JP4167750B2 - Transdermal absorption base and percutaneous absorption preparation containing the base - Google Patents

Description

【００４３】
試験例２．性状の確認
実施例３及び比較例２、４の各試験片を５０゜Ｃ・３ヶ月間保存し各試験片の外観及び性状を観察した。その結果を表２に示す。実施例３には基剤の流れだしは認められなかったが比較例２、４では基剤の流れだしが認められた。
【００４４】
【表２】

【００４５】
試験例３．皮膚透過試験
実施例３及び比較例２，３の試験片につきＦｒａｎｚ型拡散セルを用いてヘアレスマウス（６週齢、雌）背部皮膚透過試験（温度３７゜Ｃ）を行った。試験開始後所要時間ごとにレセプター液を採取しその直後にレセプター液を補充し採取レセプター液への薬物の透過量を高速液体クロマトグラフ法により測定した。各試験片のサンプル数はそれぞれ３個づつとした。結果を図１，２に示す。実施例３は及び比較例２、３に比較して良好な薬物透過性を示した。
【００４６】
試験例４．放出試験
実施例３及び比較例１、６の試験片につき放出試験を回転シリンダー法により行った。試験条件としては試験液900ml、試験液温度32.0±0.5゜C、シリンダー回転数50rpmで行った。結果を図３，４に示す。比較例１、６の試 験片に対し実施例３では良好な薬効成分の放出が得られた。
【００４７】
試験例５．付着性試験
実施例１、２、３の試験片と比較例４、５の試験片につき下記の手法により付着性試験を行った。１０人の被験者（健常人、男性）の上腕部に試験片を貼り２４時間貼付した後付着性を評価した。その結果を表３に示す。比較例では１／２以上剥離がほとんどにみられたが実施例では剥離なしがほとんどであった。
【００４８】
【表３】

【００４９】
【発明の効果】
本発明によれば、基剤成分としてスチレン−イソプレン−スチレンブロック共重合体、軟化剤、粘着付与樹脂及びヘキシレングリコールを使用することにより良好な凝集力、物性の安定化、さらに薬物の溶解性及び安定性、皮膚透過性を良好にした経皮吸収用基剤及びそれを用いた経皮吸収製剤を提供することができる。
【図面の簡単な説明】
【図１】図１は、実施例３、比較例２及び比較例３の製剤について、ヘアレスマウス皮膚透過試験によるエストラジオール（Ｅ₂）の皮膚透過性を示したものである。
【図２】図２は、実施例３、比較例２及び比較例３の製剤について、ヘアレスマウス皮膚透過試験、酢酸ノルエチステロン（ＮＥＴＡ）の皮膚透過性を示したものである。
【図３】図３は、実施例３、比較例１及び比較例６の製剤について、エストラジオール（Ｅ₂）の放出試験の結果を示したものである。
【図４】図４は、実施例３、比較例１及び比較例６の製剤について、酢酸ノルエチステロン（ＮＥＴＡ）の放出試験の結果を示したものである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to the field of transdermal drug treatment, and uses styrene-isoprene-styrene block copolymer, softener, tackifying resin, and hexylene glycol as a base component, The present invention relates to a percutaneous absorption preparation having good skin permeability, characterized in that a predetermined amount of drug can be accurately and reliably applied to a patient.
[0002]
[Prior art]
Estradiol contained in the follicular hormone is secreted from the ovary during female reproductive periods. Therefore, women before and after menopause mainly suffer from deficiency of estradiol, resulting in symptoms such as menopause and menstrual abnormalities. In order to improve these symptoms, therapies such as oral administration are currently being carried out, but they are rapidly metabolized and inactivated by gastrointestinal and other digestive tracts and liver, etc., so that sufficient efficacy can be expected. You must take a high dose of estradiol. In addition, because of the high dose, there is a risk that side effects and the like will increase.
Therefore, attempts have been made to reduce the metabolism of estradiol by transdermal administration and reach the blood for treatment. On the other hand, studies are being made to absorb side effects of estradiol administration by absorbing other hormones, lutein hormone, through the skin. JP-A-4-342532 proposes a transdermally absorbable preparation mainly composed of an acrylic adhesive composed of 2-ethylhexyl acrylate and N-vinyl-2-pyrrolidone as an adhesive with estradiol and luteinizing hormone as medicinal ingredients. Has been. However, acrylic pressure-sensitive adhesives have low drug releasability, strong skin irritation, and cannot withstand long-term continuous administration.
[0003]
Japanese Patent Publication No. 6-51623 discloses a medicinal ingredient, estradiol and norethisterone acetate, dissolved in a gel composed of hydroxypropylcellulose and ethanol. This is a reservoir type, and the permeability control membrane controls the release of the medicinal ingredient. A method has been proposed. However, ethanol has a problem of side effects such as strong skin irritation and redness occurring frequently at the site of application. On the other hand, International Publication WO91 / 17752 and JP-A-5-148145 propose a transdermal absorption patch comprising a styrene-isoprene-styrene block copolymer using crotamiton as a solubilizer. However, when crotamiton is used as a solubilizer, the styrene-isoprene-styrene block copolymer itself is dissolved in crotamiton and there is a problem in stability such that the expected cohesive force cannot be obtained.
[0004]
Hexylene glycol (generic name; chemical name is 2-methyl-2,4-pentanediol) is usually a moisturizer, solvent, industrial cleaning agent, hydraulic fluid, leather fiber and other softeners and softeners, ink agents, Used for photographic agents. JP-A-7-109220 and JP-A-8-53338 propose external preparations using hexylene glycol as an antibacterial agent.
[0005]
In addition, an external preparation using hexylene glycol as an absorption accelerator is proposed in International Publication No. WO96 / 19976 and JP-A-7-138153. However, hexylene glycol is highly compatible with the acrylic base and it is necessary to add a large amount of hexylene glycol in order to obtain a sufficient absorption promoting effect. Further, there are problems such as a decrease in adhesion due to a large amount of hexylene glycol and an influence on the basic physical properties of the preparation.
[0006]
[Problems to be solved by the invention]
In view of the above problems, the present inventors have
1) Improvement of solubility and stability of medicinal ingredients
2) Improvement of skin permeability of medicinal ingredients
3) Low skin irritation
4) Stabilization of base physical properties
As a result of intensive studies aimed at providing a percutaneously absorbable preparation or base that achieves the above, the present invention has been completed.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors have successfully used styrene-isoprene-styrene block copolymer, softener, tackifying resin and hexylene glycol as a base component. The present inventors have found that a base for percutaneous absorption having good cohesive force, stabilization of physical properties, drug solubility and stability, and skin permeability can be obtained.
[0008]
The present invention contains a styrene-isoprene-styrene block copolymer, a softener, a tackifier resin, and an amount of hexylene glycol sufficient to dissolve the drug or to dissolve the drug. It is related with the base for percutaneous absorption obtained.
The present invention also relates to a transdermal preparation containing a drug and a transdermal absorption base.
More specifically, the present invention provides a base for a transdermal patch comprising a styrene-isoprene-styrene block copolymer, a softener, a tackifier resin, and hexylene glycol as a base component, and The present invention relates to a transdermal absorption patch comprising the percutaneous absorption base and a drug.
After applying the transdermal absorption patch of the present invention to the patient's skin, a therapeutically effective amount of the drug can be accurately and reliably released, and the present invention provides a transdermal absorption patch. It is in.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The drug as an active ingredient of the transdermally absorbable preparation of the present invention must be a physiologically active substance and have transdermal absorbability. Alternatively, it may be a so-called prodrug that exhibits physiological activity after percutaneous absorption. Alternatively, it may be a pharmaceutically acceptable inorganic or organic addition salt.
The drug for the transdermally absorbable preparation of the present invention preferably includes female hormones such as follicular hormone and luteinizing hormone derivatives thereof. For example, as an active ingredient, estradiol, estrone, estriol, echrin, echilenin or a derivative thereof may be mentioned as follicular hormone, but preferably estradiol is mainly used in the transdermally absorbable preparation of the present invention. Progesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate, didrogesterone, chlormadinone acetate, etisterone, dimethisterone, norethisterone, norethisterone acetate, norethisterone enanthate, etinodiol acetate, megestrol acetate, or allylestrenol Preferably, norethisterone acetate is mainly used for the transdermally absorbable preparation of the present invention.
[0010]
Other effective drugs for the transdermally absorbable preparation of the present invention include, for example, antiemetics (eg, granisetron, azasetron, ondansetron, ramosetron, etc.), frequent urine treatment agents (eg, oxybutynin, etc.), angiotensin I converting enzyme inhibitors (Eg: captopril, delapril), Ca antagonist (eg: nifedipine etc.), coronary vasodilator (eg: diltiazem, nicorandil etc.), local anesthetic (eg: lidocaine, procaine etc.), thymic hormone (eg: serum thymus) Factor), muscle relaxants (eg, tizanidine, eperisone, dantrolene, etc.), stimulant stimulants, antihypertensives (eg, alprenolol, nifedipine, etc.), antitumor agents, psychotropic drugs (eg, imipyramine, fentanyl, morphine, etc.) ), Antibiotics, antiparkinsonian agents (eg amantadine, levodopa, etc.), antihistamines, anti-vertigo (Examples: diphenidol, betahistine, etc.), hypnotic sedatives, anti-inflammatory analgesics (eg, indomethacin, ketoprofen, diclofenac, ibuprofen, flurbiprofen, felbinac, ketorolac, etc.) Autonomic nerve agents, cardio / vascular system drugs (eg: Benzothiazepine, etc.), antitussive expectorant (eg, ketotifen, tulobuterol, tranilast, etc.), cerebral circulation metabolism improvers (eg, vinpocetine, etc.), vitamins, polypeptide hormones (routingizing hormone-releasing hormone) ), Peripheral vasodilators, immunomodulators (eg, polysaccharides, auranofin, lobenzarit, etc.), diuretics (eg, ursodeoxycholic acid, etc.), diuretics (eg, : Hydroflumethiazide, etc.), antidiabetic agents (eg, tolub) And other drugs such as colchicine can be used, and the amount effective for treatment is preferably 0.1 to 10% by weight based on the drug, although it varies depending on the purpose of combination. Used. In addition, these drugs can be used in combination of two or more as required when no inconvenience due to interaction occurs.
[0011]
The combination of styrene-isoprene-styrene block copolymer, softener, tackifying resin, and hexylene glycol in the transdermal absorption base agent of the present invention is a combination of a large amount of drugs that cannot be considered with conventional rubber bases. In addition, a high drug release that cannot be obtained with acrylic alone can be obtained.
Moreover, since hexylene glycol can be used in a range in which the base component, particularly the styrene-isoprene-styrene block copolymer, does not substantially dissolve or does not substantially dissolve, it has good cohesive strength. Stability can be obtained.
[0012]
The content of these components with respect to the total amount of the preparation is as follows.
The styrene-isoprene-styrene block copolymer is 10 to 30% by weight, preferably 13 to 27% by weight, more preferably 15 to 25% by weight, the softener is 10 to 60% by weight, preferably 12 to 55% by weight, More preferably, it is 15 to 50% by weight, and the tackifier resin is 20 to 60% by weight, preferably 23 to 57% by weight, and more preferably 25 to 50% by weight. A combination in this range has the effect of the present invention.
When the styrene-isoprene-styrene block copolymer is less than the above range, the cohesive force becomes insufficient, and when it is more than the above range, the flexibility of the preparation is low and the adhesiveness is problematic. If the amount of the softener is less than the above range, the formulation is less flexible and causes a problem in adhesion. If the amount is more than the above range, the flexibility increases, but there is a problem in the cohesion of the formulation. The tackifying resin has appropriate tackiness and compatibility with hexylene glycol within the above range. If the tackifying resin is outside the above range, sufficient blending of hexylene glycol and sufficient absorption promoting effect by hexylene glycol cannot be obtained.
[0013]
Although hexylene glycol, which is a component of the present invention, is known to be used as a moisturizing agent and antibacterial agent as a cosmetic raw material, in the present invention, a sufficient amount as an absorption promoter and / or a solubilizing agent for medicinal ingredients is used. It is necessary to mix | blend, The compounding quantity is 1 to 10 weight%, Preferably it is 1.5 to 8 weight%, More preferably, it is 2 to 7 weight%. If the blending amount is 1% by weight or less, the stability of the base properties, the solubility of the medicinal components and the effect of promoting absorption are insufficient, and if it is 10% by weight or more, bleeding due to hexylene glycol occurs.
[0014]
The hexylene glycol blended in the percutaneous absorption base of the present invention can be used in combination with other absorption enhancers and / or solubilizers, but cannot be used in combination with other absorption enhancers or solubilizers. It is preferable to use hexylene glycol alone.
The transdermally absorbable preparation of the present invention is preferably a patch, and the transdermally absorbable patch of the present invention is provided with a drug-containing layer comprising a drug and a transdermally absorbable base material as a substantially single layer on a support. This is sufficient, but if it does not affect the absorption of the drug, other layers can be provided to form a multilayer.
The dosage form of the transdermal absorption patch of the present invention is preferably a plaster, and particularly preferably a substantially anhydrous plaster.
[0015]
Examples of styrene-isoprene-styrene block copolymers include styrene-isoprene-styrene block copolymers (trade names: Califlex TR-1107, Califlex TR-1111) manufactured by Shell Chemical, and styrene-made by Nippon Synthetic Rubber Co., Ltd. Examples thereof include isoprene-styrene block copolymers (trade names: JSR5000, JSR5100), styrene-isoprene-styrene block copolymers (trade name: LINTAC 3421) manufactured by Nippon Zeon.
[0016]
Examples of the softening agent include liquid paraffin, polybutene, castor oil, cottonseed oil, palm oil, coconut oil, and process oil.
Examples of tackifying resins include alicyclic saturated hydrocarbon resins (eg, Alcon P-100 (trade name)), rosin esters (eg, KE-311, KE-100 (trade name), superester S-100 (trade name)). Hydrogen alicyclic hydrocarbons (for example, Escorets 5300 (trade name)), terpene-based hydrogenated resins (for example, Clearon P-105 (trade name)), hydrogenated rosin esters (for example, Foal 105 (trade name)), etc. A tackifying resin is exemplified.
[0017]
Next, the film used as the support of the present invention needs to have properties such as excellent so-called barrier properties to prevent leakage, volatilization, and adsorption of the drug. Moreover, it is preferable that there exists a moderate softness | flexibility at the time of sticking an apparatus to skin. The material of the support is not particularly limited as long as the above conditions are satisfied. Specifically, aluminum, ethylene vinyl acetate copolymer or a saponified product thereof, cellulose acetate, cellulose, nylon, polyester, polyethylene, polyethylene, Examples include vinylidene chloride, polycarbonate, polyvinyl alcohol, and polypropylene. These materials can be formed into a film, or paper or cloth as necessary, laminated with a film or processed into a laminated film, or treated by aluminum vapor deposition, ceramic vapor deposition, etc. The property etc. can be improved.
[0018]
For the film to be the release liner layer, it is necessary to be able to prevent leakage and volatilization from the drug layer during storage of the apparatus, and this release liner layer must be removable when the apparatus is used. Specifically, aluminum, cellulose, polyester, polyethylene, polypropylene, or the like can be used as the material for the release liner film, and these films may be laminated as necessary. Further, the surface may be treated with silicon, fluorocarbon or the like, or a known additive may be mixed in the liner material to adjust the peelability or the barrier property. The release liner can be provided with a knob for peeling so as to facilitate handling during peeling.
[0019]
Furthermore, a well-known additive can be mix | blended as needed for preparation of adhesiveness, safety | security, and stability. Specifically, pressure-sensitive adhesives or adhesives such as polyisobutylene, antioxidants such as dibutylhydroxytoluene, Sumikagel SP-520 (trade name), Aquakeep 10SH (trade name), Arasorb 800F (trade name), Sunwet Absorption of water-absorbing polymers such as 1M-1000MPS (trade name), inorganic fillers such as zinc oxide, calcium carbonate, titanium dioxide and silica, glycerin fatty acid esters such as Excel (trade name) and crotamiton as dissolution aids A suitable amount of fatty alcohol such as calcoal (trade name) as a promoter and triethyl citrate, polyethylene glycol, glycerin and the like as a humectant is appropriately contained.
[0020]
Next, the manufacturing method of the percutaneous absorption preparation of this invention is demonstrated. The transdermally absorbable preparation of the present invention is prepared by, for example, heating and dissolving all the base components except the medicinal component and hexylene glycol, and then adding the medicinal component and hexylene glycol and mixing them uniformly. It is possible to cover the support with a liner after spreading and cut it into a desired shape, or to spread it onto a film that has been subjected to a release treatment, and then press-transfer to a suitable support to obtain a product. In addition, all components are dissolved in an organic solvent such as hexane, toluene, ethyl acetate, and spread on the above support. Then, the organic solvent is removed, covered with a liner, cut into a desired shape, and a product is obtained. Alternatively, after spreading on a film that has been subjected to a peeling treatment, the organic solvent is removed, and the film can be pressure-bonded and transferred to a suitable support to obtain a product.
[0021]
【The invention's effect】
The transdermally absorbable preparation of the present invention thus obtained, preferably the transdermally absorbable patch, improves the solubility and stability of the medicinal component, the skin permeability, and has good cohesive strength and physical properties of the base. Has the effect of stabilization.
Since the percutaneously absorbable preparation of the present invention has a high degree of freedom in drug composition, the merit in designing stability and effectiveness is great.
[0022]
【Example】
Hereinafter, the transdermal absorption patch of the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited to these examples.
In addition, all the numerical values of an Example and a comparative example are weight%.
[0023]
Example 1
Styrene-isoprene-styrene block copolymer 10
Liquid paraffin 60
Tackifier (alicyclic saturated hydrocarbon resin 20
Product name: Archon P-100)
Polyisobutylene 7.4
Hexylene glycol 1
Dibutylhydroxytoluene 1
Estradiol 0.1
Norethisterone acetate 0.5
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0024]
Example 2
Styrene-isoprene-styrene block copolymer 30
Liquid paraffin 10
Tackifier (Rosin ester, trade name: KE-311) 24
Polyisobutylene 10
Hexylene glycol 10
Dibutylhydroxytoluene 1
Estradiol 5
Norethisterone acetate 10
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0025]
Example 3
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 29
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 10
Hexylene glycol 7
Dibutylhydroxytoluene 1
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0026]
Example 4
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 35
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 10
Hexylene glycol 1
Dibutylhydroxytoluene 1
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0027]
Example 5
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 24
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 12
Hexylene glycol 10
Dibutylhydroxytoluene 1
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0028]
Example 6
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 21
Tackifier (hydrogenated rosin ester 25
Product name: Foral 105)
Polyisobutylene 10
Hexylene glycol 8
Dibutylhydroxytoluene 1
Estradiol 5
Norethisterone acetate 10
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0029]
Example 7
Styrene-isoprene-styrene block copolymer 15
Liquid paraffin 15
Tackifier (hydrogenated rosin ester 60
Product name: Foral 105)
Polyisobutylene 7.4
Hexylene glycol 1
Dibutylhydroxytoluene 1
Estradiol 0.1
Norethisterone acetate 0.5
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0030]
Example 8
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 30
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 10
Hexylene glycol 7
Dibutylhydroxytoluene 1
Oxybutynin 2
This formulation is prepared according to the above manufacturing method, cut to the desired size, and oxy
A butynin preparation was obtained.
[0031]
Example 9
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 35
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 10
Hexylene glycol 1
Dibutylhydroxytoluene 1
Tizanidine 3
This formulation is prepared according to the above manufacturing method, cut into a desired size, and tizan
A gin preparation was obtained.
[0032]
Example 10
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 24
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 12
Hexylene glycol 10
Dibutylhydroxytoluene 1
Ketoprofen 3
This formulation is prepared according to the above manufacturing method, cut into a desired size,
A lofen preparation was obtained.
[0033]
Example 11
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 28
Tackifier (hydrogenated rosin ester 25
Product name: Foral 105)
Polyisobutylene 15
Hexylene glycol 8
Dibutylhydroxytoluene 1
Granisetron 3
This formulation is prepared according to the above manufacturing method, cut to the desired size and granulated.
A setron formulation was obtained.
[0034]
Example 12
Styrene-isoprene-styrene block copolymer 15
Liquid paraffin 15
Tackifier (hydrogenated rosin ester 58.6
Product name: Foral 105)
Polyisobutylene 7.4
Hexylene glycol 1
Dibutylhydroxytoluene 1
Tulobuterol 2
Prepared according to the above manufacturing method with this formulation, cut to the desired size and
A terol formulation was obtained.
[0035]
Comparative Example 1 (without hexylene glycol)
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 36
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 10
Dibutylhydroxytoluene 1
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0036]
Comparative example 2 (dissolving agent crotamiton)
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 29
Tackifier (hydrogenated rosin ester 30
Product name: Foral 105)
Polyisobutylene 10
Crotamiton 7
Dibutylhydroxytoluene 1
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0037]
Comparative Example 3 (acrylic base)
TS-620 (methyl acrylate, 2-ethylhexyl acrylate 89
Copolymer resin emulsion (manufactured by Nippon Carbide)
Hexylene glycol 8
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0038]
Comparative Example 4
Styrene-isoprene-styrene block copolymer 5
Liquid paraffin 65
Tackifier (hydrogenated rosin ester 10
Product name: Foral 105)
Polyisobutylene 3.4
Hexylene glycol 15
Dibutylhydroxytoluene 1
Estradiol 0.1
Norethisterone acetate 0.5
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0039]
Comparative Example 5
Styrene-isoprene-styrene block copolymer 35
Liquid paraffin 5
Tackifier (hydrogenated rosin ester 32
Product name: Foral 105)
Polyisobutylene 3
Hexylene glycol 7
Dibutylhydroxytoluene 1
Estradiol 6
Norethisterone acetate 11
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0040]
Comparative Example 6
Styrene-isoprene-styrene block copolymer 20
Liquid paraffin 29
Tackifier (hydrogenated rosin ester 36.5
Product name: Foral 105)
Polyisobutylene 10
Hexylene glycol 0.5
Dibutylhydroxytoluene 1
Estradiol 1
Norethisterone acetate 2
This formulation is prepared according to the above manufacturing method, cut to the desired size and
A mixed preparation of radiol and norethisterone acetate was prepared.
[0041]
Test example
Test Example 1 Dissolution stability test of medicinal ingredients in base
The test pieces of Examples 1, 2, 3, 4, 5, 6, and 7 and Comparative Examples 1, 4, and 6 were stored at 50 ° C. for 3 months, and crystal precipitation or bleeding from each test piece was observed. The results are shown in Table 1. In Comparative Examples 1 and 6, precipitation of crystals was observed. In Comparative Example 4, bleeding of hexylene glycol was observed. In the examples, crystal precipitation and bleeding were not observed.
[0042]
[Table 1]

[0043]
Test Example 2 Confirmation of properties
Each test piece of Example 3 and Comparative Examples 2 and 4 was stored at 50 ° C. for 3 months, and the appearance and properties of each test piece were observed. The results are shown in Table 2. In Example 3, no base flow was observed, but in Comparative Examples 2 and 4, the base flow was observed.
[0044]
[Table 2]

[0045]
Test Example 3 Skin permeation test
A hairless mouse (6 weeks old, female) back skin permeation test (temperature: 37 ° C.) was performed on the test pieces of Example 3 and Comparative Examples 2 and 3 using a Franz diffusion cell. The receptor solution was collected every required time after the start of the test, and immediately after that, the receptor solution was replenished, and the permeation amount of the drug into the collected receptor solution was measured by high performance liquid chromatography. The number of samples of each test piece was three. The results are shown in FIGS. Example 3 showed better drug permeability compared to Comparative Examples 2 and 3.
[0046]
Test Example 4 Release test
The release test was performed on the test pieces of Example 3 and Comparative Examples 1 and 6 by the rotating cylinder method. The test conditions were 900 ml of test solution, test solution temperature of 32.0 ± 0.5 ° C., and cylinder rotation speed of 50 rpm. The results are shown in FIGS. Good release of medicinal components was obtained in Example 3 compared to the test pieces of Comparative Examples 1 and 6.
[0047]
Test Example 5 Adhesion test
The adhesion test was performed on the test pieces of Examples 1, 2, and 3 and the test pieces of Comparative Examples 4 and 5 by the following method. Adhesiveness was evaluated after a test piece was applied to the upper arm of 10 subjects (healthy person, male) and applied for 24 hours. The results are shown in Table 3. In the comparative example, peeling of 1/2 or more was observed in most cases, but in the examples, there was almost no peeling.
[0048]
[Table 3]

[0049]
【The invention's effect】
According to the present invention, by using styrene-isoprene-styrene block copolymer, softener, tackifying resin and hexylene glycol as the base component, good cohesion, stability of physical properties, and drug solubility In addition, a base for transdermal absorption having improved stability and skin permeability and a percutaneous absorption preparation using the same can be provided.
[Brief description of the drawings]
BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows the preparations of Example 3, Comparative Example 2 and Comparative Example 3 for estradiol (E ₂ ) Skin permeability.
FIG. 2 shows a hairless mouse skin permeation test and skin permeability of norethisterone acetate (NETA) for the preparations of Example 3, Comparative Example 2 and Comparative Example 3.
FIG. 3 shows estradiol (E) for the preparations of Example 3, Comparative Example 1 and Comparative Example 6. ₂ ) Shows the results of the release test.
FIG. 4 shows the results of a release test of norethisterone acetate (NETA) for the preparations of Example 3, Comparative Example 1 and Comparative Example 6.

Claims (9)

A base for percutaneous absorption, comprising a styrene-isoprene-styrene block copolymer, a softening agent, a tackifier resin, and hexylene glycol. The base for transdermal absorption according to claim 1, wherein the content of hexylene glycol is 1 to 10% by weight. 10-30% by weight of styrene-isoprene-styrene block copolymer, 10-60% by weight of softener, 20-60% by weight of tackifying resin, and 1-10% of hexylene glycol based on the total amount of the preparation The base for percutaneous absorption according to claim 1 or 2, comprising: The base for transdermal absorption according to any one of claims 1 to 3, wherein hexylene glycol is a drug absorption accelerator and / or a solubilizer. A transdermal absorption preparation comprising a drug in the transdermal absorption base according to any one of claims 1 to 4. The percutaneous absorption preparation according to claim 5, wherein the drug is blended in an amount of 0.1 to 10% by weight. The transdermally absorbable preparation according to claim 5 or 6, wherein the drug is follicular hormone and / or luteinizing hormone. The percutaneous absorption preparation according to claim 7, wherein the follicular hormone is estradiol and a derivative thereof, and a blending amount thereof is 0.1 to 5% by weight. The transdermally absorbable preparation according to claim 7, wherein the luteinizing hormone is norethisterone acetate, norethisterone acetate and a derivative thereof, and the blending amount thereof is 0.5 to 10% by weight.

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