Topical Formulation Design Notes

  • Topical Formulation Design (外用配方設計)

  • Learning Objectives (學習目標)

    • Understand why some drug molecules can be delivered via the skin and others cannot. (了解為什麼有些藥物分子可以通過皮膚輸送，而另一些則不能。)

    • Know how topical formulation design is informed by patient demographics and the disease target site. (瞭解如何根據患者人口統計數據和疾病目標部位進行局部配方設計。)

    • Explain how to optimize drug delivery from topical formulations. (解釋如何優化局部製劑的藥物遞送。)

  • Delivery to/through Skin (交付至/通過 Skin 交付)

    • The purpose of the formulation is to present drug MOLECULES to the skin surface. (該製劑的目的是將藥物 MOLECULES 呈遞到皮膚表面。)

  • Where to Start? (從哪裡開始？)

    • Consider the molecule - Is it a realistic candidate for skin application? (考慮分子 - 它是皮膚應用的現實候選者嗎？)

    • Consider the patient - Disease, site, dosage schedule (frequency and duration). (考慮患者 - 疾病、部位、劑量方案（頻率和持續時間）。)

    • E.g., avoid alcoholic formulations on broken skin. (例如，避免在破損的皮膚上使用酒精製劑。)

    • Severity of disease may make an unpleasant formulation acceptable (e.g., coal tar for psoriasis); elegance is important for cosmetics. (疾病的嚴重程度可能使令人不快的製劑可以接受（例如，煤焦油治療銀屑病）;優雅對化妝品很重要。)

    • Consider the formulation - Follows from the above. (考慮公式 - 遵循上述內容。)

  • The Molecule (分子)

    • Sometimes initially designed for topical use but may have failed via, for example, the oral route, and so topical/transdermal becomes a fallback. (有時最初是為局部使用而設計的，但可能通過例如口服途徑失敗，因此局部/透皮給葯成為一種後備。)

    • Some general approximations correlate drug properties with relative ease of permeation. (一些一般的近似值將藥物特性與相對容易滲透性相關聯。)

    • Lipophilic molecules are better delivered than hydrophilic ones. (親脂性分子比親水性分子傳遞得更好。)

    • Lower melting points usually mean better absorption. (較低的熔點通常意味著更好的吸收。)

    • Experiential "rules" guide whether a molecule is a reasonable candidate. (經驗「規則」指導一個分子是否是一個合理的候選者。)

  • Rule 1: Select a Good Candidate (規則 1：選擇一個好的候選人)

    • From experience (and literature), a good drug candidate has: (根據經驗（和文獻），一個好的候選藥物具有：)

      • Molecular Weight (MW): 300-500 (分子量（MW）：300-500)

      • Log P (octanol/water): 1 - ~3.5 (Log P（辛醇/水）：1 - ~3.5)

      • Aqueous solubility: >100 mg/mL (水溶度： >100 mg/mL)

    • With the above, expect at best delivery of ~1 mg/cm2/day (e.g., nicotine). (對於上述情況，預計最多輸送量為 ~1 mg/cm2/天（例如，尼古丁）。)

    • Average patch size ~10-25 cm2, so up to ~10-25 mg/day. (平均貼片大小 ~10-25 cm2，因此高達 ~10-25 mg/天。)

    • Estradiol: MW is 272, lipophilic with a log P(octanol/water) of 2.7 (雌二醇：MW 為 272，親脂性，log P（辛醇/水）為 2.7)

    • Fentanyl: MW is 336 with a log P(octanol/water) of 4.4 (芬太尼：MW 為 336，log P（辛醇/水）為 4.4)

    • Nicotine: MW is 162 with a log P(octanol/water) of 1.2 (尼古丁：MW 為 162，log P（辛醇/水）為 1.2)

    • But, only guidance, e.g. (但是，只有指導，例如)

      • Fentanyl is more lipophilic (芬太尼更親脂)

      • Estradiol v. poor water solubility (0.003 mg/mL) (雌二醇 v. 水溶性差 （0.003 mg/mL）)

  • Breaking the Rules (打破規則)

    • Example of an RNA Aptamer challenging the rule that only small molecules can permeate skin. (RNA 適配子挑戰只有小分子才能滲透皮膚的規則的示例。)

    • Aptamer (適配子)

      • Mw 21,400(分子量21,400)

    • The study demonstrates that very-large-molecular-weight RNA aptamers can permeate across the intact human skin barrier to therapeutically relevant levels into both the epidermis and dermis and that the skin-penetrating aptamer retains its biologically active conformational structure capable of binding to endogenous IL-23 (該研究表明，非常大分子量的 RNA 適配體可以滲透到完整的人體皮膚屏障，達到治療相關的水平，進入表皮和真皮，並且滲透皮膚的適配體保留了其能夠與內源性 IL-23 結合的生物活性構象結構)

  • Rule 2: Estimate Drug Flux (規則 2：估計藥物通量)

    • Many simple mathematical models exist in the literature. (文獻中存在許多簡單的數學模型。)

    • Empirical relationships between flux and log P / solubility / MW. (通量和log P / 溶解度 / MW 之間的經驗關係。)

    • Work OK for “mid” range molecules, small, moderately lipophilic. (適用於「中等」範圍、小分子、中等親脂性分子。)

    • LogKp=logP(oct/water)−0.0061MW–2.74 ($Log 美元 Kp = 對數 P（十月/水）- 0.0061MW – 2.74 美元)

    • Potts, R. O., and Guy, R. H. (1992) Predicting skin permeability. Pharm. Res. 9, 663-669 (Potts， R. O. 和 Guy， RH （1992） 預測皮膚滲透性。藥學研究 9， 663-669)

    • Can be useful for a no “chance / maybe” guide. (對於沒有 「chance / maybe」 指南可能很有用。)

  • Rule 3: Be Realistic! (規則 3：現實一點！)

    • After estimating flux from equations, looking at physico-chemical properties (MW, solubility, log P, melting point), calculating dose, and comparing the molecule with similar ones in the literature, take a reality check! (在從方程中估計通量，查看物理化學性質（MW、溶解度、log P、熔點）、計算劑量並將分子與文獻中的類似分子進行比較後，進行現實檢查！)

    • If within an order of magnitude of the dose required, you may have a chance of delivering to therapeutic levels in vivo (possibly using formulation strategies). (如果在所需劑量的數量級內，您可能有機會在體內輸送到治療水準（可能使用配方策略）。)

    • If 2 orders of magnitude, unlikely! (如果2個數量級，則不太可能！)

    • Unless delivery to broken skin barrier, e.g., psoriasis. (除非交付到破損的皮膚屏障，例如牛皮癬。)

  • Think About the Patient/Client (考慮患者/客戶)

    • Lots of formulation options exist! (存在許多配方選擇！)

    • Generally: (一般：)

      • Semisolid formulations are selected for increased residence on the skin. (選擇半固體製劑以增加在皮膚上的停留。)

      • Transdermal patches for extended drug delivery through the skin. (透皮貼劑，用於延長藥物通過皮膚的輸送。)

      • Liquid formulations for rapid short-term drug input into the skin. (用於將藥物快速短期輸入皮膚的液體製劑。)

  • Think About the Patient/Client (考慮患者/客戶)

    • Clinical & cosmetic, skin type can affect the choice of formulation base: (臨床和美容，皮膚類型會影響配方基礎的選擇：)

      • For normal to oily skin types, gels are often preferred. (對於中性至油性皮膚類型，凝膠通常是首選。)

      • For normal to dry skin types, lotions are often preferred. (對於中性至乾性皮膚類型，通常首選乳液。)

      • For dry skin, creams are often preferred. (對於乾性皮膚，通常首選面霜。)

  • Think About the Patient/Client (考慮患者/客戶)

    • The skin site to be treated can affect vehicle selection: (要治療的皮膚部位會影響車輛的選擇：)

      • For hairy areas, lotions, gels, or sprays are usually preferable. (對於多毛的區域，通常最好使用乳液、凝膠或噴霧劑。)

      • For intertriginous areas (sites where skin may touch or rub such as the axilla of the arm), creams or lotions are usually preferred. (對於間擦部位（皮膚可能接觸或摩擦的部位，如手臂腋窩），通常首選乳膏或乳液。)

    • Clinically, if treating a skin lesion: (臨床上，如果治療皮損：)

      • For a wet, vesicular, or weeping lesion, a “wet,” usually aqueous-based formulation is generally preferred (cream, lotion, gel). (對於濕性、水泡性或滲出性病變，通常首選“濕性”，通常是水性製劑（乳膏、化妝水、凝膠）。)

      • For a dry, thickened scaly lesion, a “dry,” usually fatty formulation is preferred (ointments, pastes). (對於乾燥、增厚的鱗屑性病變，首選“乾燥”的通常為脂肪製劑（軟膏、糊劑）。)

  • The User Will Be Happy (用戶會很高興)

    • Lots of options for formulations: (多種配方選擇：)

      • Simple solutions and lotions, creams (aqueous or oily), ointments, gels, patches, aerosols, and foams. (簡單的溶液和乳液、乳膏（水性或油性）、軟膏、凝膠、貼劑、氣霧劑和泡沫。)

    • So, if the molecule seems reasonable, users will accept it; can think about formulation…. (因此，如果分子看起來合理，使用者就會接受它;可以考慮制定......)

  • Formulation (配方)

    • Normal rules apply! (適用正常規則！)

    • Must be stable. (必須穩定。)

    • Drug and excipients must be compatible. (藥物和輔料必須相容。)

    • The drug must be released from the dosage form following application. (應用後必須將藥物從劑型中釋放出來。)

    • Should be cosmetically acceptable with a good skin feel, texture, and fragrance. (應該在外觀上可以接受，具有良好的膚感、質地和香味。)

    • But depends on indication! (但要看指示！)

    • Alcoholic gel formulation to broken skin is unlikely to enhance patient compliance. (對破損皮膚的酒精凝膠製劑不太可能提高患者的依從性。)

    • For topical products (e.g., creams and gels), typically only between 1 and 3% of the applied dose is bioavailable. (對於外用產品（例如乳膏和凝膠），通常只有 1% 到 3% 的施用劑量具有生物利用度。)

    • Bioavailability from patches is typically 30-70% for drugs such as buprenorphine and fentanyl. (對於丁丙諾啡和芬太尼等藥物，貼劑的生物利用度通常為 30-70%。)

  • Rule 4: Release the Drug! (規則 4：釋放藥物！)

    • The formulation should be designed to ensure appropriate release of the drug. (配方的設計應確保藥物的適當釋放。)

    • Rapid release for a locally acting drug. (局部作用藥物的快速釋放。)

    • Sustained and slow release for a 7-day patch. (持續和緩慢發佈，適用於7天補丁。)

    • If the formulation contains a moderately lipophilic drug in a lipophilic oily base, the drug is less likely to partition out of the formulation and enter the lipophilic skin barrier than if it is applied from a more aqueous base. (如果製劑在親脂性油性基質中含有適度親脂性藥物，則與從水性基質中應用相比，該藥物不太可能從配方中分離出來並進入親脂性皮膚屏障。)

    • Essentially, the vehicle should allow some solubility of the drug but should not retain the drug by being a very good solvent. (從本質上講，載體應該允許藥物具有一定的溶解度，但不應通過成為非常好的溶劑來保留藥物。)

  • Rule 5: Use Thermodynamics (規則 5：使用熱力學)

    • flux=conc.xpermeabilitycoefficient(Kp) (flux=濃度x磁導率係數（Kp）)

    • So, saturated solutions deliver the most (Kp fixed for a given molecule from a given solvent). (因此，飽和溶液的輸送量最大（給定溶劑中給定分子的 Kp 固定）。)

    • Saturated solutions (suspensions) give maximum thermodynamic activity = maximum driving force for diffusion, maximum concentration (thermodynamic activity) gradient across the skin. (飽和溶液（懸浮液）給出最大的熱力學活性 = 最大的擴散驅動力，穿過皮膚的最大濃度（熱力學活性）梯度。)

    • NO point in going above saturation (unless drug depletes). (超過飽和是沒有意義的（除非藥物耗盡）。)

    • So, can use a low conc. of a saturated drug to deliver drug. (因此，可以使用低濃度的飽和藥物來輸送藥物。)

    • Dioderm© (Dermal Laboratories Ltd.) contains 0.1% hydrocortisone but is clinically equivalent to 1% Hydrocortisone Cream BP, as the drug is at the same thermodynamic activity in both formulations despite differences in concentration. (Dioderm© （Dermal Laboratories Ltd.） 含有 0.1% 氫化可的松，但在臨床上相當於 1% 氫化可的松乳膏 BP，因為儘管濃度不同，但該藥物在兩種製劑中具有相同的熱力學活性。)

  • Supersaturation (過飽和)

    • When a system contains more solute than it ought to! (當系統包含的溶質多於應有的溶質時！)

    • But is short-lived… (但這是短暫的......)

  • Supersaturation with Gels (凝膠過飽和度)

    • Happens with gels (and creams etc.) (發生在凝膠（和乳霜等）上)

    • Apply a gel, rub it in, and the formulation changes as ethanol evaporates… (塗上凝膠，揉搓，配方會隨著乙醇的蒸發而變化......)

    • As EtOH evaporates, the "solvent" gets more aqueous… (隨著 EtOH 的蒸發，「溶劑」變得更含水......)

  • Rule 7: Occlusion Helps (規則 7：遮擋說明)

    • Allows the SC to equilibrate with the underlying (wet) epidermis. (允許 SC 與底層（濕）表皮平衡。)

    • Stops Transepidermal Water Loss (TEWL). (阻止經表皮水分流失 （TEWL）。)

    • Hydrates tissue – up to 400% water content. (滋潤組織 - 含水量高達 400%。)

    • Promotes delivery of hydrophilic and hydrophobic compounds. (促進親水性和疏水性化合物的遞送。)

    • Can cause irritation of underlying skin. (可刺激底層皮膚。)

    • Patches typically occlude, thus promoting drug delivery. (貼劑通常會阻塞，從而促進藥物輸送。)

    • Some preparations require occlusion to deliver the required dose to therapeutic levels, such as EMLA cream, applied as a thick layer under an occlusive dressing. (一些製劑需要封閉才能將所需劑量輸送到治療水準，例如EMLA乳膏，在封閉敷料下作為厚層塗抹。)

    • Or, occlusion can also be inadvertent, such as when applying hydrocortisone ointments or creams to treat nappy rash when tightly-fitting waterproof pants can occlude the area. (或者，閉塞也可能是無意的，例如當使用氫化可的鬆軟膏或乳膏治療尿布疹時，緊身防水褲會堵塞該區域。)

  • Enhancers (劑)

    • Chemicals that interact reversibly with the skin to promote drug flux. (與皮膚可逆相互作用以促進藥物通量的化學物質。)

    • Typically disrupt stratum corneum inter-cellular lipid structure - lipids have to be crossed by a molecule either intercellular or transcellular pathways. (通常破壞角質層細胞間脂質結構 - 脂質必須通過分子細胞間或跨細胞途徑穿過。)

    • May also alter intracellular keratin conformation. (也可能改變細胞內角蛋白構象。)

    • Can also change partitioning into the tissue (reservoir effect). (還可以改變組織中的分配（儲液器效應）。)

  • Examples of Enhancers (增強器示例)

    • Dimethylsulphoxide (二甲基亞硯)

    • 1-Dodecylazacycloheptan-2-one (Azone) (1-十二烷環庚烷-2-酮（Azone）)

    • Dimethylformamide (二甲基甲醯胺)

    • Dimethylacetamide (二甲基乙醯胺)

    • Decylmethylsulphoxide (癸基甲基亞硯)

  • How Enhancers Work (增強器的工作原理)

    • Lipid Enhancer (脂質增強劑)

      • Lipid extraction (脂質提取)

      • Phase separation (相分離)

      • Inverted micelle (倒置膠束)

      • Fluidization (流態 化)

    • Polar Enhancer (極性增強劑)

      • Fluidization (流態 化)

      • Polarity alteration (極性改變)

  • Summary (總結)

    • If drug properties look ok (如果藥物特性看起來不錯)

    • If the patient/user has been considered (如果已考慮患者/使用者)

    • If a formulation can be made (如果可以製作配方)

    • Testing… refinement… optimisation… (測試。。。優雅。。。優化...)

    • How/what/when? (如何/什麼/何時？)

  • Formulation Testing/Refinement (配方測試/改進)

    • Usual to start with release testing (通常從發佈測試開始)

    • Polymer membrane Franz-type diffusion cells (聚合物膜 Franz 型擴散池)

    • Useful for optimising release (有助於優化釋放)

    • But, won’t show effects of vehicles / enhancers on skin (但是，不會在皮膚上顯示車輛/增強劑的效果)

    • In vitro permeation using (human) skin (使用（人類）皮膚的體外滲透)

      • Single / multiple dosing (單次/多次給葯)

      • Finite / infinite dosing (有限/無限計量)

    • Can measure what is in / goes through skin (可以測量皮膚中/穿過皮膚的成分)

    • Does it show equivalence to the existing product? (它是否與現有產品等效？)

    • Does it show bioequivalence to the existing product? (它是否顯示出與現有產品的生物等效性？)

  • In Vitro / In Vivo / In Use (體外研究 / 體內研究 / 使用中)

    • We can design an elegant formulation (我們可以設計出優雅的配方)

    • We can make it release the drug (我們可以讓它釋放藥物)

    • We can account for metabolic activity (我們可以解釋代謝活動)

    • But then we give it to a user… (但隨後我們將其提供給使用者...)

      • Who rubs it in… (誰在揉搓它......)

      • Who destroys our lovely formulation (誰破壞了我們可愛的配方)

    • So what is the drug really delivered from? (那麼，這種藥物真正是從哪裡輸送的呢？)

      • Elegant formulation? (優雅的配方？)

      • Collapsed formulation smeared on the skin? (塌陷的配方塗抹在皮膚上？)

      • Residual phase (殘餘相)

    • Adherence (忠誠)

    • Adherence to topical therapy during the course of an 8-week psoriasis clinical trial – expect it to be good! (在為期 8 周的銀屑病臨床試驗過程中堅持局部治療 – 預期效果會很好！)

    • Patient reported adherence: Carroll CL J Am Acad Dermatol 2004; 51: 212-6. (患者報告的依從性：Carroll CL J Am Acad Dermatol 2004;51: 212-6.)

    • Radio Transmitter Study (無線電發射機研究)

      • They had put a radio transmitter in the cap to send a signal each time the jar was opened… (他們在瓶蓋上放了一個無線電發射器，每次打開罐子時都會發送一個信號......)

    • The Hawthorne Effect (霍桑效應)

      • We know what we should be doing… but don’t… and then “remember” just before we go to visit the doctor / dentist/ pharmacist! (我們知道我們應該做什麼......但不要......然後在我們去看醫生/牙醫/藥劑師之前「記住」！)

    • Reasons for Non-Adherence (不依從的原因)

      • Tan X et al. Expert Opin. Drug Deliv. (2012) 9(10):1263-1271 (Tan X et al. 專家意見。藥物開發。(2012) 9(10):1263-1271)

      • Lack of efficacy or patient dissatisfaction with the efficacy (缺乏療效或患者對療效不滿意)

      • Side effects or fear of side effects. (副作用或害怕副作用。)

      • The fear of side effects of topical corticosteroids may have a larger impact on adherence than actual side effects (對局部皮質類固醇副作用的恐懼可能比實際副作用對依從性的影響更大)

      • The complexity or inconvenience of the treatment regimen (治療方案的複雜性或不方便)

      • Even twice a day can be challenging! (即使一天兩次也可能具有挑戰性！)

      • Patches adherence better than creams / ointments (貼劑的粘附性優於乳膏/軟膏)

      • The cosmetic properties of topical agents or even the smell of the drugs may be very important factors contributing to adherence. (外用藥物的美容特性甚至藥物的氣味可能是影響依從性的非常重要的因素。)

      • We know how to make nice elegant formulations – e.g., add silicones for nice skin feel, fragrances etc (我們知道如何製作美觀優雅的配方 - 例如，添加有機矽以獲得良好的膚感、香味等)

    • In Vivo Biological Variability (體內生物變異性)

      • Permeation through human skin is well known to be variable: (眾所周知，人體皮膚的滲透是可變的：)

        • Little / no difference male:female or with age (mature skin) (差異很小/沒有差異 男性：女性 或隨年齡增長 （成熟皮膚）)

        • Neonatal skin more permeable (新生兒皮膚更透氣)

        • Variable with skin site (因皮膚部位而異)

        • Also different follicular densities (shunt routes) with skin site (此外，皮膚部位的濾泡密度（分流途徑）也不同)

        • Little racial variability to most drugs (大多數藥物的種族差異很小)

        • Possible variations with skin treatments (皮膚治療的可能變化)

          • Moisturisers, soaps? (保濕霜、肥皂？)

        • Significant variations with diseased states (病態的顯著變化)

          • Psoriasis etc (銀屑病等)

        • Also less obvious conditions, dry skin (也不太明顯的情況，皮膚乾燥)

  • Key Message: Topical Formulations (關鍵資訊：外用製劑)

    • As seen above, many and varied. (如上所示，數量眾多且各不相同。)

    • Gels (凝膠)

    • Creams (o/w, w/o multiple o/w/o..) (乳霜（o/w、w/o 多個 o/w/o..）)

    • Ointments, pastes, sprays, solutions, powders… (軟膏、糊劑、噴霧劑、溶液、粉末......)

    • Think about the patient and indication (考慮患者和適應症)

    • Avoid alcoholic gels on broken skin (避免在破損的皮膚上使用酒精凝膠)

    • Avoid thick ointments on hairy areas! (避免在多毛區域塗抹濃稠的藥膏！)