201249427 六、發明說明： 【發明所屬之技術領域】 本發明係關於用於治療極性咽炎之鹽酸安布索。 【先前技術】 鹽酸安布索（反式_4-[(2·胺基-3,5_二演节基）)胺基]環己 醇鹽酸鹽）起初作為具黏液調節作用及黏液溶解作用之活 性物質研發，據藥理學研究顯示，其可促進呼吸道分泌物 形成並增加纖毛活動。亦發現其顯示局部麻醉活性。 例如經品牌MUcoangin®及Lys〇pad〇〗⑩授權之安布索以口 含錠形式（20 mg活性物質）以緩解急性咽喉痛，其為急性 咽炎之症狀。 急性咽炎係由各種原因引起的咽及/或扁桃體發炎症候 群。急性咽炎特徵係發病急及持續時間相對較短…般而 言’此為-種持續時間不超過2_4天的良性、自限二 病。急性咽炎可為上呼吸道全面感染的一部份或可作為」 局部感染發生。多數情況下都由病毒感染引起 續病毒感染或感冒發生。然而，許多其它因素亦可導 致：喉痛：諸如例如，毒素、過敏、外傷或乾燥空氣。 及：：方法可分為症狀治療(鎮痛劑、類固醇、局部麻醉) 疼痛抗生素、抑制病毒生長）。症狀治療旨在減輕 發：疾病’而病:因治療旨在治愈咽炎或儘量避免長期併 發癥，如風濕熱。 :於沒有應對急性咽炎(病毒性)的特殊療法，故 療係藉由控制症狀而直至病毒感染消退。由於咽炎的 162171.doc 201249427 主要症狀為咽喉痛，故對病人而言最重要的在於獲得緩 解因此，局部用藥及局部作用物質，如鹽酸安布索為一 種治療咽喉痛所選擇的方法。 已顯示’用鹽酸安布索治療耐受性良好且有效減輕急性 咽炎患者痛苦1管安布索口含旋有極其良好㈣受性， 但在若干個例情況下’理論上有可能產生不相容性及副作 用。 【發明内容】 本發明之目的為提供鹽酸安布索之替代劑型，其可確僻 達到已知之功效。右可能的話，可用相同的或，較佳地， 較低劑量的活性物質獲得效果。如有必要，可迅速起效， 即小於30分鐘之内。效力亦可持續相當長時間，即若干^ 時’特定言之，多於2小時。 在此情況下，EP 1 543 826句♦ — 為需以漱口水或喷霧形式用 藥之高濃度鹽酸安布索㈣mg/ml)溶液。㈣，高濃度璧 酸安布索需採用特別措施製備溶液，因為其溶解度有限。 【實施方式】 令人驚喜地係，發現如果以i，mg之劑量局部用藥， 可喷式鹽酸安布索組合物(含有MO mg/ml鹽酸安布索)適 用於治療急性咽炎。此過程可確保療效高，活性起效快及 耐受性高》 因此’本發明關於用於治嘛201249427 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to ampoule hydrochloride for the treatment of polar pharyngitis. [Prior Art] Ampsol Hydrochloride (trans-4-[(2.amino-3,5_2)]amino]cyclohexanol hydrochloride) initially acts as a mucus-regulating and mucolytic The development of active substances, according to pharmacological studies, can promote the formation of respiratory secretions and increase ciliary activity. It was also found to exhibit local anesthetic activity. For example, ABS, authorized by the brand MUcoangin® and Lys〇pad〇10, is in the form of an ingot (20 mg active) to relieve acute sore throat, which is a symptom of acute pharyngitis. Acute pharyngitis is an inflammation of the pharynx and/or tonsils caused by various causes. The symptoms of acute pharyngitis are relatively short-lived and have a relatively short duration. As a result, this is a benign, self-limiting disease with a duration of no more than 2 to 4 days. Acute pharyngitis can be part of a full infection of the upper respiratory tract or can occur as a local infection. In most cases, a viral infection or a cold is caused by a viral infection. However, many other factors can also result in sore throats such as, for example, toxins, allergies, trauma or dry air. And:: The method can be divided into symptom treatment (analgesic, steroid, local anesthesia) pain antibiotics, inhibition of virus growth). Symptomatic treatment is designed to alleviate hair disease: disease and disease: treatment is intended to cure pharyngitis or to avoid long-term complications such as rheumatic fever. : In the absence of special treatments for acute pharyngitis (viral), the treatment is controlled by symptoms until the viral infection subsides. Since phlebitis 162171.doc 201249427 The main symptom is sore throat, the most important thing for the patient is to obtain relief. Therefore, topical medications and topical substances such as ampoule hydrochloride are the methods of choice for treating sore throat. It has been shown that treatment with ambroxol hydrochloride is well tolerated and effectively alleviates the pain of patients with acute pharyngitis. The tube Ampson has a very good (4) receptivity, but in some cases it may theoretically produce a phase difference. Capacity and side effects. SUMMARY OF THE INVENTION It is an object of the present invention to provide an alternative dosage form of ambroxol hydrochloride which is capable of achieving a known efficacy. If possible, the same or, preferably, lower doses of active substance may be used to obtain the effect. If necessary, it can work quickly, that is, within less than 30 minutes. The effectiveness can also last for a long time, that is, a certain number of times, more than two hours. In this case, EP 1 543 826 ♦ — is a high concentration of ampo (a) mg/ml solution of hydrochloric acid in the form of a mouthwash or spray. (d), a high concentration of ampoule citrate requires special measures to prepare the solution because of its limited solubility. [Embodiment] Surprisingly, it has been found that a sprayable ampoule hydrochloride composition (containing MO mg/ml ampoule hydrochloride) is suitable for the treatment of acute pharyngitis if it is administered topically at a dose of i, mg. This process ensures high efficacy, fast onset of activity and high tolerance. Therefore, the present invention relates to treatment.
/σ療急性咽炎之鹽酸安布索，J 中鹽酸安布索係以可喷式組合 ' ' .,^ 1 3有卜30 mg/ml鹽酸安神 索）在1 -20 mg之劑量下局部用藥。 162I7I.doc 201249427 在本發明範圍内，振纽「 * ^〇〇 局部用樂」表示將活性物質直 接應用至所論及.之發忠AK a 赞灸部位。在本發明範圍内，術語‘‘劑 量”表不局部用藥之活性物質之量。鹽酸安布索之投與劑 量為’較佳地，2.5_10叫，更特定言之，2.5 mg、5 mg或 10 mg，較佳地，3-8 mg。 通常*酸安布索係藉由喷霧器施用於受影響的發炎部 位。因此’可直接將活性物質投與至受影響的發炎部位而 舌頭、口腔及咽腔的其它部位不與活性物質接觸。因此， 在另一態樣中，本發明係關於一種用於局部投與卜2〇 mg 鹽酸安布索之塗藥器裝置，其包括一喷霧器及一容納含有 1-30 mg/ml鹽酸安:布索的可喷式組合物之容器。 通常，喷霧器將經選擇以一次或重複啟動喷霧裝置投與 1-20 mg之劑量。 已證實，宜選擇喷霧器以偶數次啟動（例如2或4次）喷霧 裝置投與1-20 mg之劑量。此使得所需劑量均勻地投與至 口咽兩側。 較佳地，在一天内，將活性物質如上述般投與丨_丨〇次， 最佳地，達到6次。較佳地，投與1-200 mg/天之鹽酸安布 索曰劑量，特佳地，15-60 mg/天。 本發明之另一態樣係關於鹽酸安布索用於治療急性咽炎 之用途’其中該鹽酸安布索係以可噴式組合物（含有1 _3〇 mg/ml鹽酸安布索）在1-20 mg之劑量下局部投與。 本發明之另一態樣係關於一種治療急性咽炎之方法，其 中鹽酸安布索係以可喷式組合物（含有1_3〇 mg/mi鹽酸安布 16217 丨.doc 201249427 索）在1-20 mg之劑量下局部投與。 根據本發月可喷式組合物較佳地含有水及乙醇作為溶 劑K的比例通书同於乙醇。基於每種情況下組合物的總 重量可喷式組合物通常具有至少5q重量％的水含量較 佳地’至少60重量尤佳地，至少δ〇重量％及最佳地， 至少85重量〇/〇。 此外，根據本發明之可喷式組合物包含至少一種表面活 I·生劑’特U ’非離子表面活性劑，比如例如聚氧乙稀 脫水山梨糖醇單月桂酸酯(聚山梨醇酿）。基於每種情況下 組合物的總重量’表面活性劑之量通常<1重量％，特定言 之 ’ 〇_〇5-0.5重量❶/。。 ° 根據本發明之可噴式組合物為， —„,^5〇-2〇〇 活性劑及選自pH-調節物質、甜味劑、增香劑及/或防腐劑 之其它添加劑的水性組合物。 因此，本發明另一態樣係關於一種用於治療急性咽炎的 可喷式水性組合物，其含有丨—30 mg/ml鹽酸安布索、5〇_ 200 mg/ml乙醇' 〇 5_2 mg/ml表面活性劑及選自p沁調節物 質、甜味劑、增香劑及/或防腐劑之其它添加劑。在一特 殊實施例令’ 4艮據本發明所用的可噴式組合物係由13〇 mg/ml鹽酸安布索、5〇_2〇〇 mg/m丨乙醇、〇 η叫⑽表面 活性劑及選自ΡΗ·調節物質、甜味劑、増香劑及/或防腐劑 之其它添加劑組成。 在文下術浯「水性組合物」意指根據本發明之組合 162I71.doc 201249427 物含有水作為溶劑。 根據本發明$ α 赁式組合物較佳含有4-25 mg/ml鹽酸安 布索。 通吊’根據本發明之可喷式組合物具有1.4-1.6 mPa*S之 ， 黏度。 、 根據本發明之可噴式組合物具有5.2-5.8之pH。 根據本發明之含安布索組合物之投與導致止痛活性迅速 起效，效果持久。 以下藉由若干非限定性實例來充分闡明本發明。 實例 A·根據本發明之組合物 藉由混合各個組份製備含有Π.86 mg/ml(溶液丨）、8.93 mg/ml(溶液2)或4.46 mg/ml鹽酸安布索（溶液3)、乙醇㈣％， mg/ml)、聚山梨醇酯2〇(1 mg/mi)、檸檬酸單水合物/ W酸11二鈉二水合.物（2,8 mg/ml)、增香劑（13叫㈣、嚴 :素(0.8 mg/mi)及水之3〇 mi等份水性溶液試劑。將所得 溶液轉移至由棕色玻璃製成的喷霧瓶内。 B ·根據本發明之組合物之投與 根據本發明之組合物係藉由4次喷霧喷射（每次刚μ1)至 口咽的發炎組織， 溶液1 :所得劑量（560 μΐ)為1〇 mg鹽酸安布索 洛液2 .所知劑量（560 μΐ)為5 mg鹽醆安布索 溶液3 :所得劑量（56〇 4)為25 mg鹽酸安布索 一天實施投與多達6次。 162171.doc/ σ treatment of acute pharyngitis, ampoule hydrochloride, J. Ambroxol hydrochloride in a sprayable combination ' ', ^ 1 3 with 30 mg / ml hydrochloric acid Anshen) topical dose of 1 -20 mg . 162I7I.doc 201249427 Within the scope of the present invention, the "* ^ 局部 partial use music" means that the active substance is directly applied to the AK a cultivating site. Within the scope of the present invention, the term 'dosage' indicates the amount of active substance that is not administered topically. The dosage of ambroxol hydrochloride is 'better, 2.5-10, more specifically 2.5 mg, 5 mg or 10 mg, preferably, 3-8 mg. Usually * acid ampoule is applied to the affected inflamed site by a nebulizer. Therefore, the active substance can be directly administered to the affected inflamed site with the tongue, The oral cavity and other parts of the pharyngeal cavity are not in contact with the active substance. Therefore, in another aspect, the present invention relates to an applicator device for topical administration of a 2 mg of ampoule hydrochloride, which comprises a spray A mister and a container containing a sprayable composition containing 1-30 mg/ml chloramphenicol: sol. Typically, the sprayer will be selected to administer a dose of 1-20 mg once or repeatedly to the spray device. It has been shown that it is preferred to use a nebulizer to administer a dose of 1-20 mg in an even number of (eg 2 or 4) spray devices. This allows the required dose to be evenly administered to both sides of the oropharynx. In one day, the active substance is administered as described above, 最佳 丨〇 ,, optimally, up to 6 times Preferably, a dose of 1-200 mg/day of ambroxol hydrochloride is administered, particularly preferably 15-60 mg/day. Another aspect of the invention relates to the treatment of acute pharyngitis with ampoule hydrochloride Use 'The ampoule hydrochloride is administered topically in a sprayable composition (containing 1 _3 〇 mg/ml ampoule hydrochloride) at a dose of 1-20 mg. Another aspect of the invention relates to a treatment A method of acute pharyngitis, wherein ambroxol hydrochloride is administered topically at a dose of 1-20 mg in a sprayable composition (containing 1-3 mg/mi of ampule 16217 丨.doc 201249427). The sprayable composition preferably comprises water and ethanol as the solvent K in proportion to ethanol. The sprayable composition generally has a water content of at least 5 q% by weight, based on the total weight of the composition in each case. 'At least 60 by weight, particularly preferably at least δ 〇 by weight and optimally, at least 85 〇 〇 / 〇. Furthermore, the sprayable composition according to the invention comprises at least one surface active I·biocide 'U' Ionic surfactants such as, for example, polyoxyethylene sorbitan monolaurate (polysorbate). The amount of surfactant based on the total weight of the composition in each case is generally <1% by weight, specifically ''〇5〇0.5重量❶/. ° according to the invention The sprayable composition is an aqueous composition of - „,^5〇-2〇〇 active agent and other additives selected from the group consisting of pH-adjusting substances, sweeteners, flavoring agents and/or preservatives. Therefore, another aspect of the present invention relates to a sprayable aqueous composition for treating acute pharyngitis, comprising guanidine 30 mg/ml ampoule hydrochloride, 5 〇 200 mg/ml ethanol ' 〇 5 2 mg / Ml surfactant and other additives selected from the group consisting of p-conditioning substances, sweeteners, flavoring agents and/or preservatives. In a particular embodiment, the sprayable composition used in accordance with the present invention consists of 13 mg/ml ampoule hydrochloride, 5 〇 2 〇〇 mg/m 丨 ethanol, 〇η (10) surfactant and It is composed of other additives selected from the group consisting of a modulating substance, a sweetener, a musk agent and/or a preservative. As used herein, "aqueous composition" means a combination according to the invention 162I71.doc 201249427 contains water as a solvent. The $α rental composition according to the invention preferably contains 4-25 mg/ml ampoulol hydrochloride. The slingable composition according to the present invention has a viscosity of from 1.4 to 1.6 mPa*s. The sprayable composition according to the invention has a pH of from 5.2 to 5.8. The administration of the ampoule-containing composition according to the present invention results in an analgesic activity which is rapidly effective and has a long-lasting effect. The invention is fully illustrated by the following non-limiting examples. Example A· The composition according to the present invention is prepared by mixing the respective components to prepare Π.86 mg/ml (solution 丨), 8.93 mg/ml (solution 2) or 4.46 mg/ml amblomerate hydrochloride (solution 3), Ethanol (tetra)%, mg/ml), polysorbate 2〇 (1 mg/mi), citric acid monohydrate / W acid 11 disodium dihydrate. (2,8 mg/ml), flavoring agent ( 13 (4), Yan: prime (0.8 mg / mi) and water 3 〇 mi aliquots of aqueous solution reagent. Transfer the resulting solution into a spray bottle made of brown glass. B · The composition according to the invention The composition according to the invention was administered to the oropharyngeal inflamed tissue by 4 sprays (each time just μ1), solution 1: the resulting dose (560 μΐ) was 1 mg of ambroxol hydrochloride 2 . The known dose (560 μΐ) is 5 mg of salt ampoules solution 3 : the resulting dose (56 〇 4) is 25 mg of ambroxol hydrochloride administered up to 6 times a day. 162171.doc