本發明係關於新穎醫藥組合物。本發明亦關於製造此等組合物且將其調配成劑型之方法。The present invention relates to novel pharmaceutical compositions. The present invention also relates to methods for preparing such compositions and formulating them into dosage forms.
在本說明書中，對明顯先前出版之文獻的列舉或論述未必應視為承認該文獻係目前先進技術或公共常識之一部分。The citation or discussion of an apparently previously published document in this specification should not necessarily be regarded as an admission that the document is part of the current state of the art or common general knowledge.
腎上腺素(adrenaline)，又稱為腎上腺激素(epinephrine)，為主要由腎上腺髓質以及由少數神經元分泌之內源性激素。其在身體中之主要作用係作為交感神經系統之組分的刺激物。腎上腺素通常在應激情況下釋放，且藉由增加流至肌肉之血流量、心臟輸出量、瞳孔擴張及血漿葡萄糖含量而在戰或逃反應(fight-or-flight response)中起重要作用。其藉由結合及刺激α及β腎上腺素激導性受體來發揮此作用。Adrenaline, also known as epinephrine, is an endogenous hormone secreted primarily by the adrenal medulla and by a few neurons. Its primary role in the body is as a stimulator of components of the sympathetic nervous system. Adrenaline is normally released in response to stress and plays an important role in the fight-or-flight response by increasing blood flow to muscles, cardiac output, pupil dilation, and plasma glucose levels. It does this by binding to and stimulating alpha and beta adrenaline stimulatory receptors.
腎上腺素係在十九世紀末首次分離出來且現在常用作外源性藥物(腎上腺激素)，例如用以治療過敏性反應(包括全身性過敏反應)及心跳驟停，以及喉炎及哮喘。Adrenaline was first isolated in the late 19th century and is now commonly used as an exogenous drug (adrenaline), for example to treat allergic reactions (including systemic anaphylaxis) and cardiac arrest, as well as laryngitis and asthma.
為了治療重度及/或急性病況，諸如過敏性反應，包括嚴重過敏性反應、全身性過敏反應及過敏性休克(其可由昆蟲叮或咬產生的毒液、某些食品或藥物及其他化學製品，如乳膠引起)，且尤其是其急症治療，腎上腺激素目前係藉由注射來非經腸投與，例如皮下、靜脈內或肌肉內注射，同時亦投與其他緊急醫療干預。For the treatment of severe and/or acute conditions such as allergic reactions, including severe allergic reactions, systemic allergic reactions, and anaphylactic shock (which can be caused by venom from insect bites or stings, certain foods or drugs, and other chemicals such as latex), and especially for their acute treatment, adrenal hormones are currently administered parenterally by injection, e.g., subcutaneously, intravenously, or intramuscularly, along with other emergency medical interventions.
易發生此等嚴重過敏性反應者通常會隨身攜帶腎上腺激素自動注射器，以在緊急情況下自行投藥。自動注射器通常係一種單次使用、拋棄式、彈簧加載之注射器，旨在供患者自行投藥，或由未經訓練之人員或先遣急救員(first responder)投藥。People who are prone to these severe allergic reactions often carry an adrenalin autoinjector to self-administer in an emergency. An autoinjector is typically a single-use, disposable, spring-loaded syringe designed to be self-administered by the patient or by an untrained person or first responder.
最常見的腎上腺激素自動注射器裝置係以品牌名稱EpiPen®及EpiPen® Jr出售，而且亦以其他品牌名稱，諸如Adrenaclick®及Auvi-Q®出售。The most common adrenal hormone auto-injector devices are sold under the brand names EpiPen® and EpiPen® Jr., and are also sold under other brand names such as Adrenaclick® and Auvi-Q®.
注射遞送方式通常被認為是不方便的。對於患者而言，透過針自行投與藥物有時非常困難，甚至是不可能的，有時需要先遣急救員及/或醫師進行浪費且耗時的干預以確保順應性，且避免不希望的或有害的作用。Injectable delivery methods are often considered inconvenient. Self-administration of medications by needle is sometimes difficult or even impossible for patients, sometimes requiring wasteful and time-consuming intervention by first responders and/or physicians to ensure compliance and avoid undesirable or harmful effects.
此外，所有上述自動注射器皆包含化學上極其不穩定的腎上腺激素溶液。實際上，EpiPen產品標籤指示，該產品應儲存在其原始包裝中，在室溫下(尤其在20℃與25℃之間)避光保存。其不能冷藏或冷凍(為了例如增強產品穩定性)，因為此在緊急情況下可能會損害裝置之效能(因為需要透過細針注射液體溶液)。Furthermore, all of the aforementioned autoinjectors contain a chemically extremely unstable adrenal hormone solution. In fact, the EpiPen product label indicates that the product should be stored in its original packaging at room temperature (specifically between 20°C and 25°C) and protected from light. It should not be refrigerated or frozen (in order to, for example, enhance product stability) as this could compromise the efficacy of the device in an emergency (since the liquid solution needs to be injected through a thin needle).
即使在其規定儲存條件下，EpiPen亦僅有最長24個月的儲放時限，且Epipen Jr之儲放時限僅至多19個月。此外，由於在分銷期間的儲存時間，到最終使用者被開處方或獲得其裝置時，此儲放時限通常會減少多達12個月。產品標籤會指示使用者在產品到期日期之前更換該單元。Even under its specified storage conditions, the EpiPen has a maximum storage limit of 24 months, and the Epipen Jr has a maximum storage limit of 19 months. In addition, due to storage time during distribution, this storage limit is generally reduced by up to 12 months by the time the end user is prescribed or receives their device. The product label will instruct the user to replace the unit before the product expiration date.
由於腎上腺激素溶液之不穩定性，與所有自動注射器相同，EpiPen亦包含檢查窗，使用者根據產品標籤中的指示透過該檢查窗檢查產品，尤其是目視檢查其微粒(沉澱物)或變色。若存在此類粒子及/或變色，則指示使用者更換該單元，即使此情形係在到期日期之前發生。Due to the unstable nature of the adrenal hormone solution, the EpiPen, like all auto-injectors, contains an inspection window through which the user inspects the product according to the instructions on the product label, particularly visually inspecting for particles (sediment) or discoloration. If such particles and/or discoloration are present, the user is instructed to replace the unit, even if this occurs before the expiration date.
此等因素共同造成尚未使用即被浪費地棄置之腎上腺激素自動注射器的數目增加，此外，腎上腺激素溶液往往會包含使許多患者過敏的穩定劑(抗氧化劑)，更特別地，亞硫酸鹽，從而進一步限制其使用(參見例如Roth及Shields, 《麻醉與鎮痛(Anesthesia & Analgesia)》,98, 1499(2004))。These factors have combined to increase the number of adrenaline auto-injectors that are wasted and discarded without being used. In addition, adrenaline solutions often contain stabilizers (antioxidants), more specifically sulfites, to which many patients are allergic, further limiting their use (see, e.g., Roth and Shields,Anesthesia & Analgesia ,98 , 1499 (2004)).
因此，出於前述原因，對具有改良之穩定性(物理穩定性且更重要地，化學穩定性)的包含腎上腺激素之藥物遞送組合物之臨床需求遠未得到滿足。Therefore, for the reasons stated above, there is a significant unmet clinical need for drug delivery compositions comprising adrenal hormones having improved stability, both physical stability and, more importantly, chemical stability.
在急性病症之治療中，通常需要藥理學作用之快速起效。與口服藥物遞送相比，使藥物直接進入全身循環之投與原則更可能引起此類快速起效。In the treatment of acute conditions, a rapid onset of pharmacological action is often desired. Administration principles that allow the drug to enter the systemic circulation directly are more likely to result in such a rapid onset of action than oral drug delivery.
經黏膜投與活性成分係非經腸投與的一個可行之替代方案。其使藥物分子有可能透過黏膜(例如經直腸、舌下、經頰、經肺及鼻內)直接遞送至全身循環中，且可能帶來諸如以下之優點：患者順應性增加、藥物生物可用性提高且因此劑量降低、起效更快速以及副作用減少。Transmucosal administration of active ingredients is a viable alternative to parenteral administration. It allows drug molecules to be delivered directly to the systemic circulation through mucosal membranes (e.g., rectal, sublingual, buccal, pulmonary, and intranasal) and may bring advantages such as increased patient compliance, increased drug bioavailability and thus reduced dosage, more rapid onset of action, and reduced side effects.
然而，經黏膜投與藥物亦呈現出其自身的相當明顯的問題。不同於作為含有相對較大量生物流體之大型器官的胃腸道，諸如口腔及鼻腔之空間相對較小且其所含體液(諸如唾液及/或黏液)之量少得多。此必然對可以單次劑量投與之活性成分的量帶來相當大的限制。However, transmucosal administration of drugs also presents its own significant problems. Unlike the gastrointestinal tract, which is a large organ containing relatively large amounts of biological fluids, spaces such as the oral and nasal cavities are relatively small and contain much smaller amounts of body fluids (such as saliva and/or mucus). This necessarily places considerable limitations on the amount of active ingredient that can be administered in a single dose.
此外，儘管胃腸道為一種動態系統，但其在主要部分中為某種「封閉」系統。相反，在口腔及鼻腔二者中發生的快速清除機制意味著，對於本來就有限之藥物量而言，通常可用於跨黏膜表面吸收之時間亦有限。Furthermore, although the gastrointestinal tract is a dynamic system, it is in large part somewhat of a "closed" system. In contrast, the rapid elimination mechanisms that occur in both the oral and nasal cavities mean that the time available for absorption across mucosal surfaces is often limited for an already limited amount of drug.
已提出許多調配原理來解決此問題，包括例如生物黏附調配原理，諸如用於口腔黏膜藥物遞送之經頰貼片(參見例如Shojaei, 《藥學與藥物科學雜誌(J. Pharm. Pharmaceutical Sci.)》,15, 19 (1998)；及Gandhi, 《高等藥物遞送綜述(Advanced Drug Delivery Reviews)》,43, 67 (1994))，以及用於鼻內藥物遞送之原位膠凝組合物(參見例如Bertan等人, 《歐洲藥物科學雜誌(Eur. J. Pharm.Sci.)》,27, 62 (2006))。Many formulation principles have been proposed to address this problem, including, for example, bioadhesive formulation principles, such as transbuccal patches for oral mucosal drug delivery (see, e.g., Shojaei,J. Pharm. Pharmaceutical Sci. ,15 , 19 (1998); and Gandhi,Advanced Drug Delivery Reviews ,43 , 67 (1994)), and in situ gelling compositions for intranasal drug delivery (see, e.g., Bertan et al.,Eur. J. Pharm. Sci .,27 , 62 (2006)).
呈固態形式之經黏膜藥物遞送系統可在允許調配物中之更高藥物負載方面呈現出顯著優勢。然而，儘管當向直腸、頰、舌下及肺黏膜投與時，固體藥物遞送組合物更為常見，但絕大部分鼻內藥物遞送系統仍呈液體噴霧，通常水溶液形式，其中藥物溶解度扮演可用於吸收之藥物量的另一限制因素。Transmucosal drug delivery systems in solid form may present significant advantages in allowing higher drug loads in the formulation. However, although solid drug delivery compositions are more common when administered to the rectal, buccal, sublingual, and pulmonary mucosa, the vast majority of intranasal drug delivery systems are still in the form of liquid sprays, usually aqueous solutions, where drug solubility plays another limiting factor in the amount of drug available for absorption.
用於鼻內遞送之液體噴霧幾乎普遍存在，此係因為調配呈鼻用粉末形式之固體醫藥調配物並不容易。不同於常常用於將活性成分吸入至肺中之粉末，存在極少可商購的鼻內粉末調配物。Liquid sprays for intranasal delivery are almost ubiquitous because it is not easy to formulate solid pharmaceutical formulations in the form of nasal powders. Unlike powders, which are often used to inhale the active ingredient into the lungs, there are very few commercially available intranasal powder formulations.
當調配為乾燥粉末時，經肺藥物遞送組合物通常呈「聚集體」混合物之形式，其包括在較大載劑粒子上的微粉化API粒子。此等聚集體意在吸入或致動裝置時解離/分解，從而僅在肺中沉積活性成分之細粒。When formulated as a dry powder, pulmonary drug delivery compositions are usually in the form of a mixture of "aggregates" that include micronized API particles on larger carrier particles. These aggregates are intended to dissociate/break down upon inhalation or actuation of the device, thereby depositing only fine particles of the active ingredient in the lungs.
然而，應理解，此類藥物遞送系統無法在鼻內藥物遞送之情況下有效地工作。此係因為此類細粒之存在導致顯著肺暴露風險，而肺並非預定投與部位。若為了避免此問題而增加藥物粒度，則將可能導致難以確保異質性「相互作用」混合物中之適當相互作用，此依賴於兩種組分之尺寸的實質性差異以確保相互作用，由此又引起潛在的製造問題，諸如在填充期間之偏析(segregation)。嘗試藉由相應地增加載劑粒度來對此進行補償未必會解決該問題，但必定會增加本來就有限之劑型總質量中無活性賦形劑之質量，從而有可能引起活性成分之劑量降低。However, it will be appreciated that such drug delivery systems will not work effectively in the context of intranasal drug delivery. This is because the presence of such fine particles results in a significant risk of lung exposure, which is not the intended site of administration. If the drug particle size is increased in order to avoid this problem, it will likely result in difficulties in ensuring proper interaction in a heterogeneous "interactive" mixture, which relies on a substantial difference in the size of the two components to ensure interaction, which in turn leads to potential manufacturing problems such as segregation during filling. Attempting to compensate for this by a corresponding increase in the carrier particle size will not necessarily solve the problem, but will certainly increase the mass of inactive excipient to the already limited total mass of the dosage form, thereby potentially resulting in a reduced dose of the active ingredient.
在美國專利申請案US 2005/001411 A1中解決了調配用於鼻內遞送之乾燥粉末的困難。在此文獻中提出，用於經鼻投與之粉末需要足夠細以使得其可由氣流高效地輸送且高效地沉積於鼻中，但亦需要足夠粗糙以便於將粉末引入至適當粉末裝置中，此始終為鼻內投與所需的。US 2005/001411 A1藉由製備由包含活性成分之初級粒子鬆散形成之次級粒子(聚集體)明確解決了此問題。該等聚集體之尺寸有幾百微米，且據稱此能夠更高效地裝載至適當鼻內投與(施用器、分配器或吹入器)裝置中。在致動此類裝置且投與該組合物時，聚集體明顯迅速分解成活性成分之初級粒子。此等初級粒子僅有幾微米大小，據稱此有助於其溶解，及此後活性成分之鼻內吸收。The difficulty of formulating dry powders for intranasal delivery is addressed in US patent application US 2005/001411 A1. It is proposed in this document that powders for nasal administration need to be fine enough so that they can be efficiently transported by the airstream and deposited efficiently in the nose, but also coarse enough to facilitate introduction of the powder into a suitable powder device, which is always required for intranasal administration. US 2005/001411 A1 specifically addresses this problem by preparing secondary particles (aggregates) loosely formed from primary particles comprising the active ingredient. The size of these aggregates is several hundred microns, and this is said to enable more efficient loading into a suitable intranasal administration (applicator, dispenser or insufflator) device. When such a device is actuated and the composition is administered, the aggregates apparently rapidly disintegrate into primary particles of the active ingredient. These primary particles are only a few micrometers in size, which is said to facilitate their dissolution and subsequent intranasal absorption of the active ingredient.
如上所陳述，經黏膜(例如鼻內)遞送意欲用於全身性吸收之藥物將避免首過代謝，而該首過代謝為經口投與不可避免之部分。藥物代謝透過與能夠改變活性成分之化學結構、物理結構及/或生物活性之酶的化學反應發生。As stated above, transmucosal (e.g., intranasal) delivery of drugs intended for systemic absorption will avoid first-pass metabolism, which is an inevitable part of oral administration. Drug metabolism occurs through chemical reactions with enzymes that can change the chemical structure, physical structure and/or biological activity of the active ingredient.
由於大部分藥物為含有能夠經歷此類化學反應之官能基的有機分子，故當其接觸能夠與在體外之彼等官能基相互作用之物質時，通常容易受某種形式之化學分解的影響。如上文所論述，就腎上腺激素而言，化學不穩定性問題尤其嚴重。Since most drugs are organic molecules containing functional groups capable of undergoing such chemical reactions, they are often susceptible to some form of chemical breakdown when exposed to substances that can interact with those functional groups outside the body. As discussed above, the problem of chemical instability is particularly severe with respect to adrenal hormones.
如Kou及Zhou在教科書《非晶固體分散體(Amorphous Solid Dispersions)》第16章，Shah等人(編), Springer (2014)中所概述的，若藥物係調配為非晶物理狀態，則與結晶物理狀態相對，其通常以更高能態存在，且因此可能在化學上及物理上更不穩定，從而給藥物調配者帶來挑戰。As outlined by Kou and Zhou in Chapter 16 of the textbookAmorphous Solid Dispersions, Shah et al. (eds.), Springer (2014), if a drug is formulated in an amorphous physical state, it typically exists in a higher energy state relative to the crystalline physical state and may therefore be chemically and physically less stable, thus presenting challenges to the drug formulator.
因此，通常藉由以結晶狀態呈現藥物，通常透過鹽形成，來改善化學穩定性。鹽形成之主要目的通常為增加活性成分之親水性，以解決水溶性差及溶解速率問題。在製備鹽時，通常可同時解決其他物理化學及生物問題，諸如化學穩定性。舉例而言，鹼性藥物(例如含有至少一個胺基之藥物)通常以酸加成鹽形式存在，該等鹽在化學上通常比相應的「游離」胺鹼更穩定。Therefore, chemical stability is often improved by presenting the drug in a crystalline state, usually by salt formation. The primary purpose of salt formation is often to increase the hydrophilicity of the active ingredient to address poor water solubility and dissolution rate issues. In preparing salts, other physicochemical and biological issues, such as chemical stability, can often be addressed simultaneously. For example, basic drugs (e.g., drugs containing at least one amine group) often exist in the form of acid addition salts, which are often more chemically stable than the corresponding "free" amine bases.
然而，儘管有可能以更易於儲存而不會化學降解形式提供活性成分且其在投與之後在溶解速率及/或程度方面更高效，但與相應活性成分分別以非晶形及/或未離子化形式呈現之情況相比，結晶鹽一般具有更慢的溶解速率且其跨黏膜吸收之效率更低。However, despite the potential to provide the active ingredient in a form that is easier to store without chemical degradation and which is more efficient in terms of rate and/or extent of dissolution following administration, crystalline salts generally have a slower dissolution rate and are less efficiently absorbed across mucosal membranes than the corresponding active ingredient in an amorphous and/or unionized form, respectively.
因此，調配為非晶形固態分散體形式之活性醫藥成分一般具有生物可用性較高之優點，但通常存在物理及化學穩定性降低之難題，而調配為結晶及/或鹽形式之藥物儘管一般更穩定，但其生物可用性往往較低。Therefore, active pharmaceutical ingredients formulated in the form of amorphous solid dispersions generally have the advantage of higher bioavailability, but usually suffer from reduced physical and chemical stability, while drugs formulated in crystalline and/or salt forms, although generally more stable, often have lower bioavailability.
後一個問題在經黏膜，諸如鼻內或舌下藥物遞送之情況下可能尤其不利，在此情況下，如上所論述，藥物在相關空腔內的停留時間受到限制，而藥物需要在此時間內才能吸收至全身循環中。此問題加上在生理pH下跨黏膜之滲透性差可能會導致不可接受的低及/或緩慢的經黏膜吸收，使得無法提供適當的治療作用。The latter problem may be particularly detrimental in the case of transmucosal, such as intranasal or sublingual drug delivery, where, as discussed above, the residence time of the drug in the relevant cavity is limited within which the drug must be absorbed into the systemic circulation. This problem coupled with poor permeability across mucosal membranes at physiological pH may result in unacceptably low and/or slow transmucosal absorption, making it impossible to provide adequate therapeutic effect.
多年來，已設計出許多複雜的調配原理來解決經黏膜藥物遞送系統之溶解度與滲透性之間的平衡問題。此等調配原理包括添加pH調節物質，用以將活性成分之離子化鹽形式轉化成更易滲透之非離子化狀態。Over the years, many complex formulation strategies have been devised to address the balance between solubility and permeability for transmucosal drug delivery systems. These include the addition of pH-adjusting substances to convert the ionized salt form of the active ingredient into a more permeable non-ionized state.
然而，鑒於所提供的所有前述潛在優點，通常仍需要改進之固體(例如基於粉末)經黏膜且尤其鼻內藥物遞送系統。However, in view of all of the foregoing potential advantages offered, there remains a need for improved solid (e.g., powder-based) transmucosal and particularly intranasal drug delivery systems in general.
特定言之，在經黏膜遞送領域中，對於粉末狀藥物遞送組合物仍存在明顯未滿足的臨床需求，該粉末狀藥物遞送組合物： (i) 在物理上及化學上均穩定；及 (ii) 提供活性成分： • 具有足夠的劑量；及/或 • 呈具有滲透性之形式，該滲透性足以 在經黏膜背景下，諸如在鼻腔內以(相對而言)可能較低之劑量及可用的短停留時間提供所需治療作用(諸如起效及/或接近藥物目標之速度)。Specifically, in the field of transmucosal delivery, there remains a significant unmet clinical need for powdered drug delivery compositions that:(i) are physically and chemically stable; and(ii) provide the active ingredient:• in an adequate dosage amount; and/or• in a form that is permeable enoughto provide the desired therapeutic effect (e.g., speed of onset and/or access to drug target) in a transmucosal setting, such as in the nasal cavity, at a potentially (relatively) low dosage and with a short available residence time.
在鼻內藥物遞送之更特定領域中，對於此類藥物遞送組合物之臨床需求仍明顯有待滿足，該藥物遞送組合物包含適當尺寸之粒子以便能夠高效地： • 填充藥物遞送裝置；及 • 沉積於相關空腔(例如鼻腔)內。In the more specific area of intranasal drug delivery, there remains a significant unmet clinical need for drug delivery compositions comprising particles of an appropriate size to be able to efficiently: • fill a drug delivery device; and • deposit in a relevant cavity (e.g., the nasal cavity).
鼻內乾粉調配物自尤其國際專利申請案WO 2010/142696及WO 2019/038756、美國專利案第10,653,690 B2號及美國專利申請案US 2018/0092839A中獲知。亦參見美國專利第7,947,742 B2號、第8,415,397 B2號及第8,747,813 B2號。Intranasal dry powder formulations are known from, inter alia, international patent applications WO 2010/142696 and WO 2019/038756, U.S. Patent No. 10,653,690 B2 and U.S. Patent Application US 2018/0092839A. See also U.S. Patent Nos. 7,947,742 B2, 8,415,397 B2 and 8,747,813 B2.
Russo等人(《醫藥科學雜誌(J. Pharm. Sci.)》,95, 2253 (2006))揭示對類鴉片鎮痛劑化合物嗎啡鹼(morphine)與多種賦形劑一起進行噴霧乾燥。噴霧乾燥之調配物亦揭示於Vengerovich等人，《實驗生物學及醫學公報(Bulletin of Experimental Biology and Medicine)》,163, 737 (2017)中，其中嘗試將活性成分微囊封於各種物質中，包括2-羥丙基-β-環糊精，旨在開發用於緊急照護的基於聚合載劑之持續釋放製劑。Russo et al. (J. Pharm. Sci .,95 , 2253 (2006)) disclosed spray drying of the opium-like analgesic compound morphine with various excipients. Spray-dried formulations are also disclosed in Vengerovich et al., Bulletinof Experimental Biology and Medicine ,163 , 737 (2017), where attempts were made to microencapsulate the active ingredient in various substances, including 2-hydroxypropyl-β-cyclodextrin, in an effort to develop a sustained-release formulation based on a polymeric carrier for acute care.
已發現，可藉助於以下方法調配出呈非晶形乾粉組合物形式的腎上腺素激導性受體調節劑，諸如腎上腺激素，該方法例如將該活性成分與包含特定組分之載劑材料一起噴霧乾燥，如下文所揭示(亦參見國際專利申請案WO 2023/094826A1)。當與諸如EpiPen之類當前可用裝置中採用的調配物相比較時，此等組合物可按一種有利的方式(如下文中所描述)製造，且亦提供在儲存期間及投與之前相關活性成分之穩定性的令人驚訝之改善。It has been found that adrenaline agonist receptor modulators, such as adrenal hormones, can be formulated in the form of amorphous dry powder compositions by, for example, spray drying the active ingredient together with a carrier material comprising specific components, as disclosed below (see also International Patent Application WO 2023/094826A1). Such compositions can be manufactured in an advantageous manner (as described below) when compared to formulations employed in currently available devices such as EpiPen, and also provide a surprising improvement in the stability of the relevant active ingredients during storage and prior to administration.
當在I期臨床研究中將包含腎上腺激素之此等組合物投與健康志願者時，發現該等組合物展現出活性成分的優良生物可用性及吸收速度。儘管經鼻投與該等組合物被認為是安全的，且在該研究中未報告嚴重不良事件(AE)，但鼻不適較為常見，不過，此種不適通常為輕度、短暫且可忍受的。When these compositions containing adrenal hormones were administered to healthy volunteers in a Phase I clinical study, they were found to exhibit good bioavailability and absorption rate of the active ingredients. Although nasal administration of these compositions was considered safe and no serious adverse events (AEs) were reported in this study, nasal discomfort was common, however, this discomfort was usually mild, transient and tolerable.
儘管對於設計用於挽救生命、緊急使用之藥物而言，輕度不適不被認為是一個重要問題，但為了改善患者對本來就優良之產品的體驗，已作出嘗試以減小患者所經歷之鼻刺激。Although mild discomfort is not considered a significant issue for drugs designed for life-saving, emergency use, attempts have been made to reduce the nasal irritation experienced by patients in order to improve the patient experience of an already superior product.
根據本發明之第一範疇，提供一種呈固體、非晶形、單微粒粉末形式的醫藥學上可接受之組合物，其包含以下各物之混合物： (a) 藥理學上有效劑量之腎上腺素激導性受體調節劑或其醫藥學上可接受之鹽；及 (b) 醫藥學上可接受之載劑材料，該載劑材料包含麥芽糊精， 該固體組合物當溶解於水性介質中時，展現在約4.5與約8.0之間的pH值， 該等醫藥學上可接受之組合物在下文中統稱為「本發明組合物」。According to the first aspect of the present invention, a pharmaceutically acceptable composition in the form of a solid, amorphous, single particle powder is provided, which comprises a mixture of:(a) a pharmacologically effective dose of an adrenaline stimulatory receptor modulator or a pharmaceutically acceptable salt thereof; and(b) a pharmaceutically acceptable carrier material, the carrier material comprising maltodextrin,the solid composition exhibits a pH value between about 4.5 and about 8.0 when dissolved in an aqueous medium,the pharmaceutically acceptable compositions are collectively referred to as "the compositions of the present invention" hereinafter.
可提及的腎上腺素激導性受體(包括α1A、α1b、α1c、α1d、α2a、α2b、α2c、α2d、β1、β2、β3次受體)之調節劑(亦稱作「刺激劑」或「促效劑」)可包括苯腎上腺素(phenylephrine)、羥甲唑啉(oxymetazoline)、甲基多巴(methyldopa)、氯壓定(clonidine)、右美托咪定(dexmedetomidine)、洛非西定(lofexidine)、多巴酚丁胺(dobutamine)、米拉貝隆(mirabegron)、多巴胺(dopamine)、沙丁胺醇(albuterol) (舒喘靈(salbutamol))、福莫特羅(formoterol)、左旋沙丁胺醇(levalbuterol)、奧達特羅(olodaterol)、沙美特羅(salmeterol)、吡布特羅(pirbuterol)、特布他林(terbutaline)、非諾特羅(fenoterol)、利米特羅(rimiterol)、海索那林(hexoprenaline)、曲托喹酚(tretoquinol)、卡布特羅(karbuterol)、妥布特羅(tulobuterol)、克侖特羅(clenbuterol)、丙卡特羅(procaterol)、比托特羅(bitolterol)、茚達特羅(indacaterol)、可爾特羅(colterol)、假麻黃素(pseudoephedrine)、麻黃素(ephedrine)，更佳為去甲腎上腺素(norepinephrine)、異丙腎上腺素(isoprenaline)，且尤其為腎上腺激素(又稱為「腎上腺素」)，以及前述中之任一者的鹽。Mentionable modulators of adrenaline agonist receptors (including α1A , α1b , α1c , α1d , α2a , α2b , α2c , α2d , β1 , β2 , β3 subreceptors) (also called "stimulants" or "agonists") may include phenylephrine, oxymetazoline, methyldopa, clonidine, dexmedetomidine, lofexidine, dobutamine, mirabegron, dopamine, albuterol (salbutamol), formoterol, levalbuterol, olodaterol, salmeterol, pirbuterol, terbutaline, fenoterol, rimiterol, hexoprenaline, tretoquinol, karbuterol, tolbuterol The invention relates to cyclohexine, ...
本發明之組合物呈非晶形、單微粒粉末形式。「單微粒」意謂形成本發明之粉末狀組合物的複數個粒子包含均質或非均質混合物，其中腎上腺素激導性受體調節劑或其鹽視情況在其他成分之存在下以非晶態囊封於上文所定義之載劑材料內。本發明之粉末狀組合物的粒子因此呈現為腎上腺素激導性受體調節劑或其醫藥學上可接受之鹽(下文稱為「活性成分」)、前述載劑材料及視情況選用之其他成分的非晶形複合物。The composition of the present invention is in the form of an amorphous, single-particle powder. "Single-particle" means that the plurality of particles forming the powdered composition of the present invention comprises a homogeneous or heterogeneous mixture, wherein the adrenergic receptor modulator or its salt, as appropriate, is encapsulated in the carrier material defined above in an amorphous state in the presence of other ingredients. The particles of the powdered composition of the present invention thus present an amorphous complex of the adrenergic receptor modulator or its pharmaceutically acceptable salt (hereinafter referred to as "active ingredient"), the aforementioned carrier material, and other ingredients selected as appropriate.
由於本發明之組合物在性質上為非晶形的，故其可為完全非晶形的及/或可主要為非晶形的(例如超過約50重量%，諸如超過約75重量%，包括超過約80重量%，諸如超過約90重量%或約95重量%，包括超過約99重量%為非晶形)。在替代方案中，本發明之組合物可為低於約50%，諸如低於約25%，更佳低於約20%，例如低於約10%，包括低於約5%或低於約1%結晶。結晶度(%)可由熟習此項技術者使用粉末X射線繞射(PXRD)測定。亦可使用其他技術，諸如固態NMR、FT-IR、拉曼光譜法、差示掃描熱量測定(DSC)微量熱法及真密度計算。Since the compositions of the present invention are amorphous in nature, they may be completely amorphous and/or may be predominantly amorphous (e.g., more than about 50% by weight, such as more than about 75% by weight, including more than about 80% by weight, such as more than about 90% by weight or about 95% by weight, including more than about 99% by weight being amorphous). In alternative embodiments, the compositions of the present invention may be less than about 50%, such as less than about 25%, more preferably less than about 20%, such as less than about 10%, including less than about 5% or less than about 1% crystalline. The degree of crystallinity (%) may be determined by one skilled in the art using powder X-ray diffraction (PXRD). Other techniques may also be used, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) microcalorimetry, and true density calculations.
如在下文中所述，儘管呈非晶形物理狀態，但本發明之組合物展現出顯著且出人意料的物理及化學穩定性，且因此當在正常儲存條件下儲存時可以展現出極佳儲放時限之醫藥產品形式提供。As described hereinafter, despite being in an amorphous physical state, the compositions of the present invention exhibit remarkable and unexpected physical and chemical stability and can therefore be provided as pharmaceutical products that exhibit an excellent shelf life when stored under normal storage conditions.
本發明之組合物至少最初藉由適當技術製造為多個小粒子形式(亦即，粉末形式)。一般而言，適當技術屬於「基於溶劑」之方法，其包括噴霧乾燥、流體化床技術、共沉澱、超臨界流體技術、噴霧成粒、低溫技術(包括冷凍乾燥)、靜電紡絲及旋轉噴射技術，或屬於「基於融合」之方法，其包括熔融造粒、熔融擠壓、高剪切混合(例如KinetiSol®)、碾磨及使用載劑技術(例如Meltdose®)熔融材料。較佳方法包括冷凍乾燥，且更佳地，本發明之組合物係藉由噴霧乾燥方法製備。The compositions of the invention are at least initially prepared in the form of a plurality of small particles (i.e., powder form) by a suitable technique. Generally, suitable techniques are "solvent-based" methods, which include spray drying, fluidized bed techniques, coprecipitation, supercritical fluid techniques, spray granulation, low temperature techniques (including freeze drying), electrospinning and rotary spraying techniques, or "fusion-based" methods, which include melt granulation, melt extrusion, high shear mixing (e.g., KinetiSol®), milling, and use of carrier techniques (e.g., Meltdose®) to melt the material. Preferred methods include freeze drying, and more preferably, the compositions of the invention are prepared by a spray drying method.
此等粉末可適於經由任何醫藥學上可接受之投與途徑直接遞送至患者，或可作為中間組合物呈現，該中間組合物隨後可被調配成醫藥學上可接受之劑型以向一或多名患者投與。Such powders may be suitable for direct delivery to a patient via any pharmaceutically acceptable route of administration, or may be presented as an intermediate composition which may then be formulated into a pharmaceutically acceptable dosage form for administration to one or more patients.
就此而言，提供一種醫藥調配物及/或醫藥學上可接受之劑型，該調配物及/或劑型將向患者投與，且包含一種或多種本發明之組合物。In this regard, a pharmaceutical formulation and/or pharmaceutically acceptable dosage form is provided, which is to be administered to a patient and comprises one or more compositions of the present invention.
因此，適合的醫藥劑型可包含液體調配物，諸如溶液，其可藉由將本發明之組合物溶解於醫藥學上可接受之溶劑(諸如水)中來製備，以供例如藉由注射或藉由輸注遞送至此類患者。Thus, suitable pharmaceutical dosage forms may include liquid formulations, such as solutions, which can be prepared by dissolving the compositions of the invention in a pharmaceutically acceptable solvent, such as water, for delivery to such patients, for example, by injection or by infusion.
替代性醫藥劑型可包含液體或半固體調配物，諸如可包含本發明之組合物(例如其粒子)之液體懸浮液及/或凝膠組合物，本發明之組合物懸浮或溶解於適當液體或半固體載劑中，該載劑可裝載至適當劑型中或藉由例如注射或輸注遞送或可在注射(例如皮下或肌肉內)之後形成，以形成植入或儲槽式調配物。Alternative pharmaceutical dosage forms may include liquid or semisolid formulations such as liquid suspensions and/or gel compositions which may include the compositions of the invention (e.g., particles thereof) suspended or dissolved in a suitable liquid or semisolid carrier which may be loaded into a suitable dosage form or delivered by, for example, injection or infusion or which may be formed following injection (e.g., subcutaneous or intramuscular) to form an implant or reservoir formulation.
在替代方案中，本發明之組合物可呈現為基本上呈固體之醫藥劑型之一部分。熟習此項技術者應充分理解，術語「固體」包括任何形式之物質，該物質在不受限制時保持其形狀及密度，及/或其中分子一般在其之間的排斥力允許之範圍內儘可能緊密地壓縮。因此，基本上呈固體之調配物為至少約80%，諸如至少約90%，包括至少約95% (或至少約99%)呈此類形式之調配物。In an alternative embodiment, the composition of the present invention may be presented as part of a substantially solid pharmaceutical dosage form. It will be fully understood by those skilled in the art that the term "solid" includes any form of matter that retains its shape and density when not constrained, and/or in which the molecules are generally as tightly compressed as possible within the range permitted by the repulsive forces between them. Thus, a substantially solid formulation is at least about 80%, such as at least about 90%, including at least about 95% (or at least about 99%) of the formulation in such a form.
就此而言，本發明之組合物可以任何微粒形式(例如以單純粉末、顆粒、丸粒及/或珠粒形式)提供，其包含複數個可單獨地及/或可共同地基本上由一種或多種此類組合物組成及/或包含一種或多種此類組合物的粒子。In this regard, the compositions of the present invention may be provided in any particulate form (e.g., in the form of pure powders, granules, pellets and/or beads), comprising a plurality of particles that may individually and/or collectively consist essentially of and/or comprise one or more such compositions.
因此，本發明之組合物可在其製備(例如藉由噴霧乾燥)之後呈現為單純粉末混合物、粉末微球體、經塗佈之粉末微球體、凍乾脂質體分散體或其組合之形式。Thus, the composition of the invention may be in the form of a pure powder mixture, powder microspheres, coated powder microspheres, freeze-dried liposome dispersions or a combination thereof after its preparation (e.g. by spray drying).
若本發明之醫藥學上可接受之劑型「基本上由一種或多種本發明之組合物的粒子組成」，則此應理解為意謂該劑型僅包含一種或多種本發明之組合物，以及實質上不影響劑型之基本及新穎特徵的其他特徵及/或組分。或者，在本發明之劑型「基本上由一種或多種本發明之組合物組成」之情形中，此應理解為意指該劑型總共包含至少約90重量%，諸如至少約95重量%，包括至少約97重量% (例如約99重量%)的該等一種或多種本發明之組合物。If a pharmaceutically acceptable dosage form of the present invention "consists essentially of particles of one or more compositions of the present invention", this should be understood to mean that the dosage form contains only one or more compositions of the present invention, and other features and/or components that do not substantially affect the basic and novel features of the dosage form. Alternatively, in the case where the dosage form of the present invention "consists essentially of one or more compositions of the present invention", this should be understood to mean that the dosage form contains at least about 90% by weight, such as at least about 95% by weight, including at least about 97% by weight (e.g., about 99% by weight) of the one or more compositions of the present invention in total.
在替代方案中，醫藥劑型包含呈單個單位劑型形式，諸如子宮托、栓劑或另一形式之插入物、丸劑、膠囊、餅狀物、貼片(例如經頰貼片)、膜片(例如口內膜片)或錠劑(例如舌下錠劑)形式的一種或多種本發明之組合物。In an alternative embodiment, the pharmaceutical dosage form comprises one or more compositions of the invention in the form of a single unit dosage form, such as a pessary, a suppository or another form of insert, a pill, a capsule, a cookie, a patch (e.g., a buccal patch), a film (e.g., an intraoral film), or a tablet (e.g., a sublingual tablet).
膠囊可藉由以下方式製備：將呈經噴霧乾燥粉末形式的本發明之組合物直接裝載至由適當材料製造的設計用於舌下或較佳經口遞送之醫藥學上可接受之膠囊中；或混合組合物以及賦形劑，隨後裝載至此類膠囊中，此可涉及在裝載至膠囊中以用於此類遞送之前進行下文所描述的造粒步驟。Capsules can be prepared by loading the composition of the present invention in the form of a sprayable dry powder directly into a pharmaceutically acceptable capsule made of appropriate materials designed for sublingual or preferably oral delivery; or by mixing the composition and the excipient followed by loading into such capsules, which may involve a granulation step described below prior to loading into capsules for such delivery.
就此而言，本發明之組合物可經歷造粒成丸粒或丸劑，但其亦可調配(亦即，經提供以便投與)成乾燥、自由流動之粉末形式。In this regard, the composition of the invention may be subjected to granulation into pellets or pills, but it may also be formulated (ie provided for administration) in the form of a dry, free-flowing powder.
「乾燥(dry)」包括基本上不含水及其他液體溶劑，其包括低於約10%，諸如低於約6%，包括低於約5%，或低於約4%，更佳低於約3%，諸如低於約2%，例如低於約1% (以重量計或以體積計)的調配物及/或組合物包含液體，諸如水。"Dry" includes substantially free of water and other liquid solvents, including less than about 10%, such as less than about 6%, including less than about 5%, or less than about 4%, more preferably less than about 3%, such as less than about 2%, for example less than about 1% (by weight or by volume) of the formulation and/or composition containing liquids such as water.
本發明之粉末組合物的流動性可藉由熟習此項技術者已知之標準技術量測，包括容積密度量測，或在粉末流動分析儀(例如由Stable Micro Systems或Meritics出售之分析儀，二者均屬UK)上進行之量測，包括粉末流動速度依賴性測試、結塊測試、內聚力測試等。流動性之較佳量測係標準靜止角，其可使用旋轉筒、固定漏斗或擺動箱進行。The flowability of the powder composition of the present invention can be measured by standard techniques known to those skilled in the art, including bulk density measurement, or measurements performed on a powder flow analyzer (e.g., analyzers sold by Stable Micro Systems or Meritics, both UK), including powder flow velocity dependence tests, agglomeration tests, cohesion tests, etc. The preferred measure of flowability is the standard angle of repose, which can be performed using a rotating drum, a fixed funnel, or a swing box.
在本發明之上下文中，術語「自由流動」意欲包括粉末，其允許在製造期間將本發明之組合物高效填充至藥物遞送裝置中，及/或在自該裝置排出時提供足夠的注射量(見下文)。In the context of the present invention, the term "free-flowing" is intended to include powders that allow efficient filling of the composition of the present invention into a drug delivery device during manufacturing and/or provide a sufficient injection volume when discharged from the device (see below).
該術語亦可包括粉末展現出不超過約50°，諸如不超過約45°，包括不超過約40°，例如不超過約35°，且更特定地不超過約30°之靜止角；不低於約0.3 g/mL，例如不低於約0.4 g/mL，諸如不低於約0.5 g/mL，且更特定地不低於約0.6 g/mL之堆密度；及/或不低於約0.5 g/mL，諸如不低於約0.6 g/mL，例如不低於約0.7 g/mL，且更特定地不低於約0.8 g/mL之振實密度。The term can also include powders exhibiting an angle of repose of no more than about 50°, such as no more than about 45°, including no more than about 40°, for example no more than about 35°, and more specifically no more than about 30°; a bulk density of no less than about 0.3 g/mL, such as no less than about 0.4 g/mL, such as no less than about 0.5 g/mL, and more specifically no less than about 0.6 g/mL; and/or a tap density of no less than about 0.5 g/mL, such as no less than about 0.6 g/mL, for example no less than about 0.7 g/mL, and more specifically no less than about 0.8 g/mL.
用於製造包含乾燥粉末或顆粒之劑型的適當技術包括簡單的乾式混合、造粒(包括乾式造粒、濕式造粒、熔融造粒、熱塑性製粒(pelletising)、噴霧造粒)、擠出/滾圓(spheronisation)，或更佳地，冷凍乾燥或噴霧乾燥(見下文)。Suitable techniques for preparing dosage forms comprising dry powders or granules include simple dry mixing, granulation (including dry granulation, wet granulation, melt granulation, pelletising, spray granulation), extrusion/spheronisation, or, more preferably, freeze drying or spray drying (see below).
乾式造粒技術亦為熟習此項技術者所熟知且包括任何技術，其中初級粉末粒子在高壓下聚集，包括擊壓(slugging)及輥壓，例如下文中所描述。Dry granulation techniques are also well known to those skilled in the art and include any technique in which primary powder particles are aggregated under high pressure, including slugging and roller pressing, such as described below.
濕式造粒技術為熟習此項技術者所熟知且包括涉及使用造粒流體且視情況在黏合劑或黏結劑之存在下聚集(massing)乾燥初級粉末粒子之混合物的任何技術，該流體包含揮發性、惰性溶劑，諸如單獨或組合之水、乙醇或異丙醇。該技術可涉及迫使濕塊穿過篩網以產生濕顆粒，接著將其乾燥，乾燥損失較佳低於約3重量%。Wet granulation techniques are well known to those skilled in the art and include any technique involving massing a mixture of dry primary powder particles using a granulating fluid, optionally in the presence of a binder or adhesive, the fluid comprising a volatile, inert solvent such as water, ethanol or isopropanol, alone or in combination. The technique may involve forcing the wet mass through a screen to produce wet granules, which are then dried, preferably with drying losses of less than about 3% by weight.
熟習此項技術者將已知，熔融造粒包括透過添加熔融黏合劑或在該方法期間熔融之固體黏合劑(該等黏合劑材料可包含本發明之組合物的醫藥學上可接受之載劑材料)獲得顆粒之任何技術。在造粒之後，黏合劑在室溫下固化。已知熱塑性製粒將類似於熔融造粒，但其中利用黏合劑之可塑性特性。在兩種方法中，所得聚結物(顆粒)包含基質結構。Those skilled in the art will know that melt granulation includes any technique for obtaining granules by adding a molten binder or a solid binder that melts during the process (these binder materials may include pharmaceutically acceptable carrier materials of the composition of the present invention). After granulation, the binder solidifies at room temperature. Known thermoplastic granulation will be similar to melt granulation, but in which the plastic properties of the binder are utilized. In both methods, the resulting agglomerates (granules) contain a matrix structure.
擠出/滾圓將為熟習此項技術者所熟知，包括涉及各成分之乾式混合、與黏合劑一起濕式聚集、擠出、將擠出物滾圓成大小均勻之球體及乾燥之任何方法。Extrusion/spheronization will be well known to those skilled in the art and includes any method involving dry mixing of the ingredients, wet agglomeration with a binder, extrusion, spheronization of the extrudate into uniformly sized spheres, and drying.
熟習此項技術者已知噴霧造粒包括涉及乾燥液體(溶液、懸浮液、熔融物)，同時在流體床中形成顆粒之任何技術。因此，該術語包括提供外來晶種(種胚(germs))且在其上形成顆粒之方法，以及由於磨損及/或破裂而在流體床中形成固有晶種(種胚)之方法，以及任何通用噴塗造粒技術。經噴霧之液體塗佈種胚且有助於粒子之進一步聚結。接著，將其乾燥以形成呈基質形式之顆粒。Those skilled in the art know that spray granulation includes any technique involving drying a liquid (solution, suspension, melt) while forming particles in a fluid bed. Thus, the term includes methods of providing external seeds (germs) and forming particles thereon, as well as methods of forming intrinsic seeds (germs) in a fluid bed due to abrasion and/or rupture, and any general spray granulation technique. The sprayed liquid coats the germs and helps further agglomeration of the particles. It is then dried to form particles in the form of a matrix.
術語「冷凍乾燥」包括凍乾或低溫脫水(cryodesiccation)及任何低溫去溶劑(例如脫水)方法，其中將產物冷凍，壓力降低，且藉由昇華移除冷凍之溶劑(例如水)。The term "freeze drying" includes freeze drying or cryodesiccation and any cryogenic solvent removal (eg dehydration) process in which the product is frozen, the pressure is reduced, and the frozen solvent (eg water) is removed by sublimation.
在替代方案中，本發明之組合物可以供經口、經頰及/或舌下使用之錠劑形式提供。此類錠劑可視情況在將本發明之組合物與一種或多種適當賦形劑(諸如稀釋劑、崩解劑、滑動劑及/或潤滑劑)混合在一起之後，例如藉由直接壓縮/壓實該組合物形成，且可使用諸如《藥物劑型：錠劑(Pharmaceutical Dosage Forms:Tablets.)》第1卷，第3版，Augsburger等人(編), CRC Press (2008)及其中所引用之文獻中所描述之技術實現。適合之壓實設備包括標準製錠機，諸如Kilian SP300或Korsch EK0、XP1、XL 100及XL 200。In an alternative embodiment, the composition of the present invention can be provided in the form of tablets for oral, buccal and/or sublingual use. Such tablets can be formed, for example, by direct compression/compacting the composition after mixing the composition of the present invention with one or more suitable excipients (such as diluents, disintegrants, slip agents and/or lubricants), as appropriate, and can be achieved using techniques such as those describedin Pharmaceutical Dosage Forms: Tablets. , Vol. 1, 3rd Edition, Augsburger et al. (eds.), CRC Press (2008) and the literature cited therein. Suitable compacting equipment includes standard tableting machines such as the Kilian SP300 or the Korsch EK0, XP1, XL 100 and XL 200.
可用於錠劑中之適合崩解劑(如例如Rowe等人，《醫藥賦形劑手冊(Handbook of Pharmaceutical Excipients)》第6版.(2009)中所定義)包括纖維素衍生物，諸如羥丙基纖維素(HPC)、低取代HPC、甲基纖維素、乙基羥乙基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、微晶纖維素、經改質纖維素膠；澱粉衍生物，諸如適當交聯之澱粉、經改質澱粉、羥丙基澱粉及預膠凝化澱粉；及其他崩解劑，諸如海藻酸鈣、海藻酸鈉、海藻酸、聚葡萄胺糖、膠態二氧化矽、多庫酯鈉(docusate sodium)、瓜爾膠、矽酸鎂鋁、波拉克林鉀(polacrilin potassium)及聚乙烯吡咯啶酮。可使用兩種或更多種崩解劑之組合。Suitable disintegrants for use in tablets (e.g., Rowe et al.,Handbook of Pharmaceutical Excipients ) (as defined in the 6th edition of the International Standard for the Study of the Invention (2009)) include cellulose derivatives such as hydroxypropyl cellulose (HPC), low-substituted HPC, methyl cellulose, ethyl hydroxyethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, and modified cellulose gel; starch derivatives such as appropriately cross-linked starch, modified starch, hydroxypropyl starch, and pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginic acid, polyglucosamine, colloidal silica, docusate sodium, guar gum, magnesium aluminum silicate, and polacrilin potassium. Combinations of two or more disintegrants may be used.
較佳崩解劑包括所謂的「超級崩解劑(superdisintegrant)」(如例如Mohanachandran 等人, 《國際藥物科學評述與研究雜誌(International Journal of Pharmaceutical Sciences Review and Research)》,6, 105 (2011)中所定義)，諸如交聯聚乙烯吡咯啶酮、乙醇酸澱粉鈉及交聯羧甲基纖維素鈉。可使用兩種或更多種超級崩解劑之組合。Preferred disintegrants include so-called "superdisintegrants" (as defined, for example, in Mohanachandran et al.,International Journal of Pharmaceutical Sciences Review and Research ,6 , 105 (2011)), such as cross-linked polyvinyl pyrrolidone, sodium starch glycolate, and cross-linked sodium carboxymethyl cellulose. Combinations of two or more superdisintegrants may be used.
當將崩解劑及/或超級崩解劑用於錠劑中時，其用量(例如總量)按組合物之總重量計可在0.5與15重量%之間。較佳範圍為1至8重量%，諸如約2至約7重量% (例如約5重量%，諸如約4重量%)。When disintegrants and/or super disintegrants are used in tablets, the amount (e.g., total amount) thereof may be between 0.5 and 15% by weight based on the total weight of the composition. A preferred range is 1 to 8% by weight, such as about 2 to about 7% by weight (e.g., about 5% by weight, such as about 4% by weight).
若存在，黏合劑按錠劑調配物之總重量計較佳以0.5與20重量%之間的量使用。較佳範圍為1.0至15重量%，諸如約2.0至約12重量% (例如約10重量%)。適合之黏合劑包括纖維素膠及微晶纖維素。If present, the binder is preferably used in an amount between 0.5 and 20 weight % based on the total weight of the tablet formulation. A preferred range is 1.0 to 15 weight %, such as about 2.0 to about 12 weight % (e.g., about 10 weight %). Suitable binders include cellulose glue and microcrystalline cellulose.
如本文所描述，本發明之組合物較佳藉由噴霧乾燥方法製備。As described herein, the compositions of the present invention are preferably prepared by a spray drying method.
不論呈粉末形式抑或其他形式，包含本發明之組合物的劑型可另外藉由標準技術且使用熟習此項技術者已知之標準設備來製備。就此而言，本發明之組合物可與相關製劑領域中使用的習知醫藥添加劑及/或賦形劑組合，且使用標準技術併入各種醫藥製劑中以便製備包含本發明之組合物的劑型(參見例如Lachman等人, 「工業藥學理論及實踐(The Theory and Practice of Industrial Pharmacy)」, CBS, 第4版(2015)；「雷明頓：藥物科學與實踐(Remington:The Science and Practice of Pharmacy')」, Troy (編輯), Elsevier, 第23版(2020)；及/或「奧爾頓氏製藥學：藥物設計與製造(Aulton's Pharmaceutics:The Design and Manufacture of Medicines')」, Taylor及Aulton (編輯), Elsevier, 第5版, 2017)。Whether in powder form or other forms, dosage forms comprising the compositions of the present invention may otherwise be prepared by standard techniques and using standard equipment known to those skilled in the art. In this regard, the compositions of the present invention can be combined with known pharmaceutical additives and/or excipients used in the relevant formulation art and incorporated into various pharmaceutical formulations using standard techniques to prepare dosage forms containing the compositions of the present invention (see, for example, Lachman et al., "The Theory and Practice of Industrial Pharmacy ", CBS, 4th edition (2015); "Remington: The Science and Practice of Pharmacy' ", Troy (ed.), Elsevier, 23rd edition (2020); and/or "Aulton's Pharmaceutics:The Design and Manufacture of Medicines'", Taylor and Aulton (eds.), Elsevier, 5th edition, 2017).
然而，其經製造，較佳地，本發明之組合物適於及/或經調配用於將活性成分經黏膜遞送至全身循環中。However, the compositions of the invention are preferably adapted and/or formulated for transmucosal delivery of the active ingredients into the systemic circulation.
熟習此項技術者將理解，術語「經黏膜」意指儘管向患者投與組合物，但該組合物係以使得活性成分在其溶解之後可跨該黏膜表面吸收之形式呈現於相關黏膜表面處。相關黏膜表面由此包括口腔、鼻、眼、陰道、子宮頸、肺及/或肛門直腸黏膜，更特別地，口腔黏膜(包括頰及舌下黏膜)且尤其是鼻黏膜。Those skilled in the art will understand that the term "transmucosal" means that although the composition is administered to the patient, the composition is presented at the relevant mucosal surface in a form that allows the active ingredient to be absorbed across the mucosal surface after its dissolution. Relevant mucosal surfaces thus include oral, nasal, ocular, vaginal, cervical, pulmonary and/or anorectal mucosa, more particularly, oral mucosa (including buccal and sublingual mucosa) and especially nasal mucosa.
因此，包含本發明之組合物的劑型可直接投與患者之黏膜表面(包括經肺、經直腸、經陰道、經頰、舌下或鼻內投與)以進行活性成分之經黏膜遞送。Thus, dosage forms comprising the compositions of the present invention can be administered directly to the mucosal surfaces of a patient (including pulmonary, rectal, vaginal, buccal, sublingual or intranasal administration) for transmucosal delivery of the active ingredient.
若向舌下黏膜投與，則本發明之組合物可呈例如上文所描述之舌下錠劑形式，其可包含崩解劑(disintegrant/disintegrating agent)(崩解劑可定義為能夠將此類本發明之組合物的崩解/分散加速至可量測程度的任何材料)，此可例如藉由如下文所描述，當與水性介質接觸時能夠泡脹及/或膨脹之材料實現。If administered to the sublingual mucosa, the compositions of the invention may be in the form of a sublingual tablet, for example, as described above, which may include a disintegrant/disintegrating agent (a disintegrant may be defined as any material capable of accelerating the disintegration/dispersion of such compositions of the invention to a measurable degree), which may be achieved, for example, by a material capable of effervescence and/or swelling when in contact with an aqueous medium, as described below.
或者，本發明之組合物可以本文所描述之粉末形式舌下投與，該粉末可自適當容器(諸如膠囊或藥囊)倒入口中及舌下。Alternatively, the compositions of the invention may be administered sublingually in the form of a powder as described herein, which may be poured into the mouth and under the tongue from a suitable container (such as a capsule or sachet).
若本發明之組合物適合於及/或經調配用於舌下或更特別地鼻內投與，則其較佳以粉末組合物形式投與，其中活性成分之劑量不超過約100 mg。此類舌下及/或經鼻粉末組合物可包含與其他賦形劑摻合之本發明之組合物，或可基本上由如上文所定義之本發明之組合物組成。If the composition of the present invention is suitable for and/or formulated for sublingual or more particularly intranasal administration, it is preferably administered in the form of a powder composition in which the dose of the active ingredient does not exceed about 100 mg. Such sublingual and/or intranasal powder compositions may comprise the composition of the present invention admixed with other excipients, or may consist essentially of the composition of the present invention as defined above.
適合於及/或經調配用於鼻內投與之本發明之組合物較佳藉助於適合於經鼻遞送之給藥構件提供。此類給藥構件在適當施用器之儲集器內可例如含有一種經噴霧乾燥之本發明之粉末組合物，或其可含有兩種或更多種此類組合物。在後一情況下，給藥構件含有兩種或更多種給藥量之該本發明之組合物，該等給藥量將各自含有藥理學有效劑量之活性成分。Compositions of the invention suitable for and/or formulated for intranasal administration are preferably provided by means of a dosing member suitable for nasal delivery. Such dosing members may contain, for example, one spray-dried powder composition of the invention in a reservoir of a suitable applicator, or they may contain two or more such compositions. In the latter case, the dosing member contains two or more dosing amounts of the composition of the invention, each of which will contain a pharmacologically effective amount of the active ingredient.
兩種或更多種本發明之組合物可藉由重複致動包含該給藥構件或與該給藥構件連通之裝置經鼻內投與。因此，本發明之組合物可存在於適當裝置(例如經鼻施用器或分配器(吹入器)，例如下文中所述)內，及/或可存在於容器或儲集器內，該容器或儲集器係此類施用器之一部分、附屬於此類施用器及/或適合附屬於此類施用器。此類容器或儲集器可含有一種或多種本發明之組合物，其各自含有藥理學有效劑量之活性成分。Two or more compositions of the invention may be administered intranasally by repeated actuation of a device comprising or communicating with the administration member. Thus, the compositions of the invention may be present in a suitable device, such as a nasal applicator or dispenser (insufflator), such as described below, and/or may be present in a container or reservoir that is part of, attached to, and/or suitable for being attached to such an applicator. Such a container or reservoir may contain one or more compositions of the invention, each containing a pharmacologically effective amount of an active ingredient.
以此方式，適當的給藥構件及/或經鼻施用器可僅致動一次以在該致動後遞送包含適當劑量活性成分的單一本發明之組合物(亦即，單次使用給藥單位)，可多次致動以在每次此類致動時遞送各自包含適當劑量活性成分的兩種或更多種本發明之組合物(亦即，多次使用給藥單位)，及/或施用器可用包含一種或多種此類組合物的本發明之組合物的替換源(例如容器或儲集器)重新填充，以提供單劑量及/或多次劑量及/或給藥方案。In this way, an appropriate administration component and/or nasal applicator can be actuated only once to deliver a single composition of the present invention containing an appropriate dose of the active ingredient upon such actuation (i.e., a single-use administration unit), can be actuated multiple times to deliver two or more compositions of the present invention, each containing an appropriate dose of the active ingredient upon each such actuation (i.e., multiple-use administration units), and/or the applicator can be refilled with a replacement source of the composition of the present invention (e.g., a container or reservoir) containing one or more such compositions to provide single-dose and/or multiple-dose and/or administration regimens.
因此，本發明之組合物可以複數個粒子之形式投與，該等粒子可單獨地及/或共同地由本發明之組合物組成及/或包含本發明之組合物。Therefore, the composition of the present invention may be administered in the form of a plurality of particles, which may consist of and/or contain the composition of the present invention individually and/or collectively.
本發明之組合物因此可製備(最初)為固體、乾燥、自由流動之粉末形式，如本文所描述。The compositions of the invention may thus be prepared (initially) in the form of a solid, dry, free-flowing powder as described herein.
如上所陳述，本發明之組合物係以非晶形、單微粒粉末形式提供。其並非由呈混合物形式的兩個或更多個離散、單獨的不同成分之粒子集合的物理結合構成，諸如活性成分之較小粒子的有序或相互作用混合物與較大但獨立且化學性質不同之載劑物質粒子結合。亦即，本發明之組合物可以小粒子形式提供，該等小粒子可隨後黏附於相互作用混合物中單獨的較大載劑粒子，且若意欲供吸入之劑型，則此類呈遞可能適用(參見例如《藥物遞送雜誌(J. Drug Delivery)》, 文章ID 5635010, 1-19 (2018))。As stated above, the compositions of the present invention are provided in the form of amorphous, single-particle powders. They are not composed of a physical combination of two or more discrete, separate collections of particles of different components in the form of a mixture, such as an ordered or interacting mixture of smaller particles of active ingredients combined with larger but independent and chemically different particles of carrier substances. That is, the compositions of the present invention can be provided in the form of small particles that can then adhere to separate larger carrier particles in the interactive mixture, and if a dosage form for inhalation is intended, such a presentation may be applicable (see, e.g.,J. Drug Delivery , Article ID 5635010, 1-19 (2018)).
如上文所提及，製造本發明之組合物的方法能夠形成本文所定義的當在正常儲存條件儲存下時在物理及化學穩定性方面均展現出極佳儲放時限之醫藥產品。鑒於在溶液中，已知腎上腺激素在本文所描述之pH值範圍下不穩定且在更低pH值(例如低於約4)下穩定，此在某種程度上係出人意料的。參見例如Connors等人, 《藥物之化學穩定性：藥劑師手冊(Chemical Stability of Pharmaceuticals:A Handbook for Pharmacists)》, John Wiley & Sons, 第2版(1986), 第438至447頁，其揭示可使腎上腺激素之外消旋化及氧化平衡以最大限度地減少溶液中完整藥物之損失的最佳pH值係約pH 3.0-3.8。As mentioned above, the method of making the composition of the present invention enables the formation of a pharmaceutical product that exhibits an excellent shelf life in terms of both physical and chemical stability when stored under normal storage conditions as defined herein. This is somewhat surprising given that in solution, adrenal hormones are known to be unstable at the pH range described herein and stable at lower pH values (e.g., below about 4). See, e.g., Connors et al., Chemical Stability ofPharmaceuticals:A Handbook for Pharmacists, John Wiley & Sons, 2nd edition (1986), pp. 438-447, which discloses that the optimal pH for balancing the racemization and oxidation of adrenal hormones to minimize the loss of intact drug in solution is about pH 3.0-3.8.
然而，本發明之組合物經製備，其可溶於水/水性介質中且當溶解於此類水性介質中時，展現在約4.5與約8.0之間的pH值。較佳之pH值範圍可包括約7.5，諸如約7.0，諸如約6.5及約6.0之上限。較佳之pH值範圍係在約4.5與約6.0之間，諸如約5.9，諸如約5.8，諸如約5.7，諸如約5.6及更大，較佳在約4.5與約5.5之間，其包括約4.6、約4.7、約4.8、約4.9、約5.0、約5.1、約5.2、約5.3及約5.4之特定pH值。However, the compositions of the present invention are prepared so that they are soluble in water/aqueous media and exhibit a pH between about 4.5 and about 8.0 when dissolved in such aqueous media. Preferred pH ranges may include an upper limit of about 7.5, such as about 7.0, such as about 6.5 and about 6.0. Preferred pH ranges are between about 4.5 and about 6.0, such as about 5.9, such as about 5.8, such as about 5.7, such as about 5.6 and greater, preferably between about 4.5 and about 5.5, including specific pH values of about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3 and about 5.4.
pH值亦可原位量測及/或在個體之活體內量測(例如在限定時段內(例如在投與本發明之組合物後約5分鐘內，諸如約3分鐘內，包括約2分鐘內、約1分鐘內或約30秒內)藉由在個體之舌下或鼻孔內量測)。The pH value can also be measured in situ and/or in vivo in a subject (e.g., by measuring under the tongue or in the nostrils of a subject within a defined time period (e.g., within about 5 minutes, such as within about 3 minutes, including within about 2 minutes, within about 1 minute or within about 30 seconds after administration of the composition of the present invention)).
然而，pH值係更佳地離體或在活體外量測，例如藉由將本發明之組合物溶解於水性介質中且量測pH值。因此，pH值可藉由以下方式量測：在或在約室溫(例如約20℃與約28℃之間，諸如約25℃)下，將本發明之組合物溶解於固定體積(諸如約0.1 mL與約5 mL之間，例如約100 mg本發明之組合物於約5 mL中)水性介質中，且接著利用一種或多種標準技術，諸如利用pH探針(例如連接至Schott FlatrodeTM-電極(pH 0-14，0-60℃)之Schott CG 842P pH計)量測pH值。However, pH is better measured ex vivo or in vitro, for example by dissolving the composition of the invention in an aqueous medium and measuring the pH. Thus, pH can be measured by dissolving the composition of the invention in a fixed volume (e.g., between about 0.1 mL and about 5 mL, for example, about 100 mg of the composition of the invention in about 5 mL) of an aqueous medium at or about room temperature (e.g., between about 20° C. and about 28° C., such as about 25° C.), and then measuring pH using one or more standard techniques, such as using a pH probe (e.g., a Schott CG 842P pH meter connected to a Schott Flatrode™ -electrode (pH 0-14, 0-60° C.)
適當水性介質包括水性緩衝液(pH值為約6.8的此類標準磷酸鹽緩衝液)、體液(其可以包括黏液(尤其鼻黏液)、唾液或其他)、模擬體液(其可包括模擬唾液或更佳地模擬或人造鼻黏液，其可自諸如BioChemazone (Alberta, Canada)之供應商購得)，但較佳為基本上純的水(其亦可為等張的)。可溶解本發明之組合物的適當水基介質可以包括注射用水、生理鹽水溶液或較佳地，已例如藉由蒸餾純化或尤其藉由使用例如離子交換過濾系統去離子化的水(例如Milli-Q(MQ)水)。Suitable aqueous media include aqueous buffers (such as standard phosphate buffers with a pH of about 6.8), body fluids (which may include mucus (especially nasal mucus), saliva or others), simulated body fluids (which may include simulated saliva or more preferably simulated or artificial nasal mucus, which can be purchased from suppliers such as BioChemazone (Alberta, Canada), but preferably substantially pure water (which may also be isotonic). Suitable aqueous media in which the compositions of the invention can be dissolved may include water for injection, physiological saline solutions or, preferably, water that has been purified, for example by distillation or, in particular, deionized, for example by using an ion exchange filter system (e.g. Milli-Q (MQ) water).
為了確保本發明之組合物展現在上述範圍中之一者或多者內的pH值，活性成分可以鹽形式提供，諸如在腎上腺激素情況下鹽酸鹽或市售酒石酸鹽(或酒石酸氫鹽)，且在製備本發明之組合物之前，確保對包括活性成分鹽(以及視情況選用之其他必需組分(亦即，麥芽糊精，諸如右旋糖當量(DE)大於15之麥芽糊精，例如麥芽糊精19DE)及/或若存在，非必需組分，諸如一種或多種雙醣及/或蔗糖酯)之含水混合物進行某種pH調節(例如增加)步驟。此可例如藉由在諸如冷凍乾燥或更佳地噴霧乾燥之類用以移除水性溶劑之最終步驟之前，添加適量鹼水溶液，諸如(例如1M)氫氧化鈉進行。根據此方法，鹼之添加可在添加其他必需及/或非必需組分之後進行，但更佳地在添加其他必需及/或非必需組分之前進行，隨後，自該等組分混合物中移除水性溶劑。In order to ensure that the compositions of the present invention exhibit a pH value within one or more of the above ranges, the active ingredient can be provided in the form of a salt, such as a hydrochloride or a commercially available tartaric acid salt (or hydrogen tartrate) in the case of adrenal hormones, and before preparing the composition of the present invention, it is ensured that the aqueous mixture including the active ingredient salt (and optionally other essential components (i.e., maltodextrin, such as maltodextrin with a dextrose equivalent (DE) greater than 15, such as maltodextrin 19DE) and/or if present, non-essential components, such as one or more disaccharides and/or sucrose esters) is subjected to a certain pH adjustment (e.g., increase) step. This can be done, for example, by adding an appropriate amount of an aqueous alkaline solution, such as (e.g. 1 M) sodium hydroxide, prior to a final step such as freeze drying or, more preferably, spray drying to remove the aqueous solvent. According to this method, the addition of the base can be done after the addition of other essential and/or optional components, but is more preferably done before the addition of other essential and/or optional components, and then the aqueous solvent is removed from the mixture of the components.
在一個替代及/或較佳實施例中，本發明之組合物可例如藉由提供呈游離酸/鹼化合物形式之活性成分(諸如腎上腺激素)來製備。在腎上腺激素之情況下，此化合物係市售的，但已知其具有更有限之水溶性。藉由將適量酸水溶液諸如(例如0.1M)鹽酸添加至包括該腎上腺激素(以及視情況選用之其他必需組分(亦即，麥芽糊精，諸如DE大於15之麥芽糊精，例如麥芽糊精19DE)及/或若存在，非必需組分，諸如一種或多種雙醣及/或蔗糖酯)之含水混合物中來使其變得易溶。此後，可在諸如冷凍乾燥或更佳地噴霧乾燥之類用以移除水溶劑之最終步驟之前，使用適量鹼水溶液，諸如(例如0.1M)氫氧化鈉增加pH值。根據此方法，依序添加酸及鹼可在添加其他必需及/或非必需組分之後進行，但更佳在添加其他必需及/或非必需組分之前進行，隨後自該等組分混合物中移除水性溶劑。In an alternative and/or preferred embodiment, the composition of the invention can be prepared, for example, by providing the active ingredient (such as adrenal hormone) in the form of a free acid/base compound. In the case of adrenal hormone, this compound is commercially available, but is known to have more limited water solubility. It is rendered readily soluble by adding an appropriate amount of an aqueous acid solution such as (e.g., 0.1 M) hydrochloric acid to an aqueous mixture comprising the adrenal hormone (and optionally other essential components (i.e., maltodextrin, such as maltodextrin with a DE greater than 15, such as maltodextrin 19DE) and/or, if present, non-essential components such as one or more disaccharides and/or sucrose esters). Thereafter, the pH may be increased using an appropriate amount of aqueous alkaline solution, such as (e.g. 0.1 M) sodium hydroxide, prior to a final step such as freeze drying or, more preferably, spray drying to remove the aqueous solvent. According to this method, the sequential addition of acid and base may be performed after the addition of other essential and/or optional components, but preferably before the addition of other essential and/or optional components, followed by the removal of the aqueous solvent from the mixture of the components.
藉由對上文所描述之混合物(亦即，包含呈本文所描述之鹽形式，諸如氫鹵酸鹽(例如氫氯酸鹽)，或市售酒石酸鹽(或酒石酸氫鹽)，或更佳呈游離酸/鹼化合物形式的活性成分(諸如腎上腺激素)的含水混合物)進行以上所提及之pH調節步驟中之一者或多者，可如上文所描述調節pH值，以使得在例如藉由冷凍乾燥或更佳地，藉由噴霧乾燥移除水性溶劑以製備本發明之組合物之步驟之前的某一時間且較佳在即將進行該步驟之前量測該pH值在本文中所提及之pH值範圍中之一者或多者內。因此，較佳地，pH值量測值係由在移除水性溶劑之步驟之前製備的最終溶液得到。然而，為避免疑問，無論在何時獲取相關pH量測值，亦可在添加必需組分(亦即，麥芽糊精，諸如DE大於15之麥芽糊精，例如麥芽糊精19DE)及/或(若存在)非必需組分，諸如一種或多種雙醣及/或蔗糖酯之前、期間或之後進行pH調節步驟。By subjecting the mixture described above (i.e., an aqueous mixture comprising an active ingredient (e.g., adrenal hormone) in the form of a salt as described herein, such as a hydrohalide (e.g., hydrochlorate), or a commercially available tartaric acid salt (or hydrotartrate), or more preferably in the form of a free acid/base compound) to one or more of the pH adjustment steps mentioned above, the pH value can be adjusted as described above so that the pH value is measured within one or more of the pH value ranges mentioned herein at a certain time before, and preferably immediately before, the step of removing the aqueous solvent to prepare the composition of the invention, for example, by freeze drying or, more preferably, by spray drying. Therefore, preferably, the pH measurement is obtained from the final solution prepared before the step of removing the aqueous solvent. However, for the avoidance of doubt, regardless of when the relevant pH measurement is obtained, the pH adjustment step may be performed before, during or after the addition of the essential components (i.e., maltodextrin, such as maltodextrin with a DE greater than 15, such as maltodextrin 19DE) and/or (if present) non-essential components, such as one or more disaccharides and/or sucrose esters.
本發明之組合物較佳藉由噴霧乾燥方法製備。熟習此項技術者將理解，「噴霧乾燥」方法包括自包括溶液或懸浮液(包括漿料)之液體中產生乾燥粉末之任何方法，其涉及使用熱氣體快速乾燥以將液體流轉化成蒸發溶劑及固體粒子，該等固體粒子包含先前溶解於溶液中之溶質，及/或先前懸浮於蒸發液體中之粒子。The compositions of the present invention are preferably prepared by a spray drying method. Those skilled in the art will understand that a "spray drying" method includes any method of producing a dry powder from a liquid including a solution or a suspension (including a slurry), which involves the use of a hot gas to rapidly dry the liquid to convert it into a vaporized solvent and solid particles comprising a solute previously dissolved in the solution and/or particles previously suspended in the vaporized liquid.
適當噴霧乾燥設備包括某種形式之霧化構件，諸如噴嘴，其將液體分散成具有相對均勻之液滴尺寸的噴霧。此類構件可包括能夠產生乾燥、自由流動之粉末的任何構件，且可包括高壓渦流噴嘴、旋轉盤及/或霧化輪、高壓單流體噴嘴、雙流體噴嘴及/或超音波式噴嘴。Suitable spray drying equipment includes some form of atomizing means, such as a nozzle, which disperses the liquid into a spray having a relatively uniform droplet size. Such means may include any means capable of producing a dry, free-flowing powder, and may include high pressure vortex nozzles, rotating disks and/or atomizing wheels, high pressure single fluid nozzles, dual fluid nozzles, and/or ultrasonic nozzles.
噴霧乾燥器可為單效或多效噴霧乾燥器，且可包含整合式及/或外部振動流體化床、粒子分離器及/或可為轉鼓或旋風器之收集構件。The spray dryer may be a single-effect or multiple-effect spray dryer and may include an integrated and/or external vibrating fluidized bed, a particle separator and/or a collecting member which may be a rotating drum or a cyclone.
揮發性溶劑包括水性溶劑，亦即，包括水之溶劑，必要時，其亦可包括一種或多種有機溶劑作為共溶劑，諸如低碳數烷基醇類(例如甲醇、異丙醇或更特定地，乙醇)、烴類(例如C5-10烷烴)、鹵代烷烴類(例如二氯甲烷)、二甲基甲醯胺、二甲亞碸、乙酸乙酯、丙酮等，或其混合物。The volatile solvent includes an aqueous solvent, that is, a solvent including water, and if necessary, it may also include one or more organic solvents as co-solvents, such as lower alkyl alcohols (e.g., methanol, isopropanol or more specifically, ethanol), hydrocarbons (e.g., C5-10 alkanes), halogenated alkanes (e.g., dichloromethane), dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone, etc., or a mixture thereof.
吾人偏好將一種或多種活性成分、一種或多種本文所定義的醫藥學上可接受之載劑材料及本文所描述的其他視情況選用之成分(例如下文中所描述之烷基醣類)與水性溶劑混合在一起，產生溶液，該溶液可經噴霧乾燥。We prefer to mix one or more active ingredients, one or more pharmaceutically acceptable carrier materials as defined herein and other optional ingredients described herein (such as alkyl saccharides described below) with an aqueous solvent to produce a solution that can be spray dried.
根據本發明之又另一範疇，提供一種用於製造本發明之組合物的方法，其中該方法包含以下步驟： i) 將腎上腺素激導性受體調節劑(例如腎上腺激素)或其醫藥學上可接受之鹽混合或溶解於適當揮發性水性溶劑中， ii) 調節所得溶液之pH值以使得其在上述範圍中之一者或多者內，及/或在約4(諸如約4.5)與約8(諸如約7.5或較佳地約7)之間的範圍內，更佳在約4.2與約6.5之間，諸如在約4.35與約6.0之間，且尤其在約4.5與約5.5之間，及 iii) 對來自步驟ii)之混合物進行噴霧乾燥。According to another aspect of the present invention, a method for preparing the composition of the present invention is provided, wherein the method comprises the following steps: i) mixing or dissolving an adrenergic receptor modulator (e.g., adrenal hormone) or a pharmaceutically acceptable salt thereof in a suitable volatile aqueous solvent, ii) adjusting the pH value of the resulting solution so that it is within one or more of the above ranges, and/or within the range between about 4 (e.g., about 4.5) and about 8 (e.g., about 7.5 or preferably about 7), more preferably between about 4.2 and about 6.5, such as between about 4.35 and about 6.0, and especially between about 4.5 and about 5.5, and iii) The mixture from step ii) is spray dried.
如上所陳述，在以上方法中，醫藥學上可接受之載劑材料及/或其他視情況選用之組分可在步驟i)之後、在步驟ii)之同時及/或之後添加。As described above, in the above method, a pharmaceutically acceptable carrier material and/or other optional components may be added after step i), simultaneously with step ii), and/or after step ii).
用於本發明之組合物中的醫藥學上可接受之載劑材料應為適合(及/或批准)用於醫藥用途及/或經黏膜(例如舌下或尤其鼻內)遞送的，能夠在正常儲存條件下維持其物理及/或化學完整性，及/或不影響活性成分及/或存在於或可存在於組合物中的呈固態之任何其他成分(諸如烷基醣)的物理及/或化學完整性。The pharmaceutically acceptable carrier materials used in the compositions of the present invention should be suitable (and/or approved) for pharmaceutical use and/or transmucosal (e.g., sublingual or especially intranasal) delivery, capable of maintaining their physical and/or chemical integrity under normal storage conditions, and/or not affecting the physical and/or chemical integrity of the active ingredient and/or any other ingredients (such as alkyl sugars) that are or may be present in the composition in a solid state.
眾所周知，在嘗試獲得化學上及物理上均穩定的固體組合物(諸如粉末)時，可能會遇到很大困難。若組合物之物理形式在正常儲存條件下變化(例如從自由流動粉末變為難以排出之聚結物質)，則將可能導致活性成分劑量之不可再現性。當自或經由本文所描述之經鼻施用器分配組合物時，情況尤其如此，在此情況下，此類聚結可能導致完全無法分配活性成分，而此在緊急情況下可能為災難性的。As is well known, great difficulties may be encountered when attempting to obtain chemically and physically stable solid compositions such as powders. If the physical form of the composition changes under normal storage conditions (e.g., from a free-flowing powder to an agglomerated mass that is difficult to discharge), irreproducibility of the dose of the active ingredient may result. This is particularly true when dispensing the composition from or through the nasal applicator described herein, in which case such agglomeration may result in a complete inability to dispense the active ingredient, which may be catastrophic in an emergency situation.
因此，本發明之組合物可具有藉由相對於約80%，諸如約85% (例如約90%)到至多約120% (例如約115%，諸如約110%)之目標重量的個別粉末注射重量及/或相對於約85%，諸如約90% (例如約95%)到至多約115% (例如約110%，諸如約105%)之目標重量的平均粉末注射重量所量測之最小注射重量。Thus, the compositions of the present invention may have a minimum shot weight as measured by individual powder shot weights of about 80%, such as about 85% (e.g., about 90%) to up to about 120% (e.g., about 115%, such as about 110%) relative to a target weight and/or an average powder shot weight of about 85%, such as about 90% (e.g., about 95%) to up to about 115% (e.g., about 110%, such as about 105%) relative to a target weight.
類似地，對於含有兩個或更多個劑量之組合物的多個劑量單元，此類穩定性對於確保活性成分之劑量隨時間的再現性至關重要。此等問題中之任一者可能對個體之健康狀況產生不利影響，及/或使個體之健康處於重大風險下。Similarly, for multiple dosage units of compositions containing two or more dosages, such stability is critical to ensuring the reproducibility of the dosage of the active ingredient over time. Any of these problems may adversely affect the health status of an individual and/or place the health of an individual at significant risk.
對於某些本發明之組合物，暴露於大氣水可能產生固態穩定性較差的粉末組合物。舉例而言，暴露於某些(例如更高)相對濕度可能影響組合物之物理形式，例如藉由潮解，及/或藉由降低組合物及/或組合物之個別組分(諸如載劑材料)之玻璃轉化溫度，或以其他方式影響。For certain compositions of the invention, exposure to atmospheric water may produce a powder composition with poor solid stability. For example, exposure to certain (e.g., higher) relative humidity may affect the physical form of the composition, for example, by deliquescence, and/or by lowering the glass transition temperature of the composition and/or individual components of the composition (e.g., carrier materials), or in other ways.
因此，本發明之組合物以及包括其之醫藥調配物及給藥構件(諸如經鼻施用器)較佳包裝於在本文所定義之儲存條件下實質上防止大氣水進入之容器內。此類容器可包括包裝材料，諸如用於錠劑及膠囊之泡殼包裝及熱密封鋁袋及/或熱成型塑膠。此類容器亦可包含乾燥劑，諸如矽膠及/或適當分子篩，其孔徑為例如3Å或4Å。Therefore, the compositions of the present invention and pharmaceutical formulations and administration devices (such as nasal applicators) comprising the same are preferably packaged in containers that substantially prevent the ingress of atmospheric water under the storage conditions defined herein. Such containers may include packaging materials such as blister packs and heat-sealed aluminum bags and/or thermoformed plastics for tablets and capsules. Such containers may also contain desiccants such as silicone and/or appropriate molecular sieves with a pore size of, for example, 3Å or 4Å.
片語「維持物理及化學完整性」基本上意謂化學穩定性及固態穩定性。The phrase "maintaining physical and chemical integrity" basically means chemical stability and solid-state stability.
「化學穩定性」包括本發明之任何組合物在調配成醫藥調配物或劑型時，及/或當裝載至醫藥給藥構件，諸如經鼻施用器或用於該施用器之儲集器(具有或不具有本文所描述之適當醫藥包裝)或者其他構件中時，在正常儲存條件下，可以經分離之固體形式儲存，其中組合物本身或其中所包括之活性成分的化學降解或分解程度不明顯。"Chemical stability" includes that any composition of the present invention, when formulated into a pharmaceutical formulation or dosage form, and/or when loaded into a pharmaceutical administration device, such as a nasal applicator or a storage container for the applicator (with or without appropriate pharmaceutical packaging as described herein) or other components, can be stored in an isolated solid form under normal storage conditions, wherein the degree of chemical degradation or decomposition of the composition itself or the active ingredients included therein is not obvious.
術語「化學穩定性」亦包括「立體化學(stereochemical)」及/或「組態(configurational)」穩定性，意謂對在活性成分之分子內之一或多個對掌性中心處的立體化學轉化(諸如外消旋)之抗性。在腎上腺激素之情況下，此尤其重要，其中R-鏡像異構物(亦即，L-(-)-腎上腺激素)係活性鏡像異構物，而S-鏡像異構物(亦即，D-(+)-腎上腺激素)活性較低且可能因此被視為雜質。The term "chemical stability" also includes "stereochemical" and/or "configurational" stability, meaning resistance to stereochemical transformations (such as racemization) at one or more chiral centers within the molecule of the active ingredient. This is particularly important in the case of adrenal hormones, where the R-image isomer (i.e., L-(-)-adrenaline) is the active image isomer, while the S-image isomer (i.e., D-(+)-adrenaline) is less active and may therefore be considered an impurity.
「物理穩定性」或「固態穩定性」包括任何本發明之組合物在調配成醫藥調配物或劑型時及/或當裝載至醫藥給藥構件，諸如經鼻施用器或用於該施用器之儲集器(具有或不具有本文所描述的適當醫藥包裝))或者其他構件中時，在正常儲存條件下，可以經分離之固體形式儲存，其中組合物本身或其中所包括之活性成分的固態轉變(例如結晶、再結晶、結晶度損失、固態相變(例如在玻璃態或橡膠態之間轉變，或轉變為聚結形式))、水合、脫水、溶劑化或去溶劑化程度不明顯。"Physical stability" or "solid-state stability" includes that any composition of the present invention, when formulated into a pharmaceutical formulation or dosage form and/or when loaded into a pharmaceutical administration device, such as a nasal applicator or a storage container for the applicator (with or without appropriate pharmaceutical packaging as described herein) or other components, can be stored in an isolated solid form under normal storage conditions, wherein the composition itself or the active ingredient included therein undergoes no significant solid-state transformation (e.g., crystallization, recrystallization, loss of crystallinity, solid-state phase transformation (e.g., transformation between a glassy state or a rubbery state, or transformation to an aggregated form)), hydration, dehydration, solvation or desolvation.
無論呈醫藥調配物形式抑或劑型形式，及/或當裝載至醫藥給藥構件，如裝載至施用器、裝置、藥物儲集器(諸如罐或容器，其可實質上防止大氣水進入，如本文所描述)或者其他構件中時，本發明之組合物的「正常儲存條件」之實例包括在約-50℃與約+80℃之間(較佳在-25℃與約+75℃之間，諸如約50℃)的溫度，及/或在約0.1與約2巴之間(較佳大氣壓)的壓力，及/或暴露於至少約460勒克斯(lux)之UV/可見光，及/或在約5與約95%之間(較佳約10至約40%)的相對濕度，保持延長之時段(亦即，大於或等於約十二個月，諸如約六個月)。Examples of "normal storage conditions" for the compositions of the present invention, whether in pharmaceutical formulation or dosage form, and/or when loaded into a pharmaceutical administration component, such as an applicator, device, drug reservoir (such as a can or container, which can substantially prevent the ingress of atmospheric water, as described herein), or other components, include between about -50°C and about +80°C (preferably between -25°C and about + 75°C, such as about 50°C), and/or a pressure between about 0.1 and about 2 bar (preferably atmospheric pressure), and/or exposure to at least about 460 lux of UV/visible light, and/or a relative humidity between about 5 and about 95% (preferably about 10 to about 40%), for an extended period of time (i.e., greater than or equal to about twelve months, such as about six months).
在此等條件下，可發現在適當時，無論包括在施用器或用於該施用器之儲集器(具有或不具有本文所描述的適當醫藥包裝)抑或其他構件中，本發明之組合物(及/或其中所含活性成分)之化學降解/分解，及/或固態轉變均低於約15%，更佳低於約10%且尤其低於約5%。熟習此項技術者將瞭解，以上提及的溫度及壓力之上限及下限表示正常儲存條件之極值，且在正常儲存(例如50℃之溫度及0.1巴之壓力)期間將不會經歷此等極值之某些組合。Under these conditions, it may be found that, where appropriate, the chemical degradation/decomposition and/or solid-state transformation of the composition of the present invention (and/or the active ingredient contained therein), whether included in the applicator or a reservoir for the applicator (with or without suitable pharmaceutical packaging as described herein) or other components, is less than about 15%, more preferably less than about 10% and especially less than about 5%. Those skilled in the art will appreciate that the upper and lower limits of temperature and pressure mentioned above represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50° C. and a pressure of 0.1 bar).
此類化學且特別是物理穩定性在固態組合物，諸如粉末中極為重要，以確保向患者遞送適當劑量。Such chemical and especially physical stability is extremely important in solid compositions such as powders to ensure that the appropriate dose is delivered to the patient.
儘管有「正常儲存條件」之上述定義，但無論包括在施用器或用於該施用器之儲集器中(其可具有或不具有適當醫藥包裝，及該包裝可提供或可不提供針對水分之屏障，如上文所描述)抑或其他構件，本發明之組合物(及/或其中所含活性成分)可低於約10%，諸如低於約5%，諸如低於約4%(包括低於約3%，諸如低於約2.5%(例如約2%)，包括低於約1.5%，諸如低於約1%，且甚至低於約0.5%)在以下條件下儲存後經歷化學及/或立體化學降解： (a) 在40℃及75%相對濕度下儲存至少約3個月，包括至少約6個月或至少約12個月； (b) 在低於約30℃，諸如約30℃或約25℃下，及/或在例如約65%，諸如約60%的相對濕度下儲存至少約18個月，諸如至少約24個月，包括至少約36個月；及/或 (c) 在高於約1百萬勒克司之UV光下儲存至少約18小時。Notwithstanding the above definition of "normal storage conditions", whether included in an applicator or a reservoir for the applicator (which may or may not have suitable pharmaceutical packaging, and which may or may not provide a barrier to moisture, as described above) or other components, the compositions of the present invention (and/or the active ingredients contained therein) may undergo less than about 10%, such as less than about 5%, such as less than about 4% (including less than about 3%, such as less than about 2.5% (e.g., about 2%), including less than about 1.5%, such as less than about 1%, and even less than about 0.5%) chemical and/or stereochemical degradation after storage under the following conditions:(a) at 40°C and 75% relative humidity for at least about 3 months, including at least about 6 months or at least about 12 months;(b) at a relative humidity of, for example, about 65%, such as about 60%, for at least about 18 months, such as at least about 24 months, including at least about 36 months; and/or(c) under UV light greater than about 1 million lux for at least about 18 hours.
因此，本發明之組合物可以在任何溫度(例如低至約-20℃)到至多約25℃(例如至多約30℃)，較佳地偏移至多約40℃，例如至多約50℃、至多約60℃或甚至是至多約70℃，儲存在劑型中，例如施用器或用於該施用器之儲集器(具有或不具有適當醫藥包裝/防潮屏障)或者其他構件。Thus, the compositions of the present invention can be stored in a dosage form, such as an applicator or a storage container for the applicator (with or without appropriate pharmaceutical packaging/moisture barrier) or other component at any temperature (e.g., as low as about -20°C) up to about 25°C (e.g., up to about 30°C), preferably excursions up to about 40°C, such as up to about 50°C, up to about 60°C or even up to about 70°C.
本發明之組合物包含至少部分由麥芽糊精構成之載劑材料。The composition of the present invention comprises a carrier material which is at least partially composed of maltodextrin.
麥芽糊精可具有15或更低，例如3、4、5、6、7、8或9，較佳地10或11，更佳地12、13、14或15之右旋糖當量(DE)。可提及之特定DE包括DE 15或DE 12。The maltodextrin may have a dextrose equivalent (DE) of 15 or less, for example 3, 4, 5, 6, 7, 8 or 9, preferably 10 or 11, more preferably 12, 13, 14 or 15. Specific DEs that may be mentioned include DE 15 or DE 12.
更佳地，麥芽糊精具有的DE可以高於15，例如至多47，諸如38、39，較佳地23、24、25或26，或更佳地16、17、18、20、21或22，且尤其DE 19。熟習此項技術者應理解，DE高於20的麥芽糊精稱為「葡萄糖糖漿」。More preferably, the maltodextrin may have a DE higher than 15, for example up to 47, such as 38, 39, preferably 23, 24, 25 or 26, or more preferably 16, 17, 18, 20, 21 or 22, and especially DE 19. Those skilled in the art will appreciate that maltodextrin with a DE higher than 20 is referred to as "glucose syrup".
將麥芽糊精按DE分類，其中DE值愈高，葡萄糖鏈之平均長度愈短。因此，DE高於15之麥芽糊精的平均分子量低於DE為15或更低之麥芽糊精的平均分子量。所有麥芽糊精皆為具有不同鏈長之多醣混合物，且DE高於15的麥芽糊精具有較少的較大分子量糖單元。Maltodextrins are classified by DE, where the higher the DE value, the shorter the average length of the glucose chain. Thus, maltodextrins with a DE above 15 have a lower average molecular weight than maltodextrins with a DE of 15 or less. All maltodextrins are mixtures of polysaccharides with varying chain lengths, and maltodextrins with a DE above 15 have fewer larger molecular weight sugar units.
適用於本發明之組合物中之麥芽糊精應具有足夠高之分子量，以使得當該等麥芽糊精以任何給定量使用時，其仍能夠形成適用於活性成分之載劑材料，包括提供適當程度之物理穩定性。Maltodextrins suitable for use in the compositions of the present invention should have a sufficiently high molecular weight so that when used in any given amount, they can still form a suitable carrier material for the active ingredient, including providing an appropriate degree of physical stability.
可用於本發明之組合物中的更佳醫藥學可接受之載劑材料包括相關麥芽糊精與雙醣組分之組合。較佳雙醣包括麥芽糖醇、蔗糖素、蔗糖、異麥芽酮糖醇、麥芽糖，較佳乳糖(包括β-D-乳糖及α-D-乳糖，尤其α-D-乳糖單水合物)，且尤其海藻糖。More preferred pharmaceutically acceptable carrier materials that can be used in the composition of the present invention include combinations of relevant maltodextrins and disaccharide components. Preferred disaccharides include maltitol, sucralose, sucrose, isomalt, maltose, preferably lactose (including β-D-lactose and α-D-lactose, especially α-D-lactose monohydrate), and especially trehalose.
吾人已發現，具有較低DE之麥芽糊精，諸如DE為12或更低之麥芽糊精含有較長的多醣鏈(例如具有大於或等於約24個葡萄糖單元)，其具有形成螺旋結構之傾向，該等螺旋結構在與其他組分(諸如活性成分及/或界面活性劑，如蔗糖酯)一起存在於水性溶液中時可形成聚集體，其在噴霧乾燥之前可能會產生混濁溶液。此等聚集體可能在製造期間產生穩定性及/或可加工性問題，需要使用線上過濾器，及/或不利地影響活性成分之溶解及/或吸收。We have discovered that maltodextrins with lower DE, such as maltodextrins with a DE of 12 or less, contain longer polysaccharide chains (e.g., having greater than or equal to about 24 glucose units) that have a tendency to form helical structures that, when present in aqueous solutions with other components (e.g., active ingredients and/or surfactants, such as sucrose esters), can form aggregates that may produce a turbid solution prior to spray drying. Such aggregates may create stability and/or processability problems during manufacturing, requiring the use of in-line filters, and/or adversely affect the dissolution and/or absorption of the active ingredient.
儘管吾人已經發現，藉由降低包括在本發明之組合物中的麥芽糊精之相對量可以在一定程度上減輕上述聚集體/濁度問題，而降低相對量可以藉由增加其他成分(諸如其他載劑材料，例如雙醣)、活性成分或某些添加劑(例如蔗糖酯)的量來實現，麥芽糊精之分子量越高，需要添加以減小濁度的例如雙醣或蔗糖酯越多。Although we have found that the above-mentioned aggregate/turbidity problem can be alleviated to some extent by reducing the relative amount of maltodextrin included in the composition of the present invention, and reducing the relative amount can be achieved by increasing the amount of other ingredients (such as other carrier materials, such as disaccharides), active ingredients or certain additives (such as sucrose esters), the higher the molecular weight of the maltodextrin, the more disaccharides or sucrose esters, for example, need to be added to reduce turbidity.
若添加較多的蔗糖酯以便減小聚集體之數目及/或此濁度，則可能需要添加比提供適當(例如物理、化學及/或生物)作用(包括吸收增強作用)所需更多的蔗糖酯，如本文所提及。相反地，增加載劑材料中雙醣相對於麥芽糊精之量可對Tg，且因此對本文所描述之組合物之固態穩定性具有負面影響。If more sucrose ester is added in order to reduce the number of aggregates and/or the turbidity, it may be necessary to add more sucrose ester than is required to provide the appropriate (e.g., physical, chemical and/or biological) effects (including absorption enhancement effects), as mentioned herein. Conversely, increasing the amount of disaccharide relative to maltodextrin in the carrier material can have a negative effect on Tg, and therefore on the solid state stability of the compositions described herein.
吾人已發現，藉由一起使用不同麥芽糊精，亦即具有較高CE之麥芽糊精，諸如DE高於15 (例如DE 18、20或更佳19)之麥芽糊精，可減少且可能完全避免此等問題。We have found that by using different maltodextrins together, i.e. maltodextrins with higher CE, such as maltodextrins with DE higher than 15 (e.g. DE 18, 20 or more preferably 19), these problems can be reduced and possibly avoided altogether.
在任何情況下，可使用來自前述雙醣及/或麥芽糊精清單中任一者的混合物，包括DE高於15之麥芽糊精。In any case, mixtures from any of the foregoing lists of disaccharides and/or maltodextrins may be used, including maltodextrins with a DE higher than 15.
可用於本發明之組合物中的載劑材料之總量按組合物之總重量計(無論一次劑量之該組合物係包括在給藥構件中抑或其他構件中)通常在約5重量%至約99.9重量%範圍內，包括至多約99重量%(例如至多約95重量%或約90重量%)，諸如約10重量%(例如約25重量%，包括約35重量%)至約85重量%，包括約50重量%至約75重量%。The total amount of carrier materials that can be used in the compositions of the present invention is generally in the range of about 5 wt % to about 99.9 wt %, including up to about 99 wt % (e.g., up to about 95 wt % or about 90 wt %), such as about 10 wt % (e.g., about 25 wt %, including about 35 wt %) to about 85 wt %, including about 50 wt % to about 75 wt %, based on the total weight of the composition (regardless of whether a single dose of the composition is included in a dosing component or in other components).
無論以材料之組合形式抑或其他形式提供，較佳地，載劑材料能夠產生具有玻璃轉化溫度(Tg)的本發明之組合物，該Tg使得： (a) 能夠將其製造為硬的及/或脆的、「玻璃狀」、非晶形、粉末狀物理形式，可易於調配成醫藥調配物或劑型，及/或裝載至適合之給藥構件中，諸如經鼻施用器，或此類施用器內或附加於此類施用器之藥物儲集器及/或容器；及 (b) 足夠高以使得在此類醫藥調配物、劑型或給藥構件(諸如施用器或儲集器)如上文所描述包裝且隨後經歷較高外部溫度(例如高達約50℃與約80℃之間)之後，其保持在該玻璃態，而非轉變成更黏稠或橡膠態及/或結晶態。Whether provided in the form of a combination of materials or in other forms, preferably, the carrier material is capable of producing a composition of the present invention having a glass transition temperature (Tg) that allows:(a) it to be manufactured into a hard and/or brittle, "glassy", amorphous, powdery physical form that can be easily formulated into a pharmaceutical formulation or dosage form, and/or loaded into a suitable drug delivery device, such as a nasal applicator, or a drug reservoir and/or container in or attached to such an applicator; and(b) High enough so that after such pharmaceutical formulation, dosage form or administration member (such as an applicator or reservoir) is packaged as described above and subsequently subjected to a relatively high external temperature (e.g., up to between about 50°C and about 80°C), it remains in the glassy state rather than transforming into a more viscous or rubbery and/or crystalline state.
在溫暖及/或晴朗的氣候下，可以例如在車輛(例如先遣急救員之車輛)內部經歷此等極端外部溫度，該等車輛將常常在充足日照下停放延長之時段，在此情況下所產生的熱增益可能相當巨大。若本發明之組合物(例如粉末)的Tg較低，則該組合物可在暴露於此類高溫之後轉變成此類黏稠/橡膠態，如此將導致該組合物之給藥效率低下，例如在致動給藥構件或施用器後，即自給藥構件，諸如施用器或其中所含儲集器排出該組合物之效率低下(且活性成分之給藥亦如此)。此外，過低Tg可能影響呈舌下或經口使用之錠劑形式的本發明之組合物的崩解及/或溶解。In warm and/or sunny climates, such extreme external temperatures may be experienced, for example, inside a vehicle (e.g., a first responder vehicle) which will often be parked for extended periods of time in full sun, in which case the heat gain generated may be considerable. If the Tg of a composition (e.g., a powder) of the invention is lower, the composition may transform into such a viscous/rubbery state upon exposure to such high temperatures, which may result in inefficient administration of the composition, e.g., inefficient discharge of the composition from an administration member, such as an applicator or a reservoir contained therein, upon actuation of the administration member or applicator (and also in the administration of the active ingredient). Furthermore, too low a Tg may affect the disintegration and/or dissolution of a composition of the invention in the form of a tablet for sublingual or oral administration.
就此而言，吾人偏好當在至多約35%，諸如至多約30%，包括至多約25%(例如至多約20%，諸如低於約15%，例如低於約10%)之相對濕度下量測時，本發明之組合物的最低可量測Tg為至少約35℃，包括至少約40℃，諸如至少約50℃，諸如至少約55℃，包括至少約60℃。「最低可量測Tg」包括：本發明之組合物可包含在性質上為非均質的粒子。特別地，粒子可包含載劑材料之離散區或其複合混合物，且因此可具有個別及單獨的Tg值。熟習此項技術者應清楚，最低可量測Tg之值對組合物之物理穩定性具有較強影響。In this regard, we prefer that the lowest measurable Tg of the composition of the present invention is at least about 35°C, including at least about 40°C, such as at least about 50°C, such as at least about 55°C, including at least about 60°C, when measured at a relative humidity of up to about 35%, such as up to about 30%, including up to about 25% (e.g., up to about 20%, such as less than about 15%, such as less than about 10%). "Lowest measurable Tg" includes that the composition of the present invention may contain particles that are heterogeneous in nature. In particular, the particles may contain discrete regions of carrier material or a complex mixture thereof, and therefore may have individual and separate Tg values. It will be clear to those skilled in the art that the value of the lowest measurable Tg has a strong impact on the physical stability of the composition.
已發現，本發明之組合物能夠使組合物及活性成分(尤其腎上腺激素及其鹽)產生適當水平之物理及化學穩定性。事實上，特定言之，與當前用於治療過敏性反應的包含腎上腺激素之市售產品(如EpiPen)相比，化學穩定性之程度特別顯著，且與此項技術中之一般理解形成鮮明對比(其中，如上所提及的，揭示腎上腺激素在本文所描述之較高pH值範圍內不穩定，且僅在較低pH值(例如低於約4)下穩定)。It has been found that the compositions of the present invention are capable of imparting an appropriate level of physical and chemical stability to the compositions and active ingredients, particularly adrenal hormones and salts thereof. In fact, in particular, the degree of chemical stability is particularly remarkable compared to currently marketed products containing adrenal hormones for the treatment of allergic reactions, such as the EpiPen, and in stark contrast to the general understanding in the art (where, as mentioned above, adrenal hormones are disclosed to be unstable within the higher pH range described herein, and are only stable at lower pH values (e.g., below about 4)).
載劑材料之尤其較佳的組合包括海藻糖及DE高於15之麥芽糊精，例如麥芽糊精19DE。吾人已發現，此類載劑材料之組合可與活性成分以及(若存在)適當比例之烷基醣類一起噴霧乾燥，以產生本文所定義的在正常儲存條件下具有所需物理及化學穩定性兩者的本發明之組合物。A particularly preferred combination of carrier materials comprises trehalose and maltodextrin with a DE above 15, for example maltodextrin 19DE. We have found that such a combination of carrier materials can be spray dried with the active ingredient and, if present, an appropriate proportion of alkyl sugars to produce a composition of the invention as defined herein having both the desired physical and chemical stability under normal storage conditions.
當用作載劑材料之基礎時，吾人已發現，雙醣及麥芽糊精成分之相對量可經調適以確保活性成分所需水平之物理及/或化學穩定性，同時不會以影響其物理穩定性的方式降低本發明之組合物之Tg。When used as the basis for carrier materials, we have found that the relative amounts of the disaccharide and maltodextrin components can be adjusted to ensure the desired level of physical and/or chemical stability of the active ingredient, while not lowering the Tg of the composition of the invention in a way that affects its physical stability.
吾人已發現，取決於所用活性成分，按組合物之總重量計，約50:1至約1:50重量比的雙醣:麥芽糊精可以起作用。按組合物之總重量計，較佳比率在約10:1至約1:40範圍內(包括至多約1:30或至多約1:20)，例如約7:1(包括約5:1，諸如約4:1、約3:1或約2:1)與約1:10(諸如約1:8，包括約1:5，例如1:3或1:2)之間，更佳為約8:1(例如約7:1、約6:1、約5:1、約4:1、約3:1、約2:1或約1:1)低至約1:8(例如低至約1:7、約1:6、約1:5、約1:4、約1:3、約1:2或約1:1)的雙醣:麥芽糊精重量比。可以提及的雙醣:麥芽糊精之更特定比率包括約7:1、約6:1、約5:1、約4:1、約3:1、約2.5:1、約2.25:1、約2:1、約1.75:1、約1.5:1、約1.25:1、約1:1、約1:1.25、約1:1.5、約1:1.75、約1:2、約1:2.25、約1:2.5，更佳地約2:1、約1.5:1或約1.75:1。We have found that a weight ratio of about 50:1 to about 1:50 disaccharide:maltodextrin, based on the total weight of the composition, works, depending on the active ingredient used. Based on the total weight of the composition, preferred ratios are in the range of about 10:1 to about 1:40 (including up to about 1:30 or up to about 1:20), such as about 7:1 (including about 5:1, such as about 4:1, about 3:1 or about 2:1) and about 1:10 (such as about 1:8, including about 1:5, such as 1:3 or 1:2), more preferably about 8:1 (e.g., about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1 or about 1:1) as low as about 1:8 (e.g., as low as about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2 or about 1:1) disaccharide:maltodextrin weight ratio. More specific ratios of disaccharide:maltodextrin that may be mentioned include about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.25:1, about 2:1, about 1.75:1, about 1.5:1, about 1.25:1, about 1:1, about 1:1.25, about 1:1.5, about 1:1.75, about 1:2, about 1:2.25, about 1:2.5, more preferably about 2:1, about 1.5:1 or about 1.75:1.
無論其在最終混合物中之比例如何，本發明之組合物可藉由如下製備：對相關成分進行噴霧乾燥以形成複合載劑材料，隨後對該載劑材料以及其他必需成分進行噴霧乾燥以形成本發明之粉末組合物。更佳地，本發明之組合物可藉由一起對本發明之組合物之所有必需組分進行噴霧乾燥來原位製備。Regardless of their proportions in the final mixture, the composition of the present invention can be prepared by spray drying the relevant ingredients to form a composite carrier material, followed by spray drying the carrier material and other necessary ingredients to form the powder composition of the present invention. More preferably, the composition of the present invention can be prepared in situ by spray drying all necessary components of the composition of the present invention together.
腎上腺素激導性受體調節劑或其鹽之組合可用於本發明之組合物中。Combinations of adrenaline agonist receptor modulators or salts thereof can be used in the compositions of the present invention.
腎上腺素激導性受體調節劑之鹽包括此項技術中已知且針對醫學文獻(諸如《馬丁代爾大藥典(Martindale - The Complete Drug Reference)》, 第40版，Pharmaceutical Press, London (2020))及其中所提及之文獻(所有文獻中之相關揭示內容以引用的方式併入本文中)中所討論之藥物所描述的任何此類鹽。Salts of adrenergic receptor modulators include any such salts known in the art and described for drugs discussed in the medical literature (such asMartindale - The Complete Drug Reference , 40th edition, Pharmaceutical Press, London (2020)) and references mentioned therein (all relevant disclosures in the references are incorporated herein by reference).
除此以外，醫藥學上可接受之鹽包括酸加成鹽及鹼加成鹽，該等鹽可藉由習知方式形成，例如藉由使游離酸或游離鹼形式之相關活性成分與一個或多個當量之適當酸或鹼，視情況在溶劑中，或在該鹽不可溶之介質中反應，隨後使用標準技術(例如在真空中、藉由冷凍乾燥或藉由過濾)移除該溶劑或該介質。亦可使用熟習此項技術者已知之技術來製備鹽，諸如藉由例如使用適合離子交換樹脂將呈鹽形式的本發明化合物之抗衡離子與另一種抗衡離子交換來製備。In addition, pharmaceutically acceptable salts include acid addition salts and base addition salts, which can be formed by known means, for example, by reacting the relevant active ingredient in free acid or free base form with one or more equivalents of the appropriate acid or base, as the case may be, in a solvent, or in a medium in which the salt is insoluble, followed by removal of the solvent or the medium using standard techniques (e.g., in vacuo, by freeze drying or by filtration. Salts can also be prepared using techniques known to those skilled in the art, such as by exchanging the counter ion of a compound of the invention in salt form with another counter ion, for example, using a suitable ion exchange resin.
可提及之酸加成鹽包括以下各酸之酸加成鹽： • 有機酸，包括： o 脂族羧酸，諸如甲酸鹽、乙酸鹽、丙酸鹽、己酸鹽、辛酸鹽、癸酸鹽、十二烷酸鹽、油酸鹽及硬脂酸鹽； o 芳族羧酸，諸如苯甲酸鹽、萘甲酸鹽及其衍生物(包括羥基萘甲酸鹽(hydroxynaphthoate/xinafoate)及雙羥萘酸鹽)、水楊酸鹽及扁桃酸鹽； o 多官能羧酸，諸如草酸鹽、檸檬酸鹽、富馬酸鹽、依地酸鹽(edetate salt)、蘋果酸鹽、馬來酸鹽、半乳糖二酸鹽及琥珀酸鹽； o 羥基羧酸，諸如酒石酸鹽、酒石酸氫鹽、葡庚糖酸鹽、葡糖酸鹽及其衍生物(包括乳糖酸鹽)、乙醇酸鹽、乳酸鹽及聚半乳糖醛酸鹽； • 烷基磺酸或芳基磺酸，包括甲烷磺酸鹽(甲磺酸鹽)、甲基硫酸氫鹽、乙烷磺酸鹽(乙磺酸鹽)、三氟甲基磺酸鹽(三氟甲磺酸鹽)、2-羥基乙烷磺酸鹽(羥乙磺酸鹽)及其酯、苯磺酸鹽(benzenesulfonate/besylate)、甲苯磺酸鹽(toluenesulfonate/tosylate)、萘磺酸鹽(naphthalenesulfonate/napsylate)及樟腦磺酸鹽(camphorsulfonate/camsylate)； • 胺基酸，包括天冬胺酸鹽、麩胺酸鹽及泛酸鹽；及 • 其他酸，包括8-氯茶酸鹽(茶氯酸鹽)；及 • 無機酸，包括： o 氫鹵酸鹽，諸如氫氟酸鹽、氫氯酸鹽、氫溴酸鹽、氫碘酸鹽及其類似物； o 硫酸鹽，諸如硫酸鹽及硫酸氫鹽； o 磷酸鹽，諸如磷酸鹽及二磷酸鹽；硝酸鹽； o 硼酸鹽；及 o 碳酸鹽，諸如碳酸鹽及碳酸氫鹽。Acid addition salts that may be mentioned include acid addition salts of the following acids: • Organic acids, including: o Aliphatic carboxylic acids, such as formates, acetates, propionates, caproates, octanoates, decanoates, dodecanoates, oleates and stearates; o Aromatic carboxylic acids, such as benzoates, naphthoates and their derivatives (including hydroxynaphthoate/xinafoate and bis(hydroxynaphthoate)), salicylates and mandelates; o Polyfunctional carboxylic acids, such as oxalates, citrates, fumarates, edetates, hydroxynaphthoates and hydroxynaphthoates; salt), apple salt, maleate salt, galactarate salt and succinate salt;o Hydroxycarboxylic acids, such as tartrate, bitartrate, glucoheptonate, gluconate and its derivatives (including lactobionate), glycolate, lactate and polygalacturonate;• Alkyl or aryl sulfonic acids, including methanesulfonate (mesylate), methylhydrosulfate, ethanesulfonate (ethanesulfonate), trifluoromethanesulfonate (trifluoromethanesulfonate), 2-hydroxyethanesulfonate (hydroxyethanesulfonate) and their esters, benzenesulfonate (benzenesulfonate/besylate), toluenesulfonate (toluenesulfonate/tosylate), naphthalenesulfonate (naphthalenesulfonate/napsylate) and camphorsulfonate (camsylate);• Amino acids, including aspartate, glutamine and pantothenate; and• Other acids, including 8-chlorotheoate (theocyanate); and• Inorganic acids, including:o Hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodates and the like;o Sulphates, such as sulphates and hydrosulphates;o Phosphates, such as phosphates and diphosphates; Nitrates;o Borates; ando Carbonates, such as carbonates and bicarbonates.
可提及之特定酸加成鹽包括羧酸鹽，諸如琥珀酸鹽、酒石酸鹽、甲酸鹽、乙酸鹽、苯甲酸鹽、草酸鹽、富馬酸鹽、馬來酸鹽及其類似鹽；磺酸鹽，諸如甲烷磺酸鹽、乙烷磺酸鹽、甲苯磺酸鹽及其類似鹽；鹵酸鹽，諸如氫氯酸鹽、氫溴酸鹽及其類似鹽；硫酸鹽及磷酸鹽，諸如硫酸鹽或磷酸鹽，及其類似鹽。Specific acid addition salts that may be mentioned include carboxylates such as succinates, tartrates, formates, acetates, benzoates, oxalates, fumarates, maleates and the like; sulfonates such as methanesulfonates, ethanesulfonates, toluenesulfonates and the like; halide salts such as hydrochlorates, hydrobromides and the like; sulfates and phosphates such as sulfates or phosphates, and the like.
較佳之酸加成鹽包括無機酸加成鹽，更特定地氫鹵酸鹽，諸如氫溴酸鹽，且更特定地氫氯酸鹽。Preferred acid addition salts include inorganic acid addition salts, more particularly hydrohalides, such as hydrobromates, and more particularly hydrochlorides.
可提及的腎上腺激素之特定鹽包括氫氯酸鹽及酒石酸氫鹽。Specific salts of adrenal hormones that may be mentioned include hydrochloride and bitartrate.
在本發明之另一實施例中，本發明之組合物可基本上不含酒石酸及/或酒石酸根離子，其包括小於約10%，諸如小於約6%，包括小於約5%，或小於約4%，更佳小於約3%，諸如小於約2%，例如小於約1%、小於約0.1%，包括小於約0.01%，諸如小於約0.001%或甚至小於約0.0001%(按重量計)之組合物包含酒石酸及/或酒石酸根離子。In another embodiment of the present invention, the composition of the present invention may be substantially free of tartaric acid and/or tartrate ions, including less than about 10%, such as less than about 6%, including less than about 5%, or less than about 4%, more preferably less than about 3%, such as less than about 2%, for example less than about 1%, less than about 0.1%, including less than about 0.01%, such as less than about 0.001% or even less than about 0.0001% (by weight) of the composition containing tartaric acid and/or tartrate ions.
當本發明之組合物係藉由上文所描述的基於溶劑之方法(包括藉助於噴霧乾燥之方法)製造時，此可能會使活性成分之存在形式不再為結晶鹽形式，因為其以非晶形式自由分散於載劑材料內且由載劑材料囊封。然而，儘管並非通常在典型固態混合物及/或粉末組合物之情況下通常所呈現之結晶鹽形式，但本發明之組合物可在本文所提及之正常儲存條件下使該活性成分之化學穩定性極少損失或無損失。When the composition of the present invention is prepared by the solvent-based method described above (including the method by spray drying), this may cause the active ingredient to exist in a form other than a crystalline salt form, because it is freely dispersed in the carrier material in an amorphous form and encapsulated by the carrier material. However, although it is not a crystalline salt form that is usually present in typical solid mixtures and/or powder compositions, the composition of the present invention can be stored under the normal storage conditions mentioned herein with little or no loss of chemical stability of the active ingredient.
可用於單次劑量的本發明之組合物中的活性成分之量必須足以發揮其藥理學作用。對於經黏膜(例如舌下、經頰且特定言之鼻內)投與的本發明之組合物，該量在單次劑量中不應超過約100 mg。以上所提及之相關活性成分的實際劑量包括此項技術中已知且針對醫學文獻(諸如《馬丁代爾大藥典》, 第40版，Pharmaceutical Press, London (2020))及其中所提及之文獻中所討論之藥物所描述的劑量，所有文獻中之相關揭示內容以引用的方式併入本文中。然而，與包含相同活性成分之先前技術組合物相比，可發現本發明之組合物展現出良好生物可用性及/或快速吸收，從而引起更快速起效及/或更高血漿濃度。The amount of active ingredient in the composition of the present invention that can be used in a single dose must be sufficient to exert its pharmacological effect. For compositions of the present invention administered transmucosally (e.g., sublingually, transbuccally, and specifically intranasally), the amount should not exceed about 100 mg in a single dose. The actual dosages of the relevant active ingredients mentioned above include dosages known in the art and described for drugs discussed in the medical literature (e.g., Martindale's Pharmacopoeia, 40th edition, Pharmaceutical Press, London (2020)) and the literature mentioned therein, and the relevant disclosures in all literature are incorporated herein by reference. However, compared to prior art compositions comprising the same active ingredient, it may be found that the compositions of the present invention exhibit good bioavailability and/or rapid absorption, thereby leading to a faster onset of action and/or a higher plasma concentration.
在此方面，藥理學上適當量的本發明之組合物中之活性成分可低於文獻中所提及之量(參見上文)。儘管如此，此類量可藉由熟習此項技術者確定且可隨待治療之病況的類型及嚴重程度及最適於個別患者之情況而變化。此亦可能隨調配物之性質以及待治療之病況的類型及嚴重程度，以及待治療之特定患者的年齡、體重、性別、腎功能、肝功能及反應而變化。In this regard, the pharmacologically appropriate amount of the active ingredient in the composition of the present invention may be lower than the amount mentioned in the literature (see above). Nevertheless, such amounts can be determined by one skilled in the art and may vary with the type and severity of the condition to be treated and the circumstances that are most suitable for the individual patient. This may also vary with the nature of the formulation and the type and severity of the condition to be treated, as well as the age, weight, sex, renal function, liver function and response of the specific patient to be treated.
取決於活性成分之效力，且取決於待使用之最終劑型，可用於本發明之組合物中之活性成分的總量按組合物之總重量計可在約0.0002重量%，例如約0.001重量%，諸如約0.01重量%，包括約0.1重量% (例如約1重量%、約2重量%或約5重量%)，諸如約10重量% (例如約20重量%)到至多約95重量%，諸如約75重量%，例如約50重量%，例如約40重量%之範圍內。此與最初存在於根據本發明之給藥構件中的組合物之單獨劑量之數目(該等劑量應為相同的)無關。Depending on the potency of the active ingredient, and on the final dosage form to be used, the total amount of active ingredients that can be used in the composition of the present invention can be in the range of about 0.0002 wt %, such as about 0.001 wt %, such as about 0.01 wt %, including about 0.1 wt % (e.g. about 1 wt %, about 2 wt % or about 5 wt %), such as about 10 wt % (e.g. about 20 wt %) to up to about 95 wt %, such as about 75 wt %, such as about 50 wt %, such as about 40 wt %, based on the total weight of the composition. This is independent of the number of individual doses of the composition that are initially present in the administration means according to the present invention (these doses should be the same).
對於經黏膜，包括經肺、經頰、舌下或較佳鼻內投與，每公斤體重之活性成分的適當劑量(以游離酸/鹼計算)在約1 µg/kg (諸如約2 µg/kg，包括約3 µg/kg、約5 µg/kg或約6 µg/kg)到至多約15 µg/kg (諸如約13 µg/kg，包括約12 µg/kg，諸如約10 µg/kg或約8 µg/kg)之範圍內。For transmucosal, including pulmonary, buccal, sublingual or preferably intranasal administration, a suitable dosage of the active ingredient per kilogram body weight (calculated as free acid/base) is in the range of about 1 µg/kg (e.g. about 2 µg/kg, including about 3 µg/kg, about 5 µg/kg or about 6 µg/kg) up to about 15 µg/kg (e.g. about 13 µg/kg, including about 12 µg/kg, such as about 10 µg/kg or about 8 µg/kg).
在替代方案中，取決於所用活性成分，每單位劑量之活性成分的適當劑量(以游離酸/鹼計算)在約1 µg (例如約10 µg，諸如約250 µg)至約100 mg (例如約80 mg)之範圍內，諸如在約1 mg與約60 mg之間(例如約3 mg，諸如約10 mg至約50 mg)。In alternative embodiments, depending on the active ingredient used, a suitable dosage of the active ingredient per unit dose (calculated as free acid/base) is in the range of about 1 µg (e.g. about 10 µg, such as about 250 µg) to about 100 mg (e.g. about 80 mg), such as between about 1 mg and about 60 mg (e.g. about 3 mg, such as about 10 mg to about 50 mg).
當經黏膜，包括經肺、經頰、舌下或較佳鼻內投與成年患者時，腎上腺激素之特定劑量(以游離鹼計算)在約0.1 mg(例如約0.5 mg)到至多約10 mg，諸如至多約5 mg，包括至多約3 mg或至多約2 mg(例如至多約1.9 mg、約1.8 mg、約1.7 mg、約1.6 mg或至多約1.5 mg，包括至多約1.4 mg、約1.3 mg、約1.2 mg、約1.1 mg，諸如約1 mg，或約0.8 mg)範圍內。When administered to adult patients transmucosally, including transpulmonary, transbuccal, sublingually or preferably intranasally, the specific dose of adrenal hormone (calculated as free base) is in the range of about 0.1 mg (e.g., about 0.5 mg) to up to about 10 mg, such as up to about 5 mg, including up to about 3 mg or up to about 2 mg (e.g., up to about 1.9 mg, about 1.8 mg, about 1.7 mg, about 1.6 mg or up to about 1.5 mg, including up to about 1.4 mg, about 1.3 mg, about 1.2 mg, about 1.1 mg, such as about 1 mg, or about 0.8 mg).
當經黏膜，包括經肺、經頰、舌下或較佳鼻內投與兒科患者時，腎上腺激素之特定劑量(以游離鹼計算)在約0.05 mg(例如約0.25 mg)到至多約5 mg，諸如至多約2.5 mg，包括至多約1.5 mg或至多約1 mg(例如至多約0.95 mg、約0.9 mg、約0.85 mg、約0.8 mg或至多約0.75 mg，包括至多約0.7 mg、約0.65 mg、約0.6 mg、約0.55 mg，諸如約0.5 mg，或約0.45 mg或約0.4 mg)範圍內。When administered to pediatric patients transmucosally, including transpulmonary, transbuccal, sublingual or preferably intranasally, the specific dose of adrenal hormone (calculated as free base) is in the range of about 0.05 mg (e.g., about 0.25 mg) to up to about 5 mg, such as up to about 2.5 mg, including up to about 1.5 mg or up to about 1 mg (e.g., up to about 0.95 mg, about 0.9 mg, about 0.85 mg, about 0.8 mg or up to about 0.75 mg, including up to about 0.7 mg, about 0.65 mg, about 0.6 mg, about 0.55 mg, such as about 0.5 mg, or about 0.45 mg or about 0.4 mg).
舉例而言，可藉助於包括下文具體描述之組合物的組合物鼻內遞送約0.5 mg、約1 mg或約2 mg劑量之腎上腺激素(以游離鹼計算)。在替代方案中，超過該等量(諸如大於約1 mg)之劑量可藉助於將更大量之相關組合物預先裝載至鼻用裝置(亦即，增加「填充重量」，見下文)中以便提供更高預定劑量之腎上腺激素來遞送，該鼻用裝置包括如本文所定義之鼻施用器。For example, a dose of about 0.5 mg, about 1 mg, or about 2 mg of adrenal hormone (calculated as free base) may be delivered intranasally by means of a composition comprising the compositions described in detail below. In the alternative, doses exceeding such amounts (e.g., greater than about 1 mg) may be delivered by pre-loading a greater amount of the relevant composition into a nasal device (i.e., increasing the "fill weight", see below) in order to provide a higher predetermined dose of adrenal hormone, the nasal device comprising a nasal applicator as defined herein.
對於其他投與形式(例如藉由注射或經口投與)，取決於所用活性成分，每單位劑量之活性成分的適當劑量(以游離酸/鹼計算)在約1 μg至約500 mg之範圍內(例如約400 mg)，諸如在約1 mg與約300 mg之間(例如約1 mg、約3 mg，諸如約10 mg至約200 mg)。For other forms of administration (e.g., by injection or oral administration), depending on the active ingredient used, a suitable dosage of the active ingredient per unit dose (calculated as free acid/base) is in the range of about 1 μg to about 500 mg (e.g., about 400 mg), such as between about 1 mg and about 300 mg (e.g., about 1 mg, about 3 mg, such as about 10 mg to about 200 mg).
對於腎上腺激素及其鹽，當經由除經黏膜外之途徑投與時，可用於本發明之組合物中之特定劑量(在各情況下以游離鹼化合物計算)包括約0.1 mg至約10 mg，諸如約5 mg，包括約3 mg或約2 mg(例如約1 mg)。For adrenal hormones and salts thereof, when administered by a route other than transmucosal administration, specific dosage amounts useful in the compositions of the invention (in each case calculated as the free base compound) include about 0.1 mg to about 10 mg, such as about 5 mg, including about 3 mg or about 2 mg (e.g. about 1 mg).
如上文所提及，本發明之組合物亦可包括一種或多種烷基醣類，或亦可與一種或多種烷基醣類一起投與。與不包括例如烷基醣類及/或包括已知充當界面活性劑之不同賦形劑的相應組合物相比，發現本發明之組合物可在此方面展現出人意料地良好生物可用性及吸收速度。As mentioned above, the compositions of the present invention may also include one or more alkyl saccharides, or may also be administered together with one or more alkyl saccharides. Compared to corresponding compositions that do not include, for example, alkyl saccharides and/or include different excipients known to act as surfactants, it has been found that the compositions of the present invention can exhibit unexpectedly good bioavailability and absorption rate in this regard.
可用烷基醣類包括烷基糖苷，其可定義為藉由與烷基之鍵聯接合的任何糖，諸如C7-18烷基糖苷。因此，烷基糖苷可包括烷基麥芽糖苷(諸如十二烷基麥芽糖苷)、烷基葡糖苷、烷基蔗糖苷(alkyl sucroside)、烷基硫代麥芽糖苷(alkyl thiomaltoside)、烷基硫代葡糖苷(alkyl thioglucoside)、烷基硫代蔗糖(alkyl thiosucrose)及烷基麥芽三糖苷(alkyl maltotrioside)。然而，吾人偏好烷基醣為糖酯。Useful alkyl carbohydrates include alkyl glycosides, which can be defined as any sugar linked to an alkyl group, such asC7-18 alkyl glycosides. Thus, alkyl glycosides can include alkyl maltosides (such as dodecyl maltoside), alkyl glucosides, alkyl sucrosides, alkyl thiomaltosides, alkyl thioglucosides, alkyl thiosucroses, and alkyl maltotriosides. However, we prefer that the alkyl carbohydrate is a sugar ester.
可用於本發明之組合物中之糖酯包括三醣酯，諸如棉子糖酯；單醣酯，諸如葡萄糖酯、半乳糖酯及果糖酯；及/或較佳地雙醣酯，諸如麥芽糖酯、乳糖酯、海藻糖酯，及尤其一種或多種蔗糖酯。Sugar esters that can be used in the compositions of the present invention include trisaccharide esters, such as raffinose esters; monosaccharide esters, such as glucose esters, galactose esters and fructose esters; and/or preferably disaccharide esters, such as maltose esters, lactose esters, trehalose esters, and especially one or more sucrose esters.
可用於本發明之組合物中之蔗糖酯具有在6與20之間的親水性親脂性平衡值。術語「親水-親脂性平衡值」(HLB)係熟習此項技術者充分理解的技術術語(參見例如「HLB系統：簡明乳化劑選擇指南(The HLB System:A Time-Saving Guide to Emulsifier Selection)」, ICI Americas Inc出版, 1976 (1980年修訂)，在該文件第7章(第20-21頁)中提供測定HLB值之方法)。蔗糖酯中之脂肪酸鏈愈長及酯化程度愈高，HLB值就愈低。較佳HLB值在10與20之間，更佳在12與20之間。The sucrose esters that can be used in the compositions of the present invention have a hydrophilic-lipophilic balance value between 6 and 20. The term "hydrophilic-lipophilic balance value" (HLB) is a technical term that is well understood by those skilled in the art (see, for example, "The HLB System:A Time-Saving Guide to Emulsifier Selection ", published by ICI Americas Inc, 1976 (revised in 1980), which provides a method for determining the HLB value in Chapter 7 (pages 20-21)). The longer the fatty acid chain in the sucrose ester and the higher the degree of esterification, the lower the HLB value. The preferred HLB value is between 10 and 20, and more preferably between 12 and 20.
因此，蔗糖酯包括C8-22飽和或不飽和脂肪酸酯，較佳飽和脂肪酸酯，且較佳C10-18脂肪酸酯，且最佳C12脂肪酸酯。可形成此類蔗糖酯的尤其適合之脂肪酸包括芥子酸、二十二烷酸、油酸、硬脂酸、棕櫚酸、肉豆蔻酸及月桂酸。尤其較佳之此類脂肪酸為月桂酸。可商購的蔗糖酯包括以Surfhope®及Ryoto® (Mitsubishi-Kagaku Foods Corporation, Japan)商標出售之蔗糖酯。Thus, sucrose esters include C8-22 saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters, and preferably C10-18 fatty acid esters, and most preferably C12 fatty acid esters. Particularly suitable fatty acids that can form such sucrose esters include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristic acid and lauric acid. Particularly preferred such fatty acids are lauric acid. Commercially available sucrose esters include sucrose esters sold under the Surfhope® and Ryoto® (Mitsubishi-Kagaku Foods Corporation, Japan) trademarks.
蔗糖酯可為脂肪酸之二酯或單酯，較佳單酯，諸如蔗糖單月桂酸酯。熟習此項技術者將瞭解，術語「單月桂酸酯」係指月桂酸之單酯，且術語「月桂酸酯(lauric acid ester)」及「月桂酸酯(laurate)」具有相同含義且可因此可互換地使用。可商購的蔗糖單月桂酸酯產物亦有時被稱作「蔗糖月桂酸酯」。可含有少量二酯及/或高級蔗糖酯以及微量其他蔗糖酯及游離蔗糖的可商購之蔗糖單月桂酸酯(或蔗糖月桂酸酯)產品，諸如Surfhope ® D-1216 (Mitsubishi-Kagaku Foods Corporation, Japan)，適合用於本發明。熟習此項技術者將理解，本文中對特定蔗糖酯之任何提及包括包含該蔗糖酯作為主要組分之可商購的產品。The sucrose ester may be a diester or a monoester of a fatty acid, preferably a monoester, such as sucrose monolaurate. Those skilled in the art will appreciate that the term "monolaurate" refers to a monoester of lauric acid, and that the terms "lauric acid ester" and "laurate" have the same meaning and may therefore be used interchangeably. Commercially available sucrose monolaurate products are also sometimes referred to as "sucrose laurate." Commercially available sucrose monolaurate (or sucrose laurate) products, such as Surfhope® D-1216 (Mitsubishi-Kagaku Foods Corporation, Japan), which may contain small amounts of diesters and/or higher sucrose esters and trace amounts of other sucrose esters and free sucrose, are suitable for use in the present invention. Those skilled in the art will understand that any reference herein to a particular sucrose ester includes commercially available products comprising that sucrose ester as a major component.
較佳蔗糖酯僅含有一種蔗糖酯，此意謂單一蔗糖酯(例如可商購的蔗糖酯產品)含有單一蔗糖酯作為主要組分(可商購的產品可能含有雜質，例如單酯產品可能含有少量二酯及/或高級酯，此類產品在本發明之情形中可被視為「僅含有一種蔗糖酯」)。如本文中所用，術語「主要組分」應理解為指中之主要組分(例如以重量/重量或體積/體積計，大於約50%，諸如約70%)，該蔗糖酯之混合物諸如為通常可商購的界面活性劑產品，其通常以某一範圍之酯組合物出售。Preferred sucrose esters contain only one sucrose ester, which means that a single sucrose ester (e.g., a commercially available sucrose ester product) contains a single sucrose ester as the main component (commercially available products may contain impurities, e.g., a monoester product may contain a small amount of diesters and/or higher esters, and such products may be regarded as "containing only one sucrose ester" in the context of the present invention). As used herein, the term "main component" should be understood to refer to the main component (e.g., greater than about 50%, such as about 70%, by weight/weight or volume/volume), and the mixture of sucrose esters is such as a commonly available commercial surfactant product, which is usually sold with a range of ester compositions.
尤其較佳蔗糖酯為蔗糖單月桂酸酯。A particularly preferred sucrose ester is sucrose monolaurate.
無論包括在本發明之組合物內還是包括在包括一種或多種本發明組合物之最終劑型中，可用烷基醣之量按組合物之總重量計可在約0.1重量%至約10重量%，諸如約0.5重量%至約5重量%，較佳地約0.75重量%至約4.5重量%(例如至約4重量%，諸如約3重量%，包括約2.5重量%，諸如約2重量%，例如1.5重量%，諸如約1重量%)範圍內。Whether included in the composition of the present invention or in a final dosage form including one or more compositions of the present invention, the amount of alkyl sugar available can be in the range of about 0.1 wt % to about 10 wt %, such as about 0.5 wt % to about 5 wt %, preferably about 0.75 wt % to about 4.5 wt % (e.g. to about 4 wt %, such as about 3 wt %, including about 2.5 wt %, such as about 2 wt %, for example 1.5 wt %, such as about 1 wt %) based on the total weight of the composition.
此外，視情況，其他賦形劑亦可用於包括一種或多種(另外的)界面活性劑的本發明之組合物內或與本發明之組合物一起投與。可提及之界面活性劑包括聚氧化乙烯酯(例如MyrjTM)，包括聚氧乙烯8硬脂酸酯(MyrjTMS8)、聚氧乙烯32硬脂酸酯(Gelucire® 48/16)、聚氧乙烯40硬脂酸酯(MyrjTMS40)、聚氧乙烯100硬脂酸酯(MyrjTMS100)及聚氧乙烯15羥基硬脂酸酯(Kolliphor® HS 15)；聚氧化乙烯烷基醚(例如BrijTM)，包括聚氧乙烯鯨蠟硬脂基醚(例如BrijTMCS12、CS20及CS25)、聚氧乙烯月桂基醚(例如BrijTML9及L23)及聚氧乙烯硬脂基醚(例如BrijTMS10及S20)；以及聚氧甘油酯(例如Gelucire®)，包括月桂醯基聚氧甘油酯(Gelucire® 44/14)及硬脂醯基聚氧甘油酯(Gelucire® 50/13)；脫水山梨糖醇酯(例如Span™)，包括脫水山梨糖醇單棕櫚酸酯(Span™ 40)及脫水山梨糖醇單硬脂酸酯(Span™ 60)；聚山梨醇酯(TweensTM)，包括聚山梨醇酯80 (聚氧乙烯(80)脫水山梨糖醇單棕櫚酸酯)，諸如聚山梨醇酯40 (聚氧乙烯(20)脫水山梨糖醇單棕櫚酸酯)、聚山梨醇酯60 (聚氧乙烯(20)脫水山梨糖醇單硬脂酸酯)及聚山梨醇酯20 (聚氧乙烯(20)脫水山梨糖醇單月桂酸酯)；及月桂基硫酸鈉；以及單醯基甘油(單甘油酸酯)，諸如2-油醯基甘油、2-花生四烯酸甘油、單月桂酸甘油酯、甘油單肉豆蔻酸酯、甘油單棕櫚酸酯、甘油基羥基硬脂酸酯，及較佳地甘油單硬脂酸酯、甘油單油酸酯(例如Cithrol®)及甘油單辛酸酯(例如Capmul®)。其他界面活性劑可包括乳酸月桂酯、二棕櫚醯基磷脂醯膽鹼(DPPC)及泊洛沙姆(poloxamer)。Furthermore, other excipients may be used in or administered together with the compositions of the present invention including one or more (additional) surfactants, as appropriate. Surfactants that may be mentioned include polyoxyethylene esters (e.g. Myrj™ ), including polyoxyethylene 8 stearate (Myrj™ S8), polyoxyethylene 32 stearate (Gelucire® 48/16), polyoxyethylene 40 stearate (Myrj™ S40), polyoxyethylene 100 stearate (Myrj™ S100) and polyoxyethylene 15 hydroxy stearate (Kolliphor® HS 15); polyoxyethylene alkyl ethers (e.g. Brij™ ), including polyoxyethylene cetearyl ether (e.g. Brij™ CS12, CS20 and CS25), polyoxyethylene lauryl ether (e.g. Brij™ L9 and L23) and polyoxyethylene stearyl ether (e.g. Brij™ S10 and S20); and polyoxyglyceryl esters (e.g. Gelucire®), including lauryl polyoxyglyceryl ester (Gelucire® 44/14) and stearyl polyoxylglycerides (Gelucire® 50/13); sorbitan esters (e.g. Span™), including sorbitan monopalmitate (Span™ 40) and sorbitan monostearate (Span™ 60); polysorbates (Tweens™ ), including polysorbate 80 (polyoxyethylene (80) sorbitan monopalmitate), such as polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate); and sodium lauryl sulfate; and monoacylglycerols (monoglycerides), such as 2-oleylglycerol, 2-arachidonylglycerol, monolaurin, glyceryl monomyristate, glyceryl monopalmitate, glyceryl hydroxystearate, and preferably glyceryl monostearate, glyceryl monooleate (e.g., Cithrol®) and glyceryl monocaprylate (e.g., Capmul®). Other surfactants may include lauryl lactate, disalmitoylphosphatidylcholine (DPPC) and poloxamer.
可包括在本發明之組合物內或與本發明之組合物一起投與的其他視情況選用之額外成分(賦形劑)包括等張劑及/或滲透劑(例如氯化鈉)；固醇(或類固醇)，諸如膽固醇及植物固醇(例如菜油固醇、穀固醇及豆固醇)；抗氧化劑(例如偏亞硫酸氫鈉，或另外，α-生育酚、抗壞血酸、抗壞血酸鉀、抗壞血酸鈉、抗壞血基棕櫚酸酯、丁基化羥基甲苯、丁基化羥基苯甲醚、沒食子酸十二烷酯、沒食子酸辛酯、沒食子酸丙酯、油酸乙酯、單硫代甘油、維生素E聚乙二醇琥珀酸酯或瑞香草酚(thymol))；螯合(錯合)劑(例如依地酸(EDTA)、檸檬酸、酒石酸、蘋果酸、麥芽糖醇及半乳糖，包括此等試劑中之任一者的鹽形式)；防腐劑(例如苯紮氯銨(benzalkonium chloride)，或另外，苯甲醇、硼酸、對羥苯甲酸酯、丙酸、苯酚、甲酚或木糖醇)；黏度調節劑或膠凝劑(諸如纖維素衍生物，包括羥丙基纖維素、甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素等，澱粉及改質澱粉、膠態二氧化矽、偏矽酸鋁、聚卡波非(polycarbophil) (例如Noveon®)、卡波姆(例如Carbopol®)及聚乙烯吡咯啶酮)；黏膜黏附聚合物，諸如羧甲基纖維素、經改質纖維素膠及羧甲基纖維素鈉(NaCMC)；澱粉衍生物，諸如適度交聯之澱粉、經改質澱粉及乙醇酸澱粉鈉；交聯聚乙烯吡咯啶酮、丙烯酸聚合物，諸如卡波姆及其衍生物(聚卡波非、Carbopol®等)；聚氧化乙烯(PEO)；聚葡萄胺糖(聚-(D-葡糖胺))；天然聚合物，諸如明膠、海藻酸鈉、果膠；硬葡聚糖；三仙膠；瓜爾膠；聚共-(甲基乙烯基醚/順丁烯二酸酐)；及交聯羧甲纖維素(例如交聯羧甲基纖維素鈉)；pH緩衝劑(例如檸檬酸、順丁烯二酸、蘋果酸或甘胺酸，或其相應鹽，諸如檸檬酸鈉)；著色劑；穿透增強劑(例如肉豆蔻酸異丙酯、棕櫚酸異丙酯、吡咯啶酮或三辛酸甘油酯)；其他脂質(中性及極性)；芳族羧酸，諸如視情況經一個或多個選自以下之基團取代的苯甲酸：甲基、羥基、胺基及/或硝基，例如甲苯甲酸或水楊酸；及(適當時)調味劑(例如檸檬、胡椒薄荷粉末，或較佳地薄荷醇)、甜味劑(例如新橙皮苷(neohesperidin)、乙醯磺胺酸K，或較佳地，蔗糖素)及染料。其他賦形劑可包括三醣(例如棉子糖)及甘露糖醇，以及pH調節劑(例如氫氯酸及氫氧化鈉)。Other optional additional ingredients (excipients) that may be included in or administered with the compositions of the present invention include isotonic and/or osmotic agents (e.g., sodium chloride); sterols (or steroids), such as cholesterol and plant sterols (e.g., campesterol, glutathione, and stigmasterol); antioxidants (e.g., sodium metabisulfite, or in addition, α-tocopherol, ascorbic acid, potassium ascorbate, sodium ascorbate, ascorbic acid palmitate, butylated hydroxy toluene, butylated hydroxyanisole, lauryl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin E polyethylene glycol succinate or thymol); chelating agents (e.g. edetic acid (EDTA), citric acid, tartaric acid, malic acid, maltitol and galactose, including the salt form of any of these agents); preservatives (e.g. benzalkonium chloride chloride), or in addition, benzyl alcohol, boric acid, parabens, propionic acid, phenol, cresol or xylitol); viscosity regulators or gelling agents (such as cellulose derivatives, including hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, starch and modified starch, colloidal silicon dioxide, aluminum metasilicate, polycarbophil (e.g. Noveon®), carbomers (e.g. Carbopol®) and polyvinylpyrrolidone); mucoadhesive polymers such as carboxymethylcellulose, modified cellulose gel and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately cross-linked starch, modified starch and sodium glycolate starch; cross-linked polyvinylpyrrolidone, acrylic acid polymers such as carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyethylene oxide (PEO); polyglucosamine (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; tris-glucan; guar gum; poly-co-(methyl vinyl ether/maleic anhydride); and cross-linked carboxymethylcellulose cellulose (e.g. sodium cross-linked carboxymethyl cellulose); pH buffers (e.g. citric acid, maleic acid, malic acid or glycine, or their corresponding salts, such as sodium citrate); coloring agents; penetration enhancers (e.g. isopropyl myristate, isopropyl palmitate, pyrrolidone or tricaprylin); other lipids (neutral and polar); aromatic carboxylic acids, such as optionally deionized water or ethanol. Benzoic acid substituted with one or more groups selected from the following: methyl, hydroxyl, amino and/or nitro groups, such as toluic acid or salicylic acid; and (where appropriate) flavorings (such as lemon, peppermint powder, or preferably menthol), sweeteners (such as neohesperidin, acesulfame K, or preferably sucralose) and dyes. Other excipients may include trisaccharides (such as raffinose) and mannitol, as well as pH adjusters (such as hydrochloric acid and sodium hydroxide).
按組合物之總重量計，本身可包括於本發明之組合物(無論其包括於何種劑型中)之此類「額外」賦形劑(包括可存在於本發明之組合物中的非烷基醣類界面活性劑)的總量亦可為至多約15重量% (例如約10重量%)，諸如至多約5重量%。The total amount of such "additional" excipients (including non-alkyl saccharide surfactants that may be present in the composition of the present invention) that may be included in the composition of the present invention itself (regardless of the dosage form in which it is included) may also be up to about 15 wt % (e.g., about 10 wt %), such as up to about 5 wt %, based on the total weight of the composition.
例如，若一種或多種額外賦形劑為錠劑、膜片或其類似物中之填充劑或載劑，則可包括於包括一種或多種本發明組合物的最終劑型內之此類「額外」賦形劑之總量可為至多約99.99%，諸如至多約99.9%，包括至多約99%，例如至多約90%。For example, if one or more additional excipients are fillers or carriers in a tablet, film, or the like, the total amount of such "additional" excipients that can be included in the final dosage form comprising one or more compositions of the present invention can be up to about 99.99%, such as up to about 99.9%, including up to about 99%, for example up to about 90%.
熟習此項技術者將瞭解，若任何額外視情況選用之成分包括於本發明之組合物內，則出於上文所描述之原因，該等成分之性質及/或所包括之該等成分的量不應對該組合物之Tg具有不利影響。就此而言，此類視情況選用之成分可併入噴霧乾燥方法中(亦即，與活性成分及載劑材料一起混合於適當揮發性溶劑中且接著噴霧乾燥)，或可單獨地包括於噴霧乾燥之複數個粒子中。Those skilled in the art will appreciate that if any additional optional ingredients are included in the compositions of the present invention, the nature of such ingredients and/or the amounts of such ingredients included should not have an adverse effect on the Tg of the composition for the reasons described above. In this regard, such optional ingredients may be incorporated into the spray drying process (i.e., mixed with the active ingredient and carrier materials in a suitable volatile solvent and then spray dried), or may be included separately in the plurality of particles that are spray dried.
特定言之，鑒於本發明的組合物提供給高度不穩定之活性成分(諸如腎上腺激素)的增強之化學穩定性，以及本發明之組合物主要打算用於治療易發生過敏性反應(且因此可能對某些化學品敏感)之患者的事實，較佳地，本發明之組合物基本上不含此類「額外」賦形劑，特別是以上所提及的抗氧化劑及/或防腐劑，例如苯紮氯銨，更特定地亞硫酸鹽，及/或螯合劑，諸如EDTA，其包括小於約10%，諸如小於約6%，包括小於約5%，或小於約4%，更佳小於約3%，諸如小於約2%，例如小於約1%、小於約0.1%，包括小於約0.01%，例如小於約0.001%或甚至小於約0.0001%(按重量計)的組合物包含此類額外賦形劑。In particular, in view of the enhanced chemical stability that the compositions of the present invention provide to highly unstable active ingredients (such as adrenal hormones), and the fact that the compositions of the present invention are primarily intended for the treatment of patients who are susceptible to allergic reactions (and therefore may be sensitive to certain chemicals), it is preferred that the compositions of the present invention are substantially free of such "extra" excipients, in particular the antioxidants and/or preservatives mentioned above, such as benzoyl chloride. Ammonium, more particularly sulfites, and/or chelating agents, such as EDTA, including less than about 10%, such as less than about 6%, including less than about 5%, or less than about 4%, more preferably less than about 3%, such as less than about 2%, for example less than about 1%, less than about 0.1%, including less than about 0.01%, for example less than about 0.001% or even less than about 0.0001% (by weight) of the composition comprising such additional shaping agents.
就此而言，本發明之組合物可基本上由藥理學上有效劑量之腎上腺素激導性受體調節劑或其鹽、本文所定義的醫藥學可接受之載劑材料(亦即，本文所定義之麥芽糊精及視情況選用之共載劑材料，諸如雙醣)及(視情況)本文所定義之烷基醣類材料組成。若本發明之組合物「基本上由上述成分組成」，則此將理解為意謂該組合物僅包含該等成分以及實質上不影響組合物之基本及新穎特徵的其他特徵及/或組分。或者，在本發明之組合物/劑型「基本上由該等成分組成」的情況下，此可以理解為意謂該組合物總共包含至少約90重量%，諸如至少約95重量%，包括至少約97重量%(例如約99重量%或甚至約99.9重量%)的該等成分。In this regard, the composition of the present invention may consist essentially of a pharmacologically effective dose of an adrenaline stimulatory receptor modulator or a salt thereof, a pharmaceutically acceptable carrier material as defined herein (i.e., maltodextrin as defined herein and optionally co-carrier materials, such as disaccharides) and (optionally) an alkyl saccharide material as defined herein. If the composition of the present invention "consists essentially of the above ingredients", this will be understood to mean that the composition only includes these ingredients and other features and/or components that do not substantially affect the basic and novel characteristics of the composition. Alternatively, where a composition/dosage form of the present invention "consists essentially of" these ingredients, this can be understood to mean that the composition contains at least about 90% by weight, such as at least about 95% by weight, including at least about 97% by weight (e.g., about 99% by weight or even about 99.9% by weight) of these ingredients in total.
根據本發明之另一範疇，提供適用於醫學(人類及獸醫學)且因此適用於治療需要已知相關活性成分可用以治療之病況的醫學治療之患者的本發明之組合物。According to another aspect of the invention, there is provided a composition of the invention suitable for use in medicine (human and veterinary medicine) and therefore for use in the treatment of patients in need of medical treatment of conditions for which the relevant active ingredients are known to be useful for treatment.
此類病況之「治療」包括此類病況之防治/預防或診斷，以及治療性、對症性及緩解性治療。"Treatment" of such conditions includes prevention/prevention or diagnosis of such conditions, as well as therapeutic, symptomatic and palliative treatment.
因此，取決於此類組合物中所包括之活性成分，本發明之組合物可用於治療多種病症。Therefore, depending on the active ingredients included in such compositions, the compositions of the present invention can be used to treat a variety of conditions.
包含多巴胺的本發明之組合物可用於校正由於心肌梗塞、創傷、內毒素敗血症、心內直視手術、腎衰竭和慢性心臟失代償(充血性衰竭)引起的休克症候群中存在的血液動力學不平衡；包含羥甲唑啉(oxymetazoline)的本發明之組合物可用作解充血劑；包含多巴酚丁胺(dobutamine)的本發明之組合物可用於治療例如心臟衰竭；包含米拉貝隆(mirabegron)的本發明之組合物可用於治療膀胱過度活動症候群；包含支氣管擴張劑的本發明之組合物可用於治療哮喘(包括預防運動誘發之支氣管痙攣(EIB))及/或慢性阻塞性肺病(COPD，包括與其相關的支氣管痙攣)，該等支氣管擴張劑諸如為沙丁胺醇(albuterol)(羥甲異丁腎上腺素(salbutamol))、福莫特羅(formoterol)、左旋沙丁胺醇(levalbuterol)、奧達特羅(olodaterol)、沙美特羅(salmeterol)及特布他林(terbutaline)。包含特布他林的本發明之組合物亦可用於治療早產。The compositions of the present invention comprising dopamine can be used to correct the hemodynamic imbalance present in shock syndrome caused by myocardial infarction, trauma, endotoxin sepsis, open heart surgery, renal failure and chronic heart decompensation (congestive failure); the compositions of the present invention comprising oxymetazoline can be used as a decongestant; the compositions of the present invention comprising dobutamine can be used to treat, for example, heart failure; the compositions of the present invention comprising mirabegron can be used to treat overactive bladder syndrome; the compositions of the present invention comprising bronchodilation can be used to treat bronchial infarction. The compositions of the present invention containing bronchodilators such as albuterol (salbutamol), formoterol, levalbuterol, olodaterol, salmeterol and terbutaline can be used to treat asthma (including prevention of exercise-induced bronchospasm (EIB)) and/or chronic obstructive pulmonary disease (COPD, including bronchospasm associated therewith). The compositions of the present invention containing terbutaline can also be used to treat premature labor.
包含去甲腎上腺素的本發明之組合物可用於在某些急性低血壓狀態中誘導之血壓控制(及/或心跳驟停)，該等急性低血壓狀態包括交感神經切除術(sympathectomy)、脊髓灰質炎(poliomyelitis)、嗜鉻細胞瘤切除術(pheochromocytomectomy)、脊髓麻醉(spinal anaesthesia)、心肌梗塞、敗血症、輸血或藥物反應。包含異丙腎上腺素的本發明之組合物可用於治療心動徐緩(bradycardia)、心傳導阻滯及偶爾的哮喘。The compositions of the invention comprising norepinephrine may be used to induce blood pressure control (and/or cardiac arrest) in certain acute hypotensive states including sympathectomy, poliomyelitis, pheochromocytomectomy, spinal anaesthesia, myocardial infarction, sepsis, blood transfusion or drug reaction. The compositions of the invention comprising isoproterenol may be used to treat bradycardia, heart block and occasionally asthma.
特別地，包含腎上腺激素的本發明之組合物可用於治療例如心臟衰竭(例如心臟病發作)及/或更特別地，過敏性反應，包括極端或嚴重過敏性反應、全身性過敏反應及/或過敏性休克，例如其特徵為血壓由於對例如昆蟲叮/咬、食物、藥物及/或其他物質之反應而嚴重下降。極端及/或嚴重過敏性反應可進一步包括敗血症及/或敗血性休克，其可為對例如真菌、細菌及/或病毒感染之反應。全身性過敏反應及敗血症可進一步導致器官功能障礙，包括器官衰竭及/或最終死亡。In particular, the compositions of the invention comprising adrenal hormones can be used to treat, for example, heart failure (e.g., heart attack) and/or more particularly, allergic reactions, including extreme or severe allergic reactions, systemic allergic reactions and/or anaphylactic shock, for example, characterized by a severe drop in blood pressure due to a reaction to, for example, insect bites, food, drugs and/or other substances. Extreme and/or severe allergic reactions may further include sepsis and/or septic shock, which may be a reaction to, for example, fungal, bacterial and/or viral infections. Systemic allergic reactions and sepsis may further lead to organ dysfunction, including organ failure and/or ultimately death.
包含腎上腺激素的本發明之組合物亦可用於治療例如任何1型超敏反應，特別是過敏性哮喘、過敏性結膜炎、過敏性鼻炎、全身性過敏反應(包括特發性全身性過敏反應或運動誘發之全身性過敏反應)、血管性水腫、風疹、嗜伊紅血球增多、藥物過敏(包括抗生素過敏)、食物過敏、對動物血清、昆蟲叮咬、診斷測試物質及其他過敏原之過敏反應；治療急性哮喘發作以緩解支氣管痙攣；治療全身中毒反應(類過敏性反應)；治療及防治心跳驟停及/或短暫性心臟房室傳導阻滯伴隨暈厥發作(史扥克斯-亞當斯症候群(Stokes-Adams Syndrome))，包括由心跳機制之陣發性轉變引起的心輸出量突然但明顯之減少導致的突發性、短暫性意識喪失；誘導患有與敗血性休克相關之低血壓的成年患者平均動脈血壓之增加；在眼內手術期間誘導及維護瞳孔放大；治療胃腸及/或腎臟出血；治療淺表出血、早產、低血糖以及心因性、出血性及創傷性休克；及/或治療喉炎(上呼吸道感染，其阻塞呼吸且引起特有之犬吠樣咳嗽)。The compositions of the invention comprising adrenal hormones may also be used to treat, for example, any type 1 hypersensitivity reaction, in particular allergic asthma, allergic conjunctivitis, allergic rhinitis, systemic allergic reactions (including idiopathic systemic allergic reactions or exercise-induced systemic allergic reactions), angioedema, urticaria, eosinophilia, drug allergies (including antibiotic allergies), food allergies, Allergies to animals, animal sera, insect bites, diagnostic test substances and other allergens; treatment of acute asthmatic attacks to relieve bronchospasm; treatment of systemic toxic reactions (anaphylactic reactions); treatment and prevention of cardiac arrest and/or transient atrioventricular block with syncope (Stokes-Adams syndrome) Syndrome), including sudden, transient loss of consciousness due to an abrupt but marked decrease in cardiac output caused by paroxysmal changes in the heart's mechanics; inducing an increase in mean arterial blood pressure in adult patients with hypotension associated with septic shock; inducing and maintaining pupil dilation during intraocular surgery; treating gastrointestinal and/or renal bleeding; treating superficial bleeding, premature labor, hypoglycemia, and psychogenic, hemorrhagic, and traumatic shock; and/or treating laryngitis (an upper respiratory tract infection that obstructs breathing and causes a characteristic barking cough).
包含腎上腺激素的本發明之組合物尤其適用於治療及/或預防(防治)嚴重反應，包括上文所描述之全身性過敏反應及敗血症及/或過敏性休克及敗血性休克。預防及/或防治此等嚴重反應可藉由向在暴露於(或疑似暴露於)患者敏感及/或已經致敏的上文所描述之相關物質之後有發生此等嚴重反應之風險的患者投與(包括自投與)一或多種本發明組合物來實現。The compositions of the present invention comprising adrenal hormones are particularly suitable for treating and/or preventing (preventing) severe reactions, including systemic allergic reactions and septicemia and/or anaphylactic shock and septic shock as described above. Prevention and/or prevention of such severe reactions can be achieved by administering (including self-administration) one or more compositions of the present invention to patients who are at risk of such severe reactions after exposure to (or suspected exposure to) the relevant substances described above to which the patient is sensitive and/or has been sensitized.
根據本發明之三個其他範疇，提供： • 一種包含腎上腺素激導性受體調節劑(例如腎上腺激素)或其醫藥學上可接受之鹽的本發明之組合物，其用於治療過敏性反應(例如藉由經黏膜，諸如鼻內投與該組合物)； • 包含腎上腺素激導性受體調節劑(例如腎上腺激素)或其醫藥學上可接受之鹽的本發明之組合物之用途，其用於製造供治療過敏性反應用的(例如經黏膜，諸如鼻內)藥劑；及 • 一種治療過敏性反應之方法，該方法包含向患有或易患該病況之患者(例如經黏膜，例如鼻內)投與包含腎上腺素激導性受體調節劑(例如腎上腺激素)或其醫藥學上可接受之鹽的本發明之組合物。According to three other aspects of the present invention, there are provided: • A composition of the present invention comprising an adrenaline stimulatory receptor modulator (e.g., adrenal hormone) or a pharmaceutically acceptable salt thereof, which is used to treat allergic reactions (e.g., by transmucosal, such as intranasal administration of the composition); • The use of the composition of the present invention comprising an adrenaline stimulatory receptor modulator (e.g., adrenaline hormone) or a pharmaceutically acceptable salt thereof, which is used to manufacture a medicament for treating allergic reactions (e.g., transmucosal, such as intranasal); and • A method for treating an allergic reaction comprising administering (e.g., transmucosally, e.g., intranasally) a composition of the invention comprising an adrenergic agonist receptor modulator (e.g., adrenal hormone) or a pharmaceutically acceptable salt thereof to a patient suffering from or susceptible to the condition.
進一步提供一種治療人類患者之過敏性反應之方法，其包含： (a) 鑑別有過敏性反應或有發生過敏性反應危險之人類患者，及 (b) 向該患者的包括黏膜表面之體腔投與適合於治療該過敏性反應之劑量的呈本發明組合物形式之腎上腺素激導性受體調節劑(例如腎上腺激素)或其醫藥學上可接受之鹽，由此在該黏膜表面呈現該組合物以促進該黏膜表面中該腎上腺素激導性受體調節劑或其鹽之吸收，且因此治療或預防該過敏性反應。Further provided is a method for treating an allergic reaction in a human patient, comprising:(a) identifying a human patient who has an allergic reaction or is at risk of developing an allergic reaction, and(b) administering to a body cavity of the patient including a mucosal surface an adrenergic receptor modulator (e.g., adrenal hormone) or a pharmaceutically acceptable salt thereof in the form of a composition of the present invention in an amount suitable for treating the allergic reaction, thereby presenting the composition on the mucosal surface to promote absorption of the adrenergic receptor modulator or its salt in the mucosal surface, and thereby treating or preventing the allergic reaction.
本發明之組合物可藉由熟習此項技術者已知之任何適合的給藥構件投與。本發明之組合物可藉助於適合的經鼻施用器或分配器構件經黏膜且尤其經鼻內投與，該構件能夠將適合劑量的呈一或多種本發明之組合物形式的活性成分投與至鼻腔中。The compositions of the present invention may be administered by any suitable administration means known to those skilled in the art. The compositions of the present invention may be administered transmucosally and especially intranasally with the aid of a suitable nasal applicator or dispenser means capable of administering a suitable dose of the active ingredients in the form of one or more compositions of the present invention to the nasal cavity.
因此，適合之經鼻給藥構件及/或施用器應能夠容納及儲存一個或多個劑量的相關本發明之組合物本身，或能夠連接至容納及儲存一個或多個劑量之該本發明組合物的儲集器/容器，且如此不會造成組合物之物理及化學完整性之顯著損失，包括藉助於進水引起之完整性損失。以此方式，一旦施用器裝置由最終使用者致動(不論此為單次劑量或多次劑量使用)，組合物將為可用的，此時施用器將向個體之鼻黏膜遞送具有適當劑量之如本文所定義之活性成分的組合物(例如粉末)。Thus, suitable nasal administration means and/or applicators should be capable of containing and storing one or more doses of the relevant composition of the invention itself, or be connected to a reservoir/container that contains and stores one or more doses of the composition of the invention, and do so without causing significant loss of physical and chemical integrity of the composition, including loss of integrity due to water ingress. In this way, once the applicator device is actuated by the end user (whether this is for single or multiple dose use), the composition will be available, at which time the applicator will deliver the composition (e.g., powder) with an appropriate dose of the active ingredient as defined herein to the individual's nasal mucosa.
先前技術中已描述適當施用器構件。當與本發明之組合物一起使用時，此類組合物可裝入連接至此類施用器構件或形成此類施用器構件之一部分的儲集器中，在該處容納該組合物，直至致動施用器構件或分配器。在下文中，術語「施用器」、「分配器」、「裝置」、「施用構件」、「分配構件」、「施用器裝置」、「分配裝置」及「吹入器」可互換使用且表示相同事物。Suitable applicator members have been described in the prior art. When used with the composition of the present invention, such composition may be contained in a reservoir connected to or forming part of such an applicator member, where the composition is contained until the applicator member or dispenser is actuated. Hereinafter, the terms "applicator", "dispenser", "device", "application member", "dispensing member", "applicator device", "dispensing device" and "insufflator" are used interchangeably and mean the same thing.
因為本發明之組合物出人意料之穩定性，所以不需要在投與或使用之前檢查儲集器之內容物(亦即，粉末組合物)。此將與可商購的裝置(諸如EpiPen)形成對比，其中產品標籤包含出於充分理由(包括其中所含液體溶液組合物對熱、冷及光不穩定)而在分配之前檢查內容物之完整性的要求。Because of the unexpected stability of the compositions of the present invention, there is no need to inspect the contents of the reservoir (i.e., the powder composition) prior to administration or use. This is to be contrasted with commercially available devices such as the EpiPen, where the product label includes a requirement to inspect the integrity of the contents prior to dispensing for good reasons, including that the liquid solution composition contained therein is unstable to heat, cold, and light.
有鑒於此，含有本發明之組合物的儲集器可為不透明的，熟習此項技術者應理解此「包括不透明或半透明、不透光及/或不允許光穿過」。In view of this, the storage container containing the composition of the present invention may be opaque, and those skilled in the art should understand that this includes "opaque or translucent, light-proof and/or does not allow light to pass through".
因此，包含本發明之組合物的施用器不包括(不需要包括)可透過其觀測施用器之儲集器的內容物的檢查窗，且就此而言，該儲集器就其性質而言可為完全不透明的，亦即至少約98%，諸如至少約99%，且尤其約99.9%不透明，及/或不超過約2%，諸如不超過約1%，且尤其約0.1%透明、半透明及/或不透光，以便檢查儲集器之內容物。Thus, an applicator comprising a composition of the present invention does not include (need not include) an inspection window through which the contents of the applicator's reservoir can be viewed, and in this regard, the reservoir can be completely opaque in nature, i.e. at least about 98%, such as at least about 99%, and especially about 99.9% opaque, and/or not more than about 2%, such as not more than about 1%, and especially about 0.1% transparent, translucent and/or opaque to facilitate inspection of the contents of the reservoir.
因此，此類施用器構件亦可包括經由出口(或「分配」)構件自儲集器排出本文所描述之粉末組合物的機構，該分配構件包括大小設計成供置放於人類體腔(諸如鼻孔)內之各類物體，諸如形狀適宜之噴嘴。Thus, such applicator means may also include a mechanism for expelling the powder composition described herein from the reservoir via an outlet (or "dispensing") means, which dispensing means may include various objects sized to be placed in a human body cavity (such as a nostril), such as a suitably shaped nozzle.
因此，排出粉末之機構可包括用於致動裝置之構件，其可包括呼吸致動件(例如藉由鼻吸入致動)，或包括在使用者致動裝置時產生力的致動構件。Thus, the mechanism for expelling the powder may include means for actuating the device, which may include breath actuation (eg, actuation by nasal inhalation), or include actuation means that generates a force when the user actuates the device.
因此，施用器應能夠在單次投與步驟中(及以該裝置不需要「灌滿(priming)」之方式)提供可再現且足量之粉末組合物，由此將提供治療劑量之活性成分。Thus, the applicator should be capable of providing a reproducible and sufficient amount of the powder composition in a single administration step (and in such a way that "priming" of the device is not required) which will provide a therapeutic dose of the active ingredient.
此外，因為本發明組合物之出人意料的穩定性及在投與使用之前不需要檢查儲集器之內容物(亦即，粉末組合物)，一旦患者被鑑別為展現過敏性反應之症狀，或有發生過敏性反應之風險，即可使用施用器向黏膜表面投與腎上腺激素或其醫藥學上可接受之鹽，以治療或預防該過敏性反應。因此，上文所鑑別之投與步驟可在鑑別步驟之後無延遲地立即進行，該延遲可表示有足夠的時間進行以下操作： (i) 檢查本發明之組合物；及 (ii) 確定是否可安全地向患者投與相關組合物以有效治療該過敏性反應。In addition, because of the unexpected stability of the composition of the present invention and the fact that the contents of the reservoir (i.e., the powder composition) do not need to be checked prior to administration, once a patient is identified as exhibiting symptoms of, or at risk for, an allergic reaction, an applicator can be used to administer adrenal hormone or a pharmaceutically acceptable salt thereof to the mucosal surface to treat or prevent the allergic reaction. Therefore, the administration step identified above can be performed immediately after the identification step without delay, which can mean that there is sufficient time to perform the following operations:(i) Check the composition of the present invention; and(ii) Determine whether the relevant composition can be safely administered to the patient to effectively treat the allergic reaction.
可用於投與呈粉末形式之本發明組合物的經鼻施用器/吸入裝置可包括多劑量施用，諸如定量劑量吸入裝置(MDI)、乾粉吸入裝置(DPI；包括低阻力、中等阻力及高阻力DPI)及緩霧型吸入裝置(SMI)，其可基於在本領域中已知將活性成分遞送至肺之技術進行調適。Nasal applicators/inhalation devices that can be used to administer the compositions of the present invention in powder form may include multi-dose administration, such as metered dose inhalation devices (MDIs), dry powder inhalation devices (DPIs; including low resistance, medium resistance and high resistance DPIs) and slow spray inhalation devices (SMIs), which can be adapted based on techniques known in the art for delivering active ingredients to the lungs.
在MDI中，本發明之組合物應能夠在懸浮於其中通常所用之溶劑(諸如推進劑)中時形成穩定的懸浮液，該推進劑在遞送裝置致動時具有足夠的蒸汽壓，以形成氣霧劑(例如烴、碳氟化合物、含氫碳氟化合物或其混合物)。In MDI, the composition of the invention should be capable of forming a stable suspension when suspended in a solvent commonly used therein, such as a propellant, which has sufficient vapor pressure to form an aerosol (e.g., hydrocarbons, fluorocarbons, hydrofluorocarbons, or mixtures thereof) when the delivery device is activated.
然而，若經鼻施用器係在致動後分配組合物且接著在使用之後丟棄的單次劑量施用器，則用於遞送單次劑量之活性成分的適合施用器構件或裝置包括呼吸輔助及吹氣輔助設計(諸如Optinose®)，以及美國專利US 6,398,074、US 6,938,798及US 9,724,713，以及國際專利申請案WO 2017/118827 A1、WO 2018/224762A1及WO 2023/282821 A1且特別是美國專利申請案US 2019/0358417 A1及US 2023/0144040 A1中所描述之施用器，所有該等文獻之相關揭示內容均以引用的方式併入本文中。本申請案之圖1及圖2係分別基於US 6,398,074之圖1及圖2，且圖3至圖7係分別基於US 9,724,713之圖19至圖23。其均為可用於經鼻內投與本發明組合物的施用器之圖式。However, if the nasal applicator is a single-dose applicator that dispenses the composition after actuation and is then discarded after use, suitable applicator components or devices for delivering a single dose of the active ingredient include breathing-assisted and insufflation-assisted designs (such as Optinose®), as well as U.S. Patents US 6,398,074, US 6,938,798 and US 9,724,713, and international patent applications WO 2017/118827 A1, WO 2018/224762 A1 and WO 2023/282821 A1 and in particular U.S. Patent Applications US 2019/0358417 A1 and US 2023/0144040 The applicator described in A1, all relevant disclosures of these documents are incorporated herein by reference. Figures 1 and 2 of this application are based on Figures 1 and 2 of US 6,398,074, respectively, and Figures 3 to 7 are based on Figures 19 to 23 of US 9,724,713, respectively. They are all diagrams of applicators that can be used for intranasal administration of the composition of the present invention.
在圖1中，該裝置包含上部主體/分配器頭1，其併入有出口通道40 (亦即，如上文所描述之「出口構件」之一部分)及允許使用者致動該裝置之抓持構件60。在上部主體/分配器頭1內安裝一元件，在其總成中用參考數字2表示，該元件併入有儲集器10及用於噴氣20之空氣腔室22。此元件2可與主體1一體式製造。亦提供下部主體3以便能夠相對於上部主體1且相對於元件2滑動，使用者對下部主體施加推動力以致動該裝置。In FIG. 1 , the device comprises an upper body/dispenser head 1 incorporating an outlet channel 40 (i.e. part of the “outlet member” as described above) and a gripping member 60 allowing the user to actuate the device. Mounted within the upper body/dispenser head 1 is an element, indicated in its assembly by reference numeral 2, incorporating a reservoir 10 and an air chamber 22 for a spray 20. This element 2 can be made integrally with the body 1. A lower body 3 is also provided so as to be able to slide relative to the upper body 1 and relative to the element 2, to which the user applies a pushing force to actuate the device.
儲集器10含有單次劑量之本發明之組合物。儲集器10具有進氣口11及產物出口15。包含透氣的網格之產物保持裝置12安置於進氣口11中以將產物保持於儲集器10中，直至該組合物被分配。較佳以密封方式，藉由封擋球16阻擋產物出口15，該封擋球係在施用器被致動且產物被分配時藉由空氣流自其阻擋位置移開。The reservoir 10 contains a single dose of the composition of the present invention. The reservoir 10 has an air inlet 11 and a product outlet 15. A product retaining device 12 comprising an air-permeable mesh is placed in the air inlet 11 to retain the product in the reservoir 10 until the composition is dispensed. The product outlet 15 is preferably blocked in a sealed manner by a blocking ball 16, which is moved away from its blocking position by the air flow when the applicator is activated and the product is dispensed.
當使用者致動該裝置時，以使得活塞21壓縮腔室22中所含空氣20的方式對柱塞25施加壓力。由於網格12係可透氣的，故壓縮腔室22中之空氣產生噴氣，其被傳輸到儲集器10，且由此施加至阻擋產物出口15之封擋球16。When the user activates the device, pressure is applied to the plunger 25 in such a way that the piston 21 compresses the air 20 contained in the chamber 22. Since the mesh 12 is air-permeable, the air in the chamber 22 is compressed to produce a jet of gas which is transmitted to the reservoir 10 and thence to the blocking ball 16 which blocks the product outlet 15.
封擋球16之尺寸及其固定在儲集器產物出口15處使得球16當藉助於噴氣20經由儲集器10產生最小預定壓力時自其阻擋位置處移開。The dimensions of the blocking ball 16 and its fixing at the reservoir product outlet 15 are such that the ball 16 moves out of its blocking position when a minimum predetermined pressure is generated through the reservoir 10 by means of the gas jet 20.
由封擋球16產生之預壓縮確保當封擋球自其阻擋位置處移開時，使用者手中積聚的能量使得與柱塞25成一體之活塞21在該腔室22內被推動，由此產生強大的噴出空氣20，亦即適合精細噴霧出本發明組合物之劑量的氣流。The pre-compression produced by the blocking ball 16 ensures that when the blocking ball moves away from its blocking position, the energy accumulated in the user's hand causes the piston 21 integral with the plunger 25 to be pushed in the chamber 22, thereby generating a strong spray of air 20, that is, an air flow suitable for fine spraying of a dose of the composition of the present invention.
當達到此最小壓力時，球朝向該裝置之出口通道40快速移動，且由噴氣產生之空氣流20排出儲集器10內所含本發明之組合物的實質上全部劑量。When this minimum pressure is reached, the ball moves rapidly towards the outlet passage 40 of the device and the air stream 20 generated by the jet expels substantially the entire dose of the composition of the invention contained in the reservoir 10.
較佳地，出口通道40之直徑大於封擋球16之直徑，以便允許該劑量之產物藉由圍繞球16流動而經由該出口通道40排出。如圖2中所示，該圖表示在致動之後之相同裝置，通道40包含阻止或固定球16以防止在排出產物時該球自該裝置中排出之構件41。Preferably, the diameter of the outlet passage 40 is greater than the diameter of the blocking ball 16 so as to allow the dose of product to be discharged through the outlet passage 40 by flowing around the ball 16. As shown in FIG. 2 , which shows the same device after actuation, the passage 40 includes a member 41 that blocks or secures the ball 16 to prevent the ball from being discharged from the device when discharging the product.
可用於鼻內投與本發明之組合物的另一實施例係提供於US 9,724,713中之第7欄第50行至第8欄第61行及圖19至圖23，其再現為本申請案之圖3至圖7。Another embodiment of a composition of the present invention that can be used for intranasal administration is provided in US Pat. No. 9,724,713, col. 7, line 50 to col. 8, line 61 and Figures 19 to 23, which are reproduced as Figures 3 to 7 of the present application.
在此實施例中，儲集器10緊固於包括分配器出口通道40 (亦即如上文所描述之「出口構件」之一部分)之上部主體/分配器頭1中，該上部主體/分配器頭具有抓持構件或指托60，其允許使用者致動該裝置。上部主體/分配器頭1之徑向肩部37 (參見圖5)有利地限定該上部主體/分配器頭1中之儲集器10的組裝位置。In this embodiment, the reservoir 10 is secured in the upper body/dispenser head 1 including the dispenser outlet passage 40 (i.e., part of the "outlet member" as described above), and the upper body/dispenser head has a gripping member or finger rest 60 that allows the user to actuate the device. The radial shoulder 37 (see FIG. 5 ) of the upper body/dispenser head 1 advantageously defines the assembly position of the reservoir 10 in the upper body/dispenser head 1.
機械開放系統包括一組桿61、62，其中當該裝置被致動時，第二桿部分62被該第一桿部分61推動。在其致動衝程結束時，亦即在分配位置中，該組桿61、62與封擋元件16協作，該封擋元件為球狀，尤其是如上文所論述之第一實施例中之球，以便將其以機械方式自其封閉位置中排出。The mechanical opening system comprises a set of rods 61, 62, wherein when the device is actuated, the second rod part 62 is pushed by the first rod part 61. At the end of its actuation stroke, i.e. in the dispensing position, the set of rods 61, 62 cooperates with the blocking element 16, which is spherical, in particular a ball as in the first embodiment discussed above, in order to mechanically expel it from its closed position.
在此實施例中，活塞21與第一桿部分61分離，且相對於空氣腔室22及相對於緊固至第一桿部分61之圓柱形表面614兩者滑動。圖7為圖3至圖6中之裝置之空氣排出器在其靜止位置處之圖解透視圖。In this embodiment, the piston 21 is separated from the first rod portion 61 and slides both relative to the air chamber 22 and relative to the cylindrical surface 614 fastened to the first rod portion 61. Figure 7 is a diagrammatic perspective view of the air expeller of the device in Figures 3 to 6 in its rest position.
因此，空氣腔室22可為圓柱形的，且在其靜止位置處與在溝槽或凹槽615處之周圍空氣連通，該等溝槽或凹槽係形成於該圓柱形表面614中且與該活塞21協作，尤其在其靜止位置處如此。因此，該活塞21包括內唇215，其在致動期間以氣密方式在圓柱形壁614上滑動，且在其靜止位置處與該溝槽615協作。該活塞21亦包括與推動元件25 (在第一實施例中稱為「柱塞」)之頂部邊緣251協作之軸向延伸部216，該推動元件在致動期間在空氣腔室22中移動該活塞21。Thus, the air chamber 22 can be cylindrical and, in its rest position, communicate with the surrounding air at grooves or recesses 615 formed in the cylindrical surface 614 and cooperating with the piston 21, in particular in its rest position. Thus, the piston 21 comprises an inner lip 215 which slides on the cylindrical wall 614 in an airtight manner during actuation and which, in its rest position, cooperates with the groove 615. The piston 21 also comprises an axial extension 216 cooperating with the top edge 251 of the push element 25 (referred to as a "plunger" in the first embodiment), which moves the piston 21 in the air chamber 22 during actuation.
保持器部件42藉由軸向延伸部43向下延伸，該軸向延伸部在致動期間與第一桿部分61之頂部軸向端610接觸。The retainer member 42 extends downwardly by an axial extension 43 which contacts the top axial end 610 of the first rod portion 61 during actuation.
另外，在此實施例中，不存在外部主體，而僅存在組裝於空氣腔室22之底部軸向邊緣上之蓋罩27。In addition, in this embodiment, there is no external body, but only a cover 27 assembled on the bottom axial edge of the air chamber 22.
彈簧80設置於空氣腔室22之徑向凸緣225與形成第一桿部分61及圓柱形表面614之部件之間，以便在致動之後使空氣排出器自動返回至其靜止位置。A spring 80 is disposed between the radial flange 225 of the air chamber 22 and the components forming the first rod portion 61 and the cylindrical surface 614 so as to automatically return the air expeller to its rest position after actuation.
操作原理如下。在圖3中之靜止位置中，儲集器10藉由保持器部件42及藉由封擋元件/球16以密封方式封閉。空氣排出器藉由該活塞21之內唇215與圓柱形表面614之溝槽615之間協作而與大氣接觸。The operating principle is as follows. In the rest position in FIG. 3 , the reservoir 10 is sealed by the retainer member 42 and by the sealing element/ball 16 . The air expeller is in contact with the atmosphere by the cooperation between the inner lip 215 of the piston 21 and the groove 615 of the cylindrical surface 614 .
當需要致動該裝置時，使用者按下推動元件25。在此初始衝程期間，該活塞之內唇215離開溝槽615以便以氣密方式與圓柱形表面614協作，藉此封閉空氣腔室22。在同一時刻，推動元件25之頂部邊緣251與活塞21之軸向延伸部216接觸，且第一桿部分61之頂部軸向端610與保持器部件42之軸向延伸部43接觸。When it is desired to actuate the device, the user presses the push element 25. During this initial stroke, the inner lip 215 of the piston leaves the groove 615 to cooperate with the cylindrical surface 614 in an airtight manner, thereby closing the air chamber 22. At the same moment, the top edge 251 of the push element 25 contacts the axial extension 216 of the piston 21, and the top axial end 610 of the first rod portion 61 contacts the axial extension 43 of the retainer member 42.
然而，第二桿部分62之頂部軸向端621仍不與封擋元件/球16之圓形表面55接觸，如圖4中可見。However, the top axial end 621 of the second rod portion 62 still does not contact the circular surface 55 of the sealing element/ball 16, as can be seen in FIG. 4 .
因此，連續致動同時在空氣腔室中移動活塞21，藉此壓縮其中所含之空氣，且移動保持器部件42使其遠離封閉儲集器10之位置。當第二桿部分62接觸封擋元件/球16之圓形表面55時，該封擋元件/球以機械方式自其封閉位置排出，以便使組合物能夠在藉由空氣排出器壓縮之空氣的作用下排出。Thus, continuous actuation simultaneously moves the piston 21 in the air chamber, thereby compressing the air contained therein, and moves the retainer member 42 away from the position closing the reservoir 10. When the second rod portion 62 contacts the circular surface 55 of the sealing element/ball 16, the sealing element/ball is mechanically expelled from its closed position so that the composition can be expelled under the action of the air compressed by the air expellor.
分配位置顯示於圖5中。如圖5中可見，當組合物在由空氣排出器提供之壓縮空氣的作用下被排出時，保持器部件42可與第一桿部分61分離。在此位置中，該封閉元件/球自儲集器10中排出，以便使該流體或粉末能夠在壓縮空氣之作用下被分配。因此，封閉元件/球16在上部主體/分配器頭1之栓槽(spline) 3中卡住，該等栓槽尤其防止該封閉元件/球16自該上部主體分配器頭1中排出之任何風險。The dispensing position is shown in FIG5 . As can be seen in FIG5 , the retainer part 42 can be separated from the first rod portion 61 when the composition is expelled under the action of compressed air provided by the air expeller. In this position, the closing element/ball is expelled from the reservoir 10 so that the fluid or powder can be dispensed under the action of compressed air. As a result, the closing element/ball 16 is caught in the spline 3 of the upper body/dispenser head 1 , which in particular prevents any risk of the closing element/ball 16 being expelled from the upper body dispenser head 1 .
當使用者鬆開該裝置時，如圖6中所示，在致動期間被壓縮之彈簧80使第一桿部分61返回至其靜止位置。此產生吸力，由此將封閉元件16及保持器部件42吸回至其封閉位置，或接近其封閉位置。因此，此阻擋新吸力之路徑，以避免在空氣排出器自動返回至其靜止位置中時污染空氣排出器，而空的儲集器仍組裝在空氣排出器上。然而，活塞21由於與空氣腔室22之摩擦力及在儲集器30中產生之吸力而保持在其分配位置，使得圓柱形表面614在該活塞之內唇215上滑動，直至該內唇再次與溝槽615協作。此時，空氣腔室22再次與周圍空氣連通，且不再因返回該靜止位置中而產生吸力。因此，活塞21亦被帶向其靜止位置。如此使得有可能在使用之後封閉儲集器。When the user releases the device, as shown in FIG. 6 , the spring 80 compressed during actuation returns the first rod portion 61 to its rest position. This generates a suction force, thereby sucking the closing element 16 and the retainer member 42 back to its closed position, or close to its closed position. This thus blocks the path of new suction forces to avoid contaminating the air expeller when it automatically returns to its rest position, while the empty reservoir is still assembled on the air expeller. However, the piston 21 is maintained in its dispensing position due to the friction with the air chamber 22 and the suction force generated in the reservoir 30, so that the cylindrical surface 614 slides on the inner lip 215 of the piston until the inner lip cooperates with the groove 615 again. At this point, the air chamber 22 is again in communication with the surrounding air and no longer generates suction due to the return to the rest position. Therefore, the piston 21 is also brought to its rest position. This makes it possible to close the reservoir after use.
視情況，由上部主體/分配器頭1及空儲集器10形成之單元可自空氣排出器中移除且經包括全儲集器之新單元替換。Optionally, the unit formed by the upper body/distributor head 1 and the air reservoir 10 can be removed from the air evacuator and replaced by a new unit including the full reservoir.
可使用之適當施用器裝置包括可購自法國之Aptar Pharma (UDS Monopowder)的施用器裝置。參見例如國際專利申請案WO 2017/118827 A1、WO 2018/224762A1、WO 2023/282821、WO 2022/208014及WO 2021/005311，以及美國專利申請案US 2019/0358417 A1及US 2023/0144040 A1，所有該等文獻之相關揭示內容以引用的方式併入本文中。可與本發明之組合物(尤其呈粉末形式之該等組合物)結合使用的施用器裝置之其他實例包括以下中所描述者：美國專利申請案US 2011/0045088、美國專利第US 7,722,566號(參見例如圖1及圖7)及第US 5,702,362號，以及國際專利申請案WO 2014/004400、WO 2017/118827 A1及WO 2023/282821，及美國專利申請案US 2019/0358417 A1及US 2023/0144040 A1，該等文獻之相關揭示內容以引用的方式併入本文中。Suitable applicator devices that can be used include those available from Aptar Pharma (UDS Monopowder) of France. See, for example, international patent applications WO 2017/118827 A1, WO 2018/224762 A1, WO 2023/282821, WO 2022/208014, and WO 2021/005311, and U.S. patent applications US 2019/0358417 A1 and US 2023/0144040 A1, all of which are incorporated herein by reference for their relevant disclosures. Other examples of applicator devices that can be used in conjunction with the compositions of the present invention, particularly those in powder form, include those described in U.S. Patent Application Nos. 2011/0045088, 7,722,566 (see, e.g., FIGS. 1 and 7 ) and 5,702,362, and International Patent Applications Nos. WO 2014/004400, WO 2017/118827 A1 and WO 2023/282821, and U.S. Patent Applications Nos. 2019/0358417 A1 and 2023/0144040 A1, the relevant disclosures of which are incorporated herein by reference.
根據本發明之另一範疇，提供一種用於製造包含本發明之組合物之施用器裝置的方法，其中該方法包含以下步驟：將該組合物裝載至該施用器裝置內或附加於該施用器裝置的儲集器中。According to another aspect of the present invention, a method for manufacturing an applicator device comprising the composition of the present invention is provided, wherein the method comprises the following steps: loading the composition into the applicator device or into a reservoir attached to the applicator device.
根據本發明之另一範疇，提供一種無針施用器，其適用於向人類患者之體腔中投與本發明之固態非晶形單微粒粉末組合物，該空腔包括黏膜表面，其中該施用器包含： (i) 在該包含本發明之組合物之施用器內部或附加於該施用器的(視情況不透明的)儲集器； (ii) 用於在使用者致動該裝置時產生力的視情況選用之致動構件；及 (iii) 在該致動之後可分配該粉末組合物之分配構件。According to another aspect of the present invention, a needle-free applicator is provided, which is suitable for administering the solid amorphous single-particle powder composition of the present invention into a body cavity of a human patient, the cavity including a mucosal surface, wherein the applicator comprises:(i) a (optionally opaque) reservoir inside or attached to the applicator containing the composition of the present invention;(ii) an optional actuation member for generating a force when the user actuates the device; and(iii) a dispensing member that can dispense the powder composition after the actuation.
術語「無針」意謂不包含注射構件的用於投與活性醫藥成分之設備，該注射構件進一步包括例如刺穿皮膚或黏膜表面以便將該活性成分例如經皮下或經肌肉內注射至身體中的構件(與前述腎上腺激素自動注射器的操作相同)。The term "needle-free" means a device for administering an active pharmaceutical ingredient that does not include an injection member, which further includes, for example, a member that pierces the skin or mucosal surface to inject the active ingredient into the body, for example subcutaneously or intramuscularly (similar to the operation of the aforementioned adrenal hormone autoinjector).
根據本發明之另一範疇，提供一種包含一種或多種呈粉末形式之本發明組合物的施用器及/或分配器裝置，該施用器或裝置可致動一次或多次，以在每次此類致動時遞送一種或多種本發明組合物，該一種或多種本發明組合物各自包含適當劑量之活性成分，該施用器/分配器裝置包含： 出口，至少一種組合物經由該出口分配； 在使用者致動該裝置時在外部產生力(例如氣流)之構件； 含有該一種或多種本發明組合物的至少一個(視情況可替換且視情況不透明的)儲集器，該儲集器與或能夠被置放成與該分配器出口直接或間接連通； 在該裝置及/或儲集器中的可移位，視情況可倒轉之密封構件，其用於將該一種或多種組合物保留於儲集器內，直至組合物被分配； 機械開放系統，其與該密封構件協作以使得當該裝置被致動時，單一本發明組合物被加力構件以機械方式排出；及 視情況，用於重新密封該裝置及/或儲集器以將其他組合物保留於儲集器內直至另一組合物被分配之機構。According to another aspect of the present invention, an applicator and/or dispenser device containing one or more compositions of the present invention in powder form is provided, the applicator or device can be actuated once or multiple times to deliver one or more compositions of the present invention at each such actuation, the one or more compositions of the present invention each containing an appropriate dose of active ingredient, the applicator/dispenser device comprising:An outlet through which at least one composition is dispensed;A component that generates a force (such as an airflow) externally when the user actuates the device;At least one (optionally replaceable and optionally opaque) reservoir containing the one or more compositions of the present invention, the reservoir being or capable of being placed in direct or indirect communication with the dispenser outlet;a displaceable, and optionally reversible, sealing member in the device and/or reservoir for retaining the one or more compositions in the reservoir until the composition is dispensed;a mechanical opening system cooperating with the sealing member so that when the device is actuated, a single composition of the invention is mechanically expelled by a force member; anda mechanism for resealing the device and/or reservoir, as the case may be, to retain other compositions in the reservoir until another composition is dispensed.
根據本發明之又另一範疇，提供一種包含單次劑量之本發明組合物的施用器及/或分配器裝置，其適用於分配該組合物，該施用器/分配器裝置包含： 分配器出口； 空氣排出器，其用於在該裝置被致動時產生空氣流，該空氣排出器包括在空氣腔室中靜止位置與分配位置之間滑動之活塞； 該活塞在該空氣腔室內以氣密方式滑動； 含有一劑本發明組合物之至少一個(例如不透明)儲集器，該儲集器包括連接至該空氣排出器之進氣口； 連接至該分配器出口之組合物出口； 該進氣口包括可移位之密封構件(例如保持器部件)，用於將組合物保留於儲集器中，直至組合物被分配； 該組合物出口由安裝於該儲集器之組合物出口中的封閉元件封閉； 該裝置進一步包括機械開放系統，該機械開放系統與該封閉元件協作以便在該裝置被致動時將該封閉元件自其封閉位置以機械方式排出；及 該空氣排出器之該活塞當在靜止位置時以非氣密方式與該空氣腔室協作。According to yet another aspect of the present invention, an applicator and/or dispenser device containing a single dose of the composition of the present invention is provided, which is suitable for dispensing the composition, the applicator/dispenser device comprising: a dispenser outlet; an air expeller for generating an air flow when the device is actuated, the air expeller comprising a piston sliding between a rest position and a dispensing position in an air chamber; the piston slides in an airtight manner in the air chamber; at least one (e.g., opaque) reservoir containing a dose of the composition of the present invention, the reservoir comprising an air inlet connected to the air expeller; a composition outlet connected to the dispenser outlet; the air inlet comprising a displaceable sealing member (e.g., a retainer member) for retaining the composition in the reservoir until the composition is dispensed; The composition outlet is closed by a closing element mounted in the composition outlet of the reservoir;The device further comprises a mechanical opening system cooperating with the closing element to mechanically expel the closing element from its closed position when the device is actuated; andThe piston of the air expeller cooperates with the air chamber in a non-airtight manner when in the rest position.
在本發明之後一範疇中，較佳地： (i) 該空氣腔室實質上為圓柱形的，該活塞以氣密方式在該空氣腔室內滑動； (ii) 該封閉元件係強制安裝於該儲集器之組合物出口中； (iii) 該空氣腔室在該靜止位置處與大氣連通；及/或 (iv) 該活塞包括適用於與圓柱形表面協作之內唇，該圓柱形表面包括溝槽，該溝槽與處於靜止位置之該活塞之該內唇以非氣密方式協作。In the latter aspect of the invention, preferably:(i) the air chamber is substantially cylindrical and the piston slides in the air chamber in an airtight manner;(ii) the closing element is force-fitted in the composition outlet of the reservoir;(iii) the air chamber is in communication with the atmosphere in the rest position; and/or(iv) the piston comprises an inner lip adapted to cooperate with a cylindrical surface, the cylindrical surface comprising a groove, the groove cooperating in a non-airtight manner with the inner lip of the piston in the rest position.
此等裝置可在供單次使用的前述儲集器內填充適量的單一本發明組合物，該量(又稱為「填充重量」)可為至多約200 mg，諸如約至多150 mg，包括至多約100 mg或至多約75 mg，例如至多約50 mg、至多約40 mg、至多約30 mg、至多約25 mg、至多約20 mg、至多約15 mg、至多約10 mg或至多約5 mg的本發明組合物。Such devices can be filled with an appropriate amount of a single composition of the present invention in the aforementioned reservoir for a single use, which amount (also referred to as the "fill weight") can be up to about 200 mg, such as up to about 150 mg, including up to about 100 mg or up to about 75 mg, for example, up to about 50 mg, up to about 40 mg, up to about 30 mg, up to about 25 mg, up to about 20 mg, up to about 15 mg, up to about 10 mg or up to about 5 mg of the composition of the present invention.
此類經鼻施用器或分配裝置能夠提供適當且可再現之粉末噴霧圖案及/或羽流幾何形狀，從而能夠將該粉末有效遞送至鼻腔(例如鼻孔)。Such nasal applicators or dispensing devices are capable of providing an appropriate and reproducible powder spray pattern and/or plume geometry, thereby enabling effective delivery of the powder to the nasal cavity (e.g., nostrils).
在本發明之組合物中，平均粒度可表示為基於重量、數量或體積之平均直徑。熟習此項技術者將理解，如本文中所用，術語「基於重量之平均直徑」包括平均粒度係由根據重量之粒度分佈，亦即在各尺寸類別中之現有分率(相對量)定義為藉由例如篩分(例如濕法篩分)獲得之重量分率情況下的分佈來表徵及定義。術語「基於體積之平均直徑」在其含義上類似於基於重量之平均直徑，但熟習此項技術者應理解包括，平均粒度係由根據體積之粒度分佈，亦即在各尺寸類別中之現有分率(相對量)定義為藉由例如雷射繞射所量測之體積分率情況下的分佈來表徵及定義。熟習此項技術者將理解，如本文中所用，術語「基於數量之平均直徑」包括平均粒度係由根據數量之粒度分佈，亦即在各尺寸類別中之現有分率(相對量)定義為藉由例如顯微鏡檢查量測之數量分率情況下的分佈來表徵及定義。本領域中熟知之其他儀器亦可用以量測粒度，諸如由例如Malvern Instruments, Ltd (Worcestershire, UK)、Sympatec GmbH (Clausthal-Zellerfeld, Germany)及Shimadzu (Kyoto, Japan)出售之設備。In the compositions of the present invention, the average particle size can be expressed as an average diameter based on weight, number or volume. Those skilled in the art will understand that as used herein, the term "average diameter based on weight" includes that the average particle size is characterized and defined by the particle size distribution according to weight, i.e., the distribution in which the existing fraction (relative amount) in each size category is defined as the weight fraction obtained by, for example, sieving (e.g., wet sieving). The term "average diameter based on volume" is similar in meaning to the average diameter based on weight, but it will be understood by those skilled in the art to include that the average particle size is characterized and defined by the particle size distribution based on volume, i.e., the distribution in the case of volume fraction as measured by, for example, laser diffraction, where the existing fraction (relative amount) in each size class is defined. It will be understood by those skilled in the art that, as used herein, the term "average diameter based on number" includes that the average particle size is characterized and defined by the particle size distribution based on number, i.e., the distribution in the case of number fraction as measured by, for example, microscopic inspection, where the existing fraction (relative amount) in each size class is defined. Other instruments known in the art may also be used to measure particle size, such as equipment sold by, for example, Malvern Instruments, Ltd (Worcestershire, UK), Sympatec GmbH (Clausthal-Zellerfeld, Germany), and Shimadzu (Kyoto, Japan).
儘管當將本發明之組合物調配用於例如經口、局部投與口腔、眼或其他黏膜，或藉由注射或輸注投與時，粒度並不重要(或更確切地說可能不重要)，但本發明之粉末組合物的基於體積之平均直徑(VMD)通常將在約0.2 μm，諸如約0.5 μm (例如約1 μm)到至多約1,000 μm (例如至多約500 μm，諸如約400 μm或約500 μm)之範圍內，且適當粒度範圍可基於意欲包括此類組合物之劑型選擇。Although particle size is not critical (or rather may not be critical) when the compositions of the invention are formulated for, e.g., oral administration, topical administration to the oral cavity, eye or other mucous membranes, or administration by injection or infusion, the volume-based mean diameter (VMD) of the powder compositions of the invention will typically be in the range of about 0.2 μm, such as about 0.5 μm (e.g., about 1 μm) to up to about 1,000 μm (e.g., up to about 500 μm, such as about 400 μm or about 500 μm), and an appropriate particle size range can be selected based on the dosage form intended to include such a composition.
然而，熟習此項技術者將理解，為了允許有效鼻內投與，粉末之基於體積之平均直徑(VMD)通常將在約5 μm到至多約300 μm (例如至多約200 μm)之範圍內。取決於所使用之施用器裝置，VMD可在約10 μm至約100 μm，諸如約20 μm至約60 μm之範圍內。However, those skilled in the art will appreciate that to allow for effective intranasal administration, the mean diameter (VMD) of the powder based on volume will generally be in the range of about 5 μm to up to about 300 μm (e.g., up to about 200 μm). Depending on the applicator device used, the VMD may be in the range of about 10 μm to about 100 μm, such as about 20 μm to about 60 μm.
供鼻內藥物遞送的較佳粒度分佈亦可包括D10大於約3 µm且小於約75 µm(例如至多約50 µm)，諸如大於約5 µm，諸如大於約6 µm、大於約7 µm、大於約8 µm、大於約9 µm且包括大於約10 µm以及D90在約80 µm與約1,000 µm之間(例如約500 µm)，諸如小於約200、小於約150或小於約125，例如小於約100 µm的粒度分佈。熟習此項技術者將理解，參數「D10」(或「Dv(10)」)意謂粒度分佈中之這樣一種尺寸(或直徑)，低於該尺寸之粒子佔樣本中材料總體積之10%。類似地，「D90」(或「Dv(90)」)意謂使低於該尺寸之粒子佔該材料之90%的尺寸。Preferred particle size distributions for intranasal drug delivery may also include a D10 greater than about 3 µm and less than about 75 µm (e.g., up to about 50 µm), such as greater than about 5 µm, such as greater than about 6 µm, greater than about 7 µm, greater than about 8 µm, greater than about 9 µm, and including greater than about 10 µm and a D90 between about 80 µm and about 1,000 µm (e.g., about 500 µm), such as less than about 200, less than about 150, or less than about 125, such as less than about 100 µm. Those skilled in the art will understand that the parameter "D10" (or "Dv(10)") means the size (or diameter) in the particle size distribution below which particles account for 10% of the total volume of the material in the sample. Similarly, "D90" (or "Dv(90)") means the size below which particles account for 90% of the material.
具有在以上範圍內之粒度分佈及VMD之粉末包括整體VMD及/或發射之VMD，亦即當最初裝載至該裝置中時及/或當分別自其中排出時之粒度分佈。Powders having a particle size distribution and VMD within the above ranges include bulk VMD and/or emitted VMD, i.e., the particle size distribution when initially loaded into the device and/or when discharged therefrom, respectively.
粒度可藉由標準設備來量測，諸如乾法(或濕法)粒度量測技術，包括可購自諸如Sympatec及Malvern之製造商的乾法分散技術。Particle size can be measured by standard equipment, such as dry (or wet) particle size measurement techniques, including dry dispersion techniques available from manufacturers such as Sympatec and Malvern.
較佳粒子形狀包括球狀或實質上球狀，意謂該等粒子具有低於約20，更佳低於約10，諸如低於約4，且尤其低於約2之縱橫比，及/或可在至少約90%之粒子中具有不超過該平均值之約50%，諸如不超過該值之約30%，例如不超過該值之約20%的半徑變化(自重心至粒子表面量測)。Preferred particle shapes include spherical or substantially spherical, meaning that the particles have an aspect ratio of less than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2, and/or may have a radius variation (measured from the center of gravity to the particle surface) of no more than about 50% of the average, such as no more than about 30% of the value, for example no more than about 20% of the value in at least about 90% of the particles.
然而，粒子可為任何形狀，包括不規則形狀(例如「葡萄乾」形)、針形(在此情況下，粒度最佳可表示為此等針之平均長度)、圓盤形或立方形粒子。對於非球形粒子，尺寸可指示為具有例如相同重量、體積或表面積之相應球形粒子的尺寸。However, the particles may be of any shape, including irregular shapes (e.g., "raisin" shapes), needle-shaped (in which case the particle size is best expressed as the average length of the needles), disc-shaped, or cubic particles. For non-spherical particles, the size may be indicated as the size of a corresponding spherical particle having, for example, the same weight, volume, or surface area.
自經鼻施用器及/或分配器裝置發射(分配)本發明之粉末組合物的噴射角應較佳小於約90°。The spray angle at which the powder composition of the present invention is emitted (dispensed) from a nasal applicator and/or dispenser device should preferably be less than about 90°.
當本文中在量，例如絕對量，諸如劑量、重量、體積、尺寸、直徑、縱橫比、角度、pH值等，或組合物或組合物之組分中個別成分之相對量(例如百分比)(包括濃度及比率)、時間範圍以及諸如溫度、壓力、相對濕度等參數之情形中使用詞語「約」時，應瞭解，此等變量係近似的，且因此可與本文所指定之實際數值相差±10%，例如±5%，且較佳±2% (例如±1%)。即使此等數值首先以百分比表示，情況亦如此(例如，「約10%」可意謂約數值10±10%，即在9%與11%之間的任何值)。When the word "about" is used herein in the context of an amount, such as an absolute amount, such as a dose, weight, volume, size, diameter, aspect ratio, angle, pH value, etc., or a relative amount (such as a percentage) of an individual component of a composition or a component of a composition (including concentrations and ratios), a time frame, and parameters such as temperature, pressure, relative humidity, etc., it should be understood that these variables are approximate and therefore may vary from the actual numerical value specified herein by ±10%, such as ±5%, and preferably ±2% (such as ±1%). This is the case even if such numerical values are first expressed as a percentage (for example, "about 10%" can mean an approximate value of 10±10%, i.e., any value between 9% and 11%).
本發明之組合物具有以下優點：其能夠在寬範圍之溫度及/或相對濕度下單獨儲存及/或儲存在施用器或用於該施用器之儲集器中(其中任一者均可包裝在適當醫藥包裝中，該包裝可提供或可不提供上文所描述之防潮層)。因此，本發明之組合物可在不影響投與個體之活性成分之量的情況下經受低溫(例如低於冰點)。此外，含有本發明之粉末組合物的施用器可具有以下優點：該等組合物在所有(包括較高)溫度下的物理及化學穩定性比相關先前技術裝置(諸如EpiPen)中所含有之調配物高。The compositions of the present invention have the advantage that they can be stored alone and/or in an applicator or a reservoir for the applicator (either of which may be packaged in a suitable pharmaceutical packaging that may or may not provide a moisture barrier as described above) over a wide range of temperatures and/or relative humidity. Thus, the compositions of the present invention can withstand low temperatures (e.g., below freezing) without affecting the amount of active ingredient administered to a subject. In addition, applicators containing the powder compositions of the present invention may have the advantage that the compositions are physically and chemically more stable at all (including higher) temperatures than formulations contained in related prior art devices such as the EpiPen.
本發明之組合物亦可具有以下優點：與先前技術組合物(例如包含腎上腺激素之該等組合物)相比，其提供較高的活性成分生物可用性。本發明之組合物可提供此比此類先前技術及/或可商購組合物更高的生物可用性以及更快速的吸收，從而將可能引起更快速的起效，且因此滿足顯著的醫療需求。The compositions of the present invention may also have the advantage of providing higher bioavailability of the active ingredient compared to prior art compositions (e.g., those compositions comprising adrenal hormones). The compositions of the present invention may provide this higher bioavailability and faster absorption than such prior art and/or commercially available compositions, which will likely result in a faster onset of action and thus meet a significant medical need.
本文所描述之施用器、組合物、醫藥調配物、用途及方法亦可具有如下優點：在治療已知相關活性成分適用之病況時，對於先遣急救員、醫師及/或患者而言，其可能比先前技術中已知之類似調配物或方法(治療)更便利、更有效、毒性更低、活性範圍更廣、效力更強、產生的副作用更少、患者間變化性更小，或相對於先前技術中已知之類似調配物或方法(治療)，其可能具有其他有用的藥理學特性，不論藉由經黏膜(諸如鼻內投與)抑或以其他方式用於治療前述病況。The applicators, compositions, pharmaceutical formulations, uses and methods described herein may also have the following advantages: when treating conditions for which the relevant active ingredients are known to be useful, they may be more convenient, more effective, less toxic, have a broader range of activity, be more potent, produce fewer side effects, have less inter-patient variability, or have other useful pharmacological properties relative to similar formulations or methods (treatments) known in the prior art, whether used to treat the aforementioned conditions by transmucosal (such as intranasal administration) or otherwise.
比較實例1 腎上腺激素調配物Comparative Example 1Adrenal hormone preparations
用以下各物製備四種1 mg腎上腺激素鼻用粉末調配物(調配物1-4)：1.82毫克/劑腎上腺激素酒石酸氫鹽(Transo Pharm, Taiwan；對應於1.00毫克/劑之腎上腺激素游離鹼)、蔗糖單月桂酸酯D-1216(0.75毫克/劑；Mitsubishi-Kagaku Foods Corporation,Japan)及不同量之海藻糖(Sigma-Aldrich(Merck), Sweden)及DE 19之麥芽糊精(Glucidex IT 19DE；Roquette, France)。Four 1 mg adrenergic nasal powder formulations (Formulations 1-4) were prepared using 1.82 mg/dose adrenergic bitartrate (Transo Pharm, Taiwan; corresponding to 1.00 mg/dose adrenergic free base), sucrose monolaurate D-1216 (0.75 mg/dose; Mitsubishi-Kagaku Foods Corporation, Japan), and varying amounts of trehalose (Sigma-Aldrich (Merck), Sweden) and DE 19 maltodextrin (Glucidex IT 19DE; Roquette, France).
稱取整體量之成分(總量如下表1中所示)，分配於玻璃燒瓶中且藉由在室溫下攪拌，使其溶解於MQ-水(其量如表1中所示)中。 表1
以毫克/劑為單位的海藻糖(無水)及麥芽糊精之相對量示於下表2中。 表2
將所得混合物饋送至配備有以25 kHz操作之超音波噴嘴的噴霧乾燥器(ProCepT, Belgium)中。噴霧乾燥器之饋送速率設定為4.0 g/min，入口溫度設定為180℃，氣體流量設定為300 L/min且旋風器氣體設定為1.5巴。The resulting mixture was fed to a spray dryer (ProCepT, Belgium) equipped with an ultrasonic nozzle operating at 25 kHz. The feed rate of the spray dryer was set to 4.0 g/min, the inlet temperature was set to 180 °C, the gas flow was set to 300 L/min and the cyclone gas was set to 1.5 bar.
收集所得到的呈精細、乾燥且自由流動形式之噴霧乾燥粉末，具有25 mg總量的待投與之噴霧乾燥粉末中1 mg腎上腺激素游離鹼(其各自亦包括1毫克/劑殘餘水)之標稱劑量。The resulting spray dry powder was collected in a fine, dry and free-flowing form with a nominal dose of 1 mg of adrenergic free base (each of which also included 1 mg/dose of residual water) in a total amount of 25 mg of spray dry powder to be administered.
藉由乾粉雷射繞射分析粉末之粒度分佈(PSD)。在使用Mastersizer 3000雷射繞射感測器測定尺寸之前，用Aero S乾燥分散單元(使用0.5巴之壓縮空氣)分散該樣本(兩種設備均屬Malvern Panalytical，UK)，如下表3中所示。該等調配物之PSD剛好在適於經鼻投與之分佈範圍內。 表3
藉由HPLC/UV分析測定噴霧乾燥之腎上腺激素調配物之含量檢定結果(assay)及純度。整體粉末之含量檢定結果及總相關物質(亦即，雜質及降解產物)之百分比(RS%)示於下表4中。 表4
使用Quantos粉末分配器(MT, USA)將粉末填入UDS粉末裝置(Aptar, France)中，每個裝置25 mg。將填充後的裝置置放於具有乾燥劑(CSP, France)之塑膠小瓶內，且置放於一個40℃及75%相對濕度(40/75)之氣候櫃(climate cabinet)及另一個25℃及60%相對濕度(25/60)之氣候櫃中。The powder was filled into UDS powder devices (Aptar, France) using a Quantos powder dispenser (MT, USA) at 25 mg per device. The filled devices were placed in plastic vials with desiccant (CSP, France) and placed in a climate cabinet at 40°C and 75% relative humidity (40/75) and another climate cabinet at 25°C and 60% relative humidity (25/60).
對於不同組合物及包裝，在至多9個月之後原料藥之化學穩定性，以及含量檢定結果及以RS%表示的超過0.10%之雜質及降解產物之總量概括於下表5中。 表5
進行I期臨床研究，其主要目標係測定四種腎上腺激素鼻用粉末相對於參考商業產品EpiPen®之生物可用性。(「Ref」；肌肉內注射之0.3 mg腎上腺激素；Meda AB, Solna, Sweden)。A Phase I clinical study was conducted with the primary objective of determining the bioavailability of four adrenal hormone nasal powders relative to the reference commercial product, EpiPen® (“Ref”; 0.3 mg adrenal hormone for intramuscular injection; Meda AB, Solna, Sweden).
次要目標係：表徵額外PK參數；比較各治療對收縮/舒張血壓(SBP/DBP)、平均動脈血壓(MAP)及心率(HR)之藥效學(PD)作用；以及評估研究用醫藥產品(IMP)之安全性及耐受性。Secondary objectives were to characterize additional PK parameters; to compare the pharmacodynamic (PD) effects of each treatment on systolic/diastolic blood pressure (SBP/DBP), mean arterial pressure (MAP), and heart rate (HR); and to evaluate the safety and tolerability of the investigational medicinal product (IMP).
該研究係隨機化序列、單中心、開放標記、5期交叉研究，用以評價4種粉末調配物與腎上腺激素肌肉內注射劑在健康個體中之比較生物可用性。各個體根據預設隨機化時程中之序列接受調配物1至4中之每一者，以及Ref，間隔24小時清除期。This study was a randomized sequence, single-center, open-label, 5-period crossover study to evaluate the comparative bioavailability of 4 powder formulations with adrenal hormone intramuscular injection in healthy subjects. Each subject received each of formulations 1 to 4 according to a sequence in a pre-specified randomized schedule, and Ref, separated by a 24-hour washout period.
在即將投與第一劑相關IMP或Ref(若使用的話)之前，對個體進行隨機分組。使用電腦生成之隨機化時程將個體編號分配給10個治療序列中之1個。Subjects were randomized immediately prior to administration of the first dose of the relevant IMP or Ref (if used). Subject numbers were assigned to 1 of 10 treatment sequences using a computer-generated randomization schedule.
在給藥之前長達28天中，篩選約79名個體以納入研究中。在IMP投與前一天晚間(第-1天)，將40名符合條件的個體(年齡在18歲與55歲之間且身體質量指數在18.5與30.0 kg/m2之間的健康男性個體及未懷孕且非哺乳期女性個體)送入病房，且留在此地直至最後一次給藥後24小時(在接受全部5次治療之後)出院。Approximately 79 subjects were screened for inclusion in the study up to 28 days prior to dosing. On the evening before IMP administration (Day -1), 40 eligible subjects (healthy male subjects and non-pregnant and non-lactating female subjects aged between 18 and 55 years with a body mass index between 18.5 and 30.0 kg/m2 ) were admitted to the ward and remained there until discharged 24 hours after the last dose (after receiving all 5 treatments).
藉由來自法國之Aptar Pharma (UDS Monopowder)的特定鼻內裝置經鼻內投與調配物1至4。個體在第1天、第2天、第3天、第4天及第5天的早晨接受IMP或Ref，其中個體之間的適當間隔係基於邏輯要求(大約10分鐘)。在每一給藥日向不同鼻孔投與IMP。在最後一次給藥後3至5天將進行電話回訪以確保個體處於良好健康狀態。Formulations 1 to 4 were administered intranasally via a specific intranasal device from Aptar Pharma (UDS Monopowder) in France. Subjects received IMP or Ref on the morning of Days 1, 2, 3, 4, and 5, with appropriate intervals between subjects based on logistical requirements (approximately 10 minutes). IMP was administered to a different nostril on each dosing day. A follow-up telephone call was conducted 3 to 5 days after the last dose to ensure that the subject was in good health.
在入選的40名個體中，有37至39名個體接受所有IMP及Ref。出於分析目的，安全性群體、安全性分析資料集及PK群體中包括37至39名個體。Of the 40 subjects enrolled, 37 to 39 subjects received all IMPs and Ref. For analysis purposes, 37 to 39 subjects were included in the Safety Population, Safety Analysis Data Set, and PK Population.
使用非室體分析方法分析腎上腺激素之血漿濃度以獲得下文所陳述的PK參數估計值：
以下參數用於分析PD效應。
使用標準方法比較對數變換之暴露參數(AUC及Cmax)以評估相對生物可用性。針對各參數擬合單一混合效應模型以獲得所有感興趣之治療比較的幾何平均比率(GR)及相應信賴區間(CI)之估計值。模型包括關於所接受之實際治療、研究日(亦即，時段)及作為固定效應擬合之計劃序列，以及作為隨機效應擬合的序列內之個體的術語。所呈現的結果經逆變換為線性標度。以下比較係令人感興趣的： • 與Ref相比較之相對生物可用性：測定AUC(0-t)、AUC(0-inf)及Cmax之IMP:GMR。 • 與Ref相比較之部分AUC:s：測定AUC(0-10)、AUC(0-20)、AUC(0-30)、AUC(0-45)及AUC(0-60 min)之IMP:Ref GMR。Log-transformed exposure parameters (AUC and Cmax) were compared using standard methods to assess relative bioavailability. A single mixed-effects model was fit for each parameter to obtain estimates of the geometric mean ratio (GR) and corresponding confidence intervals (CI) for all treatment comparisons of interest. The model included terms for actual treatment received, study day (i.e., period), and planned sequence as fixed effects, and individuals within the sequence as random effects. Results presented were back-transformed to a linear scale. The following comparisons are of interest:• Relative bioavailability compared to Ref: IMP:GMR for determination of AUC(0-t), AUC(0-inf), and Cmax.• Partial AUC:s compared with Ref: Determination of IMP:Ref GMR of AUC(0-10), AUC(0-20), AUC(0-30), AUC(0-45) and AUC(0-60 min).
對於PD參數，使用算術平均值差值及相應90%信賴區間進行比較。For PD parameters, comparisons were made using arithmetic mean differences and corresponding 90% confidence intervals.
安全性參數之評價包含對不良事件(AE)、局部耐受性、實驗室評價、生命徵象、心電圖(ECG)及體檢發現之分析，其中終點(次要終點)包括： • 不良事件(AE)之頻率、強度及嚴重性。 • 局部耐受性、生命徵象、安全性實驗室參數、安全性12導聯心電圖(ECG)及體檢的臨床上顯著之變化。The evaluation of safety parameters included analysis of adverse events (AEs), local tolerance, laboratory evaluations, vital signs, electrocardiograms (ECGs), and physical examination findings, with the endpoints (secondary endpoints) including: • Frequency, intensity, and severity of adverse events (AEs). • Clinically significant changes in local tolerance, vital signs, safety laboratory parameters, safety 12-lead electrocardiograms (ECGs), and physical examinations.
在篩選期間，個體審閱並簽署知情同意書(ICF)，接受其健康狀況及資格之審查，並經歷安全性和耐受性評估，包括體檢、安全性實驗室測試、12導聯心電圖(ECG)以及病史、生命徵象(BP及HR)、身高、體重及身體質量指數(BMI)的收集。During the screening period, individuals reviewed and signed an informed consent form (ICF), had their health status and eligibility reviewed, and underwent safety and tolerability assessments, including physical examination, safety laboratory tests, 12-lead electrocardiogram (ECG), and collection of medical history, vital signs (BP and HR), height, weight, and body mass index (BMI).
臨床研究之次要目標包括IMP之安全性及耐受性的評估。Secondary objectives of the clinical study include the evaluation of the safety and tolerability of IMP.
在第1天進行之基線安全性及耐受性評估包括生命徵象、基線症狀、先前藥物治療及鼻腔目視檢查之收集。記錄自入院直至IMP投與的基線症狀及先前藥物治療。Baseline safety and tolerability assessments conducted on Day 1 included collection of vital signs, baseline symptoms, prior medications, and visual nasal examination. Baseline symptoms and prior medications were recorded from admission until IMP administration.
出院安全性及耐受性評估(第6天)包括體檢、安全性實驗室測試、12導聯ECG、局部耐受性評估和生命徵象之收集。Discharge safety and tolerability assessments (Day 6) included physical examination, safety laboratory testing, 12-lead ECG, local tolerability assessment, and collection of vital signs.
自第8天至第10天(或在提前退出時最後一次投與IMP之後3至5天)經由電話進行最終電話追蹤遠程訪視(第3次訪視，研究結束)以追蹤不良事件(AE)及伴隨藥物治療。A final follow-up remote visit (Visit 3, end of study) was conducted by telephone from Day 8 to Day 10 (or 3 to 5 days after the last IMP dose in case of premature withdrawal) to track adverse events (AEs) and concomitant medications.
自投與IMP(第2次訪視)開始直至追蹤訪視(第3次訪視)，藉由個體面診收集AE。AEs were collected by individual interviews from the time of IMP administration (Visit 2) until the follow-up visit (Visit 3).
在投與前＜-01:00小時(基線)以及在每次投與IMP之後01:00、04:00及23:00小時，藉由目視檢查鼻腔(對於IMP)或Ref(亦即，EpiPen)注射部位評估局部耐受性。以5級量表評估局部耐受性。在針對IMP之鼻內局部耐受性評估中亦考慮鼻及呼吸道AE。Local tolerance was assessed by visual inspection of the nasal (for IMP) or Ref (i.e., EpiPen) injection site at <-01:00 hours prior to administration (baseline) and at 01:00, 04:00, and 23:00 hours after each IMP administration. Local tolerance was assessed on a 5-point scale. Nasal and respiratory AEs were also considered in the assessment of intranasal local tolerability for IMP.
安全性評估亦包括生命徵象(收縮/舒張BP及HR)，以及體檢、安全性實驗室概況及12導聯ECG。功效結果Safetyassessments also included vital signs (systolic/diastolic BP and HR), as well as physical examination, safety laboratory profile, and 12-lead ECG.
治療引起之算術平均腎上腺激素血漿濃度隨時間之變化(線性標度)示於圖8中。治療引起之幾何平均腎上腺激素血漿濃度隨時間之變化(半對數標度)描述於下表6中。 表6
相對生物可用性(GMR，90% CI)之分析示於下表7中。 表7
與Ref相比，所有IMP調配物皆展示腎上腺激素之更高總體血漿暴露量及類似或更高的峰值血漿暴露量。All IMP formulations showed higher overall plasma exposure and similar or higher peak plasma exposure of adrenal hormones compared to Ref.
下表8顯示治療引起之腎上腺激素部分AUC (以幾何平均值顯示；幾何CV%)之描述性統計數據。表9顯示調配物1至4與Ref (GMR，90% CI)之部分AUC的比較。 表8
在給藥後前20分鐘之後，所有IMP調配物展示與Ref類似或比Ref更高的腎上腺激素血漿暴露量。After the first 20 minutes post-dose, all IMP formulations demonstrated similar or higher adrenal hormone plasma exposures than Ref.
所有IMP調配物及Ref對收縮血壓(表10)及舒張血壓(表11)之影響顯示如下。 表10
所有IMP調配物及Ref對平均動脈血壓之影響顯示於下表12中，且對心率之影響顯示下表13中。 表12
表14至表17顯示調配物1至4與Ref之PD參數的比較(算術平均值差異，90% CI)。表14顯示收縮血壓(SBP)之比較，表15表示舒張血壓(DBP)之比較，表16表示平均動脈血壓(MAP)之比較，且表17表示心率(HR)之比較。 表14
對於SPB、DBP及MAP (表14至表16)，與Ref相比，所有IMP之AUEC參數及Emax明顯較高(90% CI＞0)。對於HR (表17)，與Ref相比，大多數IMP具有更高AUEC參數，且同樣存在Emax更高之趨勢。For SPB, DBP, and MAP (Tables 14 to 16), AUEC parameters and Emax of all IMPs were significantly higher (90% CI>0) compared with Ref. For HR (Table 17), most IMPs had higher AUEC parameters compared with Ref, and there was also a trend of higher Emax.
與Ref相比，所有腎上腺激素鼻用粉末調配物(1至4)皆具有更高的腎上腺激素總暴露量(AUC(t))及類似或更高的Cmax。調配物1至4的Tmax略低於Ref，但如表9中所示，在20分鐘之後，與Ref相比，全部四種腎上腺激素鼻用粉末調配物皆具有類似或更高的腎上腺激素暴露量。All adrenal hormone nasal powder formulations (1 to 4) had higher total adrenal hormone exposure (AUC(t)) and similar or higher Cmax compared to Ref. The Tmax of formulations 1 to 4 was slightly lower than that of Ref, but as shown in Table 9, after 20 minutes, all four adrenal hormone nasal powder formulations had similar or higher adrenal hormone exposure compared to Ref.
經鼻投與腎上腺激素鼻用粉末被認為是安全的，且試驗中未報告嚴重不良事件(AE)。最常報告的AE為鼻不適、鼻痛、頭痛及心悸。安全性及耐受性結果Adrenaline nasal powder was considered safe for nasal administration, and no serious adverse events (AEs) were reported in the trial. The most commonly reported AEs were nasal discomfort, nasal pain, headache, and palpitations.Safety and Tolerability Results
所有測試調配物皆透過局部刺激而產生輕微不適，包括對鼻黏膜之明顯影響，然而，此等影響主要為輕度且耐受的。All formulations tested produced mild discomfort via local irritation, including significant effects on the nasal mucosa; however, these effects were primarily mild and well tolerated.
其他AE及其他安全性參數總體上與腎上腺激素之已知藥理學一致，包括心血管及神經作用： • 在研究中觀察到血壓及脈搏率之增加，然而，自安全性之角度看，生命徵象之變化皆不被視為臨床上顯著的；及 • 實驗室參數或個別實驗室發現不存在引起任何安全性問題的趨勢。Other AEs and other safety parameters were generally consistent with the known pharmacology of adrenal hormones, including cardiovascular and neurologic effects: • Increases in blood pressure and pulse rate were observed in the study, however, none of the changes in vital signs were considered clinically significant from a safety perspective; and • There were no trends in laboratory parameters or individual laboratory findings that raised any safety concerns.
在研究期間報告異常ECG發現及趨勢，包括導致個體退出之一個重要發現(QRS波群延長)及各種ECG參數之趨勢。Abnormal ECG findings and trends were reported during the study, including one important finding leading to subject withdrawal (QRS prolongation) and trends in various ECG parameters.
經鼻投與腎上腺激素鼻用粉末被認為是安全的，且試驗中未報告嚴重不良事件(AE)。大多數研究個體經歷鼻不適，但大部分為輕度、短暫且可耐受的。 實例1 噴霧乾燥之腎上腺激素游離鹼調配物IAdrenaline nasal powder was considered safe for nasal administration, and no serious adverse events (AEs) were reported in the trial. Most study subjects experienced nasal discomfort, but most were mild, transient, and tolerable.Example 1Spraying dry adrenaline free base formulation I
在玻璃燒瓶中，將腎上腺激素游離鹼(Cambrex, Italy)溶解於約35 mL MQ-水(10%固體負載量)中，且在攪拌下，在室溫下用7 mL(實例F及實例G)或11 mL(另外的) 0.1M HCl (水溶液)酸化。溶解之後，將pH值維持原樣，或藉由添加0.1M NaOH(水溶液；適量)調至4.5與5.5之間。在此階段量測pH值且將其呈現於下表18中。Adrenaline free base (Cambrex, Italy) was dissolved in approximately 35 mL of MQ-water (10% solid loading) in a glass flask and acidified with 7 mL (Example F and Example G) or 11 mL (additional) 0.1 M HCl (aq) at room temperature under stirring. After dissolution, the pH was maintained as is or adjusted to between 4.5 and 5.5 by adding 0.1 M NaOH (aq; qs). The pH was measured at this stage and is presented in Table 18 below.
接著，將某一量的海藻糖(二水合物；Pfanstiehl, US)、麥芽糊精(Glucidex IT 19 DE(MD19)；Roquette, France)、蔗糖單月桂酸酯D-1216(SM；Mitsubishi-Kagaku Foods Corporation, Japan)添加至該溶液中。Then, a certain amount of trehalose (dihydrate; Pfanstiehl, US), maltodextrin (Glucidex IT 19 DE (MD19); Roquette, France), and sucrose monolaurate D-1216 (SM; Mitsubishi-Kagaku Foods Corporation, Japan) were added to the solution.
接著，在以上比較實例1中描述之條件下對所得溶液進行噴霧乾燥，以產生精細、乾燥且自由流動之粉末(實例A至實例G)，其各自具有25或37.5 mg粉末中1 mg腎上腺素游離鹼之標稱劑量，且其組成如下表18中所描述(量以公克顯示)。 表18
藉由乾粉雷射繞射分析粉末之粒度分佈(PSD)。在使用Mastersizer 3000雷射繞射感測器測定尺寸之前，用Aero S乾燥分散單元(使用0.5巴之壓縮空氣)分散各樣本(兩種設備均屬Malvern Panalytical，UK)，如下表19中所示。該等調配物之PSD良好地在適於經鼻投與之分佈範圍內。 表19
藉由HPLC/UV分析來測定噴霧乾燥之調配物的含量檢定結果及純度。製備後的含量檢定結果在95與105.5%之間，且總相關物質之百分比(RS%)(亦即，雜質及降解產物)在0.04與1.43%之間的範圍內(如下表20及表21中所示)。The assay and purity of the spray dried formulations were determined by HPLC/UV analysis. The as-prepared assay was between 95 and 105.5%, and the percentage of total related substances (RS%) (i.e., impurities and degradation products) was in the range of 0.04 and 1.43% (as shown in Tables 20 and 21 below).
如以上比較實例1中所描述，量測在40℃及75%相對濕度(40/75)之氣候櫃內儲存長達6個月之後調配物之化學穩定性。對於各儲存條件，將DUMA容器中之調配物置放於該氣候櫃中，該等DUMA容器係包裝在具有乾燥劑之熱密封鋁小袋中。The chemical stability of the formulations after storage in a climate cabinet at 40°C and 75% relative humidity (40/75) for up to 6 months was measured as described above in Comparative Example 1. For each storage condition, the formulations in DUMA containers packaged in heat-sealed aluminum pouches with desiccant were placed in the climate cabinet.
概括針對不同組合物及包裝的以含量檢定結果表示之原料藥之穩定性(下表20)，以及以RS%表示的雜質及降解產物之總量(下表21)，其中NA意謂「未分析」。 表20
根據基於USP之標準方法，亦藉由對掌性HPLC測定在相同條件下儲存之樣本的鏡像異構純度。下表22中概括針對不同組合物的鏡像異構穩定性，以S-腎上腺素%)表示。 表22
意外地是，自以上結果可以看出，自pH值已調至4.5與5.5之間之溶液噴霧乾燥的調配物在此等儲存條件下不僅在化學上(相對於雜質和降解產物之總量)，而且在鏡像異構物穩定性方面更穩定。 實例2 噴霧乾燥之腎上腺激素游離鹼調配物IISurprisingly, it can be seen from the above results that the formulation spray dried from a solution adjusted to a pH between 4.5 and 5.5 is more stable under these storage conditions not only chemically (with respect to the total amount of impurities and degradation products) but also in terms of mirror image isomer stability.Example 2Spray dried adrenal hormone free base formulation II
在玻璃燒瓶中，在攪拌下，在室溫下將腎上腺激素游離鹼(Cambrex, Italy)溶解於約114 mL MQ-水中並用42 mL之0.1 M HCl (水溶液)(實例H)酸化，或溶解於167 mL之0.1 M HCl (水溶液)(實例I)中。溶解之後，藉由添加0.1 M NaOH(水溶液；適量)將pH值調節至4.9。接著，將某一量的海藻糖(二水合物；Pfanstiehl, US)、麥芽糊精(Glucidex IT 19 DE(MD19)；Roquette, France)、蔗糖單月桂酸酯D-1216(SM；Mitsubishi-Kagaku Foods Corporation, Japan)添加至該溶液中。Adrenaline free base (Cambrex, Italy) was dissolved in about 114 mL of MQ-water and acidified with 42 mL of 0.1 M HCl (aq) (Example H) or dissolved in 167 mL of 0.1 M HCl (aq) (Example I) in a glass flask under stirring at room temperature. After dissolution, the pH was adjusted to 4.9 by adding 0.1 M NaOH (aq; q.s). Then, a certain amount of trehalose (dihydrate; Pfanstiehl, US), maltodextrin (Glucidex IT 19 DE (MD19); Roquette, France), sucrose monolaurate D-1216 (SM; Mitsubishi-Kagaku Foods Corporation, Japan) was added to the solution.
接著，在以上比較實例1中描述之條件下對所得溶液進行噴霧乾燥，以產生精細、乾燥且自由流動之粉末(實例H至實例I)，其具有25 mg粉末中0.5 mg及2 mg腎上腺素游離鹼之標稱劑量，且其組成如下表23中所描述(量以公克顯示)。The resulting solution was then spray dried under the conditions described in Comparative Example 1 above to produce fine, dry and free-flowing powders (Examples H to I) having a nominal dose of 0.5 mg and 2 mg of adrenaline free base in 25 mg of powder and whose compositions are described in Table 23 below (amounts are shown in grams).
pH值係在添加賦形劑之前量測的饋料溶液之pH值。 表23
藉由乾粉雷射繞射分析粉末之粒度分佈(PSD)。在使用Mastersizer 3000雷射繞射感測器測定尺寸之前，用Aero S乾燥分散單元(使用0.5巴之壓縮空氣)分散各樣本(兩種設備均屬Malvern Panalytical，UK)，如下表24中所示。該等調配物之PSD良好地在適於經鼻投與之分佈範圍內。 表24
藉由HPLC/UV分析來測定噴霧乾燥之調配物的含量檢定結果及純度。製備後的含量檢定結果為約99%且總相關物質之百分比(RS%)低於0.1%(如下表25及下表26中所示)。The content assay and purity of the spray dried formulations were determined by HPLC/UV analysis. The content assay after preparation was about 99% and the percentage of total related substances (RS%) was less than 0.1% (as shown in Table 25 and Table 26 below).
如以上比較實例1中所描述，量測在40℃及75%相對濕度(40/75)之氣候櫃內儲存長達6個月之後調配物之化學穩定性。對於各儲存條件，將DUMA容器中之調配物置放於該氣候櫃中，該等DUMA容器係包裝在具有乾燥劑之熱密封鋁小袋中。The chemical stability of the formulations after storage in a climate cabinet at 40°C and 75% relative humidity (40/75) for up to 6 months was measured as described above in Comparative Example 1. For each storage condition, the formulations in DUMA containers packaged in heat-sealed aluminum pouches with desiccant were placed in the climate cabinet.
原料藥之穩定性以含量檢定結果表示(下表25)，且雜質及降解產物之總量以RS%表示(下表26)。 表25
腎上腺激素鼻用粉末調配物係根據實例A至實例G、如以上實例1中所描述及/或如以上實例2中所描述製備。Adrenal hormone nasal powder formulations are prepared according to Examples A to G, as described in Example 1 above, and/or as described in Example 2 above.
根據預設隨機化時程，以1 mg及2 mg腎上腺激素劑量向30名健康志願者投與調配物。每名個體均接受兩種劑量，且對於1 mg劑量，此亦在鼻過敏原攻擊之後接受。The formulation was administered to 30 healthy volunteers in doses of 1 mg and 2 mg adrenaline according to a pre-specified randomized schedule. Each individual received both doses, and for the 1 mg dose, this was also after nasal allergen challenge.
各劑量間隔約24小時之清除期，且在過敏原攻擊之前，存在12-14天之清除期。在即將投與第一次劑量之前，對個體進行隨機分組。Each dose was separated by a washout period of approximately 24 hours, and there was a washout period of 12-14 days prior to allergen challenge. Subjects were randomized immediately prior to the first dose.
藉由來自法國之Aptar Pharma(UDS Monopowder)的特定鼻內裝置經鼻內投與所有調配物，且在每個給藥日，在各鼻孔之間交替進行投與。All formulations were administered intranasally via a specific intranasal device from Aptar Pharma (UDS Monopowder), France, alternating between nostrils on each dosing day.
在投與前＜-01:00小時(基線)以及每次投與之後01:00、05:00及23:00小時，藉由目視檢查鼻腔評估局部耐受性。由研究人員評估局部耐受性且根據0-4級之5級量表進行評定，其中0級表示正常黏膜。由研究個體根據不適視覺類比量表(VAS)對不適進行自評來進一步評估局部耐受性。亦可添加評估最不適之時間點的時間分量以及研究個體在給藥後30分鐘根據VAS進行的自評。亦可藉由與鼻、鼻竇、咽喉、口及/或眼部區域中之疼痛及/或刺激相關的研究個體問卷反應進一步評估不適。Local tolerance was assessed by visual inspection of the nasal cavity at <-01:00 hours before administration (baseline) and at 01:00, 05:00 and 23:00 hours after each administration. Local tolerance was assessed by the investigator and rated on a 5-point scale of 0-4, with 0 representing normal mucosa. Local tolerance was further assessed by self-rating of discomfort by the study subject according to the Discomfort Visual Analog Scale (VAS). A time component to assess the time point of the most discomfort and a self-rating by the study subject according to the VAS 30 minutes after dosing may also be added. Discomfort may also be further assessed by the study subject questionnaire response related to pain and/or irritation in the nose, sinuses, throat, mouth and/or eye areas.
根據VAS自評，大多數個體經歷較低程度之不適，且兩種劑量之調配物均耐受性良好，尤其是與以上比較實例2中所描述之研究中個體之經歷相比。Most subjects experienced low levels of discomfort based on VAS self-assessment, and both doses of the formulation were well tolerated, especially compared to the experience of subjects in the study described in Comparative Example 2 above.
1:上部主體/分配器頭 2:元件 3:下部主體/栓槽 10:儲集器 11:進氣口 12:產物保持裝置/網格 15:產物出口 16:封擋球 20:噴氣/空氣 21:活塞 22:空氣腔室 25:柱塞/推動元件 27:蓋罩 37:徑向肩部 40:出口通道 41:構件 42:保持器部件 43:軸向延伸部 55:圓形表面 60:抓持構件 61:第一桿部分 62:第二桿部分 80:彈簧 215:內唇 216:軸向延伸部 225:徑向凸緣 251:頂部邊緣 610:頂部軸向端 614:圓柱形表面 615:溝槽或凹槽 621:頂部軸向端1: Upper body/dispenser head2: Component3: Lower body/slot10: Reservoir11: Air inlet12: Product retainer/grid15: Product outlet16: Blocking ball20: Jet/air21: Piston22: Air chamber25: Plunger/push element27: Cover37: Radial shoulder40: Outlet channel41: Component42: Retainer component43: Axial extension55: Round surface60: Gripping component61: First rod section62: Second rod section80: Spring215: Inner lip216: Axial extension225: radial flange251: top edge610: top axial end614: cylindrical surface615: groove or recess621: top axial end
參考附圖，藉由以下實例說明本發明，但絕不限制本發明，其中圖1至圖7表示可用於分配粉末組合物之致動器裝置的圖式，且圖8顯示在I期臨床研究中所獲得的由治療引起之腎上腺激素血漿濃度隨時間之變化(線性標度；算術平均值)。The present invention is illustrated by the following examples with reference to the accompanying drawings, but is in no way limiting thereof, wherein FIGS. 1 to 7 show diagrams of actuator devices that can be used to dispense powder compositions, and FIG. 8 shows the changes in adrenal hormone plasma concentrations over time (linear scale; arithmetic mean) induced by treatment in a Phase I clinical study.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2308121.9 | 2023-05-31 | ||
| GBGB2308121.9AGB202308121D0 (en) | 2023-05-31 | 2023-05-31 | New composition |
| GBGB2315885.0AGB202315885D0 (en) | 2023-10-17 | 2023-10-17 | New composition |
| GB2315885.0 | 2023-10-17 | ||
| GB2319899.7 | 2023-12-22 | ||
| GBGB2319899.7AGB202319899D0 (en) | 2023-12-22 | 2023-12-22 | New composition |
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| TW202502309Atrue TW202502309A (en) | 2025-01-16 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW113120278ATW202502309A (en) | 2023-05-31 | 2024-05-31 | Spray-dried compositions comprising adrenergic receptor modulators |
| Country | Link |
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| AR (1) | AR132834A1 (en) |
| TW (1) | TW202502309A (en) |
| WO (1) | WO2024246554A1 (en) |
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