乾粉吸入劑配方
Martin J Telko andAnthony J Hickey PhD DSc
藥物產品將藥理活性與藥物性質相結合。理想的性能特徵是物理和化學穩定性，易於處理，準確和可重複地傳遞到目標器官，以及在現場的可用性。對於乾粉吸入劑（DPI），這些目標可以通過合適的粉末配方，高效計量系統和精心挑選的設備來滿足。本篇綜述將重點介紹DPI配方和發展進程。大多數DPI製劑是由與較大載體顆粒混合的微粉化藥物組成，這樣可以增強流動、減少聚集並有助於分散。內在物理化學性質、粒度、形狀、表面積和形態的組合影響相互作用力和空氣動力學性質，這些因素反過來又決定了流化，分散，輸送到肺部以及在周邊氣道中的沉積。當DPI被促動時，製劑被流化並進入患者的氣道。在吸氣氣流的影響下，藥物顆粒與載體顆粒分離，並被攜帶深入肺部，而較大的載體顆粒撞擊口咽表面並被清除。如果作用在粉末上的內聚力太強，則氣流的剪切可能不足以將藥物與載體顆粒分離，這導致低的沉積效率。隨著對氣溶膠和固體物理學的研究深入，配方研究也從經驗活動轉向以科學基礎為根本。
[Respir Care 2005;50(9):1209–1227. © 2005Daedalus Enterprises]
介紹INTRODUCTION
製劑開發包括將活性藥物成分併入藥物產品中的一系列方法。雖然生物活性是成功劑型的先決條件，但它不是唯一的決定因素。諸如穩定性、可加工性、遞送和目標器官的可到達性等因素有助於有效的藥物系統。這些因素的優化是一項關鍵的發展任務，最終產品通常是製藥與實用（即經濟/工程）考慮之間的妥協。製劑開發具有挑戰性，因為具有藥理活性的分子經常顯示出差的物理化學性質。事實上，賦予藥理活性（例如，高受體親和力）的相同分子特徵經常限制化合物的藥物效用，使其難以甚至不適合遞送。尤其是對於由高通量篩選法得到的許多化合物。
開發用於吸入的藥物是一個特別的挑戰，因為它涉及製劑的製備和氣溶膠分散裝置的選擇。肺具有比其他遞送部位（例如胃腸道或血液）更低的緩衝能力，這樣限制了可以增強遞送結果的賦形劑的範圍。一個額外的變量，特別是肺部輸送，是患者，無論是在吸入模式和呼吸道解剖學和生理學方面。相比吞咽片劑，還有更多的因素影響吸入氣溶膠。給予個體或患者群體的遞送劑量的變異性可以是顯著的。因此難以確保可重現的治療效果。
用吸入器治療呼吸系統疾病需要向肺部輸送足夠的藥物以產生治療反應。為了獲得最佳療效，藥物給藥必須可靠，可重現和方便。該目標可以通過配方、計量和吸入器設計策略的組合來實現。設備設計和選擇的技術和臨床方面已在其他地方進行了廣泛的回顧。以下討論概述了乾粉吸入器（DPI）配方的設計，以實現遞送目標。將討論製劑開發和表徵策略和加工方法，重點是對穩定性、製造可行性、遞送和生物利用度的影響。為此，了解乾粉物理和表面化學是至關重要的。本文重點介紹廣泛的概念和例子，只需少量使用方程式。
乾粉吸入劑DRY POWDER INHALERS
DPI的發展Development of theDPI
吸入藥物遞送系統可以分為3個主要類別：壓力定量吸入器（pMDI），DPI和霧化器，每個類別具有獨特的長處和短處。這種分類是基於分散相和連續介質的物理狀態，在每個類別內，進一步的分化是基於計量、分散或設計的手段。霧化器與pMDI和DPI明顯不同，因為藥物溶解或懸浮在極性液體（通常為水）中。霧化器主要用於醫院和門診部門，通常不用於慢性病管理，因為它們較大且不太方便，並且氣溶膠在長時間內連續輸送。 pMDI和DPI是含有固體藥物，懸浮或溶解在非極性揮發性拋射劑或當患者吸入時被流化的乾粉混合物（DPI）中的推注藥物遞送裝置。各種類型的吸入裝置的臨床表現已經在許多臨床試驗中進行了徹底的檢查，這些臨床試驗已被Barry和O'Callaghan評論和最近由Dolovich等進行了綜述。這些作者得出結論，尚沒有一種裝置是臨床最優良的，裝置選擇應以其他因素為指導，如便利性、成本和患者偏好。
pMDI於1956年首次批准，是第一個現代吸入器。全球市場份額約80％，pMDI仍然是應用最廣泛的設備。 DPIs的發展是由於渴望替代pMDIs，減少用作拋射劑的消耗臭氧層物質和溫室氣體（分別含氯氟烴和氫氟烷烴）的排放，並促進大分子和生物技術產品的遞送。同時，DPIs也被證明在解決與其他設備和配方相關的pMDI缺陷方面取得了成功。 DPI更容易使用，具有更穩定和高效的系統。因為pMDI是加壓的，它以高速度發出劑量，這使得口咽更可能發生過早沉積。因此，pMDI需要仔細協調促動和吸入。儘管對其設計進行了改進（例如使用儲霧罐），但是pMDI的不正確使用仍然是普遍存在的問題; Giraud和Roche發現，在皮質類固醇激素治療的患者中，很大比例的促動和吸入協調不良導致哮喘控制減少。由於DPI被患者的吸氣氣流激活，因此它們幾乎不需要或不協調致動和吸入。這通常導致比可比較的pMDI實現的肺遞送更好。
由於DPI通常配製成單相固體顆粒共混物，所以從穩定性和加工的方面來看，它們也是優選的。乾粉末處於較低的能量狀態，這降低了化學降解速率和與接觸表面反應的可能性。相比之下，包括推進劑和助溶劑在內的pMDI製劑可以從裝置組分中提取有機化合物。表1總結了DPI（與pMDI相比）的主要優點和缺點。有關氣溶膠輸送裝置演變的更多細節，可以提供極好的評論。
表1.乾粉吸入器與定量吸入器的比較
乾粉吸入器的優點
環保可持續性，無拋射劑設計
很少或不需要患者協調
配方穩定性
乾粉吸入器的缺點
沉積率取決於患者的吸氣氣流
潛在的劑量均一性問題
開發製造更加複雜/昂貴
在其他綜述進行了研究的幾種新的DPI裝置的開發，以及支氣管擴張劑 - 皮質類固醇組合產品Advair（GlaxoSmithKline，北卡羅來納研究三角園）的商業成功進一步激發了DPIs的興趣和發展。
操作原理Principles of Operation
圖1顯示了DPI設計的原理。大多數DPI都含有與較大載體顆粒混合的微粉化藥物，可防止聚集並幫助流動。這些載體顆粒的重要作用在本文稍後討論。乾粉氣溶膠的分散體由靜態粉末床進行。為了產生氣溶膠，顆粒必須移動。運動可以通過幾種機制來實現。被動吸入器使用患者的吸氣流量。當患者促動DPI並吸入時，穿過設備的氣流產生剪切和湍流;將空氣引入粉末床中，靜態粉末混合物流化並進入患者的氣道。在那裡，藥物顆粒與載體顆粒分離並且被深深地攜帶到肺中，而較大的載體顆粒在口咽中衝擊並被清除。因此，通過患者的可變吸氣氣流來確定肺中的沉積。藥物/載體分離不足是DPIs遇到的低沉積效率的主要解釋之一。劑量均一性是一個挑戰DPI的表現。由於顆粒的尺寸和離散性質，因此粉末比液體更受關注。
圖1.乾粉吸入器設計原理製劑通常由與計量系統分配的較大載體顆粒混合的微粉化藥物組成。主動或被動分散系統將顆粒遞送到患者的氣道中，其中藥物顆粒與載體顆粒分離並攜帶到肺中。
DPIs採用各種分散機理。雖然大多數DPI是呼吸促動，依靠吸入氣溶膠生成，幾個電力輔助設備（氣動、衝擊力和振動）已經開發或正在開發中。這些裝置正在考慮用於遞送具有狹窄治療窗口的活性藥物。重要的是要注意，這些「主動」吸入器與被動式吸入器不具有相同的限制，並且具有不同的優點/缺點。此外，已經提出，如果通過使用獨立於患者呼吸的分散機制來標準化剪切和湍流，則可以實現高的輸送效率和再現性。因此，主動吸入器可以提供與製劑無關的遞送。目前沒有市售的活性分散體DPI。因此，為了簡潔起見，這裡不討論這些設備;讀者可參考其他文獻。（未完待續）
翻譯過程難免疏漏，如有不當之處還請留言告知小編，謝謝~~
原文如下
Dry Powder Inhaler Formulation
Martin J Telko andAnthony J Hickey PhD DSc
Adrug product combines pharmacologic activity with pharmaceutical properties.Desirable performance characteristics are physical and chemical stability, easeof processing, accurate and reproducible delivery to the target organ, andavailability at the site of action. For the dry powder inhaler (DPI), thesegoals can be met with a suitable powder formulation, an efficient meteringsystem, and a carefully selected device. This review focuses on the DPIformulation and development process. Most DPI formulations consist ofmicronized drug blended with larger carrier particles, which enhance flow,reduce aggregation, and aid in dispersion. A combination of intrinsicphysicochemical properties, particle size, shape, surface area, and morphologyaffects the forces of interaction and aerodynamic properties, which in turndetermine fluidization, dispersion, delivery to the lungs, and deposition inthe peripheral airways. When a DPI is actuated, the formulation is fluidizedand enters the patient’s airways. Under the influence of inspiratory airflow,the drug particles separate from the carrier particles and are carried deepinto the lungs, while the larger carrier particles impact on the oropharyngealsurfaces and are cleared. If the cohesive forces acting on the powder are toostrong, the shear of the airflow may not be sufficient to separate the drugfrom the carrier particles, which results in low deposition efficiency.Advances in understanding of aerosol and solid state physics and interfacialchemistry are moving formulation development from an empirical activity to afundamental scientific foundation. [Respir Care 2005;50(9):1209–1227. © 2005Daedalus Enterprises]
INTRODUCTION
Formulationdevelopment encompasses an array of processes in which an active pharmaceuticalingredient is incorporated into a drug product. While biological activity is aprerequisite for a successful dosage form, it is not the sole determinant.Factors such as stability, processibility,delivery, and availability to thetarget organ contribute to an efficacious pharmaceutical system. Optimizationof these factors is a key development task, and the final product is often acompromise between pharmaceutical and practical (ie, economic/engineering)considerations. Formulation development is challenging because molecules withpharmacologic activity often display poor physicochemical properties. In fact,the same molecular characteristics that confer pharmacologic activity (eg, highreceptor affinity) frequently limit a compound’s pharmaceutical utility, makingit difficult or even unsuitable for delivery.This is particularly true for manyof the compounds that are identified by high-throughput screening methods.
Development of pharmaceuticals forinhalation is a particular challenge, as it involves the preparation of aformulation and the selection of a device for aerosol dispersion. The lungshave lower buffering capacity than other delivery sites (eg, thegastrointestinal tract or the blood),which limits the range of excipients thatcould enhance delivery outcomes. An additional variable, unique to pulmonarydelivery, is the patient, both in terms of inhalation mode andrespiratory-tract anatomy and physiology. There are many more ways toadminister an inhaled aerosol than there are to swallow a tablet. Variabilityin delivered dose to an individual or a population of patients can besubstantial. Consequently, reproducible therapeutic effect is difficult toassure.
Treatingrespiratory diseases with inhalers requires delivering sufficient drug to thelungs to bring about a therapeutic response. For optimal efficacy, drugadministration must be reliable, reproducible, and convenient. This goal can beachieved by a combination of formulation, metering, and inhaler designstrategies. The technical and clinical aspects of device design and selectionhave been extensively reviewed elsewhere. The following discussion outlines thedesign of dry powder inhaler (DPI) formulations to achieve the delivery goals.Formulation development and characterization strategies and processing methodswill be discussed, with emphasis on their effect on stability, manufacturingfeasibility, delivery, and bioavailability. To that end, an understanding ofdry powder physics and surface chemistry is essential. The text focuses onbroad concepts and examples, with only sparing use of equations.
DRYPOWDER INHALERS
Developmentof the DPI
Inhaleddrug delivery systems can be divided into 3 principal categories: pressurizedmetered-dose inhalers (pMDIs), DPIs, and nebulizers, each class with its uniquestrengths and weaknesses. This classification is based on the physical statesof dispersed-phase and continuous medium, and within each class furtherdifferentiation is based on metering, means of dispersion, or design.Nebulizers are distinctly different from both pMDIs and DPIs, in that the drugis dissolved or suspended in a polar liquid, usually water. Nebulizers are usedmostly in hospital and ambulatory care settings and are not typically used forchronic-disease management because they are larger and less convenient, and theaerosol is delivered continuously over an extended period of time. pMDIs andDPIs are bolus drug delivery devices that contain solid drug, suspended ordissolved in a nonpolar volatile propellant or in a dry powder mix (DPI) thatis fluidized when the patient inhales. The clinical performance of the varioustypes of inhalation devices has been thoroughly examined in many clinicaltrials, which have been reviewed by Barry and O』Callaghan, and more recently byDolovich et al. Those authors concluded that none of the devices are clinicallysuperior and that device selection should be guided by other factors, such asconvenience, cost, and patient preference.
Firstapproved in 1956, the pMDI was the first modern inhaler device. With a globalmarket share of about 80%, the pMDI remains the most widely used device. Thedevelopment of DPIs has been motivated by the desire for alternatives to pMDIs,to reduce emission of ozone-depleting and greenhouse gases (chlorofluorocarbonsand hydrofluoroalkanes, respectively) that are used as propellants, and tofacilitate the delivery of macromolecules and products of biotechnology.Concurrently, DPIs proved successful in addressing other device andformulation-related shortcomings of the pMDI. DPIs are easier to use, morestable and efficient systems. Because a pMDI is pressurized, it emits the doseat high velocity, which makes premature deposition in the oropharynx morelikely. Thus, pMDIs require careful coordination of actuation and inhalation.Despite enhancements to their design (eg, use of spacers), incorrect use ofpMDIs is still a prevalent problem; Giraud and Roche found that poorcoordination of actuation and inhalation caused decreased asthma control in asubstantial proportion of patients treated with corticosteroid pMDIs. SinceDPIs are activated by the patient’s inspiratory airflow, they require little orno coordination of actuation and inhalation. This has frequently resulted inbetter lung delivery than was achieved with comparable pMDIs.
SinceDPIs are typically formulated as one-phase, solidparticle blends, they are alsopreferred from a stability and processing standpoint. Dry powders are at alower energy state, which reduces the rate of chemical degradation and thelikelihood of reaction with contact surfaces. By contrast, pMDI formulations,which include propellant and cosolvents, may extract organic compounds from thedevice components. Table 1 summarizes the main advantages and disadvantages ofthe DPI (versus the pMDI). For more detail on the evolution of aerosol deliverydevices, excellent reviews are available.
Table 1. Dry Powder Inhalers Versus Metered-Dose Inhalers
Advantages of the Dry Powder Inhaler
Disadvantages of the Dry Powder Inhaler
Deposition efficiency dependent on patient’s inspiratory airflow
Potential for dose uniformity problems
Development and manufacture more complex/expensive
The development of several new DPI devices,which have been reviewed elsewhere, and the commercial success of thebronchodilator-corticosteroid combination product Advair (GlaxoSmithKline,Research Triangle Park, North Carolina) have further stimulated interest in anddevelopment of DPIs.
Principlesof Operation
Figure1 shows the principles of DPI design. Most DPIs contain micronized drug blendedwith larger carrier particles, which prevents aggregation and helps flow. Theimportant role these carrier particles play is discussed later in this article.The dispersion of a dry powder aerosol is conducted from a static powder bed.To generate the aerosol, the particles have to be moved. Movement can bebrought about by several mechanisms. Passive inhalers employ the patient’sinspiratory flow. When the patient activates the DPI and inhales, airflowthrough the device creates shear and turbulence; air is introduced into thepowder bed and the static powder blend is fluidized and enters the patient’sairways. There, the drug particles separate from the carrier particles and arecarried deep into the lungs, while the larger carrier particles impact in theoropharynx and are cleared. Thus, deposition into the lungs is determined bythe patient’s variable inspiratory airflow. Inadequate drug/carrier separation isone of the main explanations for the low deposition efficiency encountered withDPIs. Dose uniformity is a challenge in the performance of DPIs. This is agreater concern with powders than with liquids because of the size and discretenature of the particulates.
Fig.1. Principle of dry powder inhaler design. The formulation typically consistsof micronized drug blended with larger carrier particles, dispensed by a meteringsystem. An active or passive dispersion system entrains the particles into thepatient’s airways, where drug particles separate from the carrier particles andare carried into the lung.
Variousdispersion mechanisms have been adopted for DPIs. While most DPIs arebreath-activated, relying on inhalation for aerosol generation, severalpower-assisted devices (pneumatic, impact force, and vibratory) have beendeveloped or are currently under development. These devices are beingconsidered for the delivery of ystemically active drugs that have narrowtherapeutic windows. It is important to note that these 「active」 inhalers arenot subject to the same limitations as passive inhalers and have a differentadvantage/disadvantage profile. Moreover, it has been suggested that if shearand turbulence could be standardized by using a dispersion mechanism that isindependent of the patient’s breath, high delivery efficiency andreproducibility might be achieved. Thus, an active inhaler might provideformulation-independent delivery. There are no commercially availableactive-dispersion DPIs. Therefore, in the interest of brevity, these devicesare not discussed here; the reader is instead referred to other literature.（To be continued）