JP2004131472A - Ointment for treatment of hemorrhoid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ointment for the treatment of hemorrhoid expected to have high treatment effect by the increase in drug releasability of a water-soluble drug while keeping the drug releasability of a scarcely water-soluble drug from a base agent for hemorrhoid and having excellent stability of the drugs. <P>SOLUTION: This ointment for the treatment of hemorrhoid contains the scarcely water-soluble drug, the water-soluble drug, a polyhydric alcohol and an oily component and has a pH of 4-7. Since an oil-based ointment widely used as an ointment for the treatment of hemorrhoid is generally difficult to hold a water-soluble drug in a solution system, it has a problem of insufficient release of the drug from the base agent. Furthermore, this invention solves the problem of the difficulty in the formulation of a scarcely water-soluble drug together with a water-soluble drug in a base agent composed mainly of an aqueous component for increasing the releasability of the water-soluble drug. <P>COPYRIGHT: (C)2004,JPO

Description

【００３２】
（製造方法）
表１に示した処方につき、実施例３、４および比較例１を実施例１と同様の製造方法で製造した。ただし、各例はｐＨ調節剤を加え、表１の所定のｐＨに調整した。
【００３３】
比較例２、３については実施例１の製造に使用した真空乳化装置を用いて油性成分を温度９０℃回転数１２０ｒｐｍで加温混合した後、温度を６０〜７０℃に下げ脂溶性成分を添加溶解し、次に難溶性薬物および水溶性薬物を添加混合し、真空下回転数１２０ｒｐｍで３０分間撹拌後、室温まで冷却して製剤を得た。
【００３４】
試験例１
以下の方法で実施例３、４、比較例１および油性軟膏の比較例２、３の薬物放出試験を行った。
試験方法はセルロースチューブ透析法（吉野廣祐ら，薬剤学Ｖｏｌ．４１，Ｎｏ．２（１９８１），１０２−１１２）を準用して行い、装置には第１４改正日本薬局方解説書　一般試験法６６．溶出試験法（２）第２法（パドル法）Ｂ−６８０頁に記載の溶出試験器を用いた。セルロースチューブ（Ｄｉａｌｙｓｉｓ　Ｍｅｍｂｒａｎｅ、Ｓｉｚｅ３６　Ｖｉｓｋａｓｅ　Ｓａｌｅｓ　Ｃｏｒｐｏｒａｔｉｏｎ　和光純薬工業）の内部に一定量の製剤を入れ両端をクローサーで閉じたものを一定量のＰＢＳ溶液（ｐＨ　７．４）中に投入し、３７℃に保持しながらパドル回転数：５０ｒｐｍで撹拌した。このＰＢＳ溶液を一定時間毎にサンプリングして薬物放出量を測定した。定量はＨＰＬＣ法にて行った。
【００３５】
結果を図１および２に示した。
図から明らかなように、本発明の痔疾用軟膏は優れた薬物放出性を示すことがわかった。
【００３６】
試験例２
アルミチューブに充填した実施例３、４および比較例１を４０℃に保存し、経時的な薬物安定性を試験例１に準じ、評価した。薬物含量の測定はＨＰＬＣ法により実施した。
【００３７】
結果を図３および４に示した。
【００３８】
図から明らかなように、本発明の痔疾用軟膏は薬物の経時的な安定性に優れることが分かった。
【図面の簡単な説明】
【図１】塩酸リドカイン（比較例３はリドカイン）の放出性を示した図であり、縦軸に薬物放出率、横軸に時間を示した。
【図２】塩酸テトラヒドロゾリンの放出性を示した図であり、縦軸に薬物放出率、横軸に時間を示した。
【図３】酢酸ヒドロコルチゾンの安定性を示した図である。
【図４】塩酸テトラヒドロゾリンの安定性を示した図である。[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to an ointment for treating hemorrhoids, which can be expected to have a high therapeutic effect due to its excellent drug release property and has improved drug stability.
[0002]
[Prior art]
Conventionally, suppositories and ointments have been used for the treatment of hemorrhoids, and various techniques have been disclosed. In general, suppositories are used to treat internal hemorrhoids, while ointments are used to treat external hemorrhoids in the anus, and anti-inflammatory agents such as corticosteroids, local anesthetics, antihistamines, and vasoconstriction Drugs such as agents, bactericides, and refreshing agents are incorporated.
[0003]
Conventionally, hemorrhoid ointments are often formulated with a drug in an oily base because the oil component is expected to have an effect of protecting the affected area, and specifically, are composed of white petrolatum, liquid paraffin, dextrin fatty acid ester, etc. It is common to mix a drug with a base (Patent Document 1).
[0004]
In order to enhance the efficacy of the hemorrhoid ointment, it is important to promptly release an analgesic component that relieves pain, which is the main complaint of hemorrhoids. In addition, a drug that rapidly releases a vasoconstrictor in order to secure a sufficient anti-inflammatory effect and has an immediate effect on the symptoms of swelling of hemorrhoids is desired.
[Patent Document 1] JP-A-7-304669 [Problems to be solved by the invention]
In general, an oil-based ointment most widely used as an ointment for treating hemorrhoids has a property that a drug is hardly released from the base because a water-soluble drug is hardly present in a dissolution system. On the other hand, when a water-soluble drug is blended in a base mainly composed of an aqueous component for the purpose of enhancing the release property of the water-soluble drug, the drug is likely to cause an interaction and the stability of a certain drug is insufficient. It turned out to be.
[0005]
The present invention is expected to have a high therapeutic effect by increasing the drug release of a water-soluble drug while maintaining the drug release of a poorly water-soluble drug from a base for hemorrhoids, and has excellent drug stability. It is intended to provide a hemorrhoid ointment.
[0006]
[Means for Solving the Problems]
The present inventors have conducted various studies to solve the above problems, and found that a poorly water-soluble drug, a water-soluble drug were blended, and the pH was adjusted to a specific range based on a cream base containing a polyhydric alcohol as a base component. It was found that an ointment excellent in drug release property and excellent in drug stability can be obtained by adjusting the amount of ointment.
[0007]
That is, the present invention is an ointment for treating hemorrhoids, comprising a poorly water-soluble drug, a water-soluble drug, a polyhydric alcohol, and an oily component, and having a pH in the range of 4 to 7.
[0008]
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the water-soluble drug is a drug having relatively high solubility in water, and a salt of lidocaine, a salt of diphenhydramine, a salt of tetrahydrozoline, a salt of naphazoline or a salt of chlorpheniramine is preferably used. As an acid forming a salt of a water-soluble drug, any of an organic acid and an inorganic acid such as hydrochloric acid, maleic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, and lactic acid can be used.
[0009]
Preferred specific examples of the water-soluble drug used in the present invention include lidocaine hydrochloride, diphenhydramine hydrochloride, tetrahyrhodrine hydrochloride, naphazoline hydrochloride, and chlorpheniramine maleate. These drugs can be used in combination of two or more.
[0010]
In the present invention, the compounding amount of the water-soluble drug can be compounded without impairing the effects of the present invention as long as it is a normal compounding amount, but the compounding amount of lidocaine hydrochloride is 0.5 to 10.0 of the whole ointment. % By mass, more preferably 1.0 to 5.0% by mass. The blending amount of diphenhydramine hydrochloride is preferably 0.05 to 10.0% by mass, more preferably 0.1 to 5.0% by mass. The compounding amount of tetrahydrorodrine hydrochloride and naphazoline hydrochloride is preferably from 0.005 to 0.5% by mass, more preferably from 0.01 to 0.1% by mass. The content of chlorpheniramine maleate is preferably 0.005 to 5.0% by mass, more preferably 0.01 to 0.5% by mass.
[0011]
The poorly water-soluble drug of the present invention is one having low solubility in water among the components used for treating hemorrhoids. Among them, corticosteroids, which are anti-inflammatory components, are preferable.
[0012]
As the corticosteroid used in the present invention, hydrocortisone acetate, prednisolone acetate, hydrocortisone, prednisolone and the like are preferable, and hydrocortisone acetate or prednisolone acetate is particularly preferable. The amount of the corticosteroid is preferably 0.01 to 5.0% by mass.
[0013]
As the polyhydric alcohol used in the present invention, one or more selected from propylene glycol, 1,3-butylene glycol, glycerin, dipropylene glycol, macrogol 300, macrogol 400 and macrogol 1450 are preferable. The blending amount of the polyhydric alcohol is preferably 5 to 50% by mass of the whole ointment, more preferably 10 to 30% by mass.
[0014]
Preferred as the oily component used in the present invention are liquid paraffin, squalane, cetanol, stearyl alcohol, medium-chain fatty acid triglyceride, isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, cetyl lactate, octyldodecanol, and hexyldecanol. And silicone oils such as methyl and polysiloxane.
[0015]
The amount of the oily component is preferably 0.01 to 20% by mass, more preferably 0.05 to 15% by mass of the whole ointment.
[0016]
In the present invention, when a nonionic surfactant is blended, it acts as a solubilizer for a poorly water-soluble drug in a polyhydric alcohol, and also acts as an emulsifier for emulsifying water and an oil component or water, a polyhydric alcohol and an oil component. This is preferable from the viewpoint of drug solubility.
[0017]
Examples of the nonionic surfactant used in the present invention include fatty acid esters such as diisopropyl adipate, glycerin fatty acid esters such as glyceride monostearate, sorbitan fatty acid esters such as sorbitan monostearate, and polyoxysorbitan monostearate and the like. Oxyethylene sorbitan fatty acid esters and the like can be mentioned.
[0018]
The compounding amount of the nonionic surfactant is preferably from 0.1 to 50% by mass, more preferably from 1 to 40% by mass of the whole ointment.
[0019]
In the present invention, it is necessary to mix water in the preparation as a solvent for the water-soluble drug. The blending amount of water is preferably 1 to 50% by mass of the whole preparation, more preferably 20 to 45% by mass.
[0020]
In the preparation of the present invention, it is necessary to adjust the pH to 4.0 to 7.0 by adding a pH adjuster as needed, and pH 5.0 to 6.0 is particularly preferable. This is because, in addition to the release and stability of the components, the formulation can be less irritating when applied.
[0021]
The ointment for hemorrhoids of the present invention may be, depending on the purpose of use, an anti-inflammatory agent (such as glycyrrhetinic acid), a bactericide (such as chlorhexidine gluconate, isopropylmethylphenol, chlorhexidine hydrochloride, decalinium chloride, hinokitiol), a wound healing agent (such as allantoin), Humectants (sodium hyaluronate, chondroitin sulfate, etc.), crude drug extracts (hamamelis, horse chestnut, etc.), antioxidants (dibutylhydroxytoluene, isopropylgallate, etc.), sequestering agents (ethylenediaminetetraacetate or its salt, etc.), Cooling agents (menthol, camphor, etc.), preservatives (paraben, benzoate, dehydroacetic acid, erythorbic acid, sorbic acid, phenoxyethanol, etc.), water-soluble polymers (hydroxypropyl methylcellulose, Ntangamu, carboxyvinyl polymer, carboxymethylcellulose, and sodium alginate, etc.), dyes, perfumes and the like may be blended as long as they do not impair the effects of the present invention.
[0022]
The ointment for hemorrhoids of the present invention can be formulated in the form of a cream or a gel cream in addition to a usual ointment.
[0023]
The ointment for hemorrhoids of the present invention can use a wide variety of liquid and solid raw materials, and if necessary, commonly used bases such as preservatives, fragrances, stabilizers, coloring agents, antioxidants, humectants, thickeners and the like. Agents can be used in a general manner, for example, in the Japanese Pharmacopoeia, 14th Edition, Ointment A-106 can be produced by the method described on page A-106.
[0024]
Specific examples thereof include the following manufacturing method. That is, when an oil component and a lipophilic nonionic surfactant are heated and melted at 70 to 80 ° C., and a fat-soluble drug is to be added, the oil-soluble drug is added to and mixed with the drug to form an oil phase. Separately, a poorly water-soluble drug is added to a polyhydric alcohol heated to 70 to 80 ° C and mixed to obtain an aqueous phase A. Next, a water-soluble polymer, a hydrophilic nonionic surfactant and a water-soluble drug are added to water heated to 70 to 80 ° C. and mixed to obtain an aqueous phase B. Using a vacuum emulsifier, the aqueous phase A and the aqueous phase B are sequentially charged into the oil phase, mixed and emulsified, and cooled to room temperature to obtain a preparation.
[0025]
【The invention's effect】
According to the present invention, the drug release of a water-soluble drug was able to be increased while maintaining the release of a poorly soluble drug from an ointment base for hemorrhoids. In particular, the initial release of the analgesic component is improved, and a high therapeutic effect on pain, which is the main complaint of hemorrhoids, can be obtained. In addition, by improving the release of a vasoconstrictor and increasing the local retention of other drugs, the therapeutic effect on various symptoms of hemorrhoids can be improved, and a stable preparation of a poorly water-soluble drug can be provided.
[0026]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
Example 1
(Prescription)
(Poorly soluble drug)
Prednisolone acetate 0.1% by mass
(Water-soluble drug)
Lidocaine hydrochloride 3.0
Tetrahydrozoline hydrochloride 0.05
(Polyhydric alcohol)
1,3-butylene glycol 15.0
(Oily component)
Stearyl alcohol 7.0
Light liquid paraffin 28.0
(Nonionic surfactant (lipophilic))
Glycerin monostearate 4.0
(Nonionic surfactant (hydrophilic))
Polyoxyethylene hydrogenated castor oil 60 8.0
(PH regulator)
Citric acid 0.03
Sodium citrate qs (adjusted to pH 6.0)
(water)
Purified water 100
105 g of stearyl alcohol as an oily component and 60 g of glyceryl monostearate as a lipophilic nonionic surfactant in the above formulation were heated and melted and mixed at 70 to 80 ° C. to obtain an oil phase. Separately, while heating 225 g of 1,3-butylene glycol, which is a polyhydric alcohol, to 70 to 80 ° C. and stirring at 700 rpm using a stirrer, 1.5 g of prednisolone acetate, a poorly water-soluble drug, was gradually added. Add and mix for 15 minutes. Thereafter, the mixture was sieved with a standard sieve No. 100 of Japanese Industrial Standard to obtain an aqueous phase A.
[0027]
Next, 521.25 g of purified water is heated to 70 to 80 ° C., and while stirring at 700 rpm using a stirrer, polyoxyethylene hydrogenated castor oil, which is a hydrophilic nonionic surfactant, is contained therein. Add and dissolve 120 g of lidocaine hydrochloride and 0.75 g of tetrahydrozoline hydrochloride, which are water-soluble drugs, and add 0.45 g of citric acid and 1.05 g of sodium citrate as pH regulators And dissolved to obtain an aqueous phase B.
[0028]
A vacuum emulsification apparatus was used for the preparation of this preparation. Aqueous phase A and aqueous phase B were sequentially charged while stirring the oil phase at a rotation speed of 120 rpm in an emulsification kettle maintained at a temperature of 70 to 80 ° C. in a vacuum. The mixture was mixed and emulsified for 5 minutes at 2500 rpm with a homomixer and stirred for 30 minutes at 120 rpm. Thereafter, the mixture was cooled to room temperature with stirring to obtain 1,400 g of the present preparation.
[0029]
Example 2
(Prescription)
(Poorly soluble drug)
Hydrocortisone acetate 0.5% by mass
(Water-soluble drug)
Lidocaine hydrochloride 3.0
Tetrahydrozoline hydrochloride 0.05
Chlorpheniramine maleate 0.2
Horse chestnut seed extract 0.5
(Fat-soluble drug)
Glycyrrhetinic acid 1.5
Eucalyptus oil 0.5
(Polyhydric alcohol)
1,3-butylene glycol 10.0
Glycerin 10.0
(Oily component)
Stearyl alcohol 3.0
Cetanol 3.0
Synthetic squalane 15.0
Medium-chain fatty acid triglyceride 15.0
(Nonionic surfactant (lipophilic))
Glycerin monostearate 8.0
Polysorbate 80 1.0
(Nonionic surfactant (hydrophilic))
Polyoxyethylene hydrogenated castor oil 60 5.0
(PH regulator)
Citric acid 0.03
Sodium citrate qs (adjusted to pH 6.0)
(Water-soluble polymer)
Xanthan gum 0.1
Human hydroxypropyl methylcellulose 0.2
(water)
Purified water 100
(Production method)
This formulation was obtained by the same manufacturing method as in Example 1 for the formulation shown above. The fat-soluble drug was added to the oily component heated and melted and mixed at 70 to 80 ° C., and the mixture was stirred and mixed at 700 rpm for 15 minutes using a stirrer, followed by sieving with a standard sieve No. 100 of Japanese Industrial Standards. Oil phase. The water-soluble polymer was added to the water phase B before adding the water-soluble drug.
[0030]
Examples 3 and 4
[0031]
[Table 1]

[0032]
(Production method)
Using the formulations shown in Table 1, Examples 3 and 4 and Comparative Example 1 were produced in the same manner as in Example 1. However, in each case, the pH was adjusted to a predetermined value in Table 1 by adding a pH adjuster.
[0033]
For Comparative Examples 2 and 3, after the oily components were heated and mixed at a temperature of 90 ° C. and a rotation speed of 120 rpm using the vacuum emulsification apparatus used in the production of Example 1, the temperature was lowered to 60 to 70 ° C., and the fat-soluble components were added. After dissolution, the poorly soluble drug and the water-soluble drug were added and mixed, and the mixture was stirred at 120 rpm for 30 minutes under vacuum, and then cooled to room temperature to obtain a preparation.
[0034]
Test example 1
The drug release tests of Examples 3, 4 and Comparative Example 1 and Comparative Examples 2 and 3 of the oil-based ointment were performed by the following methods.
The test method was performed by applying the cellulose tube dialysis method (Kosuke Yoshino et al., Pharmaceutical Sciences Vol. 41, No. 2 (1981), 102-112) mutatis mutandis. 66. Dissolution test method (2) The dissolution tester described in the second method (paddle method), page B-680, was used. A certain amount of a preparation is put in a cellulose tube (Diallysis Membrane, Size 36 Viskasales Corporation Wako Pure Chemical Industries), and the both ends are closed with a closer. While stirring at a paddle rotation speed of 50 rpm. This PBS solution was sampled at regular intervals to measure the amount of drug release. The quantification was performed by the HPLC method.
[0035]
The results are shown in FIGS.
As is clear from the figure, it was found that the ointment for hemorrhoids of the present invention exhibited excellent drug release.
[0036]
Test example 2
Examples 3 and 4 and Comparative Example 1 filled in aluminum tubes were stored at 40 ° C., and the drug stability over time was evaluated according to Test Example 1. The drug content was measured by the HPLC method.
[0037]
The results are shown in FIGS.
[0038]
As is clear from the figure, the ointment for hemorrhoids of the present invention was found to be excellent in the stability over time of the drug.
[Brief description of the drawings]
FIG. 1 is a graph showing the release of lidocaine hydrochloride (lidocaine in Comparative Example 3), in which the vertical axis represents the drug release rate and the horizontal axis represents time.
FIG. 2 is a graph showing the release of tetrahydrozoline hydrochloride, in which the vertical axis represents the drug release rate and the horizontal axis represents time.
FIG. 3 shows the stability of hydrocortisone acetate.
FIG. 4 is a diagram showing the stability of tetrahydrozoline hydrochloride.

Claims (6)

An ointment for treating hemorrhoids, comprising a poorly water-soluble drug, a water-soluble drug, a polyhydric alcohol and an oily component, and having a pH in the range of 4 to 7. The ointment for treating hemorrhoids according to claim 1, wherein the poorly water-soluble drug is at least one selected from the group consisting of hydrocortisone acetate and prednisolone acetate. 3. The ointment for treating hemorrhoids according to claim 1 or 2, wherein the water-soluble drug is one or more selected from the group consisting of lidocaine hydrochloride, diphenhydramine hydrochloride, tetrahizorodrine hydrochloride, naphazoline hydrochloride and chlorpheniramine maleate. . The polyhydric alcohol is one or more selected from the group consisting of propylene glycol, 1,3-butylene glycol, glycerin, dipropylene glycol, macrogol 300, macrogol 400, and macrogol 1450. The ointment for treating hemorrhoids according to any one of the above. The oil component is liquid paraffin, squalane, cetanol, stearyl alcohol, medium chain fatty acid triglyceride, isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, cetyl lactate, octyldodecanol, hexyldecanol, and silicone oils such as methylpolysiloxane. The ointment for treating hemorrhoids according to any one of claims 1 to 4, wherein the ointment is at least one member selected from the group consisting of: The ointment for treating hemorrhoids according to any one of claims 1 to 5, further comprising a nonionic surfactant.

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