JP2004196786A - Slightly soluble antiviral component-containing water-soluble external composition - Google Patents
Slightly soluble antiviral component-containing water-soluble external composition Download PDFInfo
- Publication number
- JP2004196786A JP2004196786A JP2003402702A JP2003402702A JP2004196786A JP 2004196786 A JP2004196786 A JP 2004196786A JP 2003402702 A JP2003402702 A JP 2003402702A JP 2003402702 A JP2003402702 A JP 2003402702A JP 2004196786 A JP2004196786 A JP 2004196786A
- Authority
- JP
- Japan
- Prior art keywords
- hydrochloride
- acyclovir
- external preparation
- preparation composition
- thiamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 53
- 230000000840 anti-viral effect Effects 0.000 title 1
- 229960004150 aciclovir Drugs 0.000 claims abstract description 75
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- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960004172 pyridoxine hydrochloride Drugs 0.000 claims abstract description 17
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- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 claims abstract description 16
- PPWHTZKZQNXVAE-UHFFFAOYSA-N Tetracaine hydrochloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 claims abstract description 16
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Abstract
Description
本発明は、常温の水に対する飽和溶解度以上のアシクロビルを含有し、皮膚や粘膜への透過性に優れ、皮膚刺激の少ない水溶性外用剤組成物に関する。 The present invention relates to a water-soluble external preparation composition containing acyclovir having a saturation solubility equal to or higher than the saturation solubility in water at ordinary temperature, having excellent permeability to skin and mucous membranes, and having little skin irritation.
アシクロビルは、プリン骨格を有するヌクレオシド類似体で、ヘルペスウイルス1型、2型、帯状疱疹ウイルスによって発症する疱疹(水疱)等の治療に有効な薬物として使用されている。これらの疾患において、アシクロビルは、全身性の重症状には経口剤や注射剤として処方され、軽度な症状には外用剤として処方されている。しかし、アシクロビルは、強酸及び強アルカリには可溶であるが、中性付近の水に対する溶解性が悪く、基剤中に結晶として分散しているものがほとんどであり、皮膚や粘膜への吸収性において障壁となり、治療効果を減弱させることとなる。 Acyclovir is a nucleoside analog having a purine skeleton, and has been used as a drug effective in treating herpes virus type 1 and type 2 and herpes zoster (vesicles) caused by herpes zoster virus. In these diseases, acyclovir is prescribed as an oral preparation or an injection for severe systemic symptoms, and as an external preparation for mild symptoms. However, acyclovir is soluble in strong acids and strong alkalis, but poorly soluble in water near neutrality, most of which are dispersed as crystals in the base, and absorbed into skin and mucous membranes It becomes a barrier in sex and diminishes the therapeutic effect.
このような難点への対策として、溶解補助剤を用いてアシクロビルの結晶析出を抑制した水溶液製剤、例えば溶解補助剤としてポリビニルピロリドンを用いて、アシクロビルの溶解性が改善している水溶液製剤(特許文献1参照)、また、溶解補助剤としてニコチン酸アミド、L−アルギニン及び塩化マグネシウムよりなる群より選ばれた1種類或いは2種類以上含有し、pH8.0に調節してアシクロビルの結晶析出を抑制している水溶液(特許文献2参照)が知られている。 As a countermeasure against such difficulties, an aqueous solution formulation in which the precipitation of acyclovir is suppressed using a solubilizing agent, for example, an aqueous solution formulation in which the solubility of acyclovir is improved using polyvinylpyrrolidone as a solubilizing agent (Patent Document 1) and one or more selected from the group consisting of nicotinamide, L-arginine and magnesium chloride as a solubilizing agent, and adjusted to pH 8.0 to suppress crystallization of acyclovir. A known aqueous solution (see Patent Document 2) is known.
上記の溶解補助剤により、アシクロビルの結晶析出は抑制されているが、一般的に皮膚刺激が少ないとされる中性あるいは酸性領域においてアシクロビルの溶解度を向上させた外用剤組成物は未だ知られていない。したがって、常温時の水に対する飽和溶解度以上のアシクロビルを含有し、使用感がよく、皮膚刺激の少ない外用剤を得たい場合には、依然としてアシクロビルを溶解することは困難であり、皮膚や粘膜への透過性に優れた外用剤を得ることはできない。 By the above-mentioned solubilizing agent, the precipitation of acyclovir crystals is suppressed, but an external preparation composition that improves the solubility of acyclovir in a neutral or acidic region where skin irritation is generally considered to be small is still known. Absent. Therefore, it is difficult to dissolve acyclovir even if it contains acyclovir having a saturation solubility or higher in water at normal temperature and has a good feeling of use and less skin irritation, and it is still difficult to dissolve acyclovir. An external preparation having excellent permeability cannot be obtained.
そこで、本発明は、上記に鑑み、中性あるいは酸性領域におけるアシクロビルの溶解度を向上させ、常温時の水に対する飽和濃度以上のアシクロビルを含有した場合でも、皮膚や粘膜への透過性に優れ、製剤化の容易な水溶性外用剤組成物を提供することを目的とするものである。 Therefore, in view of the above, the present invention improves the solubility of acyclovir in a neutral or acidic region, and even if it contains acyclovir at a saturation concentration or higher with respect to water at normal temperature, has excellent permeability to skin and mucous membranes, It is an object of the present invention to provide a water-soluble external preparation composition that can be easily converted into a composition.
本発明者らは、かかる課題を解決すべく鋭意検討を重ねた結果、塩酸ナファゾリン、塩酸テトラカイン、ベンジルアルコール、カフェイン、塩酸ジフェンヒドラミン、塩酸ピリドキシン、マレイン酸クロルフェニラミン、塩酸リドカイン、グリチルリチン酸二カリウム、塩酸チアミン及び硝酸チアミンの少なくとも1種を含有させることで、アシクロビルの溶解度が向上すること、特に中性あるいは酸性領域においてアシクロビルの溶解度が向上することを見出し、本発明を完成するに至った。 The present inventors have conducted intensive studies to solve this problem, and as a result, naphazoline hydrochloride, tetracaine hydrochloride, benzyl alcohol, caffeine, diphenhydramine hydrochloride, pyridoxine hydrochloride, chlorpheniramine maleate, lidocaine hydrochloride, glycyrrhizinate diacid By including at least one of potassium, thiamine hydrochloride and thiamine nitrate, it was found that the solubility of acyclovir was improved, especially in the neutral or acidic region, the solubility of acyclovir was improved, and the present invention was completed. .
すなわち、本発明は、(1)(a)アシクロビル、並びに、(b)塩酸ナファゾリン、塩酸テトラカイン、ベンジルアルコール、カフェイン、塩酸ジフェンヒドラミン、塩酸ピリドキシン、マレイン酸クロルフェニラミン、塩酸リドカイン、グリチルリチン酸二カリウム、塩酸チアミン及び硝酸チアミンから選ばれる少なくとも1種とを含有することを特徴とする水溶性外用剤組成物、(2)(b)が塩酸ナファゾリン、塩酸テトラカイン及びカフェインから選ばれる少なくとも1種である上記(1)に記載の外用剤組成物、(3)(a)の含有量が外用剤組成物全体に対して0.13〜10質量%である上記(1)又は(2)に記載の外用剤組成物、(4)(b)の含有量が外用剤組成物全体に対して0.5〜10質量%である上記(1)〜(3)いずれか1つに記載の外用剤組成物、(5)さらにpHを中性あるいは酸性となるように調節することを特徴とする上記(1)〜(4)いずれか1つに記載の外用剤組成物、(6)アシクロビルを水溶性外用剤組成物に含有させる際に、 (b)塩酸ナファゾリン、塩酸テトラカイン、ベンジルアルコール、カフェイン、塩酸ジフェンヒドラミン、塩酸ピリドキシン、マレイン酸クロルフェニラミン、塩酸リドカイン、グリチルリチン酸二カリウム、塩酸チアミン及び硝酸チアミンから選ばれる少なくとも1種を添加することを特徴とする、アシクロビルの溶解度を向上させる方法、(7)外用剤組成物全体に対して0.13質量%以上となる量のアシクロビルを含有する水溶性外用剤組成物を製造する際に、アシクロビルの溶解度を向上させるための(b)塩酸ナファゾリン、塩酸テトラカイン、ベンジルアルコール、カフェイン、塩酸ジフェンヒドラミン、塩酸ピリドキシン、マレイン酸クロルフェニラミン、塩酸リドカイン、グリチルリチン酸二カリウム、塩酸チアミン及び硝酸チアミンから選ばれる少なくとも1種から選ばれる少なくとも1種の使用、を提供するものである。 That is, the present invention relates to (1) (a) acyclovir, and (b) naphazoline hydrochloride, tetracaine hydrochloride, benzyl alcohol, caffeine, diphenhydramine hydrochloride, pyridoxine hydrochloride, chlorpheniramine maleate, lidocaine hydrochloride, glycyrrhizinate (2) (b) at least one selected from naphazoline hydrochloride, tetracaine hydrochloride and caffeine, wherein the composition comprises at least one selected from potassium, thiamine hydrochloride and thiamine nitrate. The external preparation composition according to the above (1), wherein the content of (3) (a) is 0.13 to 10% by mass based on the whole external preparation composition as a seed. The external preparation according to any one of the above (1) to (3), wherein the content of the external preparation composition of (4) (b) is 0.5 to 10% by mass based on the whole external preparation composition. (5) The external preparation composition according to any one of the above (1) to (4), wherein the pH is further adjusted to be neutral or acidic, and (6) acyclovir is dissolved in water. When included in the composition for external use for sex, (b) naphazoline hydrochloride, tetracaine hydrochloride, benzyl alcohol, caffeine, diphenhydramine hydrochloride, pyridoxine hydrochloride, chlorpheniramine maleate, lidocaine hydrochloride, dipotassium glycyrrhizinate, thiamine hydrochloride and A method for improving the solubility of acyclovir, characterized by adding at least one selected from thiamine nitrate, (7) a water-soluble solution containing acyclovir in an amount of 0.13% by mass or more based on the whole external preparation composition (B) nafazoline hydrochloride, tet-hydrochloride for improving the solubility of acyclovir when producing an external preparation composition Use of at least one selected from the group consisting of caine, benzyl alcohol, caffeine, diphenhydramine hydrochloride, pyridoxine hydrochloride, chlorpheniramine maleate, lidocaine hydrochloride, dipotassium glycyrrhizinate, thiamine hydrochloride and thiamine nitrate. Is what you do.
本発明により、アシクロビルの溶解度が向上し、粘膜や皮膚へのアシクロビルの吸収性が改善された外用剤を提供することが可能となった。特に中性あるいは酸性領域においてアシクロビルの溶解度が向上し、塗布による皮膚刺激の少ない外用剤組成物を得ることができる。 ADVANTAGE OF THE INVENTION According to this invention, the solubility of acyclovir was improved and it became possible to provide the external preparation in which the absorbability of acyclovir to mucous membrane and skin was improved. Particularly, the solubility of acyclovir is improved in a neutral or acidic region, and an external preparation composition with less skin irritation due to application can be obtained.
本発明でいう「アシクロビル」には、その塩類も含まれる。塩としては、塩酸、リン酸等の鉱酸の塩、マレイン酸、メタンスルホン酸等の有機酸の塩、ナトリウム、カリウム等のアルカリ金属或いはアルカリ土類金属の塩等が挙げられる。 “Acyclovir” in the present invention also includes salts thereof. Examples of the salt include salts of mineral acids such as hydrochloric acid and phosphoric acid, salts of organic acids such as maleic acid and methanesulfonic acid, and salts of alkali metals or alkaline earth metals such as sodium and potassium.
本発明で含有されるアシクロビルは、水溶性外用剤組成物全体に対して0.13〜10質量%となるように含有させることが好ましく、特に0.3〜5.0質量%含有することが好ましい。含有量が0.13質量%未満であるとアシクロビルの水に対する飽和溶解度が、25℃で0.13質量%であることから、その溶解性に差が見られず、また、10質量%を超える場合には、製剤化が困難となる。 The acyclovir contained in the present invention is preferably contained in an amount of 0.13 to 10% by mass, particularly preferably 0.3 to 5.0% by mass, based on the whole water-soluble external preparation composition. If the content is less than 0.13% by mass, the saturation solubility of acyclovir in water is 0.13% by mass at 25 ° C., so that no difference is observed in the solubility, and if it exceeds 10% by mass, Formulation becomes difficult.
また、本発明の(b)成分によるアシクロビルの溶解度を向上させる効果は、製剤化に問題とならない濃度範囲においては、水溶性外用剤組成物全体に対する(b)成分の濃度に依存して増加する。したがって、製剤化に問題とならない範囲内であればどのような濃度で含有させることも可能であるが、十分な効果を得るためには、外用剤組成物全量あたり0.5質量%以上含有させることが好ましく、製剤化が困難となることから10質量%以下とするのが好ましい。 Further, the effect of improving the solubility of acyclovir by the component (b) of the present invention is increased depending on the concentration of the component (b) with respect to the whole water-soluble external preparation composition in a concentration range that does not cause a problem in formulation. . Therefore, it can be contained at any concentration within a range that does not cause a problem in formulation, but in order to obtain a sufficient effect, it is necessary to contain 0.5% by mass or more based on the total amount of the external preparation composition. Preferably, the amount is set to 10% by mass or less because formulation becomes difficult.
さらに、一定量の(b)成分に対するアシクロビル飽和溶解度向上効果が高いものほど、少ない含有量で高い飽和溶解度向上効果が得られるため、外用剤組成物を製造する際の成分調整が容易となる。したがって、(b)成分濃度に対するアシクロビル飽和溶解度のプロットを直線で結んだ際の傾きが高いものほどよく、0.10以上のものが好ましい。特に塩酸ナファゾリン、カフェイン、塩酸テトラカインが好ましく、中でも塩酸ナファゾリンが好ましい。 Further, the higher the acyclovir saturation solubility improving effect with respect to a certain amount of the component (b), the higher the saturation solubility improving effect can be obtained with a small content, so that the component adjustment at the time of producing an external preparation composition becomes easier. Therefore, the higher the slope when a plot of the acyclovir saturation solubility with respect to the component concentration (b) is connected by a straight line, the better, and preferably 0.10 or more. Particularly, naphazoline hydrochloride, caffeine, and tetracaine hydrochloride are preferable, and naphazoline hydrochloride is particularly preferable.
本発明において「中性あるいは酸性」とは、pHの値が人の皮膚表面に近いことを意味し、外用剤組成物を塗布後、人の皮膚のpHを上昇又は下降させ肌に対して負担をかけないようなpHであればよい。本発明においては、pH3.0〜8.0とするのが好ましく、特にpH4.5〜7.5とするのが好ましい。 In the present invention, "neutral or acidic" means that the pH value is close to the surface of human skin, and after application of the external preparation composition, raises or lowers the pH of human skin and places a burden on the skin. The pH may be such that the pH is not applied. In the present invention, the pH is preferably 3.0 to 8.0, and particularly preferably 4.5 to 7.5.
本発明のアシクロビルを含有した水溶性外用剤組成物は点眼、点鼻等の液剤の他、クリーム剤、軟膏剤、ローション剤、ゲル剤、エアゾール剤にも使用することができ、次のようにして調製できる。液剤は、アシクロビル、溶解度改善成分を水性成分に溶解させて得ることが出来る。この液剤と適当な液化ガス(液化石油ガス、ジメチルエーテルなど)をアルミ製耐圧容器に入れてエアゾール剤を調製できる。また、この液剤に適当なゲル化剤を含有し剤形をゲル剤にすることも可能である。クリームの場合は、所定の水性成分にアシクロビル、溶解度改善成分を溶解・分散させホモミキサーに入れて脱気・加温する。ホッパーから油性成分と乳化剤を入れ、高速攪拌(ホモジナイズ)によりクリームが得られる。軟膏剤は水性軟膏が好ましく、室温で固体のポリエチレングリコールと室温で液状の多価アルコール、例えばプロピレングリコール、1,3-ブチレングリコール、グリセリン及びポリエチレングリコールをそれぞれ任意の量とり、これにアシクロビル、溶解度改善成分を加え、加温し溶解・分散させた後、室温まで冷却することで得られる。 The water-soluble external preparation composition containing acyclovir of the present invention can be used in creams, ointments, lotions, gels, and aerosols in addition to liquids such as eye drops and nasal drops. Can be prepared. The liquid preparation can be obtained by dissolving acyclovir and a solubility improving component in an aqueous component. An aerosol can be prepared by putting this liquid and an appropriate liquefied gas (liquefied petroleum gas, dimethyl ether, etc.) in a pressure-resistant aluminum container. It is also possible to add an appropriate gelling agent to this liquid to make the dosage form a gel. In the case of a cream, acyclovir and a solubility improving component are dissolved and dispersed in a predetermined aqueous component, and the mixture is placed in a homomixer and deaerated and heated. An oil component and an emulsifier are added from a hopper, and a cream is obtained by high-speed stirring (homogenization). The ointment is preferably an aqueous ointment, and takes any amount of polyethylene glycol which is solid at room temperature and polyhydric alcohol which is liquid at room temperature, such as propylene glycol, 1,3-butylene glycol, glycerin and polyethylene glycol. It is obtained by adding an improving component, heating, dissolving and dispersing, and then cooling to room temperature.
また、本発明の水溶性外用剤組成物には他に有効成分として、ヘルペスウイルス疾患の症状(痛み、カユミ、2次感染)を改善しうる薬物を含有することができる。たとえば、抗菌剤、抗炎症剤、鎮痛剤、抗ヒスタミン剤、局所麻酔剤、組織修復剤、鎮痒剤、保湿剤、血管収縮剤、抗アレルギー剤、清涼化剤、酸素除去剤、ビタミン、紫外線吸収剤、紫外線散乱剤などが挙げられる。 In addition, the water-soluble external preparation composition of the present invention may further contain, as an active ingredient, a drug capable of improving symptoms of herpes virus disease (pain, kaumi, secondary infection). For example, antibacterial agents, anti-inflammatory agents, analgesics, antihistamines, local anesthetics, tissue repair agents, antipruritics, humectants, vasoconstrictors, antiallergic agents, fresheners, oxygen scavengers, vitamins, ultraviolet absorbers, UV scattering agents and the like.
本発明の水溶性外用剤組成物には、医薬品や医薬部外品に含有可能な種々の基剤成分を本発明の効果を損なわない範囲で含有することができる。このような基剤成分としては、精製水、低級アルコールや多価アルコール等の溶解補助剤、炭化水素、グリセリン脂肪酸エステル、ワックス成分、界面活性剤、抗酸化剤、乳化安定剤、ゲル化剤、粘着剤等、各種動植物からの抽出物、pH調整剤、防腐剤、キレート剤、香料、色素、液化ガスなどが挙げられる。 The water-soluble external preparation composition of the present invention can contain various base components that can be contained in pharmaceuticals and quasi-drugs as long as the effects of the present invention are not impaired. Such base components include purified water, dissolution aids such as lower alcohols and polyhydric alcohols, hydrocarbons, glycerin fatty acid esters, wax components, surfactants, antioxidants, emulsion stabilizers, gelling agents, Examples include extracts from various animals and plants, such as adhesives, pH adjusters, preservatives, chelating agents, fragrances, pigments, and liquefied gases.
次に、実施例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
また、pHについて特に記載のないものについては、pH5.5〜7.0の範囲に調整している。
Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
In addition, the pH is adjusted to the range of 5.5 to 7.0 unless otherwise specified.
(実施例1〜11:液剤)
(実施例12:点眼剤)
アシクロビル 0.3g
マレイン酸クロルフェニラミン 1.0g
塩酸ナファゾリン 1.0g
プロピレングリコール 5.0g
ポリソルベート80 0.5g
pH調整剤 適量
パラベン 適量
精製水 全100mL
全成分を精製水に加え全量100mLとし、攪拌、溶解させた後、ろ過して調製液を得た。
(Example 12: eye drops)
Acyclovir 0.3g
Chlorpheniramine maleate 1.0g
1.0 g of naphazoline hydrochloride
Propylene glycol 5.0g
Polysorbate 80 0.5g
pH adjuster qs paraben qs purified water 100ml
All components were added to purified water to make a total volume of 100 mL, stirred, dissolved, and then filtered to obtain a preparation.
(実施例13:点眼剤)
アシクロビル 0.3g
マレイン酸クロルフェニラミン 1.0g
塩酸ピリドキシン 1.0g
グリチルリチン酸ニカリウム 0.5g
ポリオキシエチレン硬化ヒマシ油 0.5g
pH調整剤 適量
パラベン 適量
精製水 全100mL
全成分を精製水に加え全量100mLとし、攪拌、溶解させた後、ろ過して調製液を得た。
(Example 13: eye drops)
Acyclovir 0.3g
Chlorpheniramine maleate 1.0g
Pyridoxine hydrochloride 1.0g
Dipotassium glycyrrhizinate 0.5g
Polyoxyethylene hydrogenated castor oil 0.5g
pH adjuster qs paraben qs purified water 100ml
All components were added to purified water to make a total volume of 100 mL, stirred, dissolved, and then filtered to obtain a preparation.
(実施例14:点眼剤)
アシクロビル 0.3g
マレイン酸クロルフェニラミン 0.5g
塩酸ピリドキシン 0.5g
グリチルリチン酸ニカリウム 0.5g
塩酸ナファゾリン 0.5g
ポリオキシエチレン硬化ヒマシ油 0.5g
パンテノール 0.1g
pH調整剤 適量
パラベン 適量
エデト酸ナトリウム塩 適量
精製水 全100mL
全成分を精製水に加え全量100mLとし、攪拌、溶解させた後、ろ過して調製液を得た。
(Example 14: eye drops)
Acyclovir 0.3g
Chlorpheniramine maleate 0.5g
Pyridoxine hydrochloride 0.5g
Dipotassium glycyrrhizinate 0.5g
Naphazoline hydrochloride 0.5g
Polyoxyethylene hydrogenated castor oil 0.5g
0.1 g of panthenol
pH adjuster qs paraben qs edetate sodium salt qs purified water total 100ml
All components were added to purified water to make a total volume of 100 mL, stirred, dissolved, and then filtered to obtain a preparation.
(実施例15:ゲル剤)
アシクロビル 5.0g
塩酸テトラカイン 2.0g
塩酸チアミン 1.0g
塩酸ピリドキシン 1.0g
L-メントール 1.0g
グリセリン 10.0g
エタノール 20.0g
カルボキシビニルポリマー 0.5g
キサンタンガム 0.3g
pH調整剤 適量
パラベン 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
精製水にカルボキシビニルポリマーを溶解させ、グリセリンに分散させたアシクロビルおよびキサンタンガムを加え、溶解、分散させたのち、pH調整剤以外の成分を水溶液に入れ攪拌・溶解させる。その後、pH調整剤を加えpH7.0のゲル剤を得た。
(Example 15: gel)
Acyclovir 5.0g
2.0 g of tetracaine hydrochloride
Thiamine hydrochloride 1.0g
Pyridoxine hydrochloride 1.0g
L-menthol 1.0g
Glycerin 10.0 g
20.0 g of ethanol
Carboxyvinyl polymer 0.5g
Xanthan gum 0.3g
pH adjuster qs paraben qs dibutylhydroxytoluene qs edetate sodium salt qs purified water 100g
After dissolving the carboxyvinyl polymer in purified water, adding acyclovir and xanthan gum dispersed in glycerin, dissolving and dispersing, components other than the pH adjuster are put into an aqueous solution and stirred and dissolved. Thereafter, a pH adjusting agent was added to obtain a gel agent having a pH of 7.0.
(実施例16:ゲル剤)
アシクロビル 5.0g
塩酸テトラカイン 1.0g
塩酸ナファゾリン 1.0g
塩酸ジフェンヒドラミン 1.0g
マレイン酸クロルフェニラミン 0.5g
グリチルリチン酸二カリウム 0.5g
L-メントール 1.0g
1,3-ブチレングリコール 10.0g
エタノール 50.0g
疎水化ヒドロキシプロピルセルロース 1.0g
pH調整剤 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
精製水にアシクロビルおよび疎水化ヒドロキシプロピルセルロースを分散させた1,3ブチレングリコールを添加したのち、その他の成分を溶解させた精製水を加えた。その後、pH調整剤を加えpH6.5のゲル剤を得た。
(Example 16: gel)
Acyclovir 5.0g
1.0 g of tetracaine hydrochloride
Naphazoline hydrochloride 1.0g
Diphenhydramine hydrochloride 1.0g
Chlorpheniramine maleate 0.5g
0.5 g of dipotassium glycyrrhizinate
L-menthol 1.0g
1,3-butylene glycol 10.0g
50.0 g of ethanol
Hydrophobized hydroxypropyl cellulose 1.0g
pH adjuster qs dibutylhydroxytoluene qs edetate sodium salt qs purified water total 100g
After adding 1,3-butylene glycol in which acyclovir and hydrophobic hydroxypropylcellulose were dispersed in purified water, purified water in which other components were dissolved was added. Thereafter, a pH adjusting agent was added to obtain a gel preparation having a pH of 6.5.
(実施例17:ゲル剤)
アシクロビル 5.0g
ベンジルアルコール 4.0g
塩酸リドカイン 2.0g
硝酸チアミン 0.5g
L-メントール 1.0g
プロピレングリコール 10.0g
エタノール 40.0g
カルボキシビニルポリマー 1.0g
疎水化ヒドロキシプロピルセルロース 0.5g
pH調整剤 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
精製水にカルボキシビニルポリマーを溶解させ、1,3-ブチレングリコールにアシクロビルおよび疎水化ヒドロキシプロピルセルロースを分散させたのち、その他の成分を溶解させた精製水を加えた。その後、pH調整剤を加えpH7.5のゲル剤を得た。
(Example 17: gel)
Acyclovir 5.0g
Benzyl alcohol 4.0g
Lidocaine hydrochloride 2.0g
Thiamine nitrate 0.5g
L-menthol 1.0g
Propylene glycol 10.0g
40.0 g of ethanol
Carboxyvinyl polymer 1.0g
Hydrophobized hydroxypropyl cellulose 0.5g
pH adjuster qs dibutylhydroxytoluene qs edetate sodium salt qs purified water total 100g
The carboxyvinyl polymer was dissolved in purified water, acyclovir and hydrophobized hydroxypropylcellulose were dispersed in 1,3-butylene glycol, and then purified water in which other components were dissolved was added. Thereafter, a pH adjusting agent was added to obtain a gel agent having a pH of 7.5.
(実施例18:ゲル剤)
アシクロビル 5.0g
カフェイン 2.0g
塩酸リドカイン 2.0g
塩酸チアミン 0.5g
塩酸ピリドキシン 0.5g
L-メントール 1.0g
グリセリン 5.0g
エタノール 10.0g
カルボキシビニルポリマー 1.0g
キサンタンガム 0.3g
pH調整剤 適量
パラベン 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
精製水にカルボキシビニルポリマーを溶解させ、1,3-ブチレングリコールにアシクロビルおよびキサンタンガムを分散させたのち、その他の成分を溶解させた精製水を加えた。その後、pH調整剤を加えpH6.0のゲル剤を得た。
(Example 18: gel)
Acyclovir 5.0g
2.0g caffeine
Lidocaine hydrochloride 2.0g
Thiamine hydrochloride 0.5g
Pyridoxine hydrochloride 0.5g
L-menthol 1.0g
Glycerin 5.0g
10.0 g of ethanol
Carboxyvinyl polymer 1.0g
Xanthan gum 0.3g
pH adjuster qs paraben qs dibutylhydroxytoluene qs edetate sodium salt qs purified water total 100g
The carboxyvinyl polymer was dissolved in purified water, acyclovir and xanthan gum were dispersed in 1,3-butylene glycol, and then purified water in which other components were dissolved was added. Thereafter, a pH adjuster was added to obtain a gel preparation having a pH of 6.0.
(実施例19:クリーム剤)
アシクロビル 5.0g
塩酸テトラカイン 2.0g
塩酸チアミン 0.5g
塩酸ピリドキシン 0.5g
L-メントール 0.5g
プロピレングリコール 10.0g
スクワレン 5.0g
ミリスチン酸オクチルドデシル 5.0g
セトステアリルアルコール 5.0g
ポリソルベート60 3.0g
ステアリン酸モノグリセリド 1.5g
カルボキシルビニルポリマー 0.5g
シリコン 1.0g
pH調整剤 適量
パラベン 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
カルボキシビニルポリマーを精製水に溶解させ、アシクロビルおよび水性成分を添加し、卓上ホモミキサー(T.K.アヂホモミクサー2M-03型、特殊機化工業社製)用容器に入れ、脱気後、掻き取りミキサーで攪拌しながら80℃に加温した。これに予め加温し融解させておいた油性成分をホッパーから添加し、50℃まで冷却した。8000rpmで3分間ホモジナイズし、均一化した。掻き取りミキサーで攪拌しながら室温まで冷却し、その他の有効成分を溶解させた水溶液を添加した。最後にpH調整剤を添加しpHを7.0に調整し、ゲル化させクリーム剤を調製した。
(Example 19: cream)
Acyclovir 5.0g
2.0 g of tetracaine hydrochloride
Thiamine hydrochloride 0.5g
Pyridoxine hydrochloride 0.5g
L-menthol 0.5g
Propylene glycol 10.0g
Squalene 5.0g
Octyldodecyl myristate 5.0g
5.0 g of setosteryl alcohol
Polysorbate 60 3.0g
Stearic acid monoglyceride 1.5g
Carboxyvinyl polymer 0.5g
Silicone 1.0g
pH adjuster qs paraben qs dibutylhydroxytoluene qs edetate sodium salt qs purified water 100g
Dissolve the carboxyvinyl polymer in purified water, add acyclovir and aqueous components, put it in a container for tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo), degas, and stir with a scraping mixer While heating to 80 ° C. The oily component which had been heated and melted in advance was added thereto from a hopper, and cooled to 50 ° C. Homogenized at 8000 rpm for 3 minutes to homogenize. The mixture was cooled to room temperature while stirring with a scraping mixer, and an aqueous solution in which other active ingredients were dissolved was added. Finally, a pH adjuster was added to adjust the pH to 7.0, and the mixture was gelled to prepare a cream.
(実施例20:クリーム剤)
アシクロビル 5.0g
塩酸テトラカイン 1.0g
塩酸ナファゾリン 1.0g
塩酸ジフェンヒドラミン 1.0g
マレイン酸クロルフェニラミン 0.5g
グリチルリチン酸二カリウム 0.5g
L-メントール 1.0g
グリセリン 5.0g
1,3-ブチレングリコール 10.0g
スクワラン 10.0g
ステアリン酸 5.0g
セタノール 2.0g
ステアリン酸シュガーエステル 2.0g
キサンタンガム 0.3g
シリコン 1.0g
pH調整剤 適量
パラベン 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
キサンタンガムを精製水に溶解させ、アシクロビルおよび水性成分を添加し、卓上ホモミキサー(T.K.アヂホモミクサー2M-03型、特殊機化工業社製)用容器に入れ、脱気後、掻き取りミキサーで攪拌しながら80℃に加温した。これに予め加温し融解させておいた油性成分をホッパーから添加し、50℃まで冷却した。8000rpmで3分間ホモジナイズし、均一化した。掻き取りミキサーで攪拌しながら室温まで冷却し、その他の有効成分を溶解させた水溶液を添加した。最後にpH調整剤を添加しpHを6.5に調整し、クリーム剤を調製した。
(Example 20: cream)
Acyclovir 5.0g
1.0 g of tetracaine hydrochloride
Naphazoline hydrochloride 1.0g
Diphenhydramine hydrochloride 1.0g
Chlorpheniramine maleate 0.5g
0.5 g of dipotassium glycyrrhizinate
L-menthol 1.0g
Glycerin 5.0g
1,3-butylene glycol 10.0g
Squalane 10.0g
5.0 g of stearic acid
Cetanol 2.0g
Stearic acid sugar ester 2.0g
Xanthan gum 0.3g
Silicone 1.0g
pH adjuster qs paraben qs dibutylhydroxytoluene qs edetate sodium salt qs purified water 100g
Dissolve xanthan gum in purified water, add acyclovir and aqueous components, place in a container for tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo), degas, and stir with a scraping mixer. Heated to 80 ° C. The oily component which had been heated and melted in advance was added thereto from a hopper, and cooled to 50 ° C. Homogenized at 8000 rpm for 3 minutes to homogenize. The mixture was cooled to room temperature while stirring with a scraping mixer, and an aqueous solution in which other active ingredients were dissolved was added. Finally, a pH adjusting agent was added to adjust the pH to 6.5 to prepare a cream.
(実施例21:クリーム剤)
アシクロビル 5.0g
ベンジルアルコール 4.0g
塩酸リドカイン 2.0g
硝酸チアミン 0.5g
L-メントール 1.0g
1,3-ブチレングリコール 10.0g
グリセリン 5.0g
流動パラフィン 5.0g
ミリスチン酸イソプロピル 10.0g
セトステアリルアルコール 4.0g
ポリソルベート60 2.0g
ポリグリセリンステアリン酸エステル 1.0g
ステアリン酸モノグリセリド 1.0g
カルボキシルビニルポリマー 1.0g
シリコン 1.0g
pH調整剤 適量
パラベン 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
カルボキシビニルポリマーを精製水に溶解させ、アシクロビルおよび水性成分を添加し、卓上ホモミキサー(T.K.アヂホモミクサー2M-03型、特殊機化工業社製)用容器に入れ、脱気後、掻き取りミキサーで攪拌しながら80℃に加温した。これに予め加温し融解させておいた油性成分をホッパーから添加し、50℃まで冷却した。8000rpmで3分間ホモジナイズし、均一化した。掻き取りミキサーで攪拌しながら室温まで冷却し、その他の有効成分を溶解させた水溶液を添加した。最後にpH調整剤を添加しpHを7.0に調整し、ゲル化させクリーム剤を調製した。
(Example 21: cream)
Acyclovir 5.0g
Benzyl alcohol 4.0g
Lidocaine hydrochloride 2.0g
Thiamine nitrate 0.5g
L-menthol 1.0g
1,3-butylene glycol 10.0g
Glycerin 5.0g
Liquid paraffin 5.0g
Isopropyl myristate 10.0 g
4.0 g of setosteryl alcohol
Polysorbate 60 2.0g
Polyglycerin stearate 1.0g
Stearic acid monoglyceride 1.0g
Carboxyvinyl polymer 1.0g
Silicone 1.0g
pH adjuster qs paraben qs dibutylhydroxytoluene qs edetate sodium salt qs purified water 100g
Dissolve the carboxyvinyl polymer in purified water, add acyclovir and aqueous components, put it in a container for tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo), degas, and stir with a scraping mixer While heating to 80 ° C. The oily component which had been heated and melted in advance was added to this from a hopper, and cooled to 50 ° C. Homogenized at 8000 rpm for 3 minutes to homogenize. The mixture was cooled to room temperature while stirring with a scraping mixer, and an aqueous solution in which other active ingredients were dissolved was added. Finally, a pH adjuster was added to adjust the pH to 7.0, and the mixture was gelled to prepare a cream.
(実施例22:クリーム剤)
アシクロビル 5.0g
カフェイン 2.0g
塩酸リドカイン 2.0g
塩酸チアミン 0.5g
塩酸ピリドキシン 0.5g
L-メントール 1.0g
プロピレングリコール 10.0g
グリセリン 5.0g
流動パラフィン 5.0g
パナセート 10.0g
セトステアリルアルコール 4.0g
モノステアリン酸ソルビタン 1.5g
モノステアリン酸POE(20)ソルビタン 1.5g
カルボキシルビニルポリマー 1.0g
シリコン 1.0g
pH調整剤 適量
パラベン 適量
ジブチルヒドロキシトルエン 適量
エデト酸ナトリウム塩 適量
精製水 全100g
カルボキシビニルポリマーを精製水に溶解させ、アシクロビルおよび水性成分を添加し、卓上ホモミキサー(T.K.アヂホモミクサー2M-03型、特殊機化工業社製)用容器に入れ、脱気後、掻き取りミキサーで攪拌しながら80℃に加温した。これに予め加温し融解させておいた油性成分をホッパーから添加し、50℃まで冷却した。8000rpmで3分間ホモジナイズし、均一化した。掻き取りミキサーで攪拌しながら室温まで冷却し、その他の有効成分を溶解させた水溶液を添加した。最後にpH調整剤を添加しpHを7.0に調整し、ゲル化させクリーム剤を調製した。
(Example 22: cream)
Acyclovir 5.0g
2.0g caffeine
Lidocaine hydrochloride 2.0g
Thiamine hydrochloride 0.5g
Pyridoxine hydrochloride 0.5g
L-menthol 1.0g
Propylene glycol 10.0g
Glycerin 5.0g
Liquid paraffin 5.0g
Panassate 10.0g
4.0 g of setosteryl alcohol
Sorbitan monostearate 1.5g
1.5 g of POE (20) sorbitan monostearate
Carboxyvinyl polymer 1.0g
Silicone 1.0g
pH adjuster qs paraben qs dibutylhydroxytoluene qs edetate sodium salt qs purified water 100g
Dissolve the carboxyvinyl polymer in purified water, add acyclovir and aqueous components, put it in a container for tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo), degas, and stir with a scraping mixer While heating to 80 ° C. The oily component which had been heated and melted in advance was added thereto from a hopper, and cooled to 50 ° C. Homogenized at 8000 rpm for 3 minutes to homogenize. The mixture was cooled to room temperature while stirring with a scraping mixer, and an aqueous solution in which other active ingredients were dissolved was added. Finally, a pH adjuster was added to adjust the pH to 7.0, and the mixture was gelled to prepare a cream.
(実施例23:水性軟膏)
アシクロビル 5.0g
塩酸テトラカイン 2.0g
塩酸チアミン 0.5g
塩酸ピリドキシン 0.5g
L-メントール 0.5g
1,3-ブチレングリコール 10.0g
ポリエチレングリコール4000 25.0g
エタノール 15.0g
ポリエチレングリコール300 全100g
ポリエチレングリコール4000を卓上ホモミキサー(T.K.アヂホモミクサー2M−03型、特殊機化工業社製)用容器に入れ、掻き取りミキサーで攪拌しながら60℃で融解させた。これに予め各成分を分散させた1,3−ブチレングリコールとポリエチレングリコール300の混合液を添加し、脱気後、ホッパーからエタノールを添加し、8000rpmで3分間ホモジナイズした。均一化した後、掻き取りミキサーで攪拌しながら室温まで冷却し、水性軟膏剤を調製した。
(Example 23: aqueous ointment)
Acyclovir 5.0g
2.0 g of tetracaine hydrochloride
Thiamine hydrochloride 0.5g
Pyridoxine hydrochloride 0.5g
L-menthol 0.5g
1,3-butylene glycol 10.0g
Polyethylene glycol 4000 25.0g
15.0 g of ethanol
Polyethylene glycol 300 total 100g
Polyethylene glycol 4000 was placed in a container for a tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo KK) and melted at 60 ° C while stirring with a scraping mixer. A mixed solution of 1,3-butylene glycol and polyethylene glycol 300 in which the respective components were dispersed in advance was added thereto, and after degassing, ethanol was added from a hopper and homogenized at 8000 rpm for 3 minutes. After homogenization, the mixture was cooled to room temperature while stirring with a scraping mixer to prepare an aqueous ointment.
(実施例24:水性軟膏)
アシクロビル 5.0g
塩酸テトラカイン 1.0g
塩酸ナファゾリン 1.0g
塩酸ジフェンヒドラミン 1.0g
マレイン酸クロルフェニラミン 0.5g
グリチルリチン酸二カリウム 0.5g
L-メントール 1.0g
グリセリン 5.0g
プロピレングリコール 10.0g
ポリエチレングリコール6000 20.0g
ポリエチレングリコール400 全100g
ポリエチレングリコール6000を卓上ホモミキサー(T.K.アヂホモミクサー2M−03型、特殊機化工業社製)用容器に入れ、掻き取りミキサーで攪拌しながら60℃で融解させた。これに予め各成分を分散させておいたグリセリン、プロピレングリコールとポリエチレングリコール400の混合液を添加し、脱気後、ホッパーからエタノールを添加し、8000rpmで3分間ホモジナイズした。均一化した後、掻き取りミキサーで攪拌しながら室温まで冷却し、水性軟膏剤を調製した。
(Example 24: aqueous ointment)
Acyclovir 5.0g
1.0 g of tetracaine hydrochloride
Naphazoline hydrochloride 1.0g
Diphenhydramine hydrochloride 1.0g
Chlorpheniramine maleate 0.5g
0.5 g of dipotassium glycyrrhizinate
L-menthol 1.0g
Glycerin 5.0g
Propylene glycol 10.0g
Polyethylene glycol 6000 20.0 g
Polyethylene glycol 400 total 100g
Polyethylene glycol 6000 was placed in a container for a desk-top homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo KK) and melted at 60 ° C while stirring with a scraping mixer. A mixed solution of glycerin, propylene glycol and polyethylene glycol 400 in which the respective components were dispersed in advance was added thereto, and after degassing, ethanol was added from a hopper and homogenized at 8000 rpm for 3 minutes. After homogenization, the mixture was cooled to room temperature while stirring with a scraping mixer to prepare an aqueous ointment.
(実施例25:水性軟膏)
アシクロビル 5.0g
ベンジルアルコール 4.0g
塩酸リドカイン 2.0g
硝酸チアミン 0.5g
L-メントール 1.0g
ポリエチレングリコール400 25.0g
ポリエチレングリコール4000 25.0g
エタノール 10.0g
1,3-ブチレングリコール 全100g
ポリエチレングリコール4000を卓上ホモミキサー(T.K.アヂホモミクサー2M−03型、特殊機化工業社製)用容器に入れ、掻き取りミキサーで攪拌しながら60℃で融解させた。これに予め各成分を分散させておいた1,3−ブチレングリコールとポリエチレングリコール400の混合液を添加し、脱気後、ホッパーからエタノールを添加し、8000rpmで3分間ホモジナイズした。均一化した後、掻き取りミキサーで攪拌しながら室温まで冷却し、水性軟膏剤を調製した。
(Example 25: aqueous ointment)
Acyclovir 5.0g
Benzyl alcohol 4.0g
Lidocaine hydrochloride 2.0g
Thiamine nitrate 0.5g
L-menthol 1.0g
Polyethylene glycol 400 25.0g
Polyethylene glycol 4000 25.0g
Ethanol 10.0g
1,3-butylene glycol 100g
Polyethylene glycol 4000 was placed in a container for a tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo KK) and melted at 60 ° C while stirring with a scraping mixer. A mixed solution of 1,3-butylene glycol and polyethylene glycol 400 in which the respective components were dispersed in advance was added thereto, and after degassing, ethanol was added from a hopper and homogenized at 8000 rpm for 3 minutes. After homogenization, the mixture was cooled to room temperature while stirring with a scraping mixer to prepare an aqueous ointment.
(実施例26:水性軟膏)
アシクロビル 5.0g
カフェイン 2.0g
塩酸リドカイン 2.0g
塩酸チアミン 0.5g
塩酸ピリドキシン 0.5g
L-メントール 0.5g
ポリエチレングリコール4000 25.0g
ポリエチレングリコール400 全100g
ポリエチレングリコール4000を卓上ホモミキサー(T.K.アヂホモミクサー2M−03型、特殊機化工業社製)用容器に入れ、掻き取りミキサーで攪拌しながら60℃で融解させた。これに予め各成分を分散させておいたポリエチレングリコール400を添加し、脱気後、3分間ホモジナイズした。均一化した後、掻き取りミキサーで攪拌しながら室温まで冷却し、水性軟膏剤を調製した。
(Example 26: aqueous ointment)
Acyclovir 5.0g
2.0g caffeine
Lidocaine hydrochloride 2.0g
Thiamine hydrochloride 0.5g
Pyridoxine hydrochloride 0.5g
L-menthol 0.5g
Polyethylene glycol 4000 25.0g
Polyethylene glycol 400 total 100g
Polyethylene glycol 4000 was placed in a container for a tabletop homomixer (TK A homomixer 2M-03, manufactured by Tokushu Kika Kogyo KK) and melted at 60 ° C while stirring with a scraping mixer. To this was added polyethylene glycol 400 in which the respective components were dispersed in advance, and after deaeration, homogenized for 3 minutes. After homogenization, the mixture was cooled to room temperature while stirring with a scraping mixer to prepare an aqueous ointment.
(試験例1)各成分水溶液に対するアシクロビルの飽和溶解度(25℃)
塩酸ナファゾリン、カフェイン,塩酸テトラカイン、ベンジルアルコール、塩酸チアミン、硝酸チアミン,塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミン、塩酸ピリドキシン、塩酸リドカインおよびグリチルリチン酸二カリウムの各濃度の水溶液を調製し、十分量のアシクロビル(1質量%)を水溶液に添加する。25℃で24時間以上攪拌した後、ろ過液中のアシクロビルをHPLC法で定量した。比較例として精製水およびL-アルギニン(pH7.0に調整)についても同様に定量した。表2に各成分濃度,アシクロビルの飽和溶解度,アシクロビル飽和溶液のpHおよび各成分濃度に対するアシクロビル飽和溶解度のプロットを直線で結んだ際の傾きを示す。
(Test Example 1) Saturated solubility of acyclovir in each component aqueous solution (25 ° C)
Prepare an aqueous solution of each concentration of naphazoline hydrochloride, caffeine, tetracaine hydrochloride, benzyl alcohol, thiamine hydrochloride, thiamine nitrate, diphenhydramine hydrochloride, chlorpheniramine maleate, pyridoxine hydrochloride, lidocaine hydrochloride, and dipotassium glycyrrhizinate. Acyclovir (1% by weight) is added to the aqueous solution. After stirring at 25 ° C. for 24 hours or more, acyclovir in the filtrate was quantified by the HPLC method. As comparative examples, purified water and L-arginine (adjusted to pH 7.0) were similarly quantified. Table 2 shows the slope obtained by connecting plots of the concentration of each component, the saturated solubility of acyclovir, the pH of the saturated solution of acyclovir, and the saturated solubility of acyclovir to each component concentration with a straight line.
以上のように、各成分はアシクロビルの飽和溶解度を濃度依存的に改善した。各水溶液のアシクロビル飽和溶解度は、0.5質量%以上含有させることで、精製水の飽和溶解度(1.3mg/mL)と比較して向上している。このことから、製剤中のアシクロビル溶解性が増し、皮膚や粘膜への透過性の改善が期待される。これに対し、従来アシクロビルの溶解補助剤として使用されていたL-アルギニンは、中性付近において、アシクロビルの飽和溶解度を向上させる効果は示さなかった。
As described above, each component improved the saturated solubility of acyclovir in a concentration-dependent manner. The acyclovir saturation solubility of each aqueous solution is improved by containing 0.5% by mass or more as compared with the saturation solubility (1.3 mg / mL) of purified water. From this, it is expected that the solubility of acyclovir in the preparation is increased and the permeability to skin and mucous membrane is improved. In contrast, L-arginine, which was conventionally used as a solubilizing agent for acyclovir, did not show an effect of improving the saturated solubility of acyclovir near neutrality.
Claims (7)
(B) Nafazoline hydrochloride, hydrochloric acid for improving the solubility of acyclovir in the composition when producing a water-soluble external preparation containing acyclovir in an amount of 0.13% by mass or more based on the whole external preparation composition Use of at least one selected from tetracaine, benzyl alcohol, caffeine, diphenhydramine hydrochloride, pyridoxine hydrochloride, chlorpheniramine maleate, lidocaine hydrochloride, dipotassium glycyrrhizinate, thiamine hydrochloride and thiamine nitrate.
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JP2006069946A (en) * | 2004-09-01 | 2006-03-16 | Aska Pharmaceutical Co Ltd | Aqueous suspension for microdetermination spraying |
JP2007091713A (en) * | 2005-08-29 | 2007-04-12 | Taisho Pharmaceut Co Ltd | O/w type emulsion composition |
JP2008533052A (en) * | 2005-03-10 | 2008-08-21 | スリーエム イノベイティブ プロパティズ カンパニー | Antiviral compositions and methods of use |
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WO1998043643A1 (en) * | 1997-04-01 | 1998-10-08 | Toa Medicine Co., Ltd. | Aqueous acyclovir solution preparations |
JP2001500863A (en) * | 1996-09-11 | 2001-01-23 | バイロテックス コーポレイション | Compositions and methods for topical application of therapeutic agents |
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Patent Citations (2)
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JP2001500863A (en) * | 1996-09-11 | 2001-01-23 | バイロテックス コーポレイション | Compositions and methods for topical application of therapeutic agents |
WO1998043643A1 (en) * | 1997-04-01 | 1998-10-08 | Toa Medicine Co., Ltd. | Aqueous acyclovir solution preparations |
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