Therefore, it is known that administration of a considerably high dose is necessary to obtain a sufficient therapeutic effect, which increases the burden on the liver and affects protein synthesis and the like. The present applicant previously described in International Publication No.WO 91/17752 that the water absorption Patch for the purpose of mitigating side effects such as redness and rash by blending liposome as an essential component. In Japanese Patent Application Laid-Open No. 5-148145, polyethylene glycol, fatty acid ester and water absorption are disclosed. We have proposed a patch that uses a polymer as an essential component and reduces stuffiness due to sweating during application, redness due to drug stimulation, and touch.

However, since the above prior art uses a water-absorbing polymer for the purpose of mitigating side effects, if it is applied to the skin for a long time, the skin will be in a completely sealed state, and sweat released from the skin Absorbs all the water, reduces adhesive strength, and easily peels off. Therefore, there is a problem in maintaining the patch over a long period of time, and furthermore, a fixed amount cannot be released from the base over a long period of time, and the original advantage of the patch, which is absorbed through the skin, cannot be utilized. Had.

Disclosure of the invention

The inventors of the present invention have conducted studies to solve the above problems, and as a result, have determined the release rate of estradiol by using a specific base component and by using a specific proportion of the base component. The present inventors have found that it is possible to obtain a patch which can be controlled within the above range and can maintain the adhesive force for a long time, and completed the present invention.

That is, the present invention provides an estradiol-containing patch characterized in that the release rate of estradiol after 3 hours at a water temperature of 32 ± 0.5 ° C. is in the range of 10 to 32%.

The above-mentioned estradiol-containing patch characterized by containing an estradiol, a thermoplastic elastic body, a tackifier, a softener and / or an absorption promoter,

Thermoplastic elastomer is styrene-soprene-styrene block copolymer O 00/25792

And the above-mentioned estradiol-containing patch, which is polysobutylene,

Estradiol from 0.5 to 3 wt ^_0/0, styrene one Isopuren one Suchirenbu locking copolymer 1 5-2 4 wt. / _0, Poryisobuchiren 5.1 to 2 5 weight ^_0/0, tackifier 2 6-4 0 weight. /. And 15 to 30% by weight of a softener and / or 0.5 to 8% by weight of an absorption enhancer. / ₀ containing the above-mentioned estradiol-containing patch, and

The above-mentioned estradiol-containing patch, wherein the adhesive strength after 24 hours from the application is 90% or more of the adhesive strength after 12 hours from the application.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The estradiol-containing patch of the present invention preferably contains estradiol, a thermoplastic elastomer, a tackifier, a softener and / or an absorption promoter.

The estradiol used as a medicinal ingredient in the patch of the present invention is a substance commonly called Estra-11,3,5 (10) trien-13,17 / 3 diol.

The amount of estradiol is 0.5 to 3 times the total amount of the base including the active ingredient. / ₀ is preferable. If the amount is less than 0.5% by weight, a sufficient therapeutic effect cannot be expected, and if it exceeds 3% by weight, the therapeutic effect does not change, leading to a high cost.

The thermoplastic elastic body used as a base component in the patch of the present invention is not particularly limited, but, for example, styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS base) , Polyisobutylene and the like can be suitably used.

Examples of the SIS base include SIS base manufactured by Shell Chemical Company (trade name: Kariflex TR-111, Kariflex TR-111), SIS base manufactured by Nippon Synthetic Rubber Co., Ltd. (trade names: JSR500, JSR510), SIS manufactured by Zeon Japan One or more base materials (trade name: Quintac 3421) can be appropriately selected and used. The amount of the SIS base compounded is 15 to 24% by weight based on the total amount of the base including the active ingredient. Re, preferably with / ₀ . When the amount is less than 15% by weight, the cohesive strength becomes insufficient, and the weight is 24%. If the ratio exceeds / ₀ , the flexibility of the preparation is poor, and there is a problem in adhesion.

The SIS base can be used alone, but is preferably used in combination with polyisobutylene. The polyisobutylene is not particularly limited. For example, polyisobutylene manufactured by Nippon Petrochemical Co., Ltd. (trade name: TETRA X3T, 4T, 5T, 6T, HIMOL4H, 5Η, 5.5Η, 6Η) ), ポリ Polysobutylene manufactured by ASF (trade name: 〇 ppanol B 10, 12, 12 SF, 15, 15 SF, 30 SF, 50, 50 SF, 80, 100, 120, 1 50, 200), exison polystyrene (VIST AN EX LM—MS, LM—MH, LM—H, MM L—80, MM L—100, MM L—120, MM L—14 0) One or two or more types can be appropriately selected and used from isostatic strength.

When polyisobutylene is used, the compounding amount is 5.:! ~ 25 weight. / ₀ , preferably 10 to 20 weight. / ₀ is more preferable. By blending Poryisobuchiren within the 5.1 to 2 5 weight ^_0/0 to SIS base, it is possible to prevent cohesion in the store lifting of the pressure-sensitive adhesive (sagging, tongue out).

In addition, polyisobutylene means low molecular weight to high molecular weight polyisobutylene of various molecular weights, and the case where two or more kinds of polyisobutylenes having different molecular weights are mixed and used is also included.

The tackifier used as a base component in the patch of the present invention is not particularly limited. For example, an alicyclic saturated hydrocarbon resin (for example, trade name: Alcon P-100, etc .: manufactured by Arakawa Chemical Co., Ltd., rosin ester (for example, trade name: KE-311, KE-100: manufactured by Arakawa Chemical Co., Ltd.), hydrogenated rosin ester (for example, trade name: Foral 105, etc .: manufactured by Hercules Co., Ltd., hydrogen alicyclic hydrocarbons (for example, trade name: Escolets 5300, etc .: manufactured by Exxon), polyterpene resin, petroleum resin, phenol resin, etc. Alternatively, two or more kinds can be appropriately selected and used.

The amount of the tackifier is preferably 26 to 40% by weight based on the total weight of the base containing the medicinal ingredient, in consideration of the balance between adhesive force, skin damage and skin irritation. If the amount is less than 26% by weight, sufficient adhesive strength cannot be maintained, and the weight is 40% by weight. If the ratio exceeds / ₀ , the adhesive strength becomes too strong, and skin damage and skin irritation tend to occur.

The softening agent used as a base component of the patch of the present invention is not particularly limited, and one or more of liquid paraffin, polybutene, liquid polyisobutylene, animal and vegetable oils and the like can be appropriately selected and used. . Among them, liquid paraffin is particularly preferred because of its good compatibility with the SIS base.

The compounding amount of the softener is 15 to 30% by weight based on the total amount of the base including the active ingredient. / ₀ is preferable. 15 weight. If the ratio is less than / ₀ , the flexibility of the pressure-sensitive adhesive becomes poor, and the pressure-sensitive adhesiveness also decreases. Also 30 weight. If the ratio exceeds / ₀ , the pressure-sensitive adhesive becomes soft and generates cohesive force, which is not preferable.

The absorption enhancer used as a base component in the patch of the present invention is not particularly limited, and one or more of clotamiton, L-menthol, heart oil, pyrothiodecane and the like are used. Can be selected and used at appropriate times. Among these, crotamiton and pyrothiodecane are preferred.

When the absorption enhancer is used, its compounding amount is 0.5 to 8% by weight based on the total amount of the base including the active ingredient. / ₀ is preferable. 0.5 sufficient absorption promoting effect of weight ^_0/0 less than when it comes to E be sampled radio Ichiru can not be obtained. Also, more than 8% by weight However, no further absorption promoting effect can be expected, and it is not preferable because it has an effect on a decrease in the adhesive strength of the base or a dripping of the plaster.

In addition, either one of the above-mentioned softener and absorption enhancer may be used, or both may be used in combination.

It is preferable to add an antioxidant to the patch containing the radioactive ingredient of the present invention in addition to the above essential components in order to improve the stability of the preparation. As the antioxidant, butylhydroxytoluene and the like are preferable, and the compounding amount is 2% by weight in the total base containing the active ingredient. / ₀ or less is preferable. In addition, as an optional ingredient, a known filler or other usable additives, or a medicinal ingredient other than estradiol, and the like can be appropriately compounded in an appropriate amount.

The support in the patch of the present invention is desirably one that does not affect the release of the drug and has excellent flexibility, and is a non-stretchable or stretchable polyester, polypropylene, polyethylene, polyethylene terephthalate, or vinyl acetate. Films or woven fabrics and composites thereof can be used. Among them, a polyethylene terephthalate film having a breaking strength (longitudinal direction) of ZSSS kgf Z mm ² and a modulus of 2 <½ (longitudinal direction) of 7.5 to 9.5 kg ί Zm m ² alone is used. It is preferable to use a force to be used or a force obtained by combining the force with a flexible film.

Next, the method for producing the estradiol-containing patch of the present invention is not particularly limited, and it can be produced by any known production method. Hereinafter, a preferred production example of 1 will be described.

After heating and dissolving the base components consisting of SIS base and / or polyisobutylene, tackifier and softener, or dissolving these base components in inexpensive dissolving agents such as toluene and hexane, estradiol, Add oxidizing agent and mix evenly. Next, this is applied to a support, covered with a liner and cut into a desired shape to obtain a product, or applied to a film that has been subjected to a peeling treatment, and then transferred to a suitable support by pressure bonding. , Good as a product. In the drug release test described below, the patch of the present invention has a release rate after 3 hours at a water temperature of 32 soils and 0.5 ° C in the range of 10 to 32% of the total content of the drug. The range of 8 to 30% is more preferable. 10 hours after 3 hours. If it is less than / ₀ , stable pharmacological effects cannot be expected, and if it exceeds 32%, it will be released in a short period of time, making it impossible to expect a constant drug supply for a long time. Further, the patch of the present invention can be stuck to human skin for a long period of time and is not easily peeled off, so that a certain amount of drug can be reliably supplied.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples. The numerical values in the examples, comparative examples, test examples, unless otherwise specified, also of the means "weight. / ₀ '.

(Production method of patch containing estradiol)

After heating and dissolving the SIS base and the base components consisting of "or polyisobutylene, a tackifier and a softener, or dissolving these base components in a dissolving agent such as toluene or hexane, Add the absorption enhancer (crotamitone) and mix it evenly After plastering the support, cover it with a liner and cut it into the desired shape to obtain the product. Either one or both may be used.

(Example 1)

SIS base 1 7.0 Polyisobutylene 1 4.9 Alicyclic saturated hydrocarbon resin (trade name: Alcon P-100) 3 5.0 Liquid paraffin 3 0.0 Butylhydroxytoluene 0.1 Estradiol 3.0

With this prescription, based on the above-mentioned patch production method, To obtain a patch containing the same.

(Example 2)

S I S Group II 24.0 Polyisobutylene 1 1.0 Alicyclic saturated hydrocarbon resin (trade name: Alcon P—100) 3 3.0 Liquid paraffin 2 5.0 Crotamiton 5.0 Estradiol 2.0

With this formulation, an ester-radiol-containing patch was obtained based on the above-mentioned patch production method.

(Example 3)

SIS base 20.0 Polyisobutylene 15.0 Hydrogenated rosin glycerin ester 26.0 Liquid paraffin 30.0 Butyl hydroxytoluene 0.5 Crotamiton 8.0 Estradiol 0.5 With this formula, ester radiol based on the above patch manufacturing method An adhesive patch was obtained.

(Example 4)

SIS base 1 5.0 Polyisobutylene 2 5.0 Rosin ester (trade name: KE _ 3 1 1) 4 0.0 Liquid paraffin 1 5.0 Butylhydroxytoluene 0.3 Pyrothiodecane 2.7 Estradiol 2.0 With this formula, an ester-containing patch was obtained based on the above-mentioned patch production method.

(Example 5)

SIS base 1 7.0 Polyisobutylene 1 4.0 Hydrogen alicyclic hydrocarbon (trade name: Escolets 5300) 3 5.0 Liquid paraffin 2 7.0 Butyl hydroxytoluene 1.5 Crotamiton 4.5 Estragio monol 1.0 1.0 An estradiol-containing patch was obtained based on the preparation method of the preparation.

(Example 6)

SIS base 20.5 Polyisobutylene 5.5 Hydrogenated rosin ester (trade name: Foral 105) 37.5 Liquid paraffin 29.0 Butyl hydroxytoluene 1.0 Crotamiton 6.0 Estradiol 0 · 5 This formulation can be used to make the above-mentioned patch preparation process. Based on this, an estradiol-containing patch was obtained.

(Example 7)

SIS base 20.5 Polyisobutylene 1 3.0 Mouth gin ester (Product name: KE—100) 3 6.0 0 Liquid paraffin 2 2.5 butylhydroxytoluene 2.0 crotamiton 5.0 estrazinolone 1.0 With this formulation, an estradiol-containing patch was obtained based on the above-mentioned patch production method.

(Example 8)

SIS base 24.0 Polyisobutylene 1 1.0 Alicyclic saturated hydrocarbon resin (trade name: Alcon P—100) 3 3.0 Liquid paraffin 26.0 Crotamiton 5.0 Estradiol 1.0

With this prescription, an esterradiol-containing patch was obtained based on the above-mentioned patch production method.

(Example 9)

SIS base 24.5 Polyisobutylene 5.0 Liquid paraffin 3 7.5 Butynolexydroxytoluene 2.0 Crotamiton 5.0 Rosin ester (trade name: KE—311) 2 5.0 Estradione 1.0 On the basis of the above, a patch containing estradio and toluene was obtained.

(Comparative Example 1)

SIS base 2 2.0 Polyisobutylene 5.0 Rosin ester (trade name: KE—311) 2 5.0 Liquid paraffin 3 5.0 butylhydroxytoluene 2.0 crotamiton 5.0 Water-absorbing polymer (trade name: Sunwet IM_1000 MPS) 5.0 Estradiol 1.0 As a result, an estradiol-containing patch was obtained based on the above-mentioned method for producing a patch.

The contents of polyisobutylene (thermoplastic elastomer), rosin ester (tackifier) and liquid paraffin (softener) in this comparative example were outside the above-mentioned preferred ranges, and the water temperature was 32 ° C and 0.5 ° C. The estradiol release rate after 3 hours was less than 10% (Test Example 1 below). In addition, the adhesive strength 24 hours after application relative to the adhesive force 12 hours after application was less than 90% (Test Example 2 below).

(Comparative Example 2)

SIS base 2 2.0 Polyisobutylene 5.0 Liquid paraffin 3 2.0 Polyethylene glycol 300 3.0 Ethyl oleate 7.0 Water-absorbing polymer (trade name: Sunwet IM-1000 MPS) 5.0 mouth gin ester (trade name: KE-3 1 1) 2 5.0 Estradiol 1.0 With this formulation, an estradiol-containing patch was obtained based on the above-mentioned patch production method.

The polyisobutylene (thermoplastic elastomer) and the fluid The contents of raffin (softener) and rosin ester (tackifier) are out of the preferred ranges described above, and the release rate of Estradiol after 3 hours at a water temperature of 32 ± 0.5 ° C is 10%. % (Test Example 1 below). In addition, the adhesive strength 24 hours after application relative to the adhesive force 12 hours after application was less than 90% (Test Example 2 below).

(Test Example 1: Release test)

Each of the patches containing the estradiol obtained in Examples 4, 5, 7 to 9 and Comparative Examples 1 to ² was adjusted to have a release area of 10 cm2 and used as a sample. A release test was performed.

·Test method

Fix the support side of each sample to the center of the rotating cylinder with silicone adhesive, and peel off the liner. Using 900 ml of degassed water as the test liquid, maintain the water temperature (liquid temperature) at 32 ± 0.5 ° C, and set the distance between the lower end of the cylinder and the inside of the container bottom to 1 2 ± 2 mm Perform the test according to the following dissolution test at 50 rpm.

Three hours after the start of the test, take 10 mm of the test solution from a position at least 10 mm away from the container wall in the middle of the cylinder and use it as the sample solution. After collection, immediately add 10 ml of water heated to 0.5 ° C to the test solution. Separately, accurately weigh about 0.02 g of the estradiol standard, add ethanol (99.5) to dissolve it to make 50 ml, and add water to 5 ml of this liquid to make 100 ml. . Water is added to 2 ml of this solution to make 50 ml, and used as a standard solution. Perform a test with 50 μL of the sample solution and standard solution by liquid chromatography under the following conditions.

• Operating conditions

Detector: Fluorometer

Column: Stainless steel tube filled with 5 to 10 / m octadecyl silylated silyl gel for liquid chromatography 3 Column temperature: constant temperature around 40 ° C

Mobile phase: water mixed with Z-acetonitrile (11: 9)

Liquid volume: Adjust so that the retention time of estradiol is about 1 minute. Column selection: Weigh about 0.02 g of estradiol and dissolve in ethanol (99.5) to make 50 ml. Add water to 5 ml of the solution to make 100 ml. Also, about 0.028 g of naphthalene is dissolved in ethanol (99. 5) to make 50 ml, and water is added to 10 ml of this solution to make 100 ml. Water is added to 2 ml each of these solutions to bring the total volume to 50 ml. When this liquid 50 / L is operated under the above conditions, estradiol and naphthalene are dissolved in this order.

The estradiol release rate (./.) After 3 hours is calculated by the following formula.

Release rate of estradiol after 3 h _{(%) = W S X (} H T3 / H S) X 5 above formulas, W _s denotes estradiol standard collection fee (mg),

H _{T 3} represents the peak height of the sample solution after 3 hours, H _s represents the height of the standard solution peak.

The results of the release test after 3 hours are shown in Table 1 below.

Table 1 Example Release rate Example 4 2 1.9%

Example 5 3 2.0%

Example 7 2 6.3%

Example 8 24.2%

Example 9 1 0.1%

Comparative Example 1 8.2% Comparative Example 2 9.1% As is clear from the results shown in Table 1, the release rate of the patches of the present invention (Examples 4, 5, 7 to 9) was much higher than that of Comparative Examples 1 and 2. High, 10 ~ 32. /. It was within the range.

(Test Example 2: Adhesion test)

Each of the patches obtained in Examples 6 to 9 and Comparative Examples 1 and 2 was applied to human skin for 12 hours and 24 hours, and then tested for adhesive strength with respect to each application time. The adhesive strength after 12 hours is 100%, and the adhesive strength after 24 hours is shown. /. Indicated by The adhesive strength test was performed according to the method described below.

• Adhesion test method

The experiment was performed using a digital panel only (digital force gauge). Each patch was cut into small pieces of 2 cm × 2 cm and attached to human forearm skin. At 12 hours and 24 hours after application, the edge of the patch was sandwiched between digitally connected clips and fixed. The digital panel alone was raised at a constant speed, and the patch was kept at 90 ° against human skin so as not to be peeled off for a certain period of time, then peeled off, and the force at that time was measured. The results are shown in Table 2 below.

Table 2 Example 1 Adhesive force after 2 hours (%) 24 Adhesive force after 4 hours (%) Example 6 16 5 (100) 1 49 (90)

Example 7 1 7 5 (1 0 0) 1 7 0 (97)

Example 8 1 7 0 (1 0 0) 1 6 4 (9 6)

Example 9 1 6 8 (1 0 0) 1 6 3 (97) Comparative Example 1 1 20 (100) 78 (65)

Comparative Example 2 1 1 2 (100) 6 2 (55) As is clear from the results shown in Table 2, the adhesive preparations of the present invention (Examples 6 to 9) had an adhesive force after 24 hours, It was 90% or more of the adhesive strength after 12 hours, and the adhesive strength was extremely high as compared with the patches of Comparative Examples 1 and 2.

Industrial applicability

The patch containing the estradiol of the present invention can maintain a sufficient adhesive force even after pasting for a long time, and is excellent in controlling the release of a drug from a base. When the patch containing the estradiol of the present invention is used, the estradiol is surely transdermally absorbed from the skin and a constant drug concentration in serum can be maintained for a certain time. Therefore, the patch containing the estradiol of the present invention is expected to be used as a patch for medical use for treatment of climacteric disorders in women.

Claims

The scope of the claims

1. An estradiol-containing patch characterized in that the estradiol release rate after 3 hours at a water temperature of 32 ± 0.5 ° C is in the range of 10 to 32%.

2. The patch containing estradiol according to claim 1, wherein the patch contains estradiol, a thermoplastic elastomer, a tackifier, a softener and / or an absorption promoter.

3. The patch according to claim 2, wherein the thermoplastic elastomer is a styrene-isoprene-styrene block copolymer and polyisobutylene.

4. E scan Torajio one Honoré 0.5 to 3 wt ^_0/0, styrene unique Sopurensuchire down the block copolymer 1 5-2 4 wt. /. , Polyisobutylene 5.1 to 25 weight. /. The tackifier 26-40 weight. /. As well as a softener 15 to 30 weight. /. The estradiol-containing patch according to any one of claims 1 to 3, wherein the patch contains 0.5 to 8% by weight of an absorption promoter.

5. The storage tray according to any one of claims 1 to 4, wherein the adhesive strength 24 hours after the application is 90% or more of the adhesive strength 12 hours after the application. All-containing patch.