TW200402425A - Medicament for the treatment or prevention of acne - Google Patents
Medicament for the treatment or prevention of acne Download PDFInfo
- Publication number
- TW200402425A TW200402425A TW092115959A TW92115959A TW200402425A TW 200402425 A TW200402425 A TW 200402425A TW 092115959 A TW092115959 A TW 092115959A TW 92115959 A TW92115959 A TW 92115959A TW 200402425 A TW200402425 A TW 200402425A
- Authority
- TW
- Taiwan
- Prior art keywords
- acne
- formula
- compound
- pharmaceutically acceptable
- acid addition
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
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- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
200402425 玖、發明說明： 【發明所屬之技術領域】 本發明之目的係提供一種痤瘡之治療或預防用藥。 特別本發明之範圍係有關式（I)化合物之用途 〇
其中： R表示甲氧基甲基， R!表示甲基， R2表示甲基， Y表示 基團 以及其醫藥上可接受之酸加成鹽； 用於製造痤瘡之局部治療或預防用藥之用途。 本發明之又一目的為一種於患有皮膚病症之哺乳類局 部治療痤瘡之方法，該方法包含以足夠對痤瘡初油酸菌 (Propionibacterium a c n e )之增生提供抑制活性之用量， 對該哺乳類局部投予上式（I )化合物及其醫藥上可接受之 酸加成鹽類。 7
312/發明說明書(補件)/92-09/92115959 200402425 「醫藥上可接受之酸加成鹽類」一詞用於此處說明及申 請專利範圍意圖表示與酸生成之鹽類，該等鹽類由生物、 製造及調配觀點視之係與醫藥實務相容。 通式（I)化合物之代表性且適當的酸加成鹽，包括藉標 準反應而與有機酸及無機酸二者生成之鹽類，而酸類例如 為氫氯酸、氫溴酸、硫酸、磷酸、乙酸、三氟乙酸、三氯 乙酸、丁二酸、檸檬酸、抗壞血酸、乳酸、順丁烯二酸、 反丁稀二酸、棕櫊酸、膽酸、巴母酸（p a m 〇 i c a c i d )、黏液 酸、麩胺酸、樟腦酸、戊二酸、乙醇酸、苯二甲酸、酒石 酸、月桂酸、硬脂酸、水楊酸、曱烷磺酸、十二烷磺酸、 苯續酸、山梨酸、苦味酸、苯甲酸、桂皮酸等。 上式（I )化合物為抗生素G E 2 2 7 0因子A 3之已知醯胺衍 生物。後述化合物對應於上式（I )化合物，其中 Y表示羥 基，該化合物亦為已知。式（I)之抗生素GE 2270因子 A3 的該醯胺衍生物，其經由醯胺化抗生素 GE 2 2 7 0因子 As 之製備及其醫藥上可接受之酸加成鹽之製備述於 US 5.599.791° 【先前技術】 尋常痤瘡是皮膚科醫生最常見到的慢性皮膚病症，尋常 痤瘡是毛髮皮脂單位的病症，以丘疹、粉刺及膿胞為特徵。 臉部、背部及胸部由於含有大量皮脂腺約為身體其它部位 濃度的九倍1 >，故臉部、背部及胸部是最常見患部區域。 在美國，受尋常痤瘡影響的人超過一千七百萬，估計青少 年人口有 8 5 %曾經患過此病症。痤瘡影響兩性，痤瘡的尖 峰發生率：女性1 4 - 1 7歲，男性1 6 - 1 9歲2 >。痤瘡於2 5 - 3 4 312/發明說明書(補件)/92-09/92115959 8 Ο Μ / ^ 200402425 歲成人也有8%發生率，於35-44歲成人為3 %3)。但25歲 以上患尋常痤瘡病人數目正在增加當中。成年女性特別容 易受影響而出現經前潮紅。總而言之，比較其它年齡人口 群，嚴重痤瘡於青少年男性較為常見。 雖然痤瘡之主要起因為終端器官對血循環中的雄性素 觸發皮脂濾胞之皮脂產量過剩有高度反應性，繼發性細菌 性感染也扮演要角，由於皮脂濾胞上皮的異常脫皮結果有 利於繼發性細菌性感染。皮脂產量增加，加上來自皮脂遽 胞壁脫皮的上皮細胞數目過量堆疊於濾胞内部，擴大濾 胞，結果導致形成臨床上不明顯的前驅尋常痤瘡病灶，稱 作為微粉刺。腺管過度角化有數種解說。包括某些皮脂腺 之粉刺生成效應、雄激素控制缺陷、類視黃素控制、局部 細胞激素調節以及腺管之細菌性效應4 >。痤瘡初油酸菌為 棲息菌叢成員，棲息於皮脂濾胞。確實被堵塞的濾胞無氧 環境特別有助於痤瘡初油酸菌的增生，釋放出趨化因子以 及發炎前驅媒介物質至濾胞内及周圍的真皮，結果導致發 炎5 6 l 7 >。細胞類型及黏著分子之研究細節證實痤瘡發炎 屬於最初的7 6小時正常4型反應之觀點8〉’ 9〉’ 1G〕。 此等病理生理事件之臨床表徵包括非發炎性閉合粉刺 (黑頭粉刺）或開放性粉刺（白頭粉刺），以及發炎病灶包括 丘疹、膿胞、囊腫及結節11)。 基於病灶數目及相關皮膚表面，痤瘡可劃分為輕度、中 度及重度痤瘡。輕度痤瘡之特徵為開放式及閉合式粉刺偶 爾伴隨有少數表淺發炎病灶；中度痤瘡之特徵為大型表淺 發炎病灶增加，帶有膿胞傾向於隨著時間之經過而結痂。 9 312/發明說明書(補件)/92-09/92115959 200402425 重度痤瘡之特徵為顯著結病之結節及囊腫。 雖然痤瘡並非致命的疾病，但多年來痤瘡與精神疾病之 罹病有關。情緒壓力可能造成痤瘡的惡化，痤瘡病人由於 痤瘡結果出現精神問題12 >。痤瘡之相關精神問題包括自尊 /自信問題、身體形象問題、尷尬/社交退縮問題、憂鬱症、 焦慮症、憤怒、全神貫注於痤瘡、挫折/困擾問題、生活形 式受限制以及家庭關係問題13 \14 >。永久性結痂是痤瘡導 致之另一項後果。 痤瘡之治療及預防包括多種局部及系統性治療，依據存 在之臨床病灶形式決定。成功地治療痤瘡也需要審慎評估 病人，接著考慮若干病人相關因素，例如病人年齡、皮膚 類型、原有病症、生活作息、月經規則程度。理想治療劑 係將各項病因鎖定目標而未產生副作用。但尚無任一種單 一局部治療劑其可改善尋常痤瘡病所牽涉的全部相關因 素。局部治療由於比其它治療形式更安全，故局部治療通 常為較佳15 >。目前之局部治療劑包括粉刺分解劑例如萃提 諾（tretinoin)、阿達帕靈（adapalene)、壬二酸、塔薩羅 丁（ t a z a r 〇 t e n e )及水揚酸；抗微生物劑如過氧化苯曱醯； 抗生素如克林達黴素 （c 1 i n d a m y c i n )、 紅黴素 (erythromycin)及四環素（tetracycline)以及抗炎劑例如 磺基乙醯化鈉。當痤瘡對局部治療無法產生滿意的反應 時，經常添加口服抗生素。其它用於較為嚴重之頑痼痤瘡 之系統性治療包括雌激素類、抗雄激素類以及異萃提諾 (isotretinoin) 〇 痤瘡初油酸菌的根除為有效治療之合理辦法，原因在於 10 312/發明說明書(補件)/92-09/92115959 200402425 單純存在有痤瘡初油酸菌有機體即可部分界定為該 4)。過氧化苯甲醯係經由與皮脂濾胞產生反應性氧物 而對痤瘡初油酸菌發揮殺菌活性16 j。過氧化苯曱醯組 部用抗生素或萃提諾極為有效17 >。過氧化苯甲醯的主 良影響為局部刺激，於治療開始時，局部刺激特別顯 其它記載之不良影響包括紅斑、乾燥及過敏性接觸性 (1 - 3 %病人）。當塗擦於胸部或背部時，衣物被漂白可 問題。 局部使用紅黴素及克林達黴素於痤瘡病人可產生 功效，而可用於治療輕度至中度痤瘡18 >。此等藥劑可 種調配物形式取得，每日塗擦一或二次。經常組合過 苯曱醯或萃提諾使用。局部塗擦抗生素可能引起若干 皮膚刺激，可能受到使用的媒劑影響。局部使用克林 素可能引發腹瀉及假膜性結腸炎19)’2())。 痤瘡治療使用抗生素之最大問題為出現痤瘡初油 之抗藥性菌株、以及其它棲息菌叢革蘭氏陽性抗藥菌 今日已知痤瘡初油酸菌抗藥性為重要性日增的臨床 5 >。紅黴素及克林達黴素之組合抗藥性首先係於1 9 7 9 美國報告，出現於使用任一種藥物之局部調配物治療 病人之皮脂濾胞痤瘡初油酸菌單離株之 2 0 % ;痤瘡初 菌對四環素之抗藥性首次於1 9 8 3年於美國有文獻記章 人對口服抗生素治療無良好反應2 2 >。目前估計1 / 4的 病人帶有對克林達黴素、紅黴素及/或四環素有抗藥性 瘡初油酸菌菌株2 3 >。1 9 9 7年英國5 6 7位痤瘡病人中之 帶有抗藥性痤瘡初油酸菌菌株2 4 >。晚近研究發現先前 312/發明說明書(補件)/92-09/92115959 病症 種， 合局 要不 著。 皮炎 能成 類似 以多 氧化 輕度 達黴 酸菌 株。 議題 年於 痤瘡 油酸 ί，病 痤瘡 之痤 6 5% 接受 11 200402425 抗生素治療之痤瘡病人有 2 8 %出現抗生素抗藥性痤瘡初油 酸菌菌株，相較於未曾接受抗生素治療之痤瘡病人只有6 % 出現抗藥性菌株。也證實歐洲、美國、澳洲及日本出現對 紅黴素、克林達黴素、四環素及多種相關抗生素具有抗藥 性之痤瘡初油酸菌菌株2 6 >。皮膚表面出現紅黴素抗藥性初 油酸菌於口服紅黴素治療期間反應不足有極為強力關聯。 此外，有明確文獻記載棲息於皮膚之菌叢之凝集酶陰性葡 萄球菌抗藥性菌株，就普及性及族群密度而言，隨著痤瘡 局部抗生素治療時間的增加而增高。痤瘡病人代表此種重 要之院内感染病原菌之大倉庫而可能傳染給密切接觸者 24) 〇 目前使用之廣效性抗生素之另一項缺點為對痤瘡初油 酸菌之作用選擇性不佳，其只對全部正常於皮膚形成群落 之全部其它革蘭氏陽性菌有活性。如此導致根除該等菌 種，該等菌種其存在於皮膚是其它問題有機體的障礙，通 常可防止其它有機體之形成菌落：棲息革蘭氏陽性菌的清 除可能造成其它難以治療之革蘭氏陰性菌以及病原真菌造 成的其它感染。 因此需要有一種新穎抗生素其可提供新穎作用機轉，對 目前使用之抗菌劑中之敏感性及抗藥性初油酸菌菌株具有 活性；使用對初油酸菌有高度選擇性之抗生素可達成目前 治療之進一步改良，原因在於其它皮膚感染的可能性降 低；抗藥性突變株之選擇性頻率低，殺菌活性為其額外之 優點，因而能進一步推薦使用此種抗菌劑。 對痤瘡初油酸菌之作用選擇性對濾泡正常革蘭氏陽性 12 312/發明說明書(補件)/92-09/92115959 200402425 細菌菌叢以及葡萄球菌幾乎維持不變，因此防止病灶部 被其它致病菌（包括革蘭氏陰性病原菌及真菌）之形成 落。 對痤瘡初油酸菌之作用選擇性定義為一種情況，此處 用於治療或預防痤瘡之抗痤瘡候選化合物於尋常用於皮 抑制皮膚之痤瘡初油酸菌增生之局部調配物之劑量，對 有其它正常皮膚表面形成菌落之革蘭氏陽性菌不具有 性，如此可促成維持皮膚表面之正常生理情況。特別不 受到抗痤瘡候選化合物局部投藥影響之菌株為金黃葡萄 菌（Staphylococcus aureus)、表 皮 葡 萄 球 (Staphylococcus epidermidis)及釀 膿鏈球 (Streptococcus pyogenes)菌株。合理確定可符合前述 擇性作用條件之先決要件為抗痤瘡候選化合物於一系列 管試驗對抗前述菌株之 Μ I C (最低抑制濃度）值遠高於對 痤瘡初油酸菌菌株之Μ IC值，痤瘡初油酸菌對目前用於 療皮膚病症之其它抗生素如紅黴素及克林達黴素具有感 性及抗藥性。 此種治療亦即痤瘡局部治療性質允許施用之藥物量， 劑量實質不會影響皮膚之正常革蘭氏陽性菌叢，主要為 萄球菌，如此可避免病灶部位被其它致病菌包括革蘭氏 性菌及真菌形成群落。 【發明内容】 根據本發明發現式（I )醯胺衍生物之活性於低於抑制 述存在於正常皮膚表面之細菌生長所需濃度之 1000倍 下濃度，即可選擇性抑制痤瘡初油酸菌生長，如此表示 312/發明說明書(補件)/92-09/92115959 位 菌 欲 膚 所 活 可 球 菌 菌 選 試 抗 治 受 該 葡 陰 前 以 透 13 200402425 過局部投藥呈單一治療或組合具有粉刺分解及抗粉刺發生 活性之藥劑可用於輕度/中度痤瘡之選擇性抗微生物治 療。實際上，式（I)化合物對痤瘡初油酸菌具有選擇性試管 試驗活性，Μ I C值係於 0 . 0 6毫克/毫升（8 0 %試驗菌株）至 0 . 2 5毫克/毫升之範圍，包括對已經普遍用於治療痤瘡超 過3 0年之廣效性抗生素（亦即紅黴素、四環素及克林達黴 素）之抗藥性單離株也具有選擇性活性。其它革蘭氏陽性菌 對式（I )化合物不具敏感性，唯一差異在於長球菌，長球菌 於0 . 5至1 6毫克/毫升之濃度受抑制。但此等菌株因非屬 正常皮膚菌叢之一部分，故與本發明之内文無關。式（I) 化合物對革蘭氏陰性菌及真菌不具活性。 【實施方式】 出乎意外地透過試管試驗證實本發明式（I )化合物具有 高度選擇性作用，試管試驗已經測定對抗對紅黴素及克林 達徽素有感受性及抗藥性之痤瘡初油酸菌株之最低抑制濃 度（Μ I C )，以及測定對一系列葡萄球菌菌株之Μ I C。試驗係 對抗生素GE2270以及US5.599.791所述之四種代表性化 合物（Β、C、D及Ε)進行比較。 結果報告於下表1。 14 312/發明說明書(補件)/92-09/92115959 A / '-f 200402425 MIC(微克/毫升） GE 2270 CO c^> ◦ LO οα ◦ LO (N1 τ 1 ◦ V <0.125 LO CD* LO οα r-H Q V <0. 125 LO CNI τ-Η ο V LO CNI H ◦· V <0. 125 LO Csl τ—Η CD <0. 125 <0. 125 <0. 125 <0. 125 1—H 0. 250 LO CD OO <0. 125 0. 125 <0. 125 LO (NJ r—H o V LO CM τ—1 CD V LO οα r-H (〇 〈0. 125 <0. 125 <0. 125 <0. 125 o CNI 〇〇 C>0 >128 <0.125 <0. 125 LO CNI ◦ V LO CNI ◦ V in c<\ r-H o V <0. 125 <0. 125 <0. 125 <0. 125 <0. 125 PQ (>a oo OO >128 <0.125 <0.125 <0. 125 <0. 125 <0. 125 <0. 125 <0.125 <0. 125 <0. 125 ! <0.125 >128 >128 >128 >128 >128 <0.125 <0. 125 <0.125 <0.125 <0. 125 <0. 125 <0.125 <0.125 <0. 125 <0. 125 培養基 慕勒休頓（Mueller Hinton)(MH) MH+30%牛血清 目 目 目 威金斯察格林（Wilkins Chalgren)(WC) ο o o o ο 〇 〇 〇 菌株 Smith ATCC 19636 Smith ATCC 19636 MRSA ATCC 12228 C 203 ATCC 6919 ATCC 6922 ATCC 25746 臨床單離株 臨床單離株 臨床單離株 臨床單離株 臨床單離株 臨床單離株 臨床單離株 微生物 金黃葡萄球菌 金黃葡萄球菌 金黃葡萄球菌 表皮葡萄球菌 釀膿鏈球菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤瘡初油酸菌 痤疮初油酸菌 ?!,6ς I Ι36/60-ζ6/(φ}ϋ)*^ί^^總/Π e 200402425 上表報告資料證實全部比較性化合物B、C及D及G E 2 2 7 0 雖然呈現本發明（A )式（I )醯胺化合物對抗痤瘡初油酸菌菌 株之相等活性程度，但該等比較性化合物也對全部接受試 驗之葡萄球菌菌株具有活性，Μ I C值係於0 . 0 6微克/毫升 至8微克/毫升之範圍。此種活性可判定為對初油酸菌株具 有選擇性作用。 式（I )化合物用於尋常痤瘡之適合性已經於一系列微生 物學、毒物學、藥力效評估獲得證實，其結果報告如後。 下表 2摘述式（I )醯胺化合物對抗由痤瘡病人收集所得 對克林達黴素或紅黴素顯示抗藥性之 1 5株痤瘡初油酸菌 單離株之微生物學活性研究結果。表3報告相同式（I )醯胺 化合物對5株顯示紅黴素及克林達黴素感受性之痤瘡初油 酸菌臨床單離株之活性資料。 16 312/發明說明書(補件)/92-09/92115959 200402425 表2 紅黴素、克林達黴素及式（I )化合物對顯示抗生素抗藥 性表現型之痤瘡初油酸菌臨床單離株之最低抑制濃度值摘 要0 Μ I C微 克/毫 升 紅黴素 克林達黴素 式（I)化合物 單離株 數目 累進 % MIC 50/90 單離株 數目 累進°/〇 MIC 50/90 單離株 數目 累進°/〇 MIC 50/90 0.015 0. 03 9 6 0% MICso 0.06 6 100% MIC〇〇 0.125 0. 25 0. 5 1 2 4 3 20% 8 2 33% 16 0 32 0 64 8 8 7% MIC50 128 0 256 2 10 0% MICdo 512 1 7% 1024 11 8 0% MICso 2 0 48 3 1 0 0 % MIC〇〇 17 312/發明說明書(補件)/92-09/92115959 r't λ 200402425 表3 紅黴素、克林達黴素及式（I )化合物對顯示抗生素感受 性表現型之痤瘡初油酸菌臨床單離株之最低抑制濃度值摘 要0 Μ I C微 紅黴素 克林達黴素 式（I )化合物 克/毫 單離株 累進 MIC 單離株 累進°/〇 MIC 單離株 累進％ MIC 升 數目 % 50/90 數目 50/90 數目 50/90 0.015 0.03 4 8 0°/〇 0.06 1 10 0% 0. 125 5 10 0% MIC〇〇 3 60% MICso 0.25 1 8 0% 0. 5 1 10 0% MICso 1 Μ I C 5。及Μ I C 9。分別表示可抑制接受試驗菌株之5 0 %及9 0 % 之最低抑制濃度。 上表 2及表 3顯示式（I )化合物對紅黴素及克林達黴素 抗藥性痤瘡初油酸菌株之活性係與對抗生素敏感性痤瘡初 油酸菌菌株之活性相當。為了測定對式（I )化合物有抗藥性 之痤瘡初油酸菌突變株之選擇頻率，相同化合物以1微克/ 毫升及1 0微克/毫升攙混於固體培養基，約1 0 1C F U之細 菌懸浮液分佈於孔板表面上。基於生長之菌落數目，測得 對式（I )化合物之抗藥性頻率於1微克/毫升係於1 . 4X 1 0_9 至1 · 5 X 1 (Γ 1Q之範圍以及於1 0微克/毫升係於3 . 3 X 1 0 _ 9至 9.4xl0_1° 之範圍。 式（I )化合物之皮膚投藥試驗顯示該化合物經由皮膚之 吸收極低或為零。 局部吸收係使用如下實施例 6之 3 %凝膠調配物以及 3 % 18 312/發明說明書(補件)/92-09/92115959 200402425 聚乙二醇4 0 0溶液進行評估。 使用 3 %凝膠調配物於兔進行研究，顯示每日用藥 7日 後，只有有限數目的樣本才出現可測量之試驗化合物血漿 濃度，指示試驗化合物即使有吸收也極少。於兔之結痂以 及未結痂皮膚二者進行2 8日之耐受性試驗中，3 %凝膠調配 物於整體研究並未顯示任何可偵測之血漿濃度。 根據本發明，式（I )化合物可攙混於多種適合局部輸送 活性成分之調配物。適合局部治療及預防尋常痤瘡用之局 部用調配物為乳霜劑、洗劑、泡沫劑、喷霧劑、乳液劑、 凝膠劑等，此等調配物係根據業界常用之已知方法製造（例 如參考：局部調配物：設計及發展-Bozena Michniak /平裝 /CRC Press, LLC/1999年2月；雷明頓：製藥科學及規範 第 20 版-Alfonso L. Gennaro, Alfonso R.(編輯）Gennaro; 出版商：Lippincott Williams & Wilkins, 2000 年 12 月， 第20版；製藥技術百科-James Swarbrick(編輯），James C. Boylan(編輯）精裝 / Marcel Dekker/1997 年 5 月）。 該等調配物中，式（I )抗生素 G E 2 2 7 0之醯胺衍生物可 選擇性組合其它用於治療或預防痤瘡具有輔助作用之成分 或可提供皮膚效用之其它成分。此等額外成分例如為其它 對痤瘡初油酸菌之增生具有活性之其它成分例如紅黴素、 克林達黴素及四環素類；抗微生物劑例如可羅海西丁 (c h 1 〇 r e X i d i n e )及過氧化苯甲醢；據描述為對痤瘡初油酸 菌具有抑制活性之合成物質或天然物質如 1 -十五烷醇2 n 及其衍生物 29)、西得林（cedrene)、 卡瑞歐費林 (caryophyllene)、隆吉福尋（longifolene)及蘇吉普辛 19 312/發明說明書(補件)/92-09/92115959 200402425 (ΐ h u j 〇 p s e n e )3 Q);粉刺分解劑（例如萃提諾、阿達帕靈、 壬二酸、塔薩羅丁、水揚酸及其衍生物；抗炎劑如N S A I D (例 如乙醢基水楊酸、衣布普芬（ibuprofen)、 那普辛 (naproxen)、石黃基乙醢胺）、類固醇抗炎劑（例如氫可體松 (hydrocortisone))；維生素類（例如視黃酸及其衍生物）； 油或皮脂控制劑（例如黏土聚矽氧類）；皮膚癒合劑以及皮 膚調理劑。 通常前述本發明式（I )化合物於本發明之痤瘡治療或預 防用局部組成物之含量係於約0 . 1 % ( w / w )至約1 0 % ( w / w )之 範圍。 可用於輸送式（I)化合物之局部用組成物含有尋常醫藥 上可接受之賦形劑包括載劑、媒劑或具有其它輸送功能之 賦形劑、保藏劑、界面活性劑、保濕劑、增稠劑、香料、 螯合劑、水、醇類、抗氧化劑、防腐劑、著色劑及紫外光 吸收劑。 含有抗生素G E 2 2 7 0因子A醯胺衍生物之局部組成物之 非限制性實例，列舉如後以供舉例說明本發明。 實施例1 : 3 %乳霜劑 重量（百分比） 式（I )化合物，呈鹽酸鹽 3，0 0 0 氫氧化鈉 0，1 0 2 苄醇 0,850 一硬脂酸山梨糖醇酯 1，6 1 5 棕櫚酸鯨蠟酯 1，7 0 0 鯨蠟醇 3，4 0 0 312/發明說明書(補件)/92-09/92115959 20 200402425 硬脂醇 波麗索貝（Polysorbate)60 肉菫蔻酸異丙酯 二乙二醇一乙_ 純水 實施例2 : 3 %凝膠劑 式（I )化合物，呈乳酸鹽 羥乙基纖維素 二乙二醇一乙醚 純水 實施例3 : 3 %醇性凝膠劑I 式（I )化合物，呈鹽酸鹽 二乙二醇一乙醚 羥基丙基纖維素 乙醇96% 3,400 5,185 6,800 1 2, 000 61,948 100,000 重量（百分比） 3.000 2,500 47, 000 47.000100.000 重量（百分比） 3.00012.000 1 5, 000 70.000100.000 實施例4 : 3 %醇性凝膠劑I I 式（I )化合物 羥基丙基纖維素 純水 重量（百分比） 3,000 3, 000 或 1， 500 9,500 312/發明說明書(補件)/92·09/92115959 21 200402425 乳 酸 〇, 500 乙 醇 95% 84,000 或丨 35, 500 錄 蝶 醇 10 0,000 實 施 例 5 :3°/〇 水 .醇 性洗劑 重 量（百分 比） 式 (I )化合物 3, 000 乳 酸 2, 000 二 乙 二 醇 一乙 36 ，500 乙 醇 10 ，000 對 羥 基 苯 曱酸 曱 酯 〇, 15 0 對 羥 基 苯 曱酸 丙 酯 〇, 050 水 適 量加至 100 實 施 例 6 :1 . 5 % 或 3 %凝膠劑 重 量（百分 比） 式 (I )化合物 1， 500 或 3, 000 曱 基 纖 維 素 1, 500 二 乙 二 醇 一乙 醚 35 ，000 乙 醇 9 6% 10 ，000 乳 酸 2, 000 對 羥 基 苯 甲酸 甲 酯 〇, 150 對 羥 基 苯 甲酸 丙 酯 〇, 050 純 水 適 量加 至 100, 000 實 施 例 7 、8 及 9:0.1%、1 % 及 0· 5%凝膠劑 7) 重 量（百分 比） 式 (I )化合物 〇, 100 22 312/發明說明書(補件)/92-09/92115959 200402425 81,000 適量加至100,000 重量（百分比） 1,000 77,000 適量加至100,000 重量（百分比） 0,500 適量加至100，000 醇 SD 40 羥基丙基纖維素，乙酸鋅，丙二醇 二乙醇胺，月桂醯胺，香料 8) 式（I )化合物 醇 SD 40-2 丙二醇，羥基丙基纖維素 9) 式（I )化合物 丁基化羥基曱苯， 羥基丙基纖維素，乙醇 實施例1 0 : 5 %乳霜劑 重量（百分比） 式（I )化合物 5,000 聚氧伸乙基脂肪酸酯類， 辛酸鯨蠟基硬脂酯，蠟與甘油酯混合物， 二醇，丙二醇，苯甲酸，純水 適量加至1 0 0，0 0 0 實施例1 1 : 5 %皮膚科用懸浮液 重量（百分比） 式（I )化合物 5,000 二醇，異硬脂醇，鯨蠟基-硬脂醇， 硬脂酸，一硬脂酸甘油酯， 月桂醯基肌胺酸鈉， 對羥基苯曱酸曱酯，純水 適量加至1 0 0，0 0 0 23 312/發明說明書(補件)/92-09/92115959 200402425 參考文獻 ) Ebling FJ” Cunliffe WJ. 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30) US 5.200.429 312/發明說明書(補件)勝〇9/92115959
Claims (1)
- 200402425 拾、申請專利範圍： 1 · 一種式（I )化合物之用途其中： R表示曱氧基甲基， R!表示甲基， R2表示甲基， Y表示 基團 以及其醫藥上可接受之酸加成鹽； 用於製造痤瘡之局部治療或預防用藥之用途。 2 .如申請專利範圍第1項之用途，其中該式（I )化合物 或其醫藥上可接受之酸加成鹽係結合其它於痤瘡治療上具 有辅助作用或可提供皮膚效益之成分。 3 .如申請專利範圍第1或2項之用途，其中該式（I )化 合物或其醫藥上可接受之酸加成鹽係以占該醫藥組成物約 0 . 1至 1 0 %重量比範圍之數量攙混於一種適合供局部投藥 用之醫藥組成物。 4.如申請專利範圍第1至3項中任一項之用途，其中該 26312/發明說明書(補件)/92-09/92115959 200402425 醫藥上可接受之酸加成鹽為與鹽酸或乳酸生成之鹽。 5 . —種供痤瘡局部治療或預防用之藥物，該藥物包含一 種式（I )化合物其中： R表示甲氧基甲基， Ri表示甲基， R2表示甲基， Y表示 一NH —^基團 以及其醫藥上可接受之酸加成鹽。 6 .如申請專利範圍第 5項之藥物，其中該式（I )化合物 或其醫藥上可接受之酸加成鹽係結合其它於痤瘡治療上具 有輔助作用或可提供皮膚效益之成分。 7. 如申請專利範圍第5或6項之藥物，其中該式（I )化 合物或其醫藥上可接受之酸加成鹽係混合醫藥上可接受之 賦形劑。 8. 如申請專利範圍第5至7項中任一項之藥物，其中該 式（I )化合物或其醫藥上可接受之酸加成鹽之含量係占該 27312/發明說明書(補件)/92-09/92115959 200402425 藥物之0 . 1至1 ο %重量比之範圍。 9 .如申請專利範圍第5至7項中任一項之藥物，其係呈 乳霜劑、洗劑、泡沫劑、喷霧劑、乳液劑或凝膠劑劑型。 1 0 . —種治療或預防痤瘡之方法，該方法包含以足夠提 供痤瘡初油酸菌（P r 〇 p i ο n i b a c t e r i u m a c n e )之抑制活性或 抑制增生用量對患有該皮膚病症或暴露於該皮膚病症病人 局部投予一種式（I )化合物其中： R表示曱氧基曱基， Ri表示甲基， R2表示甲基， Y表示 一基團 或其醫藥上可接受之酸加成鹽。 1 1 .如申請專利範圍第1 0項之方法，其中該式（I )化合 物或其醫藥上可接受之酸加成鹽係結合其它於痤瘡治療上 具有辅助作用或可提供皮膚效益之成分。 1 2.如申請專利範圍第1至4項中任一項之用途，其中 該式（I )化合物或其醫藥上可接受之酸加成鹽之抑制活性 28 312/發明說明書(補件)/92-09/92115959 200402425 對痤瘡初油酸菌具有選擇性。 1 3.如申請專利範圍第5至9項中任一項之藥物，其中 該式（I)化合物或其醫藥上可接受之酸加成鹽之抑制活性 對痤瘡初油酸菌具有選擇性。 1 4.如申請專利範圍第1 0或1 1項之方法，其中該式（I ) 化合物或其醫藥上可接受之酸加成鹽之抑制活性對痤瘡初 油酸菌具有選擇性。1 5 ,如申請專利範圍第 1項之化合物之用途，其係用於 製造供痤瘡局部治療或預防用之藥物，其特徵在於該藥物 係對痤瘡初油酸菌具有選擇性。29 312/發明說明書(補件)/92-09/92115959 200402425 柒、指定代表圖： (一） 本案指定代表圖為：第（ ）圖。 (二) 本代表圖之元件代表符號簡單說明： 無 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式：其中： R表示曱氧基曱基， Ri表示甲基， R2表示曱基， Y表示312/發明說明書(補件)/92-09/92115959 6
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| EP (1) | EP1553967B1 (zh) |
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| KR (1) | KR20050026401A (zh) |
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| AR060977A1 (es) | 2006-05-31 | 2008-07-23 | Novartis Ag | Aminotiazoles y sus usos |
| ATE500259T1 (de) | 2006-12-20 | 2011-03-15 | Novartis Ag | Aminothiazolmakrocyclen, ihre verwendung als antibakterielle verbindungen und verfahren zu ihrer herstellung |
| EA200901613A1 (ru) | 2007-06-04 | 2010-06-30 | Новартис Аг | Макроциклы и их применение |
| NZ585788A (en) | 2007-12-12 | 2011-07-29 | Novartis Ag | Aminothiazoles and their uses |
| PT106679B (pt) | 2012-11-27 | 2015-03-25 | Hovione Farmaciencia Sa | Formulações tópicas de tetraciclinas, sua preparação e usos |
| FR3004939B1 (fr) * | 2013-04-26 | 2015-05-22 | Oreal | Huile essentielle de satureja montana a forte teneur en geraniol, et utilisation pour traiter les peaux grasses et/ou les defauts esthetiques associes |
| DE102013215828A1 (de) * | 2013-08-09 | 2015-02-12 | Beiersdorf Ag | Gelförmiges Sonnenschutzmittel mit Fettalkoholen |
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| LU86865A1 (fr) * | 1987-05-06 | 1989-01-19 | Oreal | Nouveaux retinoates d'ammonium quaternaires,leur utilisation en cosmetique et en dermopharmacie |
| DE365519T1 (de) * | 1987-06-12 | 1990-09-06 | Molecular Design International, Inc. | Topische vorstufen von arzneimitteln zur behandlung von akne und hautkrankheiten. |
| DK0406745T3 (da) * | 1989-07-04 | 1995-02-27 | Lepetit Spa | Antibiotiske GE 2270 faktorer A1, A2, A3 og H |
| JP2693859B2 (ja) * | 1990-09-28 | 1997-12-24 | 高砂香料工業株式会社 | 尋常性▲ざ▼瘡用皮膚外用剤 |
| IL100572A (en) * | 1991-01-03 | 1997-01-10 | Lepetit Spa | Amides of antibiotic ge 2270 factors their preparation and pharmaceutical compositions containing them |
| JP2907640B2 (ja) | 1992-06-29 | 1999-06-21 | 高砂香料工業株式会社 | 尋常性ざ瘡用皮膚外用剤 |
| JP2937667B2 (ja) * | 1992-11-19 | 1999-08-23 | 高砂香料工業株式会社 | 尋常性ざ瘡用皮膚外用剤 |
| KR100381688B1 (ko) * | 1995-02-07 | 2003-12-11 | 바이오써치 이탈리아 에스.피.에이. | Ge2270및ge2270-유사항생제의염기성프롤린-아미드유도체 |
| CA2242067A1 (en) * | 1996-02-14 | 1997-08-21 | Versicor Inc. | Derivatives of antibiotic ge2270 factors c2a, d2 and e |
| AUPN892496A0 (en) * | 1996-03-25 | 1996-04-18 | Technical Consultancy Services Pty Limited | Acne treatment |
| US6009225A (en) * | 1998-05-26 | 1999-12-28 | Ray; Craig D. | Fiber optic drop splice closure and related methods |
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| Publication number | Publication date |
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| ES2364269T3 (es) | 2011-08-30 |
| KR20050026401A (ko) | 2005-03-15 |
| TWI329650B (en) | 2010-09-01 |
| BR0305070A (pt) | 2004-09-21 |
| AU2003242647A1 (en) | 2003-12-31 |
| CA2489705A1 (en) | 2003-12-24 |
| DK1553967T3 (da) | 2011-08-29 |
| PT1553967E (pt) | 2011-08-01 |
| AR039682A1 (es) | 2005-03-09 |
| WO2003105881A1 (en) | 2003-12-24 |
| CY1111734T1 (el) | 2015-10-07 |
| EP1553967B1 (en) | 2011-05-18 |
| CA2489705C (en) | 2012-08-14 |
| AU2003242647B2 (en) | 2009-10-22 |
| EP1553967A1 (en) | 2005-07-20 |
| JP4723857B2 (ja) | 2011-07-13 |
| NO20040662L (no) | 2004-04-05 |
| HK1074402A1 (zh) | 2005-11-11 |
| US20070117825A1 (en) | 2007-05-24 |
| ATE509633T1 (de) | 2011-06-15 |
| US7655676B2 (en) | 2010-02-02 |
| JP2005529947A (ja) | 2005-10-06 |
| SI1553967T1 (sl) | 2011-07-29 |
| NO333162B1 (no) | 2013-03-25 |
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