TWI556839B - 包含活性劑－磷酸鈣粒子複合物之皮膚遞送組成物及其使用方法 - Google Patents

包含活性劑－磷酸鈣粒子複合物之皮膚遞送組成物及其使用方法 Download PDF

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TWI556839B
TWI556839B TW099114719A TW99114719A TWI556839B TW I556839 B TWI556839 B TW I556839B TW 099114719 A TW099114719 A TW 099114719A TW 99114719 A TW99114719 A TW 99114719A TW I556839 B TWI556839 B TW I556839B
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calcium phosphate
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薩拉 曼索瑞
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研究室護膚股份有限公司
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Description

包含活性劑-磷酸鈣粒子複合物之皮膚遞送組成物及其使用方法 相關申請之交互對照
根據35 U.S.C. § 119(e)，本申請案主張2009年5月6日提出申請之美國臨時申請案序號61/176,057的優先權；該申請案之揭示以引用方式納入本文中。
本發明係關於皮膚遞送組成物及將該等組成物用於活性劑遞送應用之方法。
 序言
各種不同活性劑已發展且持繼發展於治療各種不同情況(包括疾病及非疾病情況二者)之用途。關於該等應用，有效量之活性劑必須遞送至需要其之對象。已發展各種不同遞送調配物及路徑，其中該等路徑可視活性劑之性質而改變。典型地，較沒有侵入性的遞送路徑為更好容忍的且因此更令人想要。
因其最小地侵入性質而極感興趣的遞送路徑之一類型為皮膚遞送。在皮膚遞送中，活性劑組成物係施用於皮膚位置以將活性劑遞送至對象。多數目前使用中或在評估下的皮膚遞送技術並不完全人滿意。例如，某些皮膚遞送技術會瓦解角質層(Sc)之完整性及/或依賴滲透增強劑的存在，滲透增強劑會引起不想要的損害及/或刺激。除此之外，某些皮膚遞送技術可為以聚合物-及/或脂質體為主的技術，該二種技術都沒有真正地遞送通過Sc。而且這些技術不能適用於大分子量生化活性物質，等等。
就這點而論，持續需要發展克服一或多種目前皮膚遞送方法所經歷的缺點之新穎皮膚遞送技術。
 概述
提供皮膚遞送組成物。該等皮膚遞送組成物之特點包括活性劑/磷酸鈣粒子複合物之存在，其中這些複合物包括與一或多種活性劑結合之均勻剛性球形奈米孔洞磷酸鈣粒子。也提供將該等組成物用於活性劑遞送應用之方法。
發明之詳細說明
提供皮膚遞送組成物。該等皮膚遞送組成物之特點包括活性劑-磷酸鈣粒子複合物之存在，其中這些複合物包括與一或多種活性劑結合之均勻剛性球形奈米孔洞磷酸鈣粒子。也提供將該組成物用於活性劑遞送應用之方法。
在進一步描述本發明之前，應了解本發明並不侷限於所述特定體系中，就其本身而論可能改變。亦應明瞭本文中所使用之用語僅是為了闡述特定具體例，而非意欲作為限制，因為本發明之範圍僅係由所附申請專利範圍來限定。
當提供一數值範圍時，應明瞭介於該範圍上、下限之間的各個中介數值(除非前後文明確地另有指出，否則計算至該下限單位的十分之一)，以及所述範圍內之任何其他所述數值或介於中間的數值，均涵括於本發明中。這些較小範圍的上與下限可獨立地涵括在較小範圍內並且亦涵括在本發明中，受到在所述範圍中任何被特定排除的限制。當所述範圍包括限值中之一或二者時，不含有這些被包括之限值中之一或二者的範圍亦包括於本發明中。
某些範圍以前面帶有術語“約”的數值出現在本文中。術語“約”使用於本文中以對後方之準確數值以及接近或近似該數值之數值提供文字支持。在決定一數值是否接近或近似於一特別被列舉的數值時，接近或近似的未列舉數值可為一個存在於上下文的數值，提供特定所列數值的實質等效值。
本文中所列方法可以任何邏輯上可能的所列事件之順序，以及所列事件的順序進行。
除非另有定義，所有本文中所使用的技術以及科學術語具有如熟習本發明所屬技藝之一般技藝人士通常理解的相同意義。雖然任何類似或相同於該等在本文中所述者的方法以及材料也可用於實施或測試本發明，但現將說明較佳方法以及材料。
所有在本文中引用的公開資料以引用方式納入本文中以揭示及說明與該公開資料所引用者有關的方法及/或材料。提供本文中所討論之公開資料僅僅因為它們的揭示在本申請案申請日之前。在本文中不應被解釋為憑藉先前發明而承認本發明無權先於該公開資料。再者，所提供的公開日期可能不同於實際公開日期，它們可能需要分別確認。
必須注意如使用在本文及申請專利範圍中，單數形式"一(a)"、"一(an)"及"該(the)"包括複數所指物，除非本文中另有明確指示。進一步注意申請專利範圍可草擬為排除任何隨意要件。就其本身而論，這個說明意欲作為使用此等排除性用語如“僅僅(solely)”、“僅(only)”以及與申請專利範圍要件的列舉有關的類似者，或使用“負面(negative)”限定的前置基礎。
在進一步描述本發明的各種特點中，更詳細描述根據某些體系之活性劑-磷酸鈣粒子，接著包括活性劑-磷酸鈣粒子之遞送組成物的體系之說明，以及製造及使用包括活性劑-磷酸鈣粒子之複合物及遞送組成物的方法。
遞送組成物
如上文所概述，提供活性劑遞送組成物。本發明之活性劑遞送組成物包括存在於遞送媒液之活性劑-磷酸鈣粒子複合物。現更詳細地分開檢討遞送組成物之活性劑-磷酸鈣粒子複合物之遞送媒液成分。
活性劑-磷酸鈣粒子複合物
存在於本發明之遞送組成物中的活性劑-磷酸鈣粒子複合物包括與一或多種活性劑結合之均勻剛性球形奈米孔洞磷酸鈣粒子。如粒子與一或多種活性劑結合時，一或多種活性劑係以方式結合於粒子。活性劑可經由許多的不同結合型式結合於粒子，包括但不限制於：離子結合、共價結合、凡得瓦相互作用、氫結合相互作用、正相及逆相分配相互作用、等等。同樣地，粒子可描述為裝載某量之一或多種活性劑。“裝載”是指粒子包括某量之一或多種結合至粒子的活性劑(換句話說某量之單一活性劑或二或多種不同活性劑)。如活性劑被結合至粒子，當粒子存在於遞送組成物時，活性劑不會以任何實質量從粒子解離。因為實質上沒有活性劑從粒子解離，任何進行解離之量為30%或更小，諸如20%或更小，例如，10%或更小，包括5%或更小，以活性劑的原結合量的重量計。結合至粒子的活性劑成分(其由一或多種不同的活性劑製造)之量可視組成活性劑結合粒子之特定活性劑而改變，及在某些體系中，範圍從0.01至1000毫克/克，諸如從0.1至750毫克/克及包括1至300毫克/克活性劑)/克粒子。
活性劑係與磷酸鈣粒子可逆地結合。“可逆地結合”是指活性劑在遞送至對象之後(例如，將包括複合物之遞送組成物施用至皮膚位置之後)從磷酸鈣粒子釋放。如下文更詳細所檢討者，複合物之磷酸鈣粒子在酸性條件下(諸如在pH 5或更小，例如，pH 4.9或更小，pH 4.7或更小，pH 4.5或更小，pH 4.3或更小之條件下)降解。當粒子降解時，它們釋放其活性劑“載重量(payload)”。角質層(SC)，皮膚的最外層，係由大約20層的細胞組成且厚度大約為10微米。SC之pH視其深度而改變。其最外層從pH 4.3改變至7.0，視採樣之位置，或個體的性別而定。此pH在靠近顆粒層(SG)提高到7.0左右。此提高在鄰接SG的SC最後幾層中最引人注目，參見下文。同樣地，如本發明之複合物滲透進入SC，它們降解且同時地釋放與其結合之任何活性劑。
儘管在複合物已與磷酸鈣粒子結合，所釋放之活性劑保留其所要活性。因此，活性劑至磷酸鈣粒子之結合及釋放對活性劑產生實質上很少(如果有任何的話)的傷害。同樣地，活性劑之活性沒有減少至不利地影響其效用的程度，其中因與所給予之活性劑發生結合至磷酸鈣粒子所引起之任何活性的減少為10%或更小，諸如5%或更小及包括1%或更小，例如，如藉由活性檢定法測定，例如，如下述實驗段中所述。
在一些體系中，在複合物中活性劑與磷酸鈣粒子之結合保留一或多種所要的活性劑特徵，諸如穩定性。換句話說，複合物穩定活性劑，如相較於缺乏磷酸鈣粒子之對照組。
均勻剛性球形奈米孔洞磷酸鈣粒子
活性劑-磷酸鈣粒子複合物之磷酸鈣粒子為均勻剛性球形奈米孔洞磷酸鈣粒子。“均勻”是指粒子之形狀實質上不改變，所以粒子實質上具有相同的球形。“剛性”是指粒子很硬，致使它們不易曲折。術語“球形”係以其習知意義使用以表示在所有點的表面離中心實質上距離相等的圓體。感興趣者為其中平均直徑為20微米或更小，諸如10微米或更小，包括5微米或更小，在一些例子中其中平均直徑為4微米或更小，諸如3微米或更小，包括2微米或更小的磷酸鈣粒子。在所給予之磷酸鈣粒子組成物中，可存在直徑之分佈，其中在一些例子中多數(諸如60%或更大，75%或更大，90%或更大，95%或更大)之粒子具有在從0.01至20微米，諸如從0.1至10微米及包括從0.1至2微米之範圍的直徑。在一些例子中，具有2微米或更小之平均粒徑的粒子之比例為50數目%或更大，諸如70數目%或更大，包括90數目%或更大。
粒子為奈米孔洞。“奈米孔洞”是指粒子具有30%或更大，諸如40%或更大，包括50%或更大之孔隙度，其中孔隙度可在從30%至85%，諸如從40%至70%，包括從45%至55%之範圍，如使用如ASTM D 4284-88中所述之汞侵入孔隙計孔隙度測量方案“Standard Test Method for Determining Pore Volume Distribution of Catalysts by Mercury Intrusion Porosimetry”測量。孔隙度也以“孔洞體積(毫升/克)”描述且在該等例子中許多範圍在從0.1毫升/克至2.0毫升/克。在一些例子中，粒子具有致使其內表面積範圍在從10米2/克至150米2/克之孔隙度，諸如從20米2/克至100米2/克，包括30米2/克至80米2/克，如使用ASTM D3663-03觸媒及觸媒載體之表面積的標準測試方法中所述之BET氣體吸附表面積測定方案測定。孔洞直徑可改變，在某些例子中範圍在從2至100奈米，諸如5至80奈米，包括10至60奈米。除此之外，粒子可具有範圍在從0.2克/公分3至0.5克/公分3，諸如從0.25克/公分3至0.45克/公分3，包括從0.3克/公分3至0.4克/公分3之敲緊密度。該敲緊密度可使用標準ASTM WK13023-New Determination of Tap Density of Metallic Powders by a Constant Volume Measuring Method測量。
在一些例子中，粒子為化學上為純的。化學上為純的是指粒子由實質上一種類型之磷酸鈣礦物製造。在一些例子中，磷酸鈣粒子以分子式Ca10(PO4)6(OH)2描述。
在一些例子中，粒子為陶瓷粒子。陶瓷是指該等粒子係使用一種包括使粒子進行高溫條件之步驟的方法產生，其中該等條件係說明於下。高溫可在從200至1000℃，諸如300至900℃及包括300至800℃之範圍。在一些體系中，該等粒子具有範圍從20至200 Mpa(諸如從50至150 MPa及包括75至90 Mpa)之壓縮斷裂強度，如使用SHIMADZU MCT-W500微壓縮測試機器粒子強度測量方案以燒結於400℃至900℃之溫度的粒子測量，如歐洲專利EP1840661所描述。
在一些體系中，該等粒子為可生物降解的，其是指粒子在生理條件下以一些方式(例如，溶解)隨時間降解。當這些體系之粒子為在生理條件下可生物降解時，它們在5或更小之pH(諸如4.5或更小，包括4.3或更小)之條件下以可查覺的速率至少開始溶解。同樣地，粒子在pH 5或更小之酸性環境下顯示溶解度，諸如當施用於在對皮膚時。
磷酸鈣粒子為非毒性，例如，如經由US-FDA 21 CFR Part 58測量，非致突變性，例如，如以致突變性Ames測試測定及非刺激性，例如，如經由皮膚敏感性RIPT(人類)測量。
雖然遞送組成物的均勻剛性球形奈米孔洞磷酸鈣粒子可改變各種不同參數，包括如上文所檢討者，但在一些體系中，遞送組成物中所使用之粒子為具有2微米平均直徑之化學上純的粒子。
本發明之遞送組成物的均勻剛性球形奈米孔洞磷酸鈣粒子可使用任何方便的方案製備。感興趣之製造方案的例子包括但不限制於該等美國專利號4,781,904；5,039,408；5,082,566；及5,158,756中所述者；該等之揭示以引用方式納入本文中。在感興趣之方案中，粒子係藉由噴霧乾燥一種包括奈米磷酸鈣(例如，羥磷灰石)晶體(其可在從2奈米至100奈米大小之範圍)之漿料製造以產生均勻球形奈米孔洞磷酸鈣粒子。然後將所得粒子燒結一段足以提供機械及化學穩定的剛性球體之時間。在此步驟中，燒結溫度可在從200℃至1000℃(諸如300℃至900℃及包括300℃至800℃)之範圍經範圍在從1小時至10小時(諸如2小時至8小時及包括3小時至6小時)之一段時間。關於製造均勻剛性球形奈米孔洞磷酸鈣粒子之方法的另外細節係提供於美國暫時申請序號61/108,805中，其之揭示以引用方式納入本文中。
活性劑
如上文所概述，本發明之複合物包括結合至均勻剛性球形奈米孔洞磷酸鈣粒子之活性劑成分(由單一類型之活性劑或二或多種不同類型之活性劑製造)。術語“活性劑”係指任何一旦與活生物(例如哺乳動物，諸如人類)接觸時產生生理結果(例如，有益或有用的結果)的化合物或化合物之混合物。活性劑可從遞送組成物之其他成分(諸如載體、稀釋劑、潤滑劑、結合劑、著色劑、等等)區別。活性劑可為任何能夠在活對象中調整生物過程之分子，以及其結合部分或片斷。在某些體系中，該等活性劑可為使用於診斷、治療或預防疾病或作為藥物、化妝品或藥用化妝品之成分的物質。
活性劑為與活對象中之目標相互作用或影響或者調整活對象中之目標的化合物。目標可為許多不同類型的天然結構，其中感興趣之目標包括細胞內和細胞外目標兩者。活性劑可包括一或多個提供結構與所要目標相互作用之官能基。感興趣之官能基包括但不限制於：參與氫鍵結、疏水性-疏水性相互作用、靜電相互作用之基團。感興趣之特殊基團包括但不限制於胺類、醯胺類、巰基、羰基、羥基、羧基、等等。
感興趣之活性劑可包括經一或多個上述官能基取代之環碳或雜環結構及/或芳族或聚芳族結構。作為活性劑之部分也感興趣者為在生物分子中發現之結構，包括肽類、醣類、脂肪酸類、類固醇類、嘌呤類、嘧啶類、其衍生物、結構類似物或組合。可篩選該等化合物以識別感興趣者，其中各種不同篩選方案在該技藝中為已知的。
活性劑可衍生自得自廣泛種類來源(包括合成或天然化合物的資料庫)之天然或合成化合物。例如，很多的方法可用於廣泛種類的有機化合物及生物分子之隨機及指定合成，包括隨機化寡聚核苷酸類及寡聚肽類之製備。或者於細菌、真菌、植物及動物萃取物形式的天然化合物之資料庫為可利用的或快速產生。另外，天然或合成製得之資料庫及化合物透過習知化學藥、物理及生物化學的方法快速地修正，及可用以產生組合資料庫。已知藥理試劑可進行指定或隨機化學修正，諸如醯化、烷化、酯化、醯胺化、等等以產生結構類似物。
同樣地，活性劑可從天然或合成分子之資料庫獲得，包括透過組合方法所產生之化合物的資料庫，亦即化合物多樣性組合資料庫。當從該等資料庫獲得時，所使用之活性劑將已在活性的適當篩選分析中證明中一些令人想要的活性。組合資料庫，以及製備及篩選該等資料庫之方法在該技藝中為已知的且描於：5,741,713；5,734,018；5,731,423；5,721,099；5,708,153；5,698,673；5,688,997；5,688,696；5,684,711；5,641,862；5,639,603；5,593,853；5,574,656；5,571,698；5,565,324；5,549,974；5,545,568；5,541,061；5,525,735；5,463,564；5,440,016；5,438,119；5,223,409，該等之揭示以引用方式納入本文中。
感興趣之活性劑包括小、中及大分子活性劑。小分子活性劑為該等具有範圍從18至2500(諸如1000至1500及包括250至1000)之分子量的活性劑。中分子活性劑為該等具有範圍從2500至10,000(諸如4,000至8,000及包括5000至7000)之分子量的活性劑。大分子活性劑為該等具有10,000或更大之分子量(諸如100,000或更大)之分子量的活性劑，其中在某些例子中這些大分子活性劑範圍在從1百萬至30百萬，諸如5百萬至20百萬及包括10百萬至15百萬。
在某些體系中，該等活性劑以其鹽形式存在，致使它們具有電荷，而允許它們以所要方式結合至遞送組成物之均勻剛性球形奈米孔洞磷酸鈣粒子。
感興趣之活性劑包括但不限制於該等美國申請案序列號61/176,057之附錄中所列者；該申請案之揭示以引用方式納入本文中。
感興趣之活性劑的廣泛種類包括但不限制於：心血管劑；疼痛緩解劑，例如，止痛劑、麻醉劑、消炎劑、等等；神經作用劑；化學治療(例如，抗腫瘤)劑；等等。感興趣之活性劑包括但不限制於：抗生素，諸如：胺基醣苷類，例如丁胺卡那黴素(amikacin)、安痢黴素(apramycin)、阿貝卡辛(arbekacin)、巴黴素(bambermycins)、丁苷菌素(butirosin)、戴貝卡辛(dibekacin)、二氫鏈黴素(dihydrostreptomycin)、福提黴素(fortimicin)、建它黴素(gentamicin)、異帕米辛(isepamicin)、卡尼亞黴素(kaniamycin)、小諾黴素(micronomcin)、新黴素(neomycin)、奈替黴素(netilmicin)、巴龍黴素(paromycin)、核糖黴素(ribostamycin)、希索黴素(sisomicin)、觀黴素(spectinomycin)、鏈黴素(streptomycin)、妥布黴素(tobramycin)、丙大觀黴素(trospectomycin))、安非尼可類(amphenicols)，例如疊氮氯黴素(azidamfenicol)、氯黴素(chloramphenicol)、氟甲磺氯黴素(florfenicol)、及塞馬非尼可(theimaphenicol)；安沙黴素類(ansamycins)，例如雷發醯胺(rifamide)、雷發平(rifampin)、雷福黴素(rifamycin)、利福噴汀(rifapentine)、利福昔明(rifaximin))；b-內醯胺，例如頭碳頭孢烯類(carbacephems)、碳醯胺基類(carbapenems)、頭孢菌素(cephalosporins)、頭黴素類(cehpamycins)、單環胺基類(monobactams)、氧頭孢烯(oxaphems)、青黴素；林可醯胺類(lincosamides)，例如克林那黴素(clinamycin)、林可黴素(lincomycin)；大環內酯類，例如克拉黴素(clarithromycin)、第理黴素(dirthromycin)、紅黴素(erythromycin)、等等；多肽類，例如安福黴素(amphomycin)、枯草菌素(bacitracin)、捲曲黴素(capreomycin)、等等；四環素類，例如阿哌環素(apicycline)、氯四環素(chlortetracycline)、氯莫環素(clomocycline)、米諾環素(minocycline)、等等；合成抗菌劑，諸如2,4-二胺基嘧啶類、硝基呋喃類、喹啉酮類與及其類似物、磺醯胺類、碸類；抗真菌劑，諸如：多烯類，例如兩性黴素B(兩性黴素B)、克念菌素(candicidin)、製皮菌素(dermostatin)、非律平(filipin)、製黴色基素(fungichromin)、曲古黴素(hachimycin)、哈黴素(hamycin)、光明黴素(lucensomycin)、美帕曲星(mepartricin)、納他黴素(natamycin)、制黴菌素(nystatin)、培西洛星(pecilocin)、表黴素(perimycin)；合成抗真菌劑，諸如烯丙胺類、布替萘芬(butenafine)、萘替芬(naftifine)、特比萘芬(terbinafine)、咪唑類(例如，聯苯苯甲唑(bifonazole)、布康唑(butoconazole)、氯檔妥因(chlordantoin)、氯米達唑(chlormidazole)、等等、硫胺甲酸類(例如托昔拉酯(tolcilate)、三唑類(例如氟康唑(fluconazole)、伊曲康唑(itraconazole)、特康唑(terconazole))；驅腸蟲劑，諸如：檳榔鹼(arecoline)、綿馬素(aspidin)、綿馬酚(aspidinol)、二氯苯(dichlorophen)、恩貝靈(embelin)、苦辛(kosin)、萘、氯硝柳胺(niclosamide)、派樂替因(pellertierine)、奎納克林(quinacrine)、木香內酯(alantolactone)、阿莫卡嗪(amocarzine)、硝硫氰胺(amoscanate)、驅蛔腦(ascaridole)、苯甲酚寧(bephenium)、雙硫氰苯(bitoscanate)、四氯化碳、香芹酚(carvacrol)、環苯咪唑(cyclobendazole)、乙胺嗪(diethylcarbamazine)、等等；抗瘧劑，諸如：醋胺苯碸(acedapsone)、胺酚喹(amodiaquin)、蒿乙醚(arteether)、蒿甲醚(artemether)、青蒿素(artemisinin)、青蒿琥酯(artesunate)、阿托娃孔(atovaquone)、比比林(bebeerine)、小檗鹼(berberine)、獐芽菜(chirata)、氯胍、氯喹、氯丙胍(chlorproguanil)、金雞納皮(cinchona)、金雞納啶(cinchonidine)、金雞納寧(cinchonine)、環氯胍(cycloguanil)、龍膽苦甙(gentiopicrin)、鹵泛群(halofantrine)、羥基氯喹、鹽酸甲氟喹(mefloquine)、3-甲基醋氨苯胂(methylarsacetin)、帕馬喹(pamaquine)、抗瘧素(plasmocid)、首喹(primaquine)、比利美胺(pyrimethamine)、奎納克林(quinacrine)、奎尼啶(quinidine)、奎寧、喹西特(quinocide)、喹啉、砷酸氫二鈉；抗原生動物劑，諸如：安可拉尼(acranil)、替硝唑(tinidazole)、異丙硝唑(ipronidazole)、乙基銻胺鈉(ethylstibamine)、戊烷脒(pentamidine)、乙醯胂酚(acetarsone)、胺硝噻唑(aminitrozole)、大茴香黴素(anisomycin)、硝呋太爾(nifuratel)、替硝唑(tinidazole)、苯立達唑(benzidazole)、蘇拉明(suramin)；心臟保護劑，例如，佐生(Zinecard)(右雷佐生(dexrazoxane))；血液改良劑，包括抗凝血劑(例如，可邁丁(Coumadin)(華法林(warfarin)鈉、法安明(fragmin)(達肝素鈉)、肝素、印諾希(innohep)(亭扎肝素(tinzaparin)鈉)、羅文諾司(lovenox)(依諾肝素(enoxaparin)鈉)、歐干仁(orgaran)(達那帕羅鈉(danaparoid鈉)))；抗血小板劑(例如，亞瓜司達(aggrasta)(替羅非班(tirofiban)鹽酸鹽)、亞仁諾司(aggrenox)(阿司匹靈/延長釋放雙嘧達莫(dipyridamole))、亞桂林(agrylin)(阿那格雷(anagrelide)鹽酸鹽)、艾克群(ecotrin)(乙醯基水楊酸)、佛蘭(folan)(依前列醇(epoprostenol)鈉)、亥夫平(halfprin)(腸溶性阿司匹靈)、印特貴林(integrlilin)(埃替非巴(eptifibatide))、潘生丁(persantine)(雙嘧達莫(dipyridamole)USP)、帕拉唯司(plavix)(氯吡多(clopidogrel)硫酸氫鹽)、帕雷它(pletal)(西洛他唑(cilostazol))、瑞歐破(reopro)(阿昔單抗(abciximab))、提西力(ticlid)(噻氯匹定(ticlopidine)鹽酸鹽))、溶解血栓劑(activase(鏈激酶(alteplase))、瑞它飛(retavase)(瑞替普酶(reteplase))、鏈激酶(鏈球菌致活酶(streptokinase))；腎上腺素能阻斷劑，諸如可多華(cardura)(多沙唑嗪(doxazosin)甲磺酸鹽)、酚苄明(dibenzyline)(苯氧苯甲胺(phenoxybenzamine)鹽酸鹽)、定脈平(hytrin)(特拉唑嗪(terazosin)鹽酸鹽)、脈寧平(minipress)(哌唑嗪(prazosin)鹽酸鹽)、米尼在(minizide)(哌唑嗪(prazosin)鹽酸鹽/泊利噻嗪(polythiazide))；腎上腺素興奮劑，諸如阿多克(aldoclor)(甲基多巴-氯噻嗪(chlorothiazide))、亞多力(aldomet)(甲基多巴、甲基多巴乙酯(methyldopate)HCl)、aldoril(甲基多巴-氫氯噻嗪(hydrochlorothiazide))、楷它波伊(catapres)(可尼丁(clonidine)鹽酸鹽USP、可尼丁)、氯波伊(clorpres)(可尼丁鹽酸鹽及氯噻酮(chlorthalidone))、孔必波伊(combipres)(可尼丁鹽酸鹽/氯噻酮(chlorthalidone))、它尼司(tenex)(胍法辛(guanfacine)鹽酸鹽)；α/β腎上腺素能阻斷劑，諸如可瑞格(coreg)(卡唯地洛(carvedilol))、諾莫代(normodyne)(拉貝洛爾(labetalol)鹽酸鹽)；血管緊縮素轉化酶(ACE)抑制劑，諸如亞求普利(accupril)(奎那普利(quinapril)鹽酸鹽)、亞司翁(aceon)(培哚普利(Perindopril erbumine))、亞它司(altace)(雷米普利(ramipril))、卡托普利(captopril)、羅騰新(lotensin)(本那普利(benazepril)鹽酸鹽)、馬畏(mavik)(群多普利(trandolapril))、單普利(monopril)(福辛普利(fosinopril)鈉錠)、披瑞尼畏(prinivil)(賴諾普利(lisinopril))、優尼飛(univasc)(莫西普利(moexipril)鹽酸鹽)、畏首克(vasotec)(依那普利拉(enalaprilat)、依那普利(enalapril)順丁烯二酸鹽)、瑞司崔(zestril)(賴諾普利(lisinopril))；血管緊縮素轉化酶(ACE)抑制劑與鈣通道阻斷劑，諸如雷司索(lexxel)(依那普利(enalapril)順丁烯二酸鹽-非洛地平(felodipine)ER)、羅崔(lotrel)(阿洛地平(amlodipine)及本那普利(benazepril)鹽酸鹽)、它卡(tarka)(群多普利(trandolapril)/維拉帕米(verapamil)鹽酸鹽ER)；血管緊縮素轉化酶(ACE)抑制劑與利尿劑，諸如亞求瑞替(accuretic)(奎那普利(quinapril)HCl/氫氯噻嗪)、羅騰新(本那普利(benazepril)鹽酸鹽及氫氯噻嗪USP)、披尼在(prinizide)(賴諾普利(lisinopril)-氫氯噻嗪)、優你瑞替(uniretic)(莫西普利(moexipril)鹽酸鹽/氫氯噻嗪)、畏色瑞替(vaseretic)((依那普利(enalapril)順丁烯二酸鹽-氫氯噻嗪)、在多瑞替(zestoretic)(賴諾普利(lisinopril)及氫氯噻嗪)；血管收縮素II受體拮抗劑，諸如阿他肯得(atacand)(坎地沙坦西酯(candesartan cilexetil))、阿威普羅(avapro)厄貝沙坦(irbesartan)、可悅您(cozaar)(洛沙坦(losartan)鉀)、代歐文(diovan)(纈沙坦(valsartan))、米卡迪司(micardis)(替米沙坦(telmisartan))、太唯亭(teveten)(依普羅沙坦(eprosartan)甲磺酸鹽)；血管收縮素II受體拮抗劑與利尿劑，諸如氫氯噻嗪(avalide)(厄貝沙坦(irbesartan)-氫氯噻嗪)、代歐文(纈沙坦(valsartan)及氫氯噻嗪)、好悅您(洛沙坦(losartan)鉀-氫氯噻嗪)；抗心律不整藥，諸如第I組(例如，脈序律(mexitil)(美西律(mexiletine)鹽酸鹽、USP)、諾佩司(norpace)(丙吡胺(disopyramide)磷酸鹽)、坡坎必(procanbid)(普魯卡因(procainamide)鹽酸鹽)、奎那谷(quinaglute)(奎尼啶(quinidine)葡萄糖酸鹽)、奎尼得(quinidex)(奎尼啶硫酸鹽)、奎尼啶(奎尼啶葡萄糖酸鹽注射劑，USP)、力絲摩(rythmol)(普羅帕酮(propafenone)鹽酸鹽)、淡波口(tambocor)(氟卡尼(flecainide)乙酸酯)、拖諾卡(tonocard)(妥卡尼(tocainide)HCl))、第II組(例如，貝他佩司(betapace)(索他洛爾(sotalol)HCl)、背畏布落(brevibloc)(艾司洛爾(esmolol)鹽酸鹽)、思特來(普萘洛爾(propranolol)鹽酸鹽)、心施德(醋丁洛爾(acebutolol)鹽酸鹽))、第III組(例如，貝他佩司(索他洛爾(sotalol)HCl)、臟得樂(胺碘酮(amiodarone)鹽酸鹽)、口唯得(corvert)(伊布利特(ibutilide)反丁烯二酸鹽注射劑)、披色隆(pacerone)(胺碘酮(amiodarone)HCl)、提克塞(tikosyn)(多非利特(dofetilide)))、第IV組(例如，克攔(calan)(維拉帕米(verapamil)鹽酸鹽)、凱帝心(地爾硫卓(diltiazem)HCl)、以及亞登卡(adenocard)(腺核苷)、雷諾司卡(lanoxicaps)(地谷新(digoxin))、雷諾新(lanoxin)(地谷新(digoxin)))；降血脂酸類，包括膽汁酸螯合劑(例如，克雷司替(colestid)(微粉考來替泊(colestipol)鹽酸鹽)、唯口(welchol)(考來維崙(colesevelam)鹽酸鹽))、纖維酸衍生物(例如，亞挫米(atromid)(克氯吩貝(clofibrate))、洛脂(lopid)(吉米吩扎(gemfibrozal)錠、USP)、崔可(tricor)(非諾貝特(fenofibrate)膠囊))、HMG-CoA還原酶抑制劑(例如，貝伊可(baycol)(西伐他汀(cerivastatin)鈉錠)、來司可(lescol)(氟伐他汀(fluvastatin)鈉)、立普妥(阿托伐他汀(atorvastatin)鈣)、買唯可(mevacor)(洛伐他汀(lovastatin))、坡畏可(pravachol)(普伐他汀(pravastatin)鈉)、柔可(zocor)(辛伐他汀(simvastatin)))、菸鹼酸(例如，尼亞司本(Niaspan)(菸鹼(niacin)緩釋錠))；β腎上腺素阻斷劑，例如，貝他佩司(betapace)(索他洛爾(sotalol)HCl)、布羅卡春(blocadren)(噻嗎洛爾(timolol)順丁烯二酸鹽)、背畏布落(艾司洛爾(esmolol)鹽酸鹽)、卡挫(Cartrol)(卡替洛爾(carteolol)鹽酸鹽)、思特來(普萘洛爾(propranolol)鹽酸鹽)、卡爾侖(kerlone)(倍他洛爾(betaxolol)鹽酸鹽)、納多洛爾(nadolol)、sectral(醋丁洛爾(acebutolol)鹽酸鹽)、天諾敏(tenormin)(阿替洛爾(atenolol))、托柔(toprol)(美托洛爾(metoprolol)丁二酸鹽)、任貝他(zebeta)(比索洛爾(bisoprolol)反丁烯二酸鹽)；β腎上腺素阻斷劑與利尿劑，例如，扣在(corzide)(納多洛爾(nadolol)及苄氟噻嗪(bendroflumethiazide)錠)、印得艾(inderide)(普萘洛爾(propranolol)鹽酸鹽及氫氯噻嗪)、田諾瑞替(tenoretic)(阿替洛爾(atenolol)及氯噻酮)、提莫來(timolide)(噻嗎洛爾(timolol)順丁烯二酸鹽-氫氯噻嗪)、才可(ziac)(比索洛爾(bisoprolol)反丁烯二酸鹽及氫氯噻嗪)；鈣通道阻斷劑，例如，拜新同(adalat)(尼菲迪平(nifedipine))、卡蘭(calan)(維拉帕米(verapamil)鹽酸鹽)、卡地尼(cardene)(尼卡地平(nicardipine)鹽酸鹽)、合心爽(cardizem)(地爾硫卓(diltiazem)HCl)、克維拉(covera)(維拉帕米(verapamil)鹽酸鹽)、異博定(isoptin)(維拉帕米(verapamil))鹽酸鹽)、尼膜同(nimotop)(尼莫地平(nimodipine))、諾維昔(norvace)(阿洛地平(amlodipine)苯磺酸鹽)、波依定(plendil)(非洛地平(felodipine))、硝苯地平(procardia)(尼菲迪平(nifedipine))、蘇拉(sular)(尼索地平(nisoldipine))、替氮雜(tiazac)(地爾硫卓(diltiazem)鹽酸鹽)、伐斯可(vascor)(苯甲普地爾(bepridil)鹽酸鹽)、維爾寧(verelan)(維拉帕米(verapamil)鹽酸鹽)；利尿劑，包括碳酸酐酶抑制劑(例如，氯苯磺胺(daranide)(雙氯非那胺(dichlorphenamide)))、組合利尿劑(例如，阿打它在(aldactazide)(螺內酯(spironolactone)與氫氯噻嗪)、代在(dyazide)(氨苯蝶啶(triamterene)及氫氯噻嗪)、梅司在(maxzide)(氨苯蝶啶(triamterene)及氫氯噻嗪)、武都力(moduretic)(阿米洛利(amiloride)HCl-氫氯噻嗪))、亨利氏環(loop)利尿劑(得馬司(demadex)(托拉塞米(torsemide))、艾得平(edecrin)(依他尼酸(ethacrynic acid)、依他尼酸鈉)、呋塞米(furosemide))、留鉀利尿劑(阿德通(aldactone)(螺內酯(spironolactone))、代瑞寧(dyrenium)(氨苯蝶啶(triamterene))、米大摩(midamor)(阿米洛利(amiloride)HCl))、噻嗪類(thiazides)及相關利尿劑(例如，丟卡定(diucardin)(氫氟噻嗪(hydroflumethiazide))、代優你(diuril)(氯噻嗪(chlorothiazide)、氯噻嗪鈉)、伊都隆(enduron)(甲氯噻嗪(methyclothiazide))、氫戴若(hydrodiuril)氫氯噻嗪)、吲達帕胺(indapamide)、微在(microzide)(氫氯噻嗪)麥扣司(mykrox)(甲苯喹唑酮(metolazone)錠)、任內西(renese)(泊利噻嗪(polythiazide))、泰利通(thalitone)(氯噻酮、USP)、乍落索林(zaroxolyn)(甲苯喹唑酮(metolazone)))；強心(inotropic)劑，例如，地吉克(digitek)(地谷新)、多別克(dobutrex)(多巴酚丁胺(dobutamine))、雷諾司卡(地谷新)、雷諾新(地谷新)、披馬扣(米利酮(milrinone)乳酸鹽)；活化酶(activase)(鏈激酶(alteplase)重組)；腎上腺素氯化物(腎上腺素注射劑、USP)；丹舍(demser)(甲基酪胺酸(metyrosine))、印為善(inversine)(美加明(mecamylamine)HCl)、瑞歐破(阿昔單抗)、瑞它飛(瑞替普酶)、鏈激酶(鏈球菌致活酶(streptokinase))、替酶(tnkase)(替奈普酶(tenecteplase))；血管舒張劑，包括冠狀血管舒張劑(例如，印獨(imdur)(異山梨醇一硝酸鹽)、伊司摩(ismo)(異山梨醇一硝酸鹽)、異帝(isordil)(異山梨醇二硝酸鹽)、硝獨(nitrodur)(硝基甘油)、硝林瓜(nitrolingual)(硝基甘油舌噴霧)、硝司代(nitrostat)(硝基甘油錠、USP)、索必崔(sorbitrate)(異山梨醇二硝酸鹽))、末梢血管舒張劑及組合(例如，克羅半(corlopam)(非諾多泮(fenoldopam)甲磺酸鹽)、佛蘭(依前列醇鈉)、披馬扣(米利酮乳酸鹽))、血管加壓劑，例如，亞拉胺(aramine)(間羥胺(metaraminol)酒石酸氫鹽)、艾匹本(epipen)(EpiPen 0.3毫克品牌腎上腺素自動注射器、EpiPen Jr. 0.15毫克品牌腎上腺素自動注射器)、波阿馬亭(proamatine)(米多君(midodrine)鹽酸鹽)；等等。
精神藥理劑，諸如(1)中樞神經系統抑制劑，例如一般麻醉劑(巴比妥酸鹽類、苯二氮呯類、類固醇類、環己酮衍生物、及雜劑)、鎮靜劑-安眠藥(苯二氮呯類、巴比妥酸鹽類、哌啶二酮類及三酮類、喹唑啉衍生物、胺甲酸酯類、醛類及衍生物、醯胺類、無環醯脲類、苯並氮呯類及相關藥物、啡噻類、等等)、中央隨意肌張力改良藥(抗痙劑，諸如海因(hydantoin)類、巴比妥酸鹽類、噁唑啶二酮類類、琥珀醯亞胺類、醯基醯脲類(acylureides)、環戊醯亞胺類、苯二氮呯類、二級及三級醇類、二苯並氮呯衍生物、丙戊酸及衍生物、GABA類似物、等等)、止痛劑(嗎啡及衍生物、奧帕凡(oripavine)衍生物、嗎啡喃衍生物、苯基哌啶類、2,6-甲烷-3-苯唑卡因衍生物、二苯基丙基胺類及同電子排列體、水楊酸鹽類、對-胺基酚衍生物、5-二氫吡唑酮衍生物、芳基乙酸衍生物、芬那酸鹽類(fenamates)及同電子排列體、等等)及止吐藥(抗膽鹼劑、抗組織胺類、抗多巴胺能藥(antidopaminergics)、等等)、(2)中樞神經興奮劑，例如興奮劑(呼吸興奮劑、驚厥興奮劑、精神運動興奮劑)、麻醉性拮抗劑(嗎啡衍生物、奧帕凡(oripavine)衍生物、2,6-甲烷-3-苯並衍生物、嗎啡喃衍生物)親精神性藥物、(3)精神藥理劑，例如抗焦慮鎮靜劑(苯二氮呯類、丙二醇胺甲酸酯類)抗精神病劑(啡噻衍生物、硫黃嘌呤衍生物、其他三環化合物、丁酸酚酮衍生物及同電子排列體、二苯基丁基胺衍生物、經取代之苯醯胺類、芳基哌衍生物、吲哚衍生物、等等)、抗抑鬱劑(三環化合物、MAO抑制劑、等等)、(4)呼吸道藥，例如中樞性鎮咳藥(鴉片生物鹼類及其衍生物)；藥效劑，諸如(1)末梢神經系統藥，例如局部麻醉劑(酯衍生物、醯胺衍生物)、(2)作用於突觸或神經效應連接位置之藥物，例如膽鹼能劑、膽鹼能阻斷劑、神經肌肉阻斷劑、腎上腺素劑、抗腎上腺素劑、(3)平滑肌活性藥，例如解攣藥(抗膽鹼劑、向肌肉性解攣藥)、血管舒張劑、平滑肌興奮劑、(4)組織胺類及抗組織胺類，例如組織胺及其衍生物(倍他唑(betazole))、抗組織胺類(H1-拮抗劑、H2-拮抗劑)、組織胺代謝藥、(5)心血管藥物，例如強心藥(植物萃取物、丁烯酸內酯類(butenolides)、戊二烯酸內酯類(pentadienolids)、來自格木屬種之生物鹼類、離子載體(ionophore)、-腎上腺素受體興奮劑、等等)、抗心律不整藥、抗高血壓劑、抗血脂劑(對氯苯氧異丁酸衍生物、菸鹼酸酸衍生物、激素及類似物、抗生素、水楊酸及衍生物)、抗靜脈曲張藥、止血藥、(6)血液及造血系統藥，例如抗貧血藥、凝血藥(止血藥、抗凝血劑、抗血栓劑、溶栓劑、血蛋白質及其部分)、(7)胃腸道藥，例如消化劑(健胃藥、利膽劑)、抗潰瘍藥、止瀉劑、(8)局部作用藥；化學治療劑，諸如(1)抗感染劑，例如殺外寄生蟲藥(氯化烴類、pyrethins、硫化化合物)、驅腸蟲劑、抗原蟲劑、抗瘧劑、抗阿米巴劑(antiamebic agent)、抗利什曼蟲藥、抗滴蟲劑、抗錐體蟲劑(antitrypanosomal)、磺醯胺類、抗分支桿菌劑藥、抗病毒化學治療劑、等等、及(2)細胞抑制劑，也就是抗腫瘤劑或細胞毒素藥，諸如烷化劑，例如甲氮芥(Mechlorethamine)鹽酸鹽(氮Mustard、Mustargen、HN2)、環磷醯胺(Cytovan、Endoxana)、異環磷醯胺(ifosfamide)(IFEX)、苯丁酸氮芥(Chlorambucil)(Leukeran)、美法侖(Melphalan)(苯基丙胺酸芥末、L-沙可來新(sarcolysin)、威克瘤(Alkeran)、L-PAM)、白消安(Busulfan)(Myleran)、塞替派(Thiotepa)(三伸乙基塞替派(Triethylenethiophosphoramide))、卡莫司汀(Carmustine)(BiCNU、BCNU)、洛莫司汀(Lomustine)(CeeNU、CCNU)、鏈佐星(Streptozocin)(Zanosar)等等；植物生物鹼類，例如長春新鹼(Oncovin)、長春鹼(Velban、Velbe)、紫杉醇(Taxol)、等等；抗代謝物，例如甲氨蝶呤(Methotrexate)(MTX)、巰嘌呤(嘌呤硫醇(Purinethol)、6-MP)、硫鳥嘌呤(6-TG)、氟尿嘧啶(5-FU)、阿拉伯糖基胞嘧啶(Cytosar-U、Ara-C)、阿扎胞苷(Azacitidine)(Mylosar、5-AZA)等等；抗生素，例如更生黴素(Actinomycin D、放線菌素(Cosmegen))、阿黴素(Doxorubicin)(阿德力黴素(Adriamycin))、道諾黴素(Daunorubicin)(道諾黴素(duanomycin)、柔紅黴素(Cerubidine))、去甲氧伊達比星(Idarubicin)(柔紅黴素Idamycin)、博萊黴素(Bleomycin)(平陽黴素(Blenoxane))、普卡黴素(Picamycin)(米拉黴素(Mithramycin)、光輝黴素(Mithracin))、絲裂黴素(Mitomycin)(絲裂黴素(Mutamycin))等等及其他抗細胞增殖劑，例如羥脲(Hydrea)、丙卡巴肼(Procarbazine)(Mutalane)、達卡巴嗪(Dacarbazine)(DTIC-Dome)、順鉑(Cisplatin)(順鉑(Platinol))卡鉑(Carboplatin)(Paraplatin)、天冬醯胺酶(Asparaginase)(Elspar)依托泊苷(Etoposide)(VePesid、VP-16-213)、安殺克寧(Amsarcrine)(AMSA、m-AMSA)、米托坦(Mitotane)(Lysodren)、米托蒽醌(Mitoxantrone)(Novatrone)、等等。
感興趣之藥物化合物也列於：Goodman & Gilman's,The Pharmacological Basis of Therapeutics(第9版)(Goodman等人編輯)(McGraw-Hill)(1996)；及2001醫師書桌參考。
活性劑的特殊種類及例子包括但不限制於：該等出現於下表中者：
感興趣之特定化合物也包括但不限制於：抗腫瘤劑，如美國專利號5880161、5877206、5786344、5760041、5753668、5698529、5684004、5665715、5654484、5624924、5618813、5610292、5597831、5530026、5525633、5525606、5512678、5508277、5463181、5409893、5358952、5318965、5223503、5214068、5196424、5109024、5106996、5101072、5077404、5071848、5066493、5019390、4996229、4996206、4970318、4968800、4962114、4927828、4892887、4889859、4886790、4882334、4882333、4871746、4863955、4849563、4845216、4833145、4824955、4785085、476925、4684747、4618685、4611066、4550187、4550186、4544501、4541956、4532327、4490540、4399283、4391982、4383994、4294763、4283394、4246411、4214089、4150231、4147798、4056673、4029661、4012448中所揭示者；精神藥理/精神科劑，如美國專利號5192799、5036070、4778800、4753951、4590180、4690930、4645773、4427694、4424202、4440781、5686482、5478828、5461062、5387593、5387586、5256664、5192799、5120733、5036070、4977167、4904663、4788188、4778800、4753951、4690930、4645773、4631285、4617314、4613600、4590180、4560684、4548938、4529727、4459306、4443451、4440781、4427694、4424202、4397853、4358451、4324787、4314081、4313896、4294828、4277476、4267328、4264499、4231930、4194009、4188388、4148796、4128717、4062858、4031226、4020072、4018895、4018779、4013672、3994898、3968125、3939152、3928356、3880834、3668210中所揭示者；心血管劑，如美國專利號4966967、5661129、5552411、5332737、5389675、5198449、5079247、4966967、4874760、4954526、5051423、4888335、4853391、4906634、4775757、4727072、4542160、4522949、4524151、4525479、4474804、4520026、4520026、5869478、5859239、5837702、5807889、5731322、5726171、5723457、5705523、5696111、5691332、5679672、5661129、5654294、5646276、5637586、5631251、5612370、5612323、5574037、5563170、5552411、5552397、5547966、5482925、5457118、5414017、5414013、5401758、5393771、5362902、5332737、5310731、5260444、5223516、5217958、5208245、5202330、5198449、5189036、5185362、5140031、5128349、5116861、5079247、5070099、5061813、5055466、5051423、5036065、5026712、5011931、5006542、4981843、4977144、4971984、4966967、4959383、4954526、4952692、4939137、4906634、4889866、4888335、4883872、4883811、4847379、4835157、4824831、4780538、4775757、4774239、4771047、4769371、4767756、4762837、4753946、4752616、4749715、4738978、4735962、4734426、4734425、4734424、4730052、4727072、4721796、4707550、4704382、4703120、4681970、4681882、4670560、4670453、4668787、4663337、4663336、4661506、4656267、4656185、4654357、4654356、4654355、4654335、4652578、4652576、4650874、4650797、4649139、4647585、4647573、4647565、4647561、4645836、4639461、4638012、4638011、4632931、4631283、4628095、4626548、4614825、4611007、4611006、4611005、4609671、4608386、4607049、4607048、4595692、4593042、4593029、4591603、4588743、4588742、4588741、4582854、4575512、4568762、4560698、4556739、4556675、4555571、4555570、4555523、4550120、4542160、4542157、4542156、4542155、4542151、4537981、4537904、4536514、4536513、4533673、4526901、4526900、4525479、4524151、4522949、4521539、4520026、4517188、4482562、4474804、4474803、4472411、4466979、4463015、4456617、4456616、4456615、4418076、4416896、4252815、4220594、4190587、4177280、4164586、4151297、4145443、4143054、4123550、4083968、4076834、4064259、4064258、4064257、4058620、4001421、3993639、3991057、3982010、3980652、3968117、3959296、3951950、3933834、3925369、3923818、3898210、3897442、3897441、3886157、3883540、3873715、3867383、3873715、3867383、3691216、3624126中所揭示者；抗微生物劑，如美國專利號號5902594、5874476、5874436、5859027、5856320、5854242、5811091、5786350、5783177、5773469、5762919、5753715、5741526、5709870、5707990、5696117、5684042、5683709、5656591、5643971、5643950、5610196、5608056、5604262、5595742、5576341、5554373、5541233、5534546、5534508、5514715、5508417、5464832、5428073、5428016、5424396、5399553、5391544、5385902、5359066、5356803、5354862、5346913、5302592、5288693、5266567、5254685、5252745、5209930、5196441、5190961、5175160、5157051、5096700、5093342、5089251、5073570、5061702、5037809、5036077、5010109、4970226、4916156、4888434、4870093、4855318、4784991、4746504、4686221、4599228、4552882、4492700、4489098、4489085、4487776、4479953、4477448、4474807、4470994、4370484、4337199、4311709、4308283、4304910、4260634、4233311、4215131、4166122、4141981、4130664、4089977、4089900、4069341、4055655、4049665、4044139、4002775、3991201、3966968、3954868、3936393、3917476、3915889、3867548、3865748、3867548、3865748、3783160、3764676、3764677中所揭示者；消炎劑，如美國專利號5872109、5837735、5827837、5821250、5814648、5780026、5776946、5760002、5750543、5741798、5739279、5733939、5723481、5716967、5688949、5686488、5686471、5686434、5684204、5684041、5684031、5684002、5677318、5674891、5672620、5665752、5656661、5635516、5631283、5622948、5618835、5607959、5593980、5593960、5580888、5552424、5552422、5516764、5510361、5508026、5500417、5498405、5494927、5476876、5472973、5470885、5470842、5464856、5464849、5462952、5459151、5451686、5444043、5436265、5432181、RE034918、5393756、5380738、5376670、5360811、5354768、5348957、5347029、5340815、5338753、5324648、5319099、5318971、5312821、5302597、5298633、5298522、5298498、5290800、5290788、5284949、5280045、5270319、5266562、5256680、5250700、5250552、5248682、5244917、5240929、5234939、5234937、5232939、5225571、5225418、5220025、5212189、5212172、5208250、5204365、5202350、5196431、5191084、5187175、5185326、5183906、5177079、5171864、5169963、5155122、5143929、5143928、5143927、5124455、5124347、5114958、5112846、5104656、5098613、5095037、5095019、5086064、5081261、5081147、5081126、5075330、5066668、5059602、5043457、5037835、5037811、5036088、5013850、5013751、5013736、500654、4992448、4992447、4988733、4988728、4981865、4962119、4959378、4954519、4945099、4942236、4931457、4927835、4912248、4910192、4904786、4904685、4904674、4904671、4897397、4895953、4891370、4870210、4859686、4857644、4853392、4851412、4847303、4847290、4845242、4835166、4826990、4803216、4801598、4791129、4788205、4778818、4775679、4772703、4767776、4764525、4760051、4748153、4725616、4721712、4713393、4708966、4695571、4686235、4686224、4680298、4678802、4652564、4644005、4632923、4629793、4614741、4599360、4596828、4595694、4595686、4594357、4585755、4579866、4578390、4569942、4567201、4563476、4559348、4558067、4556672、4556669、4539326、4537903、4536503、4518608、4514415、4512990、4501755、4495197、4493839、4465687、4440779、4440763、4435420、4412995、4400534、4355034、4335141、4322420、4275064、4244963、4235908、4234593、4226887、4201778、4181720、4173650、4173634、4145444、4128664、4125612、4124726、4124707、4117135、4027031、4024284、4021553、4021550、4018923、4012527、4011326、3998970、3998954、3993763、3991212、3984405、3978227、3978219、3978202、3975543、3968224、3959368、3949082、3949081、3947475、3936450、3934018、3930005、3857955、3856962、3821377、3821401、3789121、3789123、3726978、3694471、3691214、3678169、3624216中所揭示者；免疫抑制劑，如美國專利號4450159、4450159、5905085、5883119、5880280、5877184、5874594、5843452、5817672、5817661、5817660、5801193、5776974、5763478、5739169、5723466、5719176、5696156、5695753、5693648、5693645、5691346、5686469、5686424、5679705、5679640、5670504、5665774、5665772、5648376、5639455、5633277、5624930、5622970、5605903、5604229、5574041、5565560、5550233、5545734、5540931、5532248、5527820、5516797、5514688、5512687、5506233、5506228、5494895、5484788、5470857、5464615、5432183、5431896、5385918、5349061、5344925、5330993、5308837、5290783、5290772、5284877、5284840、5273979、5262533、5260300、5252732、5250678、5247076、5244896、5238689、5219884、5208241、5208228、5202332、5192773、5189042、5169851、5162334、5151413、5149701、5147877、5143918、5138051、5093338、5091389、5068323、5068247、5064835、5061728、5055290、4981792、4810692、4410696、4346096、4342769、4317825、4256766、4180588、4000275、3759921中所揭示者；止痛劑，如美國專利號5292736、5688825、5554789、5455230、5292736、5298522、5216165、5438064、5204365、5017578、4906655、4906655、4994450、4749792、4980365、4794110、4670541、4737493、4622326、4536512、4719231、4533671、4552866、4539312、4569942、4681879、4511724、4556672、4721712、4474806、4595686、4440779、4434175、4608374、4395402、4400534、4374139、4361583、4252816、4251530、5874459、5688825、5554789、5455230、5438064、5298522、5216165、5204365、5030639、5017578、5008264、4994450、4980365、4906655、4847290、4844907、4794110、4791129、4774256、4749792、4737493、4721712、4719231、4681879、4670541、4667039、4658037、4634708、4623648、4622326、4608374、4595686、4594188、4569942、4556672、4552866、4539312、4536512、4533671、4511724、4440779、4434175、4400534、4395402、4391827、4374139、4361583、4322420、4306097、4252816、4251530、4244955、4232018、4209520、4164514 4147872、4133819、4124713、4117012、4064272、4022836、3966944中所揭示者；膽鹼能劑，如美國專利號5219872、5219873、5073560、5073560、5346911、5424301、5073560、5219872、4900748、4786648、4798841、4782071、4710508、5482938、5464842、5378723、5346911、5318978、5219873、5219872、5084281、5073560、5002955、4988710、4900748、4798841、4786648、4782071、4745123、4710508中所揭示者；腎上腺素劑，如美國專利號5091528、5091528、4835157、5708015、5594027、5580892、5576332、5510376、5482961、5334601、5202347、5135926、5116867、5091528、5017618、4835157、4829086、4579867、4568679、4469690、4395559、4381309、4363808、4343800、4329289、4314943、4311708、4304721、4296117、4285873、4281189、4278608、4247710、4145550、4145425、4139535、4082843、4011321、4001421、3982010、3940407、3852468、3832470中所揭示者；抗組胺劑，如美國專利號5874479、5863938、5856364、5770612、5702688、5674912、5663208、5658957、5652274、5648380、5646190、5641814、5633285、5614561、5602183、4923892、4782058、4393210、4180583、3965257、3946022、3931197中所揭示者；類固醇劑，如美國專利號5863538、5855907、5855866、5780592、5776427、5651987、5346887、5256408、5252319、5209926、4996335、4927807、4910192、4710495、4049805、4004005、3670079、3608076、5892028、5888995、5883087、5880115、5869475、5866558、5861390、5861388、5854235、5837698、5834452、5830886、5792758、5792757、5763361、5744462、5741787、5741786、5733899、5731345、5723638、5721226、5712264、5712263、5710144、5707984、5705494、5700793、5698720、5698545、5696106、5677293、5674861、5661141、5656621、5646136、5637691、5616574、5614514、5604215、5604213、5599807、5585482、5565588、5563259、5563131、5561124、5556845、5547949、5536714、5527806、5506354、5506221、5494907、5491136、5478956、5426179、5422262、5391776、5382661、5380841、5380840、5380839、5373095、5371078、5352809、5344827、5344826、5338837、5336686、5292906、5292878、5281587、5272140、5244886、5236912、5232915、5219879、5218109、5215972、5212166、5206415、5194602、5166201、5166055、5126488、5116829、5108996、5099037、5096892、5093502、5086047、5084450、5082835、5081114、5053404、5041433、5041432、5034548、5032586、5026882、4996335、4975537、4970205、4954446、4950428、4946834、4937237、4921846、4920099、4910226、4900725、4892867、4888336、4885280、4882322、4882319、4882315、4874855、4868167、4865767、4861875、4861765、4861763、4847014、4774236、4753932、4711856、4710495、4701450、4701449、4689410、4680290、4670551、4664850、4659516、4647410、4634695、4634693、4588530、4567000、4560557、4558041、4552871、4552868、4541956、4519946、4515787、4512986、4502989、4495102中所揭示者；該等之揭示以引用方式納入本文中。
也感興趣者為上述化合物之類似物。關於所有上述活性劑，該活性劑可以醫藥上可接受的鹽類存在，如上所述。
遞送媒液成分
本發明之遞送組成物為調配用於將活性劑遞送至局部位置(諸如哺乳動物對象(諸如人類對象)之角質化的皮膚表面或黏膜表面)的組成物。角質化的皮膚表面是指對象之皮膚位置，也就是，動物身體的外部覆層或外皮的位置。黏膜表面是指包括黏膜之對象的部位，諸如口腔內側、鼻內側、等等。
因為本發明之皮膚遞送調配物係調配用於遞送至局部位置，所以將它們調配成致使與它們所調配之局部位置生理上相容。因此，當與它們所調配之目標角質化的皮膚表面或黏膜表面接觸時，該遞送組成物不會引起將使遞送組成物之使用不適合於局部應用之實質生理反應(諸如發炎或刺激)，如果任何的有話。
本發明之遞送組成物包括某量之包括在遞送媒液成分中的活性劑-磷酸鈣粒子複合物。遞送媒液成分係指不是活性劑-磷酸鈣粒子複合物成分之遞送組成物的部分。
本發明之遞送組成物的遞送媒液成分可根據需要改變，其中所給予之遞送媒液成分的特定成分將視(至少部分)特定組成物之性質而定。感興趣之遞送組成物包括液體調配物，諸如洗劑(於懸浮液或乳液形式的包含不溶物質之液體，欲用於外部施用，包括噴霧洗劑)及水溶液、半固體調配物，諸如凝膠(其中分散相已與分散介質混合而產生半固體物質之膠體，諸如凝膠)、乳霜(軟固體或稠液)及軟膏(軟、油膏製劑)、及固體調配物，諸如局部貼片。同樣地，感興趣之遞送媒液成分包括但不限制於：油包水(O/W)及油包水(W/O)型之乳液、乳製劑、洗劑、乳霜、軟膏、凝膠、漿液、粉末、面膜、敷料、噴霧、氣溶膠或條狀物。
洗劑
洗劑為其中黏度為50,000 cP或更小(諸如10,000 cP或更小)之液體組成物，如使用旋轉式黏度計測量(其藉由浸入樣品中之圓筒形轉子的操作力矩測量黏度)，黏度測量方案在25℃之溫度，如JIS K 7117中所述：用於以樹脂在液體中之旋轉式黏度計的黏度之測試方法或ASTM D 2196-86：用於以旋轉式(布氏)黏度計對非牛頓物質的流變性質之測試方法。
感興趣之洗劑遞送媒液成分可包括許多的不同成分，包括但不限制於：水、軟化劑、天然油類、聚矽氧油類、增稠劑或黏度改良劑、合成或天然酯類、脂肪酸類、醇類、保濕劑、乳化劑、防腐劑系統、著色劑、香料、等等。這些物質之量根據需要可在從0.001至99%之範圍，諸如從0.1至50%，包括從1至20%，以組成物之重量計。
軟化劑為取代或加至皮膚中的脂質類及天然油類之化合物。術語軟化劑，如使用在本文中，意欲包括習知脂質物質(例如，脂肪類、蠟類及其水不溶物質)、極性脂質(例如，已改良而使其更具水溶性之脂質物質)、聚矽氧類及烴類。感興趣之軟化劑包括但不限制於：己二酸二異丙酯、肉荳蔻酸異丙酯、棕櫚酸異丙酯、棕櫚酸乙基己酯、新戊酸異癸酯、苯甲酸C12-15醇酯、順丁烯二酸二乙基己酯、PPG-14丁基醚、PPG-2肉豆蔻基醚丙酸酯、蓖麻醇酸鯨蠟酯、膽固醇硬脂酸酯、膽固醇異硬脂酸酯、膽固醇乙酸酯、荷荷巴油、可可脂、牛油樹油脂、羊毛脂及羊毛脂酯類。
聚矽氧油類可分成揮發性及非揮發性種類。術語“揮發性”如使用在本文中係指該等在周圍溫度下具有可測量的蒸汽壓之物質。感興趣之揮發性聚矽氧油類包括但不限制於：包含從3至9(諸如從4至5)個矽原子之環狀或直鏈聚二甲基矽氧烷類。直鏈揮發性聚矽氧物質在25℃下可具有5厘拖或更小之黏度，而環狀物質可具有10厘拖或更小之黏度。感興趣之非揮發性聚矽氧油類包括但不限制於：聚烷基矽氧烷類、聚烷芳基矽氧烷類及聚醚矽氧烷共聚物。感興趣之基本上非揮發性聚烷基矽氧烷類包括(例如)在25℃下具有黏度5至100,000厘拖之聚二甲基矽氧烷類。
適當酯類包括但不限制於：具有10至20碳原子之脂肪酸類的烯基或烷基酯類，諸如棕櫚酸異丙酯、異硬脂酸異丙酯、異壬酸異壬酯、肉荳蔻酸油酯、硬脂酸油酯及油酸油酯；醚-酯類，諸如乙氧基化脂肪醇類之脂肪酸酯類；多元醇酯類；乙二醇單及二-脂肪酸酯類；二乙二醇單-及二-脂肪酸酯類、聚乙二醇(200-6000)單-及二-脂肪酸酯類；丙二醇單-及二-脂肪酸酯類，諸如聚丙二醇2000單油酸酯、聚丙二醇2000單硬脂酸酯、乙氧基化丙二醇單硬脂酸酯；單-及二-脂肪酸甘油酯類；聚甘油聚-脂肪酯類，諸如乙氧基化單硬脂酸甘油酯、1,3-丁二醇單硬脂酸酯、1,3-丁二醇二硬脂酸酯；聚氧乙烯多元醇脂肪酸酯；山梨醇酐脂肪酸酯類；及聚氧乙烯山梨醇酐脂肪酸酯類為令人滿意的多元醇酯類；蠟酯類諸如蜂蠟、鯨蠟、肉荳蔻酸肉豆蔻酯、硬脂酸硬脂酯；固醇酯類、其大豆固醇及膽固醇脂肪酸酯類為其例子。可使用這些化合物之植物及動物來源二者。該等油類的例子包括但不限制於：蓖麻油、羊毛脂油、C10-18三甘油酯類、辛酸/癸酸三甘油酯類、甜杏仁油、杏仁油、芝麻籽油、亞麻薺籽油、瓊崖海棠(tamanu)籽油、玉米油、棉籽油、亞麻仁油、墨油、橄欖油、棕櫚油、婆羅洲(illipe)脂、菜籽油、大豆油、葡萄籽油、葵花籽油、核桃油、等等。也適當者為合成或半合成甘油酯類，諸如脂肪酸單-、二-及三甘油酯類，其為已改良之天然脂肪類或油類，例如，多元醇類諸如甘油之單-、二-或三酯類。在一例子中，脂肪(C12-22)羧酸係與一或多種重複甘油基反應。硬脂酸甘油酯、二異硬脂酸二甘油酯、聚甘油基-3異硬脂酸酯、聚甘油基-4異硬脂酸酯、聚甘油基-6蓖麻醇酸酯、二油酸甘油酯、二異硬脂酸甘油酯、四異硬脂酸甘油酯、三辛酸甘油酯、二硬脂酸二甘油酯、亞麻油酸甘油酯、肉荳蔻酸甘油酯、異硬脂酸甘油酯、PEG蓖麻油類、PEG油酸甘油酯類、PEG硬脂酸甘油酯類及PEG牛脂酸甘油酯。
感興趣之脂肪酸類包括但不限制於：該等具有從10至30個碳原子者，諸如壬酸、月桂酸、肉荳蔻酸、棕櫚酸、硬脂酸、異硬脂酸、羥基硬脂酸、油酸、亞麻油酸、蓖麻油酸、花生酸、山嵛酸及芥酸。
多元醇類型之保濕劑也可發現使用於組成物中，其中多元醇類包括但不限制於：甘油(也稱為甘油)、聚烷二醇類、烯二醇類及其衍生物的例子，包括丙二醇、二丙二醇、聚丙二醇、聚乙二醇及其衍生物、山梨醇、羥丙基山梨醇、己二醇、1,3-丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油及其混合物。也感興趣者為糖類，例如，葡萄糖、果糖、蜂蜜、氫化蜂蜜、纖維醇、麥芽糖、甘露醇、氫化麥芽糖、山梨醇、蔗糖、木糖醇、木糖、等等。如果存在，保濕劑之量可在從0.001至25%之範圍，諸如從約0.005至20%，包括從約0.1至15%，其中在一些例子中保濕劑之量在介於組成物的以重量計從0.5至30%之範圍，諸如1及15%之間。
乳化劑也可存在於媒液組成物中。如果存在，乳化劑的總濃度可在以總組成物重量計從0.01至40%，諸如從1至20%，包括從1至5%的範圍。感興趣之乳化劑包括但不限制於：陰離子性、非離子性、陽離子性及兩性活性物質。感興趣之非離子性界面活性劑包括該等具有與每莫耳的疏水物從約2至約100莫耳的環氧乙烷或環氧丙烷縮合之C10-C20脂肪醇或酸疏水物者；與從2至20莫耳的環氧烷縮合之C2-C10烷基酚類；乙二醇之單-及二-脂肪酸酯類；脂肪酸單甘油酯；山梨醇酐、單-及二-C8-C20脂肪酸類；及聚氧乙烯山梨醇酐以及其組合。烷基聚醣苷類及醣脂肪醯胺類(例如甲基葡糖醯胺類)也為感興趣之非離子性乳化劑。感興趣之陰離子性乳化劑包括肥皂、烷基醚硫酸酯及磺酸酯類、硫酸烷基酯類及磺酸烷基酯類、烷基苯磺酸酯類、磺酸基丁二酸烷基及二烷基酯類、羥乙基磺酸C8-C20醯基酯、C8-C20烷基醚磷酸酯類、烷基醚羧酸酯類及其組合。
需要時，防腐劑可包括在組成物中，例如，用以防止可能有害的微生物生長。感興趣之防腐劑包括對-羥基苯甲酸之烷酯類、海因(hydantoin)衍生物、丙酸鹽類及各種四級銨化合物。感興趣之特定防腐劑包括但不限制於：胺甲酸碘丁炔酯丁酯、苯氧基乙醇、對羥苯甲酸甲酯、對羥苯甲酸丙酯、咪唑基尿素、去氫乙酸鈉、苯甲醇、苯甲基半甲縮醛、對羥苯甲酸苯甲酯、5-溴-5-硝基-1,3-二噁烷、2-溴-2-硝基丙烷-1,3-二醇、辛二醇、乙基己基甘油、苯氧基乙醇山梨酸、對羥苯甲酸甲酯、對羥苯甲酸丙酯、對羥苯甲酸乙酯、對羥苯甲酸丁酯、苯甲酸鈉、山梨酸鉀、伸乙二胺四乙酸之二鈉鹽、氯二甲苯酚、DMDM海因(hydantoin)、胺甲酸3-碘-2-丙基丁酯、氯己定(chlorhexidine)二葡萄糖酸鹽、苯氧基乙醇、尿素醛(diazolidinyl urea)、雙胍衍生物、苯甲酸鈣、丙酸鈣、辛二醇、雙胍衍生物、卡普坦(captan)、氯己定二乙酸鹽、氯己定二葡萄糖酸鹽、氯己定二鹽酸鹽、氯乙醯胺、氯丁醇、對-氯-間-甲酚、苄氯酚(chlorophene)、氯瑞香草酚、氯二甲苯酚、間-甲酚、鄰-甲酚、DEDM海因、DEDM海因二月桂酸鹽、去氫乙酸、尿素醛、羥乙磺酸雙溴丙脒(dibromopropamidine diisethionate)、DMDM海因、等等。如果存在，防腐劑可以組成物之重量計範圍在從約0.01%至約10%之量存在於遞送組成物中。
增稠劑或黏度改良劑可包括在遞送組成物中。感興趣之增稠劑包括但不限制於：多醣類，諸如澱粉、然天/合成膠類及纖維素。感興趣之澱粉包括但不限制於化學改質之澱粉，諸如辛烯基丁二酸鋁澱粉。感興趣之膠類包括但不限制於：黃原膠、菌絲團、果膠、梧桐膠、阿拉伯膠、瓊脂、瓜爾膠、鹿角菜膠、海藻酸鹽及其組合。適當纖維素包括但不限制於：羥丙基纖維素、羥丙基甲基纖維素、乙基纖維素及羧甲基纖維素鈉。合成聚合物仍為另外種類之有效增稠劑。此種類包括交聚丙烯酸酯諸如卡波姆(Carbomers)及聚丙烯醯胺類諸如Sepigel 305。如果存在，增稠劑之量可在以重量計從0.001至5%，諸如從0.1至2%，包括從0.2至0.5%之範圍。
在一些例子中，天然或合成有機蠟可存在，例如，一或多種天然或合成蠟諸如動物、植物或礦物蠟。在一些例子中，該等蠟將具有從20至150℃，諸如從30至100℃，包括35至75℃的範圍之熔點。該等蠟的例子包括蠟類諸如聚乙烯或合成蠟；或各種植物蠟諸如月桂果實、蠟大數、地蠟、阿拉伯膠、蜂蠟、純地蠟、鯨蠟酯類、花蠟、柑桔蠟、棕櫚蠟、荷荷巴蠟、日本蠟、聚乙烯、微晶、米糠、羊毛脂蠟、貂、褐煤、月桂果實、小冠椰子(ouricury)、地蠟、棕櫚仁蠟、烷烴、酪梨蠟、蘋果蠟、蟲漆蠟、鼠尾草蠟、廢麥芽粕蠟、葡萄蠟、及其聚烷二醇衍生物諸如PEG6-20蜂蠟、或PEG-12棕櫚蠟；或脂肪酸類或脂肪醇類，包括其酯類，諸如羥基硬脂酸類(例如12-羥基硬脂酸)、三硬脂精(tristearin)、及三山嵛精(tribehenin)。也感興趣者為格鲁椰子(Acrocomia aculeata)籽脂、杏仁脂、蘆薈脂、杏仁(Apricot Kernel)脂、摩洛哥堅果脂、美國油棕櫚樹(Attalea Maripa)籽脂、酪梨脂、巴西果脂、Bacuri脂、Bagura軟脂、猴麵包樹軟脂、藏欖籽脂、闊葉霧冰藜籽脂、黑醋栗籽脂、巴西堅果脂、山茶(Camelina)脂、山茶(Camellia)脂、蠟大數脂、棕櫚脂、Carpotroche Brasiliensis籽脂、甘菊脂、可可脂、椰子脂、咖啡脂、棉花軟脂、蔓越莓脂、古樸阿蘇果脂、葡萄籽脂、榛堅果脂、麻籽脂、木賊草脂、霧冰草脂、Irvingia Gabonensis仁脂、荷荷芭脂、乳油木脂、藤黃果脂、堅果脂、歐薄荷脂、檸檬脂、酸橙脂、澳洲堅果脂、芒果脂、馬魯拉樹脂、摩諾依脂、羅勒籽脂、Mucaja脂、Murumuru脂、洋橄欖脂、橄欖脂、柑橘脂、棕櫚油、百香果脂、Phulwara脂、開心果脂、石榴脂、南瓜脂、覆盆子脂、稻脂、婆羅雙樹脂、Sapucainha脂、芝麻脂、牛油樹油脂、大豆脂瓊崖海棠脂、向日葵籽脂、甜杏仁脂、紅橘脂、Tucuma籽脂、黃蠟樹脂及小麥胚芽脂。
著色劑、香料及磨料也可包括在遞送組成物中。這些物質各範圍可在以重量計從0.05至5%，諸如從0.1及3%。感興趣之著色劑包括二氧化鈦，其中適當表面處理(根據參照CI 77,891之顏色索引編碼)、錳紫(CI 77,742)、群青(CI 77,007)、氧化鉻(CI 77,288)、水合氧化鉻(CI 77,289)、鐵藍(CI 77,510)、氧化鋅、二氧化鋯。感興趣之特殊著色劑包括：D & C紅色19號(CI 45,170)、D & C紅色9號(CI 15,585)、D & C紅色21號(CI 45,380)、D & C橘色4號(CI 15,510)、D & C橘色5號(CI 45,370)、D & C紅色27號(CI 45,410)、D & C紅色13號(CI 15,630)、D & C紅色7號(CI 15,850:1)、D & C紅色6號(CI 15,850:2)、D & C黃色5號(CI 19,140)、D & C紅色36號(CI 12,085)、D & C橘色10號(CI 45,425)、D & C黃色6號(CI 15,985)、D & C紅色30號(CI 73,360)、D & C紅色3號(CI 45,430)、碳黑(CI 77,266)、胭脂紅(CI 75,470)、天然或合成黑色素及鋁色淀。
感興趣之香料包括：阿爾巴冷杉葉油、乙醛、乙醯苯胺、乙酸、千葉蓍油、獼猴桃(奇異果)水果水、己二酸、瓊脂、變性酒精、褐藻膠、蘆薈葉、乙酸戊酯、苯甲酸戊酯、戊基肉桂醛、茴香腦、茴香醇、洋甘菊花水、苯甲醛、苯甲醇、白樺油、齒葉乳香樹(Boswellia Serrata)油、乙酸丁酯、乳酸丁酯、金盞花油、茶樹(Camellia Sinensis)葉水、樟腦、辣椒素、雪松醇、肉桂醛、檸檬醛、香茅醇、來檬(酸橙)油、橘子(柑橘)油、柚子(葡萄柚)油、紅桔(柑橘)果皮油、香豆素、二丙酮醇、肉桂酸乙酯、乙醚、桉樹丁香(丁香)花油、菌綠烯醇、梔子油、野生天竺葵油、己基肉桂醛、氫化松香、八角(茴香)油、乙酸異戊酯、德州雪松(Juniperus mexicana)油、月桂樹油、薰衣草(薰衣草)油、澳洲茶樹(Melaleuca Alternifolia)(茶樹)葉油、香蜂草(Melissa Officinalis)葉油、薄荷(Mentha piperita)(薄荷)油、薄荷醇、2-萘酚、馬郁蘭(Origanum majorana)葉油、人參根萃取物、天竺葵酸、天竺葵花油、歐洲赤松(Pinus Silvestris Cone)油、山杏(Prunus Armeniaca)(杏仁)仁油、狗牙薔薇(Rosa Canina)花油、迷迭香(迷迭香)葉油、檀香(檀香木)油、百里香(Thyme)油、香草精、葡萄(葡萄)葉油、生薑(薑)根油。
半固體遞送組成物
也感興趣者為半固體遞送組成物，諸如凝膠、乳霜及軟膏。該等組成物可為(除了活性劑-磷酸鈣粒子複合物之外)水、水溶性聚合物、防腐劑、醇類、多價醇類、乳化劑、保濕劑、蠟、溶劑、增稠劑、塑化劑、pH調節劑、保水劑等等之混合物。此外，該等組成物也可包含其他生理上可接受的賦形劑或其他次添加劑，諸如香料、染料、乳化劑、緩衝劑、抗生素、穩定劑或類似者。這些類型之化合物的例子提供於上。
局部貼片
也感興趣者為固體調配物，諸如局部貼片調配物。局部貼片調配物可顯著地改變。局部貼片調配物可包括活性劑層、載體及離型襯墊。活性劑層在基質中可包括某量之活性劑/粒子複合物，其中基質可包括一或多種：黏合劑，諸如感壓橡膠及丙烯酸類、水凝膠、生理上可接受的賦形劑或其他次添加劑，諸如香料、染料、乳化劑、緩衝劑、抗生素、穩定劑或類似者。載體可由能夠適合人體運動的彈性物質製造且包括(例如)塑膠薄膜、各種非織物、織物、彈性纖維、等等。可使用各種惰性覆蓋層，其包括各種可發現使用於石膏中之物質，如下所述。或者，可使用允許熱及蒸汽傳送之非織物或織物覆蓋層，特別是彈性體覆蓋層。這些覆蓋層允許疼痛位置的冷卻，其提供較大舒適性，同時防止凝膠機械移除。離型襯墊可由習知物質製造，其中代表性離型薄膜包括聚酯類，諸如PET或PP、等等。
氣溶膠組成物
也感興趣者為經由吸入投藥之氣溶膠組成物調配物。這些氣溶膠調配物被放置進入加壓可接受的推進劑中，諸如二氯二氟甲烷、丙烷、氮、等等。它們也可調配用於非加壓製劑，諸如用於噴霧器或霧化器。在一些體系中，該等調配物為粉末氣溶膠調配物，其包括懸浮或分散在推進劑或推進劑及溶劑中之活性劑給結合粒子。推進劑可為液化氯氟碳(CFCs)之混合物，選擇其以提供所要的調配物之蒸汽壓力及穩定性。推進劑11、12及114為用於吸入投藥之氣溶膠調配物中最廣泛地使用的推進劑。其他常用推進劑包括推進劑113、142b、152a、124及二甲醚。化合物1,1,1,2-四氟乙烷也為醫藥氣溶膠組成物常用的推進劑。推進劑可為以總吸入組成物重量計之40至90%。
製造遞送組成物之方法
本發明之特點另外包括製造遞送組成物之方法。雖然可使用任何方便的製造方案，但在一些例子中製造方案包括首先製備活性劑-粒子複合物。製備活性劑-粒子複合物之後，然後使用任何方便的方案將所得複合物合併於遞送組成物成分中。
活性劑-粒子複合物可使用任何方便的方案製備。一感興趣之方案包括首先製備活性劑之液體組成物，諸如活性劑之水性組成物，及然後在足以產生所要活性劑-粒子複合物之條件下合併液體組成物與某量之均勻剛性球形奈米孔洞磷酸鈣粒子(需要時並攪拌)。同樣地，在某些體系中，非結合粒子之流體組成物，例如，非結合粒子在適當溶劑系統(諸如水性或非水性溶劑系統)中之漿料與適當量之活性劑合併。
粒子預處理
根據需要，該等非結合粒子可在與活性劑合併之前以一些方法預處理。同樣地，活性劑結合粒子之製備可包括預處理步驟，諸如最初pH調整步驟。在此步驟中，該等非結合粒子藉由使其與一或多種試劑(諸如pH調節劑)接觸而改質以便提供結合至粒子之所要活性劑。如使用，pH調整之特殊性質，視要結合至粒子的活性劑之類型而改變。感興趣之活性劑的一種類為該等包括酸性及/或鹼性帶電部分及大於幾千道耳頓，例如，具有3000道耳頓或更大之質量，諸如5,000道耳頓或更大，例如，10,000道耳頓或更大，25,000道耳頓或更大，50,000道耳頓或更大，75,000道耳頓或更大，100,00道耳頓或更大，250,000道耳頓或更大，500,000道耳頓或更大，750,000道耳頓或更大，1,000,000道耳頓或更大之分子質量者。該等活性劑的例子包括但不限制於蛋白質、核酸類及多醣類。該等活性劑在寬廣範圍的pH條件下可強結合至粒子之鈣及/或磷酸鹽位置。因此，關於這些類型之活性劑，根據需要可實施或可不實施pH改變。若需要pH改變，可藉由使用任何方便的pH調節劑(例如，酸或鹼試劑)實施pH改變。感興趣之pH調節劑包括但不限制於：乳酸、乙醇酸、三乙醇胺及氫氧化鈉。在一些例子中，選擇不阻擋粒子的結合鈣及/或磷酸鹽位置之pH調節劑。
感興趣的活性劑之另一種類為該等包括酸性及/或鹼性帶電部分且不超過幾千道耳頓，例如，具有2500道耳頓或更小，諸如1500道耳頓或更小之質量的分子質量者。該等活性劑的例子包括但不限制於有機酸及胺化合物。該等活性劑在特定pH結合至粒子。根據需要，可使用藉由最佳化pH的粒子之預處理，及/或將特定離子化合物添加至結合溶液(更詳細描述於下文中)。
感興趣之活性劑的另一種類為具有非帶電或弱帶電之水溶性小分子。該等化合物的例子包括但不限制於：醣類、醣苷類及胺基酸衍生物。關於此種類的活性劑，根據需要，一種水性及/或有機溶劑混合物，諸如乙醇/水或乙腈/水可被使用於預處理及活性劑結合。
感興趣之活性劑的另一種類為具有疏水部分之水溶性小分子。關於該等活性劑，預處理可包括使粒子與表面改良劑(例如，包括一或多個帶電基及一或多個疏水尾巴之試劑，諸如但不限制於硫酸十二基酯鈉、硫酸月桂酯鈉及磷酸月桂酯鈉、等等)接觸。
感興趣之活性劑的另一種類為水不溶分子。感興趣之水不溶分子的例子包括但不限制於：胺基酸衍生物、多酚類及類視色素類。關於該等活性劑，根據需要，使用有機溶劑諸如乙醇及二甲亞碸(DMSO)作為預處理試劑及/或可使用填充溶劑。
在一些例子中，粒子係用離子改質劑預處理。離子改質劑包括但不限制於鈣離子改質劑，諸如CaCl2、磷酸鹽離子改質劑，諸如磷酸鈉、等等。
任何粒子預處理步驟之後，例如，如上所述，在一些體系中，該等粒子係進行洗滌步驟。例如，在一些例子中，可能想要在活性劑結合之前藉由洗滌、過濾或傾析粒子而從粒子除去過量鹽或離子。任何方便的洗滌方案及液體可被使用此步驟中。
複合物形成
在任何預處理及/或洗滌之後，諸如如上所述(如果需要)，非結合粒子與活性劑合併以產生活性劑結合粒子。根據需要，活性劑可於粉末或溶液形式。可使用任何合併活性劑及粒子之適當方案，諸如在簡單容器中靜態混合、等等。在結合期間組成物之pH可選擇以提供最大結合，例如，藉由使用pH調節劑，諸如上述。例如，在一些例子中鹼性活性劑係在鹼性條件下與粒子合併及酸性活性劑係在酸性條件下與粒子合併。因此，複合物形成反應之pH在一些例子中可在從5至14之範圍。在某些例子中，pH為10或更小，其中，視使用於複合物形成之時間長度而定，可選擇pH以使避免實值粒子降解，例如，可選擇為5.2或更大。
如上所示，可使用任何方便的溶劑系統來製備活性劑-粒子複合物。如上所示，使用於活性劑結合至粒子以產生活性劑-粒子複合物之溶劑系統可改變。發現使用於製備活性劑-粒子複合物之溶劑系統可由單一溶劑或二或多種之多數個不同溶劑製造。感興趣之存在於溶劑系統中的溶劑可為極性(也就是，它們具有15或更大之介電常數)或非極性(也就是，它們具有小於15之介電常數)及質子性(致使它們經由氫鍵結而強溶劑化陰離子(帶負電溶質))或質子性(也就是，它們具有足夠大的偶極矩以經由它們的偶極將帶正電成分溶劑化)。
感興趣之質子溶劑包括但不限制於：醇類，諸如甲醇、乙醇、丙醇、異丙醇、丁醇、戊醇、己醇、庚醇、辛醇、三氟乙醇、酚、苯甲醇、甘油、乙二醇、二乙二醇；羧酸類/醯胺類，諸如甲酸、乙酸、乳酸、丙酸、三氟乙酸、甲醯胺；胺類，諸如氨、二乙胺、丁胺、丙胺；及水。感興趣之非質子溶劑包括但不限制於：烴類，諸如戊烷、己烷類、庚烷、環己烷、甲基環己烷、十氫萘；酮類/醛類，諸如丙酮、甲基乙基酮(MEK)、甲基異丁基酮、丁酮、戊酮、環己酮、苯甲醛；芳族化合物，諸如苯、甲苯、三氟甲苯、二甲苯、苯甲醚、氯苯、苯胺、N,N-二甲基苯胺、苯甲腈；醚類，諸如二甲氧基乙烷、二甲醚、二乙醚、二異丙醚、甲基第三-丁基醚(MTBE)、四氫呋喃、二噁烷、甘醇二甲醚、二甘醇二甲醚、聚乙二醇(PEG)、PEG酯類、PEG山梨醇酐類、PEG醚類、PEG酯類、聚丙二醇(PPG)、PPG酯類、烷氧基化直鏈烷二醇類、烷氧基化烷基葡萄糖醚、PPG烷基醚類；酯類/醯胺類，諸如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸丁酯、乙酸戊酯、苯甲酸乙酯、苯甲酸苯甲酯、酞酸二甲酯、酞酸二丁酯、二甲基乙醯胺、二甲基甲醯胺(DMF)；腈類，諸如乙腈；碳酸酯類，諸如二甲基碳酸酯、二乙基碳酸酯、碳酸丙二酯、碳酸乙二酯；鹵化化合物，諸如四氯化碳、氯仿、二氯甲烷、二氯乙烷、三氯乙烷、氟氯烷-11、BMIM-PF6離子液體；含硫/磷化合物，諸如二甲亞碸(DMSO)、二硫化碳、環丁碸、六甲基磷酸三胺；及胺類，諸如吡啶、三乙胺、N-甲基吡咯啶酮(NMP)。
感興趣之溶劑包括但不限制於：酒精、變性酒精、苯甲基乙二醇、月桂酸苯甲酯、月桂酸苯甲酯/肉荳蔻酸苯甲酯/棕櫚酸苯甲酯、1,4-丁二醇、2,3-丁二醇、Buteth-3、丁氧基二甘醇、丁氧基乙醇、乙酸丁氧基乙酯、正-丁醇、第三-丁醇、肉荳蔻酸丁酯、丁二醇、丁二醇丙酸酯、乙基己酸丁基乙基丙二基酯、乳酸丁酯、丁基辛醇、苯甲酸丁基辛酯、水楊酸丁基辛酯、硬脂酸丁酯、丁基酞醯亞胺、丁內酯、苯甲酸C12-15烷酯、癸酸、辛醇、辛酸鯨蠟硬脂酯、辛酸鯨蠟基硬脂酯、氯丁醇、C8-12酸三甘油酯、C12-18酸三甘油酯、C9-12烷、C10-13烷、C13-14烷、C13-15烷、C14-17烷、C14-19烷、C15-19烷、C15-23烷、C18-21烷、C8-9烷/環烷、C9-10烷/環烷、C9-11烷/環烷、C9-16烷/環烷、C10-12烷/環烷、C11-14烷/環烷、C11-15烷/環烷、C12-13烷/環烷、C8-10烷/環烷/芳族烴類、C12-15烷/環烷/芳族烴類、C9-10芳族烴類、C10-11芳族烴類、CD醇19、氯化烷烴、C7-8異烷烴、C8-9異烷烴、C9-11異烷烴、C9-13異烷烴、C9-14異烷烴、C9-16異烷烴、C10-11異烷烴、C10-12異烷烴、C10-13異烷烴、C22-12異烷烴、C11-13異烷烴、C11-14異烷烴、C12-14異烷烴、C12-20異烷烴、C13-14異烷烴、C13-16異烷烴、C20-40異烷烴、薏芢(薏仁)種子水、C6-12全氟烷基乙醇、克羅米通(Crotamiton)、C10-18三甘油酯類、環乙氧基聚甲基聚矽氧烷、環庚矽氧烷、環己烷二甲醇、環己矽氧烷、環聚甲基聚矽氧烷、環戊矽氧烷、環丁矽氧烷、環丙矽氧烷、癸烷、1,10-癸二醇、癸烯、癸醇、脫臭煤油、二醋精、二丙酮醇、己二酸二丁酯、蘋果酸二丁基辛酯、癸二酸二丁基辛酯、草酸二丁酯、酞酸二丁酯、癸二酸二丁酯、順丁烯二酸二-C12-15烷酯、二乙氧基二甘醇、丁二酸二乙氧乙酯、二乙二醇二苯甲酸酯、己二酸二乙基己酯、順丁烯二酸二乙基己酯、2,6-萘酸二乙基己酯、酞酸二乙基己酯、癸二酸二乙基己酯、丁二酸二乙基己酯、草酸二乙酯、酞酸二乙酯、癸二酸二乙酯、丁二酸二乙酯、己二酸二(十七基)酯、己二酸二己酯、癸二酸二(十六基)酯、蘋果酸二異戊酯、己二酸二異丁酯、草酸二異丁酯、己二酸二異辛酯、己二酸二異癸酯、己二酸二異壬酯、己二酸二異辛酯、己二酸二異丙酯、草酸二異丙酯、癸二酸二異丙酯、二甲氧基二甘醇、己二酸二甲酯、二甲基癸醯胺、戊二酸二甲酯、二甲基異山梨醇、順丁烯二酸二甲酯、草酸二甲酯、酞酸二甲酯、丁二酸二甲酯、二甲碸、己二酸二辛酯、丁二酸二辛酯、癸二酸二(十八基)酯、二氧戊環、二苯基甲烷、二-PPG-3肉豆蔻基醚己二酸酯、己二酸二丙酯、二丙二醇、二丙二醇二苯甲酸酯、二丙二醇二甲醚、草酸二丙酯、己二酸二(十三基)酯、十二烯、車前葉藍薊(Echium Plantagineum)籽油、二十烷、乙氧基二甘醇、乙氧基二甘醇乙酸酯、乙氧基乙醇、乙氧基乙醇乙酸酯、碳酸乙二酯、乙醚、乙基己二醇、苯甲酸乙基己基酯、乳酸乙酯、澳洲堅果油酸乙酯(Ethyl Macadamiate)、肉荳蔻酸乙酯、油酸乙酯、乙基全氟丁基醚、呋喃甲醛、甘油醚-7苯甲酸酯、甘油醚-18苯甲酸酯、甘油醚-20苯甲酸酯、甘油醚-7二異壬酸酯、甘油醚-4,5-乳酸酯、甘油醚-5乳酸酯、甘油醚-7乳酸酯、甘油醚-7三乙酸酯、野生大豆(大豆)油、乙氧基化四氫糠醇(Glycofurol)、乙二醇、十六碳稀、己二醇、1,2-己二醇、1,2,6-己三醇、己烯、己醇、苯甲酸十六酯、水楊酸己基十二酯、己二醇、氫化聚癸烯、氫化聚十二烯、羥甲基二氧戊環酮、乙酸異戊酯、異丁氧基丙醇、乙酸異丁酯、苯甲酸異丁酯、硬脂酸異丁酯、水楊酸異鯨蠟酯、苯甲酸異癸酯、異壬酸異癸酯、辛酸異癸酯、油酸異癸酯、異十二烷、異二十烷、異十六烷、異壬酸異壬酯、異辛烷、異戊烷、異戊二醇、乙酸異丙酯、檸檬酸異丙酯、月桂酸異丙酯、肉荳蔻酸異丙酯、棕櫚酸異丙酯、異丙基酞醯亞胺、乙醇酸異硬脂酯、異硬脂基硬脂醯基硬脂酸酯、羊毛脂醇聚醚(Laneth)-5、羊毛脂油、月桂醇聚醚(Laureth)-2乙酸酯、薴烯、3-甲氧基丁醇、甲氧基二甘醇、甲氧基乙醇、甲氧基乙醇乙酸酯、甲氧基異丙醇、乙酸甲氧基異丙酯、甲氧基甲基丁醇、甲氧基PEG-7、甲氧基PEG-10、甲氧基PEG-16、甲氧基PEG-25、甲氧基PEG-40、甲氧基PEG-100、乙酸甲酯、二甲氧基甲烷、苯甲酸甲酯、甲基丁烯類、甲基葡糖醇聚醚(Gluceth)-20苯甲酸酯、甲基乙基醚、乳酸甲酯、甲基全氟丁基醚、甲基丙二醇、甲基吡咯啶酮、大豆油酸甲酯、葵花籽油甲酯、甲基三聚甲基聚矽氧烷、MIBK、礦物油、礦油精、混合萜烯類、羅漢果果汁、嗎福啉、貂油酸/棕櫚酸三甘油酯、新戊二醇、新戊二醇二辛酸酯、壬苯醇醚(Nonocynol)-9、十八烷、十八烯、辛烷、辛烯、苯甲酸辛酯、乳酸十八酯、辛基十二基酸辛基十二酯、異壬酸辛酯、異硬脂酸辛酯、月桂酸辛酯、棕櫚酸辛酯、硬脂酸辛酯、油醇、橄欖油PEG-6酯類、花生油PEG-6酯類、PBG-33蓖麻油、PEG-4、PEG-6、PEG-7、PEG-8、PEG-9、PEG-10、PEG-12、PEG-14、PEG-16、PEG-18、PEG-20、PEG-32、PEG-33、PEG-40、PEG-45、PEG-55、PEG-60、PEG-75、PEG-80、PEG-90、PEG-100、PEG-135、PEG-150、PEG-180、PEG-200、PEG-220、PEG-240、PEG-350、PEG-400、PEG-450、PEG-500、PEG-2苯甲醚、PEG-15丁二醇、PEG-3甲醚、PEG-4甲醚、PEG-6甲醚、PEG-7甲醚、PEG-50椰油酸甘油酯、PEG-20氫化蓖麻油、PEG/PPG-1/2共聚物、PEG/PPG-4/2共聚物、PEG/PPG-5/30共聚物、PEG/PPG-6/2共聚物、PEG/PPG-7/50共聚物、PEG/PPG-8/17共聚物、PEG/PPG-10/70共聚物、PEG/PPG-17/6共聚物、PEG/PPG-18/4共聚物、PEG/PPG-19/21共聚物、PEG/PPG-23/17共聚物、PEG/PPG-23/50共聚物、PEG/PPG-25/30共聚物、PEG/PPG-26/31共聚物、PEG/PPG-30/33共聚物、PEG/PPG-35/9共聚物、PEG/PPG-38/8共聚物、PEG/PPG-116/66共聚物、PEG/PPG-125/30共聚物、PEG/PPG-160/31共聚物、PEG/PPG-200/70共聚物、PEG/PPG-240/60共聚物、PEG-10丙二醇、1,5-戊二醇、季戊四醇四辛酸酯/四癸酸酯、戊二醇、全氟辛基溴、全氟十氫萘、全氟二甲基環己烷、全氟己烷、全氟甲基環戊烷、全氟全氫苯甲基四氫萘、全氟全氫菲、全氟四氫萘、石油餾分、苯氧基異丙醇、苯基丙醇、聚甘油基-3二異硬脂酸酯、聚甘油基-2二油酸酯、聚氧基乙二醇二苯甲酸酯、聚全氟乙氧基甲氧基二氟甲基醚、PPG-3、PPG-7、PPG-10丁二醇、PPG-2-丁醇聚醚(Buteth)-3、PPG-3-丁醇聚醚-5、PPG-5-丁醇聚醚-7、PPG-7-丁醇聚醚-4、PPG-7-丁醇聚醚-10、PPG-12-丁醇聚醚-16、PPG-15-丁醇聚醚-20、PPG-20-丁醇聚醚-30、PPG-20羊毛脂醇醚、PPG-2肉豆蔻基醚丙酸酯、PPG-2丁基醚、PPG-3丁基醚、PPG-24-甘油醚-24、PPG-25-甘油醚-22、PPG-10甘油醚、PPG-55甘油醚、PPG-67甘油醚、PPG-70甘油醚、PPG-2甲醚、PPG-3甲醚、PPG-2甲醚乙酸酯、PPG-2丙醚、丙二醇、乙酸丙酯、碳酸丙二酯、丙二醇、丙二醇丁醚、丙二醇辛酸酯、丙二醇二苯甲酸酯、丙二醇甲醚、丙二醇肉荳蔻酸酯、丙二醇丙醚、蓖麻(蓖麻)籽油、SD醇1、SD醇3-A、SD醇3-B、SD醇3-C、SD醇23-A、SD醇23-F、SD醇23-H、SD醇27-B、SD醇30、SD醇31-A、SD醇36、SD醇37、SD醇38-B、SD醇38-C、SD醇38-D、SD醇38-F、SD醇39、SD醇39-A、SD醇39-B、SD醇39-C、SD醇39-D、SD醇40、SD醇40-A、SD醇40-B、SD醇40-C、SD醇46、海水、芝麻(芝麻)油、鯊魚肝油、山梨醇聚醚(Sorbeth)-6、山梨醇聚醚-20、山梨醇聚醚-30、山梨醇聚醚-40、山梨醇酐三油酸酯、苯甲酸硬脂酯、庚酸硬脂酯、十四烯、十四基丙酸酯類、乙酸四氫呋喃甲酯、四氫呋喃甲醇、四氫噻吩二醇、甘油三乙酸酯、檸檬酸三丁酯、三丁基甲酚丁烷、三氯乙烷、磷酸三乙酯、三甲基己醇、2,2,4-三甲基戊烷、三甲基戊醇羥乙基醚。
需要時，溶劑系統可以一或多種改質劑，諸如緩衝劑、pH調整劑(酸或鹼)、親水分子、疏水分子或具有疏水基及親水基之分子(例如，界面活性劑)改質。感興趣之緩衝劑包括但不限制於：HCl/檸檬酸鈉、檸檬酸/檸檬酸鈉、乙酸/乙酸鈉、K2HPO4/KH2PO4、Na2HPO4/NaH2PO4、硼砂/氫氧化鈉以及生物緩衝劑，例如，TAPS(3{[參(羥甲基)甲基]胺基}丙磺酸)、二羥乙甘胺酸(N,N-雙(2-羥乙基)甘胺酸)、參(參(羥甲基)甲基胺)、Tricine(N-參(羥甲基)甲基甘胺酸)、HEPES(4-2-羥乙基-1-哌乙磺酸)、TES(2-[參(羥甲基)甲基]胺基)乙磺酸)、MOPS(3-(N-嗎福啉基)丙磺酸)、PIPES(哌-N,N-雙(2-乙磺酸)、卡可酸酯(二甲基胂酸)、SSC(鹽水檸檬酸鈉)及MES(2-(N-嗎福啉基)乙磺酸)；等等。
特定溶劑系統之成分及性質，諸如pH、組成物、溫度、等等可考慮一或多種與粒子複合之活性劑的性質而選擇，其中該等性質可包括活性劑溶解度、結構、pKa、logP、等等。
製備活性劑-粒子複合物之後，然後使用任何方便的方案將所得複合物與遞送組成物成分合併。所使用之特殊方案可視遞送組成物成分之性質而改變，其中在某些例子中裝載遞送組成物成分及活性劑之粒子可使用混合而合併以產生所要遞送組成物。雖然在組合期間溫度可改變，但在一些例子中溫度為80℃，諸如40℃或更小，諸如30℃或更小，例如，室溫或更冷。與遞送媒液合併之活性劑-粒子複合物的量可改變。在一些體系中，與遞送媒液合併之活性劑-粒子複合物的量係足以產生最終遞送組成物，其中活性劑-粒子複合物之量在從0.001至1000毫克/克，諸如0.1至200毫克/克之範圍且每克遞送組成物成分包括1至50毫克/克活性劑-粒子複合物。在某些體系中，該等避免螯合劑存在。調配物之pH為5.0或更大，諸如5.5或更大。
利用性
本發明之遞送組成物發現使用於將活性劑遞送至對象的局部位置之方法，其中局部位置可為皮膚表面部位或黏膜部位。在活性劑遞送至對象之局部部位中，本發明之遞送組成物可將活性劑-粒子複合物遞送至少進入在對象皮膚表面下方之表皮部位。同樣地，本發明之體系包括將裝載活性劑之粒子遞送進入對象角質層之方法，其中該方法可導致複合物遞送至對象深角質層及/或真皮。“進入角質層”表示複合物被遞送至在皮膚表面之下至少1個細胞層的區域。“深角質層”是指在皮膚表面之下2個或更多細胞層，諸如在皮膚表面之下5個或更多細胞層，包括在皮膚表面之下10個或更多細胞層之區域。在一些例子中，該等複合物係遞送至在皮膚表面之下2微米或更多諸如5微米或更多及包括15微米或更多的角質層區域。
本發明之體系包括將裝載活性劑之粒子遞送至對象角質層之的方法，其中該方法可導致複合物遞送進入對象之真皮。“進入真皮”是指複合物被遞送至在皮膚表面之下至少20個細胞層的區域。
一旦達成其目標皮膚部位時，在一些例子中該等活性劑結合粒子開始釋放其活性劑“載重量(payload)”。活性劑從粒子釋放可根據許多不同的機制發生。例如，在皮膚的環境中可逆轉試劑對粒子的任何結合交互作用。除了此機制之外或另外，皮膚的環境可破壞磷酸鈣粒子(例如，經由皮膚的梯度所引起之溶解)，致使均勻剛性球形奈米孔洞粒子在酸性條件，例如，pH 5或更低，諸如4.5或更低，包括4.3或更低之條件，諸如角質層之生理酸條件下溶解。粒子在角質層中溶解所需時間可改變及在某些體系中，在從1分鐘至72小時，諸如10分鐘至24小時且包括30分鐘至12小時之範圍，超過該時段，活性劑從活性劑結合粒子釋放出來。本發明一特點包括所有活性劑之釋放。
本發明之方法因此導致活性劑遞送至少進入對象之角質層。在一些體系中，該等活性劑保留在角質層中以發揮其所要活性。在其他體系中，活性劑可在一或多個身體之其他目標部位發揮其所要活性。所感興趣之另外的目標部位包括另外的表皮區域，諸如但不限制於透明層、顆粒層、棘層(stratum spinusom)、基層及真皮。在某些體系中，該等活性劑係遞送至真皮之區域。在某些體系中，該等活性劑係遞送至真皮以下的區域，例如，進入皮下組織。
在一些例子中，活性劑可被全身性遞送至對象。當活性劑被全身性遞送至對象時，達到活性劑之治療血漿含量。活性劑之治療血漿含量視特定活性劑及要治療狀況而改變。在某些體系中，所達到之治療活性含量範圍從0.1至100微克，諸如1微克至20微克，諸如1奈克至1微克及包括10奈克至100奈克。
在實施本發明方法中，將遞送組成物施用於對象之局部區域且以足以如上所述產生活性劑至對象之所要遞送的方式維持於局部區域。在某些體系中，該局部區域為角質化皮膚區域。角質化皮膚區域，包括毛囊、汗腺及皮脂腺，可存在於各種原或損壞的皮膚部位，其中感興趣之部位包括但不限制於：四肢、雙臂、手、腿、腳；軀幹，例如，胸、背、胃；頭，例如，脖子、臉；等等。在某些體系中，該等區域將為頭部區域，諸如臉部區域，例如，前額、枕骨區域、嘴部四圍、等等。關於組成物施用之局部區域的面積可改變，在某些體系中，在從1毫米2至300公分2或更大，諸如從1至50公分2及包括從3至10公分2之範圍。
在實施標的方法中，對象可在給定的一段時間中被投予單一量或二或多個劑量。例如，在給定的一個月治療期，1或多個劑量，諸如2或多個劑量，3或多個劑量，4或多個劑量，5或多個劑量，等等可施用於對象之局部位置，其中該劑量可每週或每天施用或甚至可每天施用多次。
如相較於活性劑不是以與磷酸鈣粒子之複合物遞送的對照組，根據本發明之活性劑複合物的遞送可賦予一或多種優點。例如，在一些例子中該活性劑被穩定在磷酸鈣複合物中，致使其活性被維持。在一些例子中，將活性劑與磷酸鈣粒子複合成根據本發明之體系的複合物中提供活性劑至在其中不會正常地遞送之部位的遞送，例如，遞送進入角質層，如果該等試劑不存在於磷酸鈣粒子複合物中，其遞送會被限制在皮膚表面。在一些例子中，如相較於適當對照組，本發明之方法產生提高活性劑的滲透。適當對照組為一種包括相同活性劑及遞送媒液成分但沒有均勻剛性球形奈米孔洞磷酸鈣粒子之遞送組成物。在一些例子中，如相較於該等對照組，該滲透被提高2或多倍，諸如5或多倍，包括10或多倍之倍數。在其他體系中，該等複合物用作來自角質層的活性劑之控制釋放貯藏體(depot)，藉此提供所要的活性劑之延長釋放及遞送輪廓。
雖然活性劑-磷酸鈣複合物在本文中已主要地依據其皮膚遞送應用之用途描述，但在一些例子中它們可用於其他應用。例如，本發明之活性劑-磷酸鈣複合物在一些例子中發現在活性劑非皮膚遞送至對象之用途。非皮膚遞送調配物的例子包括但不限制於：膠囊、錠劑、丸劑、小丸劑、菱形錠、粉劑、粒劑、糖漿、酏劑、溶液、懸浮液、乳液、栓劑、或其緩釋調配物，或任何適合於投藥至哺乳動物之其他形式。在一些例子中，為了投藥該等醫藥組成物係根據例行步驟被調配呈適合口服或靜脈內投予至人類之醫藥組成物。適當醫藥媒液及其調配方法的例子係描述於Remington：The Science and Practice of Pharmacy，Alfonso R. Gennaro編輯，伊斯頓麥克出版公司，賓夕法尼亞州，第19版，1995，第86、87、88、91及92章，以引用方式納入本文中。
標的方法及組成物可被使用於各種不同類型動物，其中該等動物典型為“哺乳動物”或“哺乳動物(mammalian)”，其中這些術語被廣泛地用以描述哺乳綱中的生物，包括食肉動物目(例如，狗和貓)、囓齒目(例如，小鼠、天竺鼠及大鼠)、複齒目(例如，兔子)及靈長目(例如，人類、黑猩猩及猴子)。在某些體系中，該等對象或病患為人類。
下列實例以說明方式且不限制的方式提供。
 實驗 實驗 I.　均勻剛性球形奈米孔洞磷酸鈣粒子之製備及示性 A.　製備
藉由在溫度、pH、壓力、氣體、攪拌速度、試劑濃度、添加速度及老化時間之控制條件下，將磷酸鹽複合物水溶液逐滴加入水性鈣複合物溶液或懸浮液製備磷酸鈣奈米-晶體漿料。藉由使用具有氣-液流體噴嘴之壓力噴嘴型噴霧乾燥器將漿料噴霧乾燥以形成球形多孔粉末。在300至900℃範圍之溫度下用氣體或電爐或窯將乾燥粉末燒結1至24小時範圍之時間。
B.　示性
圖1A及1B顯示所得2微米均勻剛性球形奈米孔洞磷酸鈣粒子(如上所述製備)之多孔結構，使用SEM(A)10,000 X、(B)50,000 X。圖2A及2B顯示2微米均勻剛性球形奈米孔洞磷酸鈣粒子(如上所述製備)的外部及內部結構，使用SEM(A)及TEM(B)(15000 X)二者。大(25-50米2/克)內及外表面積為實質上允許與活性劑結合的高能力。圖3顯示粒子之粒徑分佈，如以Coulter Multi-sizer 3粒子計數器測定及以掃描電子顯微鏡確認。平均粒徑為2微米。
II.　活性劑-磷酸鈣粒子複合物之製備 A.　包括某些活性劑之預處理的一般結合準則
磷酸鈣粒子結合廣泛範圍的生物分子且在一些例子中穩定該等生物分子。與磷酸鈣粒子之結合係以離子的交互作用為基礎。磷酸鈣粒子之官能基由帶正電鈣離子(Ca++)及帶負電磷酸根離子(PO4 -3)組成。此表示生物材料的陰離子化羧基之量在酸性條件下將減少。因此生物分子的陰離子化羧基和磷酸鈣粒子的鈣離子之間的結合將被減弱。此情形在鹼性條件下被生物分子的陽離子化胺基及磷酸鈣粒子的磷酸根官能基之間的交互作用逆轉。
pH及離子強度直接地影響磷酸鈣粒子及生物材料之間的結合。磷酸鈣粒子具有結合具有寬範圍分子量(例如，200至10,000,000)及等電點(例如，2.0至12)之生物材料的能力。
除了pH及離子強度，生物材料的分子量、形狀及位向也影響對磷酸鈣粒子的結合。例如，具有於90毫克/克之較低分子量的BSA及於較大分子量之DNA以1毫克/克之比率結合至磷酸鈣粒子。大生物分子諸如DNA之結合能力將以磷酸鈣粒子的外表面積測定。總結，影響磷酸鈣粒子和生物分子之間的結合之主要參數為pH、離子強度、立體化學作用及分子量。
B.　特定活性劑-磷酸鈣粒子複合物 1. pH對結合的影響 a.　水楊酸 物質：
磷酸鈣粒子
水楊酸，Fisher Scientific，料號A277-500
方法
i.　將23.2毫克的水楊酸溶解在1毫升的乙醇中。
ii.　將4克的磷酸鈣粒子懸浮在39.8毫升的水中且用HCl將pH調整至接近目標pH。
iii.　將0.2毫升的水楊酸溶液(23.2毫克/毫升)混合於磷酸鈣粒子之懸浮液中。
iv.　用HCl將pH調整至各目標pH(11.36、8.34、7.47、7.07、5.99)。
v.　在各pH下，從懸浮液取得4.8毫升樣品。所有的樣品分開地以2000 x g離心10分鐘。
vi.　以UV光譜儀於297奈米(水楊酸之檢測波長)測量上澄液的吸光度。
vii.　對照組係以相同步驟而沒有磷酸鈣粒子進行。
結果
結果係顯示於下表中且證明水楊酸以被水楊酸的pKa驅使之pH依賴性方式結合至磷酸鈣粒子。
b.　多酚複合物(PPC)至磷酸鈣粒子 物質：
2微米磷酸鈣粒子
多酚複合物(PPC)
方法：
1.　將33.98毫克的PPC溶解在6.8毫升的水中。
2.　將2克的磷酸鈣粒子懸浮在19.9毫升的水中且用HCl將pH調整至pH 9.62。
3.　將0.1毫升的PPC溶液(5毫克/毫升)混合於磷酸鈣粒子之懸浮液中，取得2毫升樣品。
4.　用HCl將pH調整至各目標pH(8.58、8.07、7.49、7.21、6.75、6.08)。
5.　在各pH下，從懸浮液取得2毫升樣品。所有的樣品分開地以3,000 rpm離心10分鐘。
6.　於280奈米(PPC之檢測波長)測量上澄液的吸光度。
7.　對照組係以相同步驟而沒有磷酸鈣粒子進行。
結果
磷酸鈣粒子之結合能力總結於下表10及圖19中。與多酚之結合可在任何pH下進行。
2.　牛血清白蛋白(BSA) a.　物質：
磷酸鈣粒子
BSA，冷凍乾燥粉末，Fisher Scientific，產品編號BP-671-10
b.　方法：
i.　將0.5克的磷酸鈣粒子懸浮在1毫升的水中，用HCl將pH調整至接近目標7。將懸浮液混合10分鐘。
ii.　將BSA溶解在水中及逐漸地混合以製備20毫克/毫升溶液。將4毫升的BSA溶液加至各磷酸鈣粒子懸浮液並混合30分鐘。測定懸浮液之最終pH。
iii.　將懸浮液以2000 x g離心5分鐘。將上澄液轉移到新試管並以2000 x g離心5分鐘。
iv.　用Shimadzu 10A HPLC系統分析最終上澄液。使用Bio-Scale CHT2-I羥磷灰石管柱(7×52毫米，產品編號157-0020)在Shimadzu 10A系統中達成分離。將樣品裝載在管柱上且以1毫升/分鐘之流速用從1mM磷酸鈉緩衝液(pH 6.8)至400mM磷酸鈉緩衝液(pH 6.8)之15-分鐘直線梯度溶析。於280奈米監測溶析液。BSA被觀察為在具有約8.8分鐘之滯留時間的層析圖中之主峰。BSA的定量係藉由外部標準校正達成。
v.　對照組係以相同步驟而沒有磷酸鈣粒子進行。
c.　結果：
BSA以95.1毫克/克結合至磷酸鈣粒子。
3.乳鐵素
a.　物質：
磷酸鈣粒子
自人乳之乳鐵素來，Sigma Aldrich，產品編號0520-100MG
b.　方法：
i.　將乳鐵素溶液以4.98毫克/毫升製備於水中。
ii.　將0.3克的磷酸鈣粒子懸浮在1.2毫升的水中並及混合5分鐘。
iii.　將1.8毫升的乳鐵素溶液以4.98毫克/毫升加入以達成於3.0毫克/毫升之最終濃度及最終體積為3毫升。
iv.　將懸浮液混合30分鐘且在台式離心機中以5000 x g離心10分鐘。
v.　藉由UV光譜儀於280奈米(乳鐵素之檢測波長)測量上澄液的吸光度。
vi.　對照組係以相同步驟而沒有磷酸鈣粒子進行。
vii.　藉由從結合懸浮液中之總最初量減去上澄液中所檢測之乳鐵素量計算乳鐵素結合。
c.　結果：
29.63毫克/克乳鐵素被測定以2.99毫克/毫升之結合濃度結合至磷酸鈣粒子。
C.　生物活性物質之預處理的實例
用硫酸月桂酯鈉預處理結合至磷酸鈣粒子之六胜肽(Argireline)
物質：
磷酸鈣粒子
六胜肽，(乙醯基六肽-8)，Lipotec S.A.
酸月桂酯鈉(SLS)，Colonial化學公司
方法：
1.　將六胜肽溶解在水中呈10毫克/毫升溶液。
2.　磷酸鈣粒子與10毫升的0.1% SLS混合5分鐘。在台式離心機中在2000 x g下將懸浮液離心10分鐘以及移出上澄液。將團塊再懸浮於20毫升水中，以2000 x g離心10分鐘並拋棄洗滌之上澄液。該洗滌步驟重複兩次。測定團塊中包含之水。將最終團塊使用於結合研究。
3.　將磷酸鈣粒子(SLS處理或沒有SLS處理)與水混合。添加HCl(或NaOH)以調整磷酸鈣粒子懸浮液之pH至包括中及pH~10之目標pH。
4.　六胜肽儲備液以10毫克/毫升加至各結合懸浮液而為0.5毫克/毫升之最終濃度。將懸浮液混合30分鐘之後及測定最終pH。
5.　將結合懸浮液在台式離心機中以2000 x g離心10分鐘。用連接至Shimadzu HPLC20A系統之折射率偵檢器分析上澄液以定量溶液中游離六胜肽。發展大小排除HPLC方法以定量在結合混合物之澄液中的六胜肽。使用在Shimadzu 20A系統中之Phenomenex BioSepTM-SEC-S3000管柱(7.8×300毫米,5微米)達成分離。移動相為100%水且以1毫升/分鐘之速率溶析。於205奈米或藉由折射率偵檢器(Shimadzu，型號RID-10A)監測溶析液。六胜肽被觀察為在具有約14分鐘之滯留時間的層析圖中之主峰。六胜肽的定量係藉由外部標準校正達成。
6.　然後藉由從在結合懸浮液中的總起始量減去在上澄液中所檢測之六胜肽計算結合的六胜肽。
結果：
D.　另外的活性劑-磷酸鈣複合物
使用上述說明的方案，如下表中所概述者製造活性劑-磷酸鈣複合物。
III活性劑之釋放 A. pH依賴性的釋放 1.　溶菌酶
在角質層中，pH在從大約4.3至5.0之範圍且pH隨角質層深度減少。為了研究磷酸鈣粒子在類似於皮膚的條件下釋放活性劑，將二種溶菌酶磷酸鈣複合物於ph 4.8(0.5M乙酸鈉)及7.0(10mM Bis Tris)之緩衝液中暴露8小時。緩衝液以1毫升/小時速率流經樣品且每小時收集並藉由以UV光譜儀在280奈米監測而分析溶菌酶釋放。相等質量的溶菌酶磷酸鈣粒子複合物在pH 4.8緩衝液中渦旋攪動以評估樣品中的總可得溶菌酶。在pH 4.8下，觀察到溶菌酶從磷酸鈣粒子很快地釋放且大部份溶菌酶在第一小時內釋放。相比之下，在pH 7，在8小時內沒有觀察到溶菌酶從磷酸鈣粒子釋放。
B.　經由Hydroxysome降解之釋放 C.　釋放不改變活性劑的活性 1. BSA磷酸鈣複合物
如上所製備BSA-磷酸鈣複合物。用水及然後用0.2 M磷酸鈉鹽洗滌所得複合物以釋放任何結合BSA。用HPLC分析釋放之BSA及測定與非結合對照組相同，證明結合及釋放磷酸鈣粒子沒有不利地影響BSA活性。
IV.　調配物的例子 1.　磷酸鈣粒子-核黃素單磷酸鹽軟膏調配物
步驟：
步驟1.在燒杯中添加蜂蠟及Protachem IPP。開始加熱70℃-75℃直到均勻。冷卻到50℃。加SonneNaturalTM及Capmul MCM。混合直到均勻。
步驟2.　在分開的燒杯中添加1%水及核黃素單磷酸鹽。在R.T下混合直到均勻。加磷酸鈣粒子(用乳酸調整pH至pH7)。以500 RPM旋轉10分鐘。
步驟3.　在室溫下步驟1轉移至步驟2。混合直到均勻。
B.　活性劑在調配物中的穩定性 1.　維生素C a.　方法：
將11.9毫克的抗壞血酸溶解在30毫升的水中。將2克2微米磷酸鈣粒子懸浮在19.5毫升的水中及用HCl將pH調整到pH 7.14。將0.5毫升的抗壞血酸溶液(0.40毫克/毫升)混合在磷酸鈣粒子之懸浮液中，其將pH減少到7.05。包括10微克/毫升的抗壞血酸的磷酸鈣粒子之懸浮液(pH 7.05)，在50℃下培養0.5至5小時。藉由在冰浴中冷卻懸浮液15分鐘將抗壞血酸之熱變性結束。為了從磷酸鈣粒子釋放結合之抗壞血酸以測量穩定效果，用HCl將各懸浮液之pH調整至pH 5及以3,000 rpm離心10分鐘。在265奈米測量所得上澄液。作為對照組，也培養10微克/毫升之抗壞血酸溶液且以相同步驟而沒有磷酸鈣粒子測量。抗壞血酸之活性係以下式計算：
抗壞血酸之活性(%)=(培養後上澄液之A265nm/培養前抗壞血酸之A265nm)×100
用10微米磷酸鈣粒子重複相同步驟。
b.　結果
該等結果總結於下表中。藉由在50℃下培養0.5小時將抗壞血酸之活性減少至36%；當在相同期間抗壞血酸附著至2微米磷酸鈣粒子時，此活性增加至85%。沒有磷酸鈣粒子之抗壞血酸在50℃下培養3小時之後完全地變性而沒有活性。然而，結合至2微米磷酸鈣粒子之抗壞血酸在50℃下經相同3小時期間具有48%活性。
V.　遞送研究 A.　遞送進入角質層 1.　磷酸鈣粒子滲入角質層中
磷酸鈣粒子在水中之懸浮液藉由擦拭10秒以一濃度施用於活人前臂。然後實施角質層之第一、第二及第三層的膠帶剝離。磷酸鈣粒子滲入角質層之第三層。磷酸鈣粒子在皮膚的低pH環境中慢慢地破裂且當粒子崩解成較小取代部分時可進一步滲入。磷酸鈣粒子投藥7小時之後，在顆粒層中Ca++沈積增加及檢測出現緊成群之Ca++沈積物，指示較大的崩解。
2.　磷酸鈣粒子滲入顆粒層中 a.　物質：
使用2微米磷酸鈣粒子。
b.　製備：
將磷酸鈣粒子懸浮在70%乙二醇及30%乙醇中以製造10%懸浮液。將所得懸浮液局部地施用在無毛老鼠的皮膚表面上(1×1公分面積)。在施用期間，將老鼠給予麻醉劑。投予第一次施用(0.2毫升)及離開，第二次為投予4小時後在相同地方且為相同量。第一次施用七小時後，將老鼠犧牲，移除皮膚及以Ca++處理。定位方法依照EM技術。
c.　結果：
用磷酸鈣粒子處理之前，表皮之檢驗顯示在顆粒層區域的典型Ca++梯度，而在此區域沒有可檢測的Ca++。如上所述在局部施用磷酸鈣粒子之後，在角質層可看到磷酸鈣粒子，且最小粒子移入較深層中。
3.　鈣滲透研究 a.　物質
氯化鈣係購自Sigma(C 7902)。使用磷酸鈣粒子(平均粒徑2微米)。
b.　臨床研究
臨床測試最初使用5位人類對象(n=5)的專家組，接著另外3位的人類對象專家組(n=3)進行。每位專家組成員的標準先前為沒有皮膚疾病，包括異位性皮膚炎的歷史且個體在研究同時不允許使用任何不是溫和肥皂的皮膚保養產品。所有人類對象為皮膚類型2-3個染色。在志願者左右前臂上用神奇筆標記四個2.5公分2直徑面積。一個面積表示未經治療的面積。1%磷酸鈣粒子之水溶液(pH 5.0)(100微升)每日自我施用兩次於包含三個這些位置的右前臂。1% CaCl2之水溶液(pH 5.0)同樣施用於包含三個位置的左前臂。樣品用吸量管施用且在室溫下乾燥。室溫為大約21℃±1℃。相對濕度測定為約45%±5%。
實驗以每天施用兩次(一次在早晨及一次在傍晚)在星期一早上開始且持續至星期五早上。在星期五下午最後施用之後四小時，測量下列功能研究：在二個位置上，使用Tewameter(Courage & KhazakaModel #TM210)測量基本TEWL。用corneometer(Courage & Khazaka Model #CM820)測量SC水合作用，評估為電導，及用平面電極(皮膚-pH-計：Courage & Khazaka Model #PH900)測量SC表面pH。
角質層完整性：在這些初測量之後，各前臂上之二處理區域以連續D-Squame(CuDerm)膠帶剝離破裂，在各前臂上最多至18個。在各3次剝離之後測量TEWL，直到TEWL為大於最初基本讀數至少10倍。在TEWI中因剝離之改變速率為角質層完整性之測量。膠帶剝離之後，使用於pH 5之相同1%磷酸鈣粒子溶液再次挑戰右前臂上的區域之一，及使用於pH 5之相同%CaCl2溶液挑戰左手臂中二區域之一。最終挑戰之後，在2及4小時測量滲透阻隔恢復動力學。
1%磷酸鈣粒子之第三個處理位置及1%Cl2-處理位置上進行刮去生物檢體，接著評估表皮鈣梯度，包括半定量評估鈣在角質層的各種水平之量。
用於另外3位人類對象(n=3)之第二臨床研究的方案與最初5位人類對象專家組相同，除了使用3% CaCl2溶液(n=3)替代1% CaCl2之外。
c.　結果： i.　人類臨床研究結果-滲透研究：
觀察磷酸鈣粒子滲透至角質層的所有深度，而非常少的氯化鈣到達該等深度。顯微照相進一步顯示小量之鈣在角質層之更低水平釋放。這些結果顯示磷酸鈣粒子，“Ca之對準系統”，其不只幫助Ca滲透至SC之深度，且也表現為“Ca緩釋系統”。
4. CTC a.　研究目的
此研究之目的為檢測在局部施用2微米均勻剛性球形奈米孔洞磷酸鈣粒子之後在角質層中的鈣，如上述實例1中所述。選擇氯四環素(來自Sigma之CTC，料號C-4881)，因為其允許在角質層內藉由螢光將鈣顯影及因此以共聚焦顯微鏡檢測。
b.　製備
藉由將80毫克的CTC溶解在10毫升的水中製造CTC溶液。以3,000 rpm離心10分鐘移除不溶解CTC。將200毫克的粒子與2毫升的CTC溶液混合且旋渦攪動1分鐘。藉由用水洗滌接著以3,000 rpm離心10分鐘的三次循環移除游離CTC。將所得CTC結合粒子以1:10稀釋率懸浮在水。
c.　局部施用
在上述II.B中製備之懸浮液(大約0.2毫升)局部地施用在無毛老鼠皮膚上(1×1公分面積)。在施用期間，將老鼠給予麻醉劑。7小時之後，將老鼠犧牲且使用共聚焦顯微鏡(在380奈米波長激發的510奈米波長發射)檢查其皮膚。
d.　結果
所得共聚焦顯微鏡影像顯示於圖4中(在圖4中放大率為300 x)。圖4中所見之結果顯示鈣在局部施用2微米均勻剛性球形奈米孔洞磷酸鈣粒子之後滲透進入角質層。
2.　用STAY-C50-磷酸鈣複合物之膠帶剝離顯示STAY-C50之遞送至至少角質層的第10層。
B.　活性劑之受控緩釋 1.　核黃素 a.　物質及方法 i.　皮膚樣品：
低從較大腹部檢體切割之圓形6公分2圓片的全厚度豬皮。
從真皮用剪刀移除脂肪。
儲存於-20℃直到使用。
ii.　滲透系統：
在玻璃擴散室中之流通條件。
擴散室，實驗室玻璃裝置，型#LG-1084-LPCT，5公分2之暴露皮膚面積及4.5毫升之接受器隔間體積。
水套溫度維持在37℃。
iii.　滲透條件
8及16小時之施用間隔。
該室用石蠟膜封閉及以鋁套遮蔽光。
磷酸鹽緩衝液的靜態接受器液體用旋轉桿以60rpm環流。
iv.　施用之調配物
核黃素單磷酸鹽-磷酸鈣粒子複合物在PBS中以遞送0.35-1.15毫克核黃素(20-38%懸浮液)。
核黃素單磷酸鹽在PBS中於1.5毫克/毫升以遞送0.3-0.45毫克核黃素。
以吸量管施用50-100微升之體積的調配物。使核黃素-HYDRO磷酸鈣複合物施用空氣乾燥及然後將相同體積之0.5M乙酸鈉緩衝液吸量在皮膚上。
對照組由只有懸浮液的磷酸鈣粒子之相同施用組成。
v.　樣品收集
皮膚表面，同時仍然保留在擴散室中，藉由吸量管重複投予而用1毫升PBS用洗滌二次。從擴散室移出皮膚，放置在鋁箔上及藉由將紙巾壓進皮膚3次用Kim紙巾擦乾。將皮膚包裝在鋁箔中並儲存用於分析。以吸量管從擴散室取出接受器液體。
vi.　樣品分析
洗滌及接受器液體：測定液體的大約體積。將樣品以10,000rpm旋轉30秒並將磷酸鈣粒子團塊分離、乾燥及秤重。將上澄液移出並以UV光譜儀分析。如果UV吸光度為飽和的(超過>2.0)，則用水稀釋樣品。記錄於369奈米之UV吸光度值。(核黃素之*比UV吸光度峰為260奈米、375奈米及465奈米)。
皮膚：將皮膚切碎且與5毫升的10%三氯乙酸溶液混合。將樣品用超音波清洗機於50℃超音波清洗1小時。將樣品以10,000rpm離心10分鐘，移出上澄液及以UV光譜儀分析。如果UV吸光度為飽和的(超過>2.0)，則用水稀釋樣品。記錄於372奈米之最大UV吸光度值。
b.結果
如在皮膚施用側反面的細胞中核黃素代謝產物之外觀所檢測的，核黃素來自水溶液及來自磷酸鈣粒子複合物二者滲透通過皮膚。磷酸鈣粒子複合物引起活性的緩慢釋放。發現來自水溶液之組織含量高於來自磷酸鈣複合物，即使當磷酸鈣複合物施用於皮膚經8小時。該等結果圖解式地顯示於圖5中。
雖然前述發明為了清楚了解已經由說明和實例較詳細地描述，然而一般技藝人士根據本發明的教示顯而易知可對其進行某些改變以及修正而不偏離所附申請專利範圍的精神以及範疇。
因此，前文僅僅說明本發明的原則。應了解的是：熟 習該項技術者能夠設計出各種實施本發明原則並且包括在本發明精神以及範疇內的排列，雖然在本文中未被清楚地描述或顯示。再者，本文中所列舉的全部實例以及條件語言主要地意欲來協助讀者了解發明人所提供的促進該技藝之本發明的原則及概念，且將被解釋為不被限制於該等具體列舉的實例及條件。再者，本文中所有列舉本發明之原則、特點及體系的說明以及其特定實例係意欲涵括其結構性以及功能性等效物二者。除此之外，該等等效物意欲包括目前已知的等效物以及在將來被發展的等效物，亦即，任何實施相同功能(無關乎結構)而被發展的元件。因此，本發明的範疇不被意欲為限定於本文中所顯示與描述的示範性體系。而是，本發明的範疇以及精神是透過所附申請專利範圍來體現。
圖1A至2B提供用於本發明遞送組成物之均勻剛性球形奈米孔洞磷酸鈣粒子的掃描電子顯微鏡圖像。
圖3提供用於本發明遞送組成物之均勻剛性球形奈米孔洞磷酸鈣粒子的粒徑分布之圖示。
圖4為顯示附著至本發明均勻剛性球形奈米孔洞磷酸鈣粒子之活性劑在局部施用之後滲透進入深角質層的照片。在該照片中，紫色(箭頭)處指出遞送至角質層的磷酸鈣粒子。
圖5提供顯示從本發明之核黃素單磷酸鹽-磷酸鈣粒子複合物經皮遞送核黃素單磷酸鹽活性劑的圖示。

Claims (13)

  1. 一種包含均勻剛性球形奈米孔洞磷酸鈣粒子之組成物，其中75%或更多的該等粒子具有在0.1至2微米之尺寸範圍的直徑且其中該等粒子係結合至活性劑，且其中該組成物係為配置成施用至哺乳動物之角質化皮膚表面的局部調配物。
  2. 如申請專利範圍第1項之組成物，其中該等粒子具有範圍從30至85%之孔洞體積。
  3. 如申請專利範圍第2項之組成物，其中該等粒子具有範圍從2奈米至100奈米之孔徑。
  4. 如申請專利範圍第1項之組成物，其中該等粒子係藉由下列步驟製得：製備磷酸鈣晶體之流體組成物；乾燥該流體組成物以產生前驅物粒子；及對該等前驅物粒子施以高溫及高壓以產生均勻剛性球形奈米孔洞磷酸鈣粒子。
  5. 如申請專利範圍第4項之組成物，其中該乾燥包含噴霧乾燥。
  6. 如申請專利範圍第1項之組成物，其中結合至該等粒子的活性劑之量係在每克粒子從0.01至300毫克活性劑之範圍。
  7. 一種用於美容而將活性劑遞送至對象的方法，該方法包括： 將包含下列之組成物施用至該對象的局部區域以將該活性劑遞送至該對象：均勻剛性球形奈米孔洞磷酸鈣粒子，其中該等粒子係結合至該活性劑且其中75%或更多的該等粒子具有在0.1至2微米之尺寸範圍的直徑。
  8. 如申請專利範圍第7項之方法，其中該等粒子具有範圍從30至85%之孔洞體積。
  9. 如申請專利範圍第8項之方法，其中該等粒子具有範圍從2奈米至100奈米之孔徑。
  10. 如申請專利範圍第9項之方法，其中結合至該等粒子的活性劑之量係在每克粒子從0.01至200毫克活性劑之範圍。
  11. 如申請專利範圍第7項之方法，其中該局部位置為角質化的皮膚表面。
  12. 如申請專利範圍第11項之方法，其中該方法為一種將活性劑遞送進入該對象的角質層之方法。
  13. 如申請專利範圍第12項之方法，其中該方法為一種將活性劑遞送進入該對象的深角質層之方法。
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