TWI712429B

TWI712429B - Water-based pharmaceutical composition

Info

Publication number: TWI712429B
Application number: TW104109754A
Authority: TW
Inventors: 三戶靖子
Original assignee: 日商小林製藥股份有限公司
Priority date: 2014-03-31
Filing date: 2015-03-26
Publication date: 2020-12-11
Also published as: WO2015152079A1; KR102288699B1; JP2015196652A; TW201622700A; KR20160138179A; JP6333023B2

Abstract

本發明以提供搭配尿囊素且安定的水性醫藥組成物為課題。 The present invention provides stable water-based medicine with allantoin The composition is the subject.

本發明提供含有尿囊素以及氯化氫之水性醫藥組成物等。本發明之水性醫藥組成物為，即使在高pH下尿囊素仍然穩定，對洗眼劑等也有用。 The present invention provides water containing allantoin and hydrogen chloride Sex medicine composition, etc. The aqueous pharmaceutical composition of the present invention is stable even at high pH, and is useful for eye washes and the like.

Description

Water-based pharmaceutical composition

本發明與尿囊素安定化之水性醫藥組成物有關。 The present invention is related to the stabilized water-based medical composition of allantoin.

尿囊素為，已知具有細胞增殖力的強化作用、創傷的促進修復作用、結膜的鎮炎作用、抗過敏作用等之化合物，被用來搭配醫藥品或化妝品。然而，尿囊素對水的溶解度極低，也欠缺在高溫下的安定性。此外，因為在pH5附近開始分解，在pH6則幾乎完全分解(例如非專利文獻1)，所以能搭配的製品有限。 Allantoin is a compound known to have a strengthening effect of cell proliferation, an effect of promoting repair of wounds, an anti-inflammatory effect of conjunctiva, an anti-allergic effect, etc., and it is used in combination with medicines or cosmetics. However, allantoin has extremely low solubility in water and lacks stability at high temperatures. In addition, since it starts to decompose at around pH 5, it decomposes almost completely at pH 6 (for example, Non-Patent Document 1), so products that can be matched are limited.

尤其是，因為洗眼劑在醫藥品製造販賣承認基準(DRUG APPROVAL AND LICENSING PROCEDURES IN JAPAN)中被規定為pH5.5以上，因此被認為很難搭配尿囊素。 In particular, because eye washes are specified as pH 5.5 or higher in the DRUG APPROVAL AND LICENSING PROCEDURES IN JAPAN (DRUG APPROVAL AND LICENSING PROCEDURES IN JAPAN), it is considered difficult to mix allantoin.

[Prior technical literature] 〔Non-patent literature〕

[非專利文獻1]日本藥學雜誌 113(7) 515-524 (1993) [Non-Patent Document 1] The Japanese Journal of Pharmaceuticals 113(7) 515-524 (1993)

尿囊素的細胞增殖力的強化作用、創傷的促進修復作用、結膜的鎮炎作用、抗過敏作用，是做為以滴眼劑或洗眼劑為首的眼科用水性醫藥組成物、外皮用殺菌消毒劑、皮膚炎治療藥、痔疾用藥、口腔內殺菌劑、滴鼻劑、洗鼻劑等各種醫藥組成物也有用的。在此，本發明以提供搭配尿囊素之安定的水性醫藥組成物為課題。 Allantoin's cell proliferation enhancement effect, wound promotion and repair effect, conjunctival anti-inflammatory effect and anti-allergic effect. It is used as an ophthalmic water-based pharmaceutical composition, including eye drops or eye washes, and sterilization and disinfection of the skin Various medical compositions such as medicines, dermatitis treatment medicines, hemorrhoids medicines, intraoral bactericides, nose drops, and nasal washes are also useful. Here, the subject of the present invention is to provide a stable aqueous pharmaceutical composition with allantoin.

本發明者群，為了解決上述課題經過反覆專注研討，結果發現藉由在搭配尿囊素的水溶液中添加氯化氫，尿囊素的安定性會顯著提升。 The inventors of the present invention have conducted repeated intensive studies in order to solve the above-mentioned problems and found that by adding hydrogen chloride to an aqueous solution with allantoin, the stability of allantoin can be significantly improved.

進一步界定，使尿囊素特別安定的氯化氫添加量和pH，以及其他添加物，並完成本項發明。 Further define the addition amount of hydrogen chloride and pH, and other additives that make the allantoin particularly stable, and complete this invention.

即，本發明為， That is, the present invention is,

[1]一種含有尿囊素以及氯化氫的水性醫藥組成物。 [1] An aqueous pharmaceutical composition containing allantoin and hydrogen chloride.

[2]如[1]之水性醫藥組成物，其中，前述氯化氫的含有量為0.18mg/100mL~2.19mg/100mL。 [2] The aqueous pharmaceutical composition according to [1], wherein the content of the aforementioned hydrogen chloride is 0.18 mg/100 mL to 2.19 mg/100 mL.

[3]如[1]或[2]之水性醫藥組成物，其中，進一步含有鹽酸吡哆醇。 [3] The aqueous pharmaceutical composition according to [1] or [2], which further contains pyridoxine hydrochloride.

[4]如[1]~[3]中任一項之水性醫藥組成物，其中，前述水性醫藥組成物之pH為5.5~6.3。 [4] The aqueous pharmaceutical composition according to any one of [1] to [3], wherein the pH of the aforementioned aqueous pharmaceutical composition is 5.5 to 6.3.

[5]如[1]~[4]中任一項之水性醫藥組成物，其中，前述水性醫藥組成物為眼科用水性組成物。 [5] The aqueous pharmaceutical composition as in any one of [1] ~ [4], wherein the former The aqueous medical composition is an ophthalmic aqueous composition.

[6]如[5]之水性醫藥組成物，其中，前述眼科用水性組成物為洗眼劑。 [6] The aqueous pharmaceutical composition according to [5], wherein the aforementioned ophthalmic aqueous composition is an eye wash.

[7]一種方法，其係水性醫藥組成物中之尿囊素的安定化方法，其特徵為包含將氯化氫添加於前述水性醫藥組成物之步驟。 [7] A method, which is a method for stabilizing allantoin in an aqueous pharmaceutical composition, characterized by including the step of adding hydrogen chloride to the aforementioned aqueous pharmaceutical composition.

[8]如[7]之方法，其中，前述氯化氫的添加量為0.18mg/100mL~2.19mg/100mL。 [8] The method of [7], wherein the addition amount of the aforementioned hydrogen chloride is 0.18 mg/100 mL to 2.19 mg/100 mL.

[9]如[7]或[8]之方法，其進一步包含將鹽酸吡哆醇添加於前述水性醫藥組成物之步驟。 [9] The method of [7] or [8], which further comprises a step of adding pyridoxine hydrochloride to the aforementioned aqueous pharmaceutical composition.

[10]如[7]~[9]中任一項之方法，其包含將前述水性醫藥組成物的pH調整至5.5~6.3。 [10] The method according to any one of [7] to [9], which comprises adjusting the pH of the aforementioned aqueous pharmaceutical composition to 5.5 to 6.3.

[11]如[7]~[10]中任一項之方法，其中，前述水性醫藥組成物為眼科用水性組成物。 [11] The method according to any one of [7] to [10], wherein the aforementioned aqueous pharmaceutical composition is an ophthalmic aqueous composition.

[12]如[11]之方法，其中，前述眼科用水性組成物為洗眼劑。 [12] The method of [11], wherein the aforementioned ophthalmic aqueous composition is an eye wash.

藉由本發明，由於尿囊素安定地與水性組成物搭配，因此可得到具有細胞增殖力的強化作用、創傷的促進修復作用、結膜的鎮炎作用、抗過敏作用等的水性醫藥組成物。本發明之水性醫藥組成物，做為發揮尿囊素作用的眼科用水性組成物、外皮用殺菌消毒劑、蟲叮咬藥、止癢藥、皮膚炎治療藥、痔疾用藥、口腔內殺菌劑、滴鼻劑、洗鼻劑等是有用的。此外，本發明之水性醫藥組成物，因為即使在高pH尿囊素也安定，所以做為洗眼劑也是有用的。 According to the present invention, since allantoin is stably matched with the aqueous composition, an aqueous pharmaceutical composition having a strengthening effect of cell proliferation, an effect of promoting repair of wounds, an anti-inflammatory effect of conjunctiva, an anti-allergic effect, etc. can be obtained. The aqueous pharmaceutical composition of the present invention is used as an ophthalmic aqueous composition that exerts the effect of allantoin, an antiseptic for skin, insect bite medicine, antipruritic, dermatitis treatment, hemorrhoid medication, intraoral bactericide, drops Nasal agent, Nasal wash etc. are useful. In addition, the aqueous pharmaceutical composition of the present invention is also useful as an eye wash because allantoin is stable even at high pH.

[圖1]圖1所示為，改變氯化氫的量調製含有尿囊素之眼科用水性組成物，在60℃下保存1週後之尿囊素量的分析結果(殘存率)。 [Figure 1] Figure 1 shows the analysis results (residual rate) of the amount of allantoin after preparing an aqueous ophthalmic composition containing allantoin by changing the amount of hydrogen chloride, and storing it at 60°C for 1 week.

[圖2]圖2所示為，添加眼科用水性組成物常用的各種成分並調製含有尿囊素之眼科用水性組成物，在60℃下保存1週後之尿囊素量的分析結果(殘存率)。 [Figure 2] Figure 2 shows the analysis results of the amount of allantoin after adding various components commonly used in ophthalmic aqueous compositions to prepare an ophthalmic aqueous composition containing allantoin and storing it at 60°C for 1 week ( Survival rate).

本發明之水性醫藥組成物為，含有尿囊素及氯化氫。本說明書中所謂「水性醫藥組成物」，意指水性的醫藥組成物，其適用對象並無特殊限制。做為水性醫藥組成物，例如，可舉出眼科用水性組成物、外皮用殺菌消毒劑、蟲叮咬藥、止癢藥、皮膚炎治療藥、痔疾用藥、口腔內殺菌劑、滴鼻劑、洗鼻劑等，但並不受限於此等。 The aqueous pharmaceutical composition of the present invention contains allantoin and hydrogen chloride. The term "aqueous pharmaceutical composition" in this specification means an aqueous pharmaceutical composition, and there is no particular limitation on its applicable object. As an aqueous pharmaceutical composition, for example, ophthalmic aqueous composition, bactericidal disinfectant for outer skin, insect bite medicine, antipruritic medicine, dermatitis treatment medicine, hemorrhoid medicine, intraoral disinfectant, nasal drops, wash Nasal agents, but not limited to these.

尿囊素為，CAS編號97-59-6的化合物，已知具有細胞增殖力的強化作用、創傷的促進修復作用、結膜的鎮炎作用、抗過敏作用等。本發明之水性醫藥組成物中尿囊素的搭配量為，只要能得到做為目的之尿囊素具有的作用，且尿囊素安定搭配即無特殊限制，但舉例來說，0.006 w/v%(=g/100mL)以上，0.01w/v%以上，0.02w/v%以上，0.025w/v%以上，0.03w/v%以上亦可，0.3w/v%以下，0.15w/v%以下，0.08w/v%以下，0.06w/v%以下亦可。 Allantoin is a compound with CAS number 97-59-6, and is known to have a strengthening effect of cell proliferation, an effect of promoting repair of wounds, an anti-inflammatory effect of conjunctiva, an anti-allergic effect, etc. The amount of allantoin in the aqueous pharmaceutical composition of the present invention is as long as the purpose of allantoin can be obtained, and there is no special restriction on the stability of allantoin, but for example, 0.006 Above w/v% (=g/100mL), above 0.01w/v%, above 0.02w/v%, above 0.025w/v%, above 0.03w/v% is acceptable, below 0.3w/v%, 0.15 w/v% or less, 0.08w/v% or less, or 0.06w/v% or less.

本發明之水性醫藥組成物中氯化氫的搭配量為，只要尿囊素能被安定化即無特殊限制，但舉例來說，0.09mg/100mL以上，0.12mg/100mL以上，0.15mg/100mL以上，0.18mg/100mL以上亦可，2.92mg/100mL以下，2.56mg/100mL以下，2.19mg/100mL以下，1.83mg/100mL以下亦可。相對於本發明之水性醫藥組成物中所包含之尿囊素1重量份，氯化氫的比例為，舉例來說，0.001以上，0.005以上，0.006以上亦可，0.097以下，0.085以下，0.073以下，0.061以下亦可。而且，以設定在0.001~0.097重量份為佳，0.005~0.85重量份為更佳，0.005~0.073重量份為進一步更佳，0.005~0.061為特佳，0.006~0.061重量份為最佳之範圍內為宜。 The amount of hydrogen chloride in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as allantoin can be stabilized, but for example, 0.09mg/100mL or more, 0.12mg/100mL or more, 0.15mg/100mL or more, 0.18mg/100mL or more, 2.92mg/100mL or less, 2.56mg/100mL or less, 2.19mg/100mL or less, 1.83mg/100mL or less. With respect to 1 part by weight of allantoin contained in the aqueous pharmaceutical composition of the present invention, the proportion of hydrogen chloride is, for example, 0.001 or more, 0.005 or more, 0.006 or more, 0.097 or less, 0.085 or less, 0.073 or less, 0.061 The following is also possible. Moreover, it is preferably set at 0.001 to 0.097 parts by weight, more preferably 0.005 to 0.85 parts by weight, still more preferably 0.005 to 0.073 parts by weight, particularly preferably 0.005 to 0.061, and most preferably within the range of 0.006 to 0.061 parts by weight Appropriate.

本發明之水性醫藥組成物，可進一步含有鹽酸吡哆醇。鹽酸吡哆醇的搭配量為，只要尿囊素能被安定化即無特殊限制，也可為普通搭配水性醫藥組成物的量。鹽酸吡哆醇的搭配量為，舉例來說，0.001w/v%以上，0.002w/v%(=g/100mL)以上，0.003w/v%以上，0.004w/v%以上，0.005w/v%以上亦可，0.1w/v%以下，0.09w/v%以下，0.08w/v%以下，0.07w/v%以下，0.06w/v%以下，0.05w/v%以下亦可。 The aqueous pharmaceutical composition of the present invention may further contain pyridoxine hydrochloride. The amount of pyridoxine hydrochloride is not particularly limited as long as the allantoin can be stabilized, and it can also be the amount of ordinary water-based pharmaceutical compositions. The matching amount of pyridoxine hydrochloride is, for example, 0.001w/v% or more, 0.002w/v% (=g/100mL) or more, 0.003w/v% or more, 0.004w/v% or more, 0.005w/ V% or more is acceptable, 0.1w/v% or less, 0.09w/v% or less, 0.08w/v% or less, 0.07w/v% or less, 0.06w/v% or less, or 0.05w/v% or less.

本發明之水性醫藥組成物，為了使尿囊素安定化，可調高pH，舉例來說，pH5.5以上，pH5.6以上，pH5.7以上，pH5.8以上亦可，pH6.3以下，pH6.2以下，pH6.1以下，pH6.0以下亦可。 In order to stabilize the allantoin, the aqueous pharmaceutical composition of the present invention can Adjust the pH, for example, pH 5.5 or higher, pH 5.6 or higher, pH 5.7 or higher, or pH 5.8 or higher, pH 6.3 or lower, pH 6.2 or lower, pH 6.1 or lower, or pH 6.0 or lower can.

pH的調整可循眾所周知的方法進行，舉例來說，也可藉由適量添加氫氧化鈉、碳酸氫鈉、碳酸鈉、三乙醇胺、或其乙醇胺，調整至期望的pH。 The pH can be adjusted by a well-known method. For example, it can be adjusted to a desired pH by adding an appropriate amount of sodium hydroxide, sodium bicarbonate, sodium carbonate, triethanolamine, or ethanolamine thereof.

本發明之水性醫藥組成物中，可視需要，添加可使用於水性醫藥組成物的其他成分。添加的其他成分，只要尿囊素能被安定化，且所得的水性醫藥組成物可做為水性醫藥組成物使用即無特殊限制，例如可舉出，抗發炎成分、收斂成分、抗組織胺成分、抗過敏成分、維生素類、胺基酸類、抗菌成分、殺菌成分、糖類、多醣類及其衍生物、纖維素及其衍生物、水溶性高分子、局部麻醉成分、類固醇成分。 In the aqueous pharmaceutical composition of the present invention, other components that can be used in the aqueous pharmaceutical composition can be added as needed. There are no special restrictions on the other ingredients added as long as the allantoin can be stabilized, and the resulting aqueous pharmaceutical composition can be used as an aqueous pharmaceutical composition, for example, anti-inflammatory ingredients, astringent ingredients, and antihistamine ingredients , Anti-allergic ingredients, vitamins, amino acids, antibacterial ingredients, bactericidal ingredients, sugars, polysaccharides and their derivatives, cellulose and their derivatives, water-soluble polymers, local anesthetic ingredients, steroid ingredients.

做為抗發炎藥成分或收斂藥成分，例如可舉出，硫酸鋅、乳酸鋅、ε-胺基己酸、消炎痛、溶菌酶素、硝酸銀、普拉洛芬、甘草酸二鉀、雙氯芬酸鈉、溴芬酸鈉、水楊酸甲酯等。 As an anti-inflammatory drug component or an astringent component, for example, zinc sulfate, zinc lactate, ε-aminocaproic acid, indomethacin, lysozyme, silver nitrate, pranoprofen, dipotassium glycyrrhizinate, diclofenac sodium , Bromfenac sodium, methyl salicylate, etc.

做為抗組織胺成分，例如可舉出，富馬酸氯苯苄咯、鹽酸二苯胺、月桂基硫酸苯海拉明、單寧酸苯海拉明、馬來酸氯菲安明、鹽酸普敏太定、甲基二水楊酸普敏太定、羧乙基雙羥萘酸、鹽酸苯甲庚嗪、鹽酸氮卓斯汀、歐查妥邁、雙羥萘酸歐查妥邁、富馬酸酮替芬、富馬酸依美斯汀、鹽酸艾來錠、鹽酸偽麻黃鹼、鹽酸依匹斯汀、鹽酸奥洛他定、依巴斯汀、鹽酸西替利嗪、苯磺酸貝他斯汀、及鹽酸左西替利嗪、鹽酸二苯胺、馬來酸氯苯那敏等。 As an antihistamine component, for example, chlorpheniramine fumarate, diphenylamine hydrochloride, diphenhydramine lauryl sulfate, diphenhydramine tannate, clophenhydramine maleate, chlorpheniramine hydrochloride Mintaidine, Prmintaidine Methyldisalicylate, Carboxyethyl Pamoic Acid, Benzoheptazine Hydrochloride, Azelastine Hydrochloride, Ochatomai, Ochatomai Pamoate, Fu Ketotifen Marate, Emestine Fumarate, Allidium Hydrochloride, Pseudoephedrine Hydrochloride, Epinastine Hydrochloride, Oleum Hydrochloride Lopatidine, Ebastine, Cetirizine Hydrochloride, Bepotastine Besilate, Levocetirizine Hydrochloride, Diphenylamine Hydrochloride, Chlorpheniramine Maleate, etc.

做為維生素，例如可含有選自維生素A類、維生素B類(除了維生素B12類以外)、維生素C類、維生素D類、維生素E類、及其他維生素類所成群之至少1種維生素類。做為維生素A類，例如可舉出，視黃醛、視黃醇、視黃酸、胡蘿蔔素、脫氫視黃醛、番茄紅素及其藥理學上容許的鹽類等。做為維生素B類，例如可舉出，硫胺素、二硫化硫胺、地賽硫胺素(Dicethiamine)、硫辛酸硫胺、噻內酯硫胺(Cycothiamine)、舒布硫胺(Bisibuthiamine)、雙苯硫胺、丙硫硫胺、苯磷硫胺、呋喃硫胺、核黃素、黄素腺嘌呤二核苷酸、吡哆醇、吡哆醛、葉酸、四氫葉酸、二氫葉酸、菸鹼酸、菸鹼酸醯胺、菸鹼醇、泛酸、泛醇、生物素、膽鹼、肌醇及其藥理學上容許的鹽類等。做為維生素C類，例如可舉出，抗壞血酸及其衍生物、異抗壞血酸及其衍生物及其藥理學上容許的鹽類等。做為維生素D類，例如可舉出，麥角鈣化醇、膽鈣化醇、羥基膽鈣化醇、二羥基膽鈣化醇、二氫速變固醇及其藥理學上容許的鹽類等。做為維生素E類，例如可舉出，生育酚及其衍生物、泛醌及其衍生物及其藥理學上容許的鹽類等。做為其他維生素類，例如可舉出，肉鹼、阿魏酸、γ-米糠醇、乳清酸、芸香素、聖草次苷、橙皮苷及其藥理學上容許的鹽類等。 As the vitamin, for example, it may contain at least one vitamin selected from the group consisting of vitamin A, vitamin B (except vitamin B12), vitamin C, vitamin D, vitamin E, and other vitamins. Examples of vitamin A include retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, and pharmacologically acceptable salts thereof. As vitamin Bs, for example, thiamine, thiamine disulfide, Dicethiamine, lipoic acid thiamine, Cycothiamine, Bisibuthiamine , Diphenylthiamine, Prothioamide, Benfotiamine, Furathiamine, Riboflavin, Flavin Adenine Dinucleotide, Pyridoxine, Pyridoxal, Folic Acid, Tetrahydrofolate, Dihydrofolate , Nicotinic acid, nicotinic acid amide, nicotinic acid, pantothenic acid, panthenol, biotin, choline, inositol and pharmacologically acceptable salts, etc. Examples of vitamin Cs include ascorbic acid and its derivatives, erythorbic acid and its derivatives, and pharmacologically acceptable salts. Examples of vitamin Ds include ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol, and pharmacologically acceptable salts thereof. Examples of vitamin Es include tocopherol and its derivatives, ubiquinone and its derivatives, and pharmacologically acceptable salts. As other vitamins, for example, carnitine, ferulic acid, γ-rice furol, orotic acid, rutin, eriocidin, hesperidin, and pharmacologically acceptable salts thereof can be cited.

做為胺基酸，例如可舉出，胺基乙基磺酸(牛磺酸)、麩胺酸、肌酸酐、麩胺酸鈉、硫酸軟骨素鈉、天門冬胺酸、天門冬胺酸鉀、天門冬胺酸鎂等。此等可為d型、l型或dl型之任何型。 As an amino acid, for example, amino ethyl sulfonic acid (taurine), Glutamate, creatinine, sodium glutamate, sodium chondroitin sulfate, aspartic acid, potassium aspartate, magnesium aspartate, etc. These can be any of d-type, l-type or dl-type.

做為抗菌藥成分或殺菌藥成分，例如可舉出，硫酸胺基去氧康黴素、硫酸康黴素、硫酸慶大黴素、硫酸西索黴素、硫酸鏈黴素、托普霉素、硫酸小諾黴素、烷基聚胺基乙基甘胺酸、氯黴素、鹽酸四環素、鹽酸土黴素、氧氟沙星(Ofloxacin)、諾氟沙星(Norfloxacin)、左氧氟沙星(Levofloxacin)、鹽酸洛美沙星、磺苄西林鈉、鹽酸頭孢甲肟、苄基青黴素鉀、黏菌素甲基磺酸鈉、紅黴素、乳醣酸紅黴素、北里黴素、螺旋黴素、硫酸新黴素(Fradiomycin Sulfate)、硫酸多黏菌素、地貝卡星(Dibekacin)、阿米卡星(Amilacin)、硫酸阿米卡星、阿昔洛韋(acyclovir)、碘脫氧胞苷、碘苷、環胞苷、阿糖胞苷、三氟胸腺嘧啶核苷、溴脫氧尿嘧啶核苷、聚乙烯醇碘、碘、兩性黴素B、異康唑、依康唑、克黴唑、制黴菌素、匹馬菌素、氟胞嘧啶、咪康唑等。 As an antibacterial component or a bactericidal component, for example, deoxycomycin sulfate, kangmycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin , Micronomycin Sulfate, Alkyl Polyaminoethyl Glycine, Chloramphenicol, Tetracycline Hydrochloride, Oxytetracycline Hydrochloride, Ofloxacin, Norfloxacin, Levofloxacin , Lomefloxacin Hydrochloride, Sulbenicillin Sodium, Cefmenoxime Hydrochloride, Benzylpenicillin Potassium, Colistin Methanesulfonate Sodium, Erythromycin, Erythromycin Lactobionate, Beirisomycin, Spiramycin, Sulfuric Acid Neomycin (Fradiomycin Sulfate), polymyxin sulfate, dibekacin (Dibekacin), amikacin (Amilacin), amikacin sulfate, acyclovir (acyclovir), iododeoxycytidine, iodine Glycosides, cyclocytidine, cytarabine, trifluorothymidine, bromodeoxyuridine, polyvinyl iodine, iodine, amphotericin B, isoconazole, itconazole, clotrimazole, Mycotoxins, pimaricin, flucytosine, miconazole, etc.

做為糖類，例如，單糖類、雙糖類，具體來說可舉出葡萄糖、海藻糖、乳糖、果糖等。 Examples of sugars include monosaccharides and disaccharides, and specific examples include glucose, trehalose, lactose, and fructose.

做為多醣類及其衍生物，例如可舉出，玻尿酸鈉、硫酸軟骨素鈉等。 Examples of polysaccharides and derivatives thereof include sodium hyaluronate, sodium chondroitin sulfate and the like.

做為纖維素及其衍生物或其鹽類，例如可舉出，羧甲基纖維素鈉、羥基乙基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、甲基纖維素等。 As cellulose and its derivatives or salts thereof, for example, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, etc. .

水溶性高分子除了上述以外，例如可舉出，聚乙烯醇(全部或部分皂化物)、聚乙烯吡咯啶酮、糊精、聚乙二醇等。， In addition to the above, the water-soluble polymer includes, for example, polyvinyl alcohol (fully or partially saponified), polyvinylpyrrolidone, dextrin, polyethylene glycol, and the like. ,

做為局部麻醉成分，例如可舉出，利多卡因、奧布卡因、待布卡因、普魯卡因、胺基苯甲酸乙酯、美普卡因、及彼等之鹽類等。 As the local anesthetic component, for example, lidocaine, obucaine, dibucaine, procaine, ethyl aminobenzoate, meplacaine, and their salts can be cited.

做為類固醇成分，例如可舉出，氫化可體松、腎上腺皮質酮、及彼等之鹽類等。 Examples of the steroid component include hydrocortisone, corticosterone, and their salts.

當本說明書之水性醫藥組成物為眼科用水性組成物時，也可以進一步在上述成分以外，添加眼科用水性組成物可使用的其他成分。添加的其他成分，只要尿囊素能被安定化，且所得的水性組成物能做為眼科用水性組成物使用即無特殊限制，例如可舉出，減充血成分、眼調節成分、青光眼治療成分、以及白內障治療成分等。 When the aqueous pharmaceutical composition of this specification is an ophthalmic aqueous composition, it is also possible to further add other components that can be used in the ophthalmic aqueous composition in addition to the above-mentioned components. As long as allantoin can be stabilized and the resulting aqueous composition can be used as an ophthalmic aqueous composition, there are no special restrictions on the other ingredients added. For example, decongestion ingredients, eye regulation ingredients, and glaucoma treatment ingredients , And cataract treatment components.

此外，本說明書中所謂的「眼科用水性組成物」意指適用於，眼、直接安裝在眼睛上的東西、或摘取出來之眼組織的水性組成物。做為眼科用水性組成物的具體例子，可舉出，滴眼劑，洗眼劑，人工淚液，眼軟膏，隱形眼鏡配戴液，隱形眼鏡護理用劑(包含清潔劑、保存液、沖洗液、消毒液等)、摘取出來之眼組織的保存劑、以及眼內注射劑等，但並不受限於此等。 In addition, the "aqueous ophthalmic composition" in this specification means an aqueous composition suitable for use in eyes, things directly attached to the eyes, or extracted ocular tissues. Specific examples of ophthalmic aqueous compositions include eye drops, eye washes, artificial tears, eye ointments, contact lens fitting solutions, contact lens care agents (including detergents, preservation solutions, rinses, Disinfectant, etc.), preservatives for the extracted eye tissues, and intraocular injections, but not limited to these.

做為減充血成分，例如可舉出，α-腎上腺素劑，具體來說可舉出腎上腺素、鹽酸腎上腺素、鹽酸麻黃鹼、鹽酸羥間唑啉、硝酸四氫唑啉、鹽酸萘唑啉、硝酸萘唑啉、鹽酸脫羥腎上腺素、鹽酸甲基麻黃鹼、酒石酸氫腎上腺素等。此等可為d型、l型或dl型之任何型。 As the decongestant component, for example, α-adrenergic agents can be cited, specifically, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxazoline hydrochloride, tetrahydrozoline nitrate, naphthazole hydrochloride Morpholine, naphthazoline nitrate, salt Acid phenylephrine, methylephedrine hydrochloride, hydrogen tartrate, etc. These can be any of d-type, l-type or dl-type.

做為眼肌調節藥成分，例如可舉出，具有與乙醯膽鹼類似的活性中心之膽鹼脂酶抑制劑，具體來說可舉出硫酸甲酯新斯狄明等四級銨化合物以及彼等在藥理學上容許的鹽類等。 As an ocular muscle regulator component, for example, cholinesterase inhibitors having an active center similar to acetylcholine can be cited, specifically, quaternary ammonium compounds such as neostigmine methyl sulfate and Their pharmacologically acceptable salts, etc.

做為青光眼治療成分，例如可舉出，左旋布諾洛爾(Levobunolol)、噻嗎心安(Timolol)、以及彼等之鹽類等。 As the glaucoma treatment ingredient, for example, Levobunolol, Timolol, and their salts can be cited.

做為白內障治療成分，例如可舉出，吡諾克辛等。 As a cataract treatment component, for example, Pirenoxine can be cited.

本發明之水性醫藥組成物中，此等成分之含有比例，視用途及含有成分的種類等做適當決定。舉例來說，在眼科用水性組成物，相對於組成物全體，可為0.0001~50w/v%、0.0001~25w/v%、0.001~10w/v%等。 In the aqueous pharmaceutical composition of the present invention, the content ratio of these components is appropriately determined depending on the application and the types of components contained. For example, in an ophthalmic water-based composition, the composition may be 0.0001-50w/v%, 0.0001-25w/v%, 0.001-10w/v%, etc. relative to the entire composition.

此外，本發明之水性醫藥組成物中，只要是在不損及各醫藥效果的範圍內，可視需要更進一步含有該領域常用的添加劑。做為這種成分，例如可舉出，防腐劑、殺菌劑或抗菌劑、增稠劑、可溶化劑或增溶劑、pH調整劑、等滲壓劑、香料、清涼劑、螯合劑、緩衝劑、穩定劑、基劑等。 In addition, the aqueous pharmaceutical composition of the present invention may further contain additives commonly used in the field as long as they are within a range that does not impair each medical effect. As such ingredients, for example, preservatives, bactericides or antibacterial agents, thickeners, solubilizers or solubilizers, pH adjusters, isotonic pressure agents, fragrances, cooling agents, chelating agents, buffers , Stabilizers, bases, etc.

做為防腐劑、殺菌劑或抗菌劑，例如可舉出，烷基二胺基乙基甘胺酸鹽酸鹽、安息香酸鈉、乙醇、氯丁醇、山梨酸、山梨酸鉀、去水醋酸鈉、對羥基安息香酸甲酯、對羥基安息香酸乙酯、對羥基安息香酸丙酯、對羥基安息香酸丁酯、羥基喹啉硫酸鹽、苯乙醇、苯甲醇、雙胍化合物、利凡諾(acrinol,rivanol)等。 As preservatives, bactericides or antibacterial agents, for example, alkyl diamino ethyl glycine hydrochloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, dehydrated acetic acid Sodium, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, hydroxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compound , Rivanol (acrinol, rivanol), etc.

做為增稠劑，例如可舉出，羧甲基纖維素鈉、葡聚糖、聚乙二醇、羧基乙烯聚合物、羥基乙基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、甲基纖維素、聚乙烯醇(全部，或部分皂化物)、聚乙烯吡咯啶酮、聚乙二醇、硫酸軟骨素鈉等。 As the thickener, for example, sodium carboxymethyl cellulose, dextran, polyethylene glycol, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl fiber Polyvinyl alcohol, methyl cellulose, polyvinyl alcohol (full or partial saponification), polyvinylpyrrolidone, polyethylene glycol, sodium chondroitin sulfate, etc.

做為可溶化劑或增溶劑，例如可舉出，烷基二胺基乙基甘胺酸等甘胺酸型兩性界面活性劑、烷基醚羧酸鹽、十四烯磺酸鈉等磺酸鹽、月桂基硫酸鈉等烷基硫酸鹽、N-椰油醯基甲基牛磺酸鈉等N-醯基牛磺酸鹽、POE(10)月桂基醚磷酸鈉等之POE烷基醚磷酸及其鹽類、月桂醯基甲基丙胺酸鈉等N-醯基胺基酸鹽、POE(3)月桂基醚硫酸鈉等之POE烷基醚硫酸鹽、α-烯烴磺酸鹽等之陰離子界面活性劑等。具體來說有聚氧乙烯硬化蓖麻油60、聚氧乙烯(20)去水山梨醇單月桂酸酯、聚氧乙烯(20)去水山梨醇單油酸酯、聚氧乙烯(20)去水山梨醇三硬脂酸酯、聚氧乙烯(20)去水山梨醇油酸酯、聚氧乙烯硬脂酸酯40、蔗糖硬脂酸酯、單硬脂酸十甘油酯、月桂基葡萄醣苷、聚乙二醇4000。此外，括弧內的數字代表所加入的莫耳數。 As a solubilizer or solubilizer, for example, glycine type amphoteric surfactants such as alkyldiaminoethylglycine, alkyl ether carboxylates, sulfonic acids such as sodium tetradecene sulfonate, etc. Salt, sodium lauryl sulfate and other alkyl sulfates, N-cocoyl methyl taurate sodium and other N-acid taurates, POE (10) sodium lauryl ether phosphate and other POE alkyl ether phosphoric acid And its salts, sodium lauryl methyl alanine and other N-amino acid salts, POE(3) sodium laureth sulfate and other POE alkyl ether sulfates, anions such as α-olefin sulfonates Surfactant, etc. Specifically, there are polyoxyethylene hardened castor oil 60, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, and polyoxyethylene (20) dewatering Sorbitol tristearate, polyoxyethylene (20) sorbitan oleate, polyoxyethylene stearate 40, sucrose stearate, decaglyceryl monostearate, lauryl glucoside, Polyethylene glycol 4000. In addition, the numbers in parentheses represent the number of moles added.

做為pH調整劑，例如可舉出，胺基乙基磺酸、ε-胺基己酸、醋酸、氫氧化鈉、碳酸氫鈉、碳酸鈉、三乙醇胺、乙醇胺等。 As the pH adjuster, for example, aminoethyl sulfonic acid, ε-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, triethanolamine, ethanolamine, etc. can be mentioned.

做為等滲壓劑，例如可舉出，亞硫酸氫鈉、亞硫酸鈉、氯化鉀、氯化鈣、氯化鈉、氯化鎂、醋酸鈣、醋酸鈉、碳酸氫鈉、碳酸鈉、硫代硫酸鈉、硫酸鎂、甘油、丙二醇等。 As an isotonic pressure agent, for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, calcium acetate, acetic acid Sodium, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, etc.

做為香料或清涼劑，例如可舉出，萜烯類(具體來說有，茴香腦、丁香酚、樟腦、香葉醇、桉油醇、莰醇、薄荷醇、檸檬烯、龍腦等。此等可為d型、l型或dl型之任何型)。精油(具體來說有，茴香油、清涼薄荷油、肉桂油、留蘭香葉池、薄荷水、薄荷油、胡椒薄荷油、佛手柑油、桉葉油、玫瑰油等)等。 As a fragrance or cooling agent, for example, terpenes (specifically, anethole, eugenol, camphor, geraniol, eucalyptol, camphenol, menthol, limonene, borneol, etc.) can be mentioned. Etc. can be any of d-type, l-type or dl-type). Essential oils (specifically, fennel oil, cooling peppermint oil, cinnamon oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.) and the like.

做為螯合劑，例如可舉出，抗壞血酸、乙二胺四乙酸四鈉、乙二胺四乙酸鈉、檸檬酸等。 Examples of the chelating agent include ascorbic acid, tetrasodium edetate, sodium edetate, and citric acid.

做為緩衝劑，例如可舉出，檸檬酸、檸檬酸鈉、醋酸、醋酸鉀、醋酸鈉、碳酸氫鈉、碳酸鈉、硼酸、硼砂等。 As the buffer, for example, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax, etc. can be mentioned.

做為穩定劑，例如可舉出，環糊精、二丁基羥基甲苯、氨丁三醇、生育酚、焦亞硫酸鈉、單乙醇胺、單硬脂酸鋁等。 Examples of stabilizers include cyclodextrin, dibutylhydroxytoluene, tromethamine, tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate, and the like.

做為基劑，例如可舉出，辛基十二醇、橄欖油、芝麻油、氧化鈦、溴化鉀、大豆油、茶樹油、玉米油、菜籽油、石蠟、蓖麻油、樹脂基質、花生油、羊毛脂、凡士林等。 As a base, for example, octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, tea tree oil, corn oil, rapeseed oil, paraffin, castor oil, resin base, peanut oil , Lanolin, Vaseline, etc.

本發明之水性醫藥組成物，視需要調整至在生物體可容許的範圍內的滲透壓。對生理食鹽水的滲透壓比也可以為，0.3~4.0、0.5~2.0、0.5~1.4等。滲透壓比的調整，除了使用前述pH調整劑以外，可以適當使用緩衝劑、等滲壓劑、及鹽類等來進行。 The aqueous pharmaceutical composition of the present invention is adjusted to an osmotic pressure within the allowable range of the organism as necessary. The osmotic pressure ratio to physiological saline may also be 0.3 to 4.0, 0.5 to 2.0, 0.5 to 1.4, etc. To adjust the osmotic pressure ratio, in addition to the aforementioned pH adjusters, buffers and isotonic Press agent, salt, etc.

本發明之水性醫藥組成物，可經由眾所周知的方法製造。例如，滴眼藥、洗眼劑等，先混合各成分，然後進一步視需要進行過濾滅菌處理，最後經由填充至容器中來製備。 The aqueous pharmaceutical composition of the present invention can be produced by a well-known method. For example, eye drops, eye washes, etc., are prepared by mixing the ingredients first, then further filtering and sterilizing if necessary, and finally filling the container.

本發明還提供在水性醫藥組成物中尿囊素的安定化方法。本發明之水性醫藥組成物中尿囊素的安定化方法，包含將氯化氫加入水性醫藥組成物之步驟。 The present invention also provides a method for stabilizing allantoin in an aqueous pharmaceutical composition. The method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention includes the step of adding hydrogen chloride to the aqueous pharmaceutical composition.

於本發明之水性醫藥組成物中尿囊素的安定化方法中所使用的用語，其中也被用於上述本發明之水性醫藥組成物者，除有特別說明，與在水性醫藥組成物時同義。 The terms used in the method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention, which are also used in the above-mentioned aqueous pharmaceutical composition of the present invention, have the same meaning as in the case of the aqueous pharmaceutical composition unless otherwise specified .

氯化氫的添加量為，只要尿囊素能被安定化即無特殊限制，也可與本發明之水性醫藥組成物等量。 The amount of hydrogen chloride added is not particularly limited as long as the allantoin can be stabilized, and it may be the same amount as the aqueous pharmaceutical composition of the present invention.

本發明之水性醫藥組成物中尿囊素的安定化方法，可進一步包含將鹽酸吡哆醇加入水性醫藥組成物之步驟。將尿囊素、氯化氫、鹽酸吡哆醇及其他成分加入水性醫藥組成物中的順序並無特殊限制。 The method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention may further include the step of adding pyridoxine hydrochloride to the aqueous pharmaceutical composition. The order of adding allantoin, hydrogen chloride, pyridoxine hydrochloride and other ingredients to the aqueous pharmaceutical composition is not particularly limited.

本發明之水性醫藥組成物中尿囊素的安定化方法，可包含將水性醫藥組成物的pH調整至5.5~6.3的步驟。只要最後得到的水性醫藥組成物的pH被調整至5.5~6.3，無論在哪個階段進行pH的調整皆可。 The method for stabilizing allantoin in the aqueous pharmaceutical composition of the present invention may include the step of adjusting the pH of the aqueous pharmaceutical composition to 5.5 to 6.3. As long as the pH of the finally obtained aqueous pharmaceutical composition is adjusted to 5.5 to 6.3, the pH adjustment may be performed at any stage.

本說明書中被引用的所有專利文獻及非專利文獻所揭示的所有內容，以引用的方式併入本說明書。 All contents disclosed in all patent documents and non-patent documents cited in this specification are incorporated into this specification by reference.

[Example]

以下，在實施例的基礎上將本發明做具體的說明，但本發明並不受此等之任何限制。本領域技術人員，可以在不脫離本發明之意義的前提下將本發明變更成各種形式，有關變更也被包含在本發明的範圍之內。 Hereinafter, the present invention will be specifically described on the basis of the embodiments, but the present invention is not limited by these. Those skilled in the art can change the present invention into various forms without departing from the meaning of the present invention, and related changes are also included in the scope of the present invention.

[Experimental example 1]

依照下述的搭配量，調配眼科用水性組成物。以氫氧化鈉調整pH，以滅菌純水使全量達100mL。氯化氫為使用1N的鹽酸並調配至成為表中的濃度。 Prepare the ophthalmic water-based composition according to the following mixing amount. Adjust the pH with sodium hydroxide, and use sterile pure water to make the total volume 100 mL. Hydrogen chloride uses 1N hydrochloric acid and is adjusted to the concentration in the table.

在60℃下保存1週後之搭配例1~6的尿囊素分析值示於圖1。尿囊素為，使用(株)島津製作所生產之高效液相層析儀經由通常方法分析。確認了一旦適量添加氯化氫，則尿囊素的分解即會被顯著減輕。 The allantoin analysis values of the combination examples 1 to 6 after storage at 60°C for 1 week are shown in Figure 1. Allantoin was analyzed by a normal method using a high performance liquid chromatograph manufactured by Shimadzu Corporation. It was confirmed that the decomposition of allantoin would be significantly reduced once the proper amount of hydrogen chloride was added.

[Experimental example 2]

以氯化鈉取代氯化氫，與實驗例1同樣地調配眼科用水性組成物，在60℃下保存1週後，分析尿囊素的量。各搭配例的組成與尿囊素量的分析結果示於下表。 Sodium chloride was substituted for hydrogen chloride, and an ophthalmic aqueous composition was prepared in the same manner as in Experimental Example 1, and after storage at 60°C for 1 week, the amount of allantoin was analyzed. The analysis results of the composition and the amount of allantoin of each combination example are shown in the table below.

如表中所示，即使添加氯化鈉，尿囊素仍無法被安定化。由此可知，尿囊素的安定化效果並非來自氯離子，而是來自氯化氫。 As shown in the table, even if sodium chloride is added, allantoin cannot be stabilized. This shows that the stabilizing effect of allantoin does not come from chloride ions, but from hydrogen chloride.

[Experimental example 3]

改變pH，與實驗例1同樣地調配眼科用水性組成物，在60℃下保存1週後，分析尿囊素的量。各搭配例的組成與尿囊素量的分析結果示於下表。 The pH was changed, an ophthalmic aqueous composition was prepared in the same manner as in Experimental Example 1, and after storage at 60°C for 1 week, the amount of allantoin was analyzed. The analysis results of the composition and the amount of allantoin of each combination example are shown in the table below.

確認了即使是在pH6.0，尿囊素仍是安定的。 It was confirmed that allantoin is stable even at pH 6.0.

[Experimental example 4]

添加眼科用水性組成物常用的成分，與實驗例1同樣地調配眼科用水性組成物，在60℃下保存1週後，分析尿囊素的量。各搭配例的組成與尿囊素量的分析結果示於下表。 The components commonly used in ophthalmic aqueous compositions were added, and the ophthalmic aqueous compositions were prepared in the same manner as in Experimental Example 1, and after storing at 60°C for 1 week, the amount of allantoin was analyzed. The analysis results of the composition and the amount of allantoin of each combination example are shown in the table below.

將搭配例16~18的尿囊素量的分析結果與搭配例4的結果一起示於圖2。確認了當添加鹽酸吡哆醇時，尿囊素的安定性顯著提升。 The analysis results of the amounts of allantoin of the combination examples 16 to 18 are shown in FIG. 2 together with the results of the combination example 4. It was confirmed that when pyridoxine hydrochloride was added, the stability of allantoin was significantly improved.

[Preparation example]

與實驗例1同樣地，調配表5所示組成之眼科用醫藥組成物。 In the same manner as in Experimental Example 1, the ophthalmic medical composition of the composition shown in Table 5 was formulated.

Claims

An aqueous pharmaceutical composition containing allantoin and hydrogen chloride, wherein the content of the hydrogen chloride is 0.1825mg/100mL~3.285mg/100mL.

The aqueous pharmaceutical composition of claim 1, which further contains pyridoxine hydrochloride.

The aqueous pharmaceutical composition of claim 1 or 2, wherein the pH of the aforementioned aqueous pharmaceutical composition is 5.5 to 6.3.

The aqueous pharmaceutical composition of claim 1 or 2, wherein the aforementioned aqueous pharmaceutical composition is an ophthalmic aqueous composition.

The aqueous pharmaceutical composition of claim 4, wherein the aforementioned ophthalmic aqueous composition is an eye wash.

A method for stabilizing allantoin in an aqueous pharmaceutical composition is characterized by including the step of adding hydrogen chloride to the aforementioned aqueous pharmaceutical composition so that the content of hydrogen chloride becomes 0.1825 mg/100 mL to 3.285 mg/100 mL.

The method of claim 6, which further comprises the step of adding pyridoxine hydrochloride to the aforementioned aqueous pharmaceutical composition.

Such as the method of claim 6 or 7, which comprises adjusting the pH of the aforementioned aqueous pharmaceutical composition to 5.5 to 6.3.

The method of claim 6 or 7, wherein the aforementioned aqueous pharmaceutical composition is an ophthalmic aqueous composition.

The method of claim 9, wherein the aforementioned ophthalmic aqueous composition is an eye wash.