TW202233078A - Aqueous formulation for aerosolizing and inhaling using electronic devices - Google Patents

Aqueous formulation for aerosolizing and inhaling using electronic devices Download PDF

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TW202233078A
TW202233078A TW110140601A TW110140601A TW202233078A TW 202233078 A TW202233078 A TW 202233078A TW 110140601 A TW110140601 A TW 110140601A TW 110140601 A TW110140601 A TW 110140601A TW 202233078 A TW202233078 A TW 202233078A
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aqueous formulation
nicotine
mixture
acid
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嘉恒 鄭
約瑟夫 吉恩 沃爾什
馬里奧 達內克
布萊恩 奎格利
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美商瑞斯比拉科技公司
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    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
    • A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

An aqueous formulation for aerosolizing and inhaling using electronic device includes a saline component, an acid component, and a nicotine component. The acid component includes a lactic acid. The aqueous formulation optionally includes one or more of a menthol component, an ethanol component, and a surfactant component.

Description

用於使用電子裝置氣溶膠化與吸入之水性調配物Aqueous formulations for aerosolization and inhalation using electronic devices

版權聲明Copyright Notice

本文件中的任何新著作品及原創著作品均受美國及其他國家版權法的版權保護。准許任何人複製如政府官方記錄中所呈現的本文件，但保留除此之外的所有其他版權權利。Any new and original works in this document are protected by copyright under the copyright laws of the United States and other countries. Permission is granted to anyone to reproduce this document as it appears in official government records, but all other copyright rights otherwise reserved.

本發明大體上係關於與個人出於個人或娛樂用途或為了投予藥物而使用電子裝置氣溶膠化與吸入的液體有關的調配物及方法。The present invention generally relates to formulations and methods related to the use of electronic devices by individuals for aerosolizing and inhaling liquids for personal or recreational use or for drug administration.

吸入遞送系統現今在活性成分至人類肺部系統之靶向遞送中發揮著越來越大的作用。對於醫學目的（諸如抗癌藥品至肺之靶向遞送）以及娛樂／個人目的（諸如抽電子菸，其中包括活性成分之液體使用加熱氣化，使得活性成分可被吸入人體中）都是如此。Inhalation delivery systems are now playing an increasing role in the targeted delivery of active ingredients to the human pulmonary system. This is true for both medical purposes (such as targeted delivery of anticancer drugs to the lungs) and recreational/personal purposes (such as vaping, where the liquid containing the active ingredient is vaporized using heat so that the active ingredient can be inhaled into the body).

令人遺憾地，隨著使用加熱之吸入遞送系統越來越常見，對其短期及長期安全性之擔憂成為焦點。對於電子菸而言尤其如此，其中對吸入蒸氣中可能存在有害及潛在有害組分（harmful and potentially harmful constituent，HPHC）存在持續擔憂。Unfortunately, as the use of heated inhalation delivery systems becomes more common, concerns about their short- and long-term safety come into focus. This is especially true for e-cigarettes, where there are ongoing concerns about the possible presence of harmful and potentially harmful constituents (HPHC) in inhaled vapors.

在電子菸之情境下，菸鹼為氣溶膠化與吸入之液體調配物中所包括最常見的組分之一。現今可用之許多含菸鹼液體調配物使用諸如丙二醇或甘油之溶劑。然而，鑒於現存研究及健康擔憂，人們對研發呈水性溶液之含菸鹼調配物的興趣越來越大。在研發水性調配物時，在確定可獲得既安全且又為使用者提供宜人的感官體驗的調配物之有效組分組合方面，可能出現挑戰。舉例而言，已知在較高菸鹼濃度下，調配物為使用者帶來「刺激性（harsh）」的感官體驗。In the context of electronic cigarettes, nicotine is one of the most common components included in liquid formulations for aerosolization and inhalation. Many of the nicotine-containing liquid formulations available today use solvents such as propylene glycol or glycerol. However, in view of existing research and health concerns, there is growing interest in developing nicotine-containing formulations in aqueous solutions. When developing aqueous formulations, challenges can arise in determining effective ingredient combinations that result in a formulation that is both safe and provides a user with a pleasant sensory experience. For example, at higher nicotine concentrations, formulations are known to provide the user with a "harsh" sensory experience.

因此，需要一種用於使用電子裝置氣溶膠化與吸入之水性調配物，其平衡安全性問題及合意的使用者體驗。咸信此需求及其他需求可藉由本發明之一或多個態樣及特徵解決。Therefore, there is a need for an aqueous formulation for aerosolization and inhalation using electronic devices that balances safety concerns with a desirable user experience. It is believed that this and other needs are addressed by one or more aspects and features of the present invention.

本發明包括許多態樣及特徵。此外，雖然許多態樣及特徵係關於且描述於基於菸鹼之水性調配物之情境下，但本發明不限於僅在基於菸鹼之水性調配物中使用，如將自以下的本發明之態樣、特徵及一或多個實施方式之概述及詳細描述變得顯而易見。The present invention includes many aspects and features. Furthermore, while many aspects and features are related and described in the context of nicotine-based aqueous formulations, the present invention is not limited to use only in nicotine-based aqueous formulations, as will be seen from the aspects of the invention below A summary and detailed description of the features, features, and one or more implementations will become apparent.

根據一個態樣，用於使用電子裝置氣溶膠化與吸入之水性調配物包括鹽水組分、酸組分、及菸鹼組分。該酸組分包括乳酸。According to one aspect, an aqueous formulation for aerosolization and inhalation using an electronic device includes a saline component, an acid component, and a nicotine component. The acid component includes lactic acid.

在一特徵中，該鹽水組分包括0.9% NaCl鹽水溶液。In one feature, the brine component includes a 0.9% NaCl saline solution.

在一特徵中，該鹽水組分為該調配物之大約30質量%至大約99.998質量%。In one feature, the brine component is about 30% to about 99.998% by mass of the formulation.

在一特徵中，該酸組分進一步包括苯甲酸、蘋果酸、酒石酸、水楊酸、乙醯丙酸、及鹽酸中之一或多者。In one feature, the acid component further comprises one or more of benzoic acid, malic acid, tartaric acid, salicylic acid, acetylpropionic acid, and hydrochloric acid.

在一特徵中，該酸組分為該調配物之大約0.001質量%至大約25質量%。In one feature, the acid component is from about 0.001% to about 25% by mass of the formulation.

在一特徵中，該菸鹼組分包括呈質子化形式之菸鹼及呈非質子化形式之菸鹼。In one feature, the nicotine component includes nicotine in protonated form and nicotine in unprotonated form.

在一特徵中，該菸鹼組分為該調配物之大約0.001質量%至大約5質量%。In one feature, the nicotine component is from about 0.001% to about 5% by mass of the formulation.

在一特徵中，該水性調配物之pH值量測在大約2與大約5之間。In one feature, the pH of the aqueous formulation is measured between about 2 and about 5.

在一特徵中，該水性調配物之該pH值量測為大約3.38。In one feature, the pH of the aqueous formulation measures about 3.38.

在一特徵中，該水性調配物進一步包括薄荷醇組分。In one feature, the aqueous formulation further includes a menthol component.

在一特徵中，該薄荷醇組分為該調配物之大約0.001質量%至大約15質量%。In one feature, the menthol component is from about 0.001% to about 15% by mass of the formulation.

在一特徵中，該水性調配物進一步包括乙醇組分。In one feature, the aqueous formulation further includes an ethanol component.

在一特徵中，該乙醇組分為該調配物之大約0.001質量%至大約10質量%。In one feature, the ethanol component is from about 0.001 mass % to about 10 mass % of the formulation.

在一特徵中，該水性調配物進一步包括界面活性劑組分，其中該界面活性劑組分包括一或多種不同界面活性劑。In one feature, the aqueous formulation further includes a surfactant component, wherein the surfactant component includes one or more different surfactants.

在一特徵中，該界面活性劑組分包括聚氧乙烯山梨糖醇酐單油酸酯、聚氧乙烯山梨糖醇酐單硬脂酸酯、聚氧乙烯山梨糖醇酐單月桂酸酯、卵磷脂及泊洛沙姆（poloxamer）中之一或多者。In one feature, the surfactant component includes polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate, egg One or more of phospholipids and poloxamers.

在一特徵中，該界面活性劑組分為該調配物之大約0.001質量%至大約10質量%。In one feature, the surfactant component is from about 0.001 mass % to about 10 mass % of the formulation.

在一特徵中，該水性調配物進一步包括乙醇組分及界面活性劑組分。In one feature, the aqueous formulation further includes an ethanol component and a surfactant component.

根據另一態樣，製備用於使用電子裝置氣溶膠化與吸入之水性調配物的方法包括：將菸鹼組分與酸組分混合以形成第一混合物；分開地，將薄荷醇組分與鹽水組分混合以形成第二混合物；及將該第一混合物與該第二混合物混合以形成目標水性調配物。According to another aspect, a method of preparing an aqueous formulation for aerosolization and inhalation using an electronic device comprises: combining a nicotine component with an acid component to form a first mixture; separately, combining a menthol component with The brine components are mixed to form a second mixture; and the first mixture is mixed with the second mixture to form the target aqueous formulation.

根據另一態樣，製備用於使用電子裝置氣溶膠化與吸入之水性調配物的方法包括：將菸鹼組分與酸組分混合以形成第一混合物；分開地，將薄荷醇組分與乙醇組分混合以形成第二混合物；將鹽水組分與該第二混合物混合以形成第三混合物；及將該第一混合物與該第三混合物混合以形成目標水性調配物。According to another aspect, a method of preparing an aqueous formulation for aerosolization and inhalation using an electronic device comprises: combining a nicotine component with an acid component to form a first mixture; separately, combining a menthol component with The ethanol component is mixed to form a second mixture; the brine component is mixed with the second mixture to form a third mixture; and the first mixture is mixed with the third mixture to form the target aqueous formulation.

根據另一態樣，製備用於使用電子裝置氣溶膠化與吸入之水性調配物的方法包括：將菸鹼組分與酸組分混合以形成第一混合物；將鹽水組分與該第一混合物混合以形成第二混合物；分開地，將薄荷醇組分、乙醇組分、與界面活性劑組分混合以形成第三混合物；及將該第二混合物與該第三混合物混合以形成目標水性調配物。According to another aspect, a method of preparing an aqueous formulation for aerosolization and inhalation using an electronic device comprises: combining a nicotine component with an acid component to form a first mixture; combining a saline component with the first mixture mixing to form a second mixture; separately, mixing the menthol component, the ethanol component, and the surfactant component to form a third mixture; and mixing the second mixture with the third mixture to form the target aqueous formulation thing.

在一特徵中，該酸組分包括乳酸，且該界面活性劑組分包括聚氧乙烯山梨糖醇酐單油酸酯。In one feature, the acid component includes lactic acid and the surfactant component includes polyoxyethylene sorbitan monooleate.

除本發明之前述態樣及特徵之外，應注意，本發明進一步涵蓋此等態樣及特徵之各種合理組合及子組合。因此，舉例而言，在此專利申請案或一或多個分割或接續專利申請案中之申請專利範圍可分別係關於本文所揭示之任何態樣、特徵、或實施方式、或其等之組合，而不需要任何其他態樣、特徵、或實施方式。In addition to the foregoing aspects and features of the invention, it is to be noted that the invention further covers various reasonable combinations and subcombinations of these aspects and features. Thus, for example, the scope of claims in this patent application or one or more divisional or continuation patent applications, respectively, may relate to any aspect, feature, or implementation disclosed herein, or a combination thereof , without requiring any other aspect, feature, or implementation.

首先，所屬技術領域中具有通常知識者（「一般技術人員（Ordinary Artisan）」）可輕易理解，本發明具有廣泛的實用性及應用性。此外，任何所論述且被鑑別為「較佳（preferred）」的實施方式應視為被考慮用於實施本發明之最佳模式之一部分。亦可出於額外說明性目的論述其他實施方式以提供本發明之完整且可據以實現的揭示內容。此外，本發明之實施方式可併有本文所揭示之發明之僅一個或複數個態樣；本文所揭示之僅一個或複數個特徵；或其等之組合。因而，許多實施方式被隱含地揭示於本文中且落入被視為是本發明者之範圍內。First, those with ordinary knowledge in the technical field (“Ordinary Artisan”) can easily understand that the present invention has wide practicability and applicability. Furthermore, any embodiments discussed and identified as "preferred" should be considered part of the best mode contemplated for carrying out the invention. Other embodiments may also be discussed for additional illustrative purposes in order to provide a complete disclosure of the invention from which it can be practiced. Furthermore, embodiments of the invention may incorporate only one or more aspects of the invention disclosed herein; only one or more of the features disclosed herein; or combinations thereof. Thus, many embodiments are implicitly disclosed herein and are considered to be within the scope of the present inventors.

因此，儘管本文中以一或多個實施方式詳細地描述本發明，但應理解，此揭示內容對本發明而言為說明性的及例示性的且僅僅出於提供本發明之完整且可據以實現的揭示內容的目的而產生。本文中之一或多個實施方式之詳細揭示內容並不意欲亦不應被視為限制基於本文授予之專利之任何申請專利範圍請求項中之受專利保護的發明之範圍，該範圍應由申請專利範圍請求項及其等之等效者界定。以下者非意欲的：受專利保護的發明之範圍藉由在任何申請專利範圍請求項中讀入在本文中找到但在該請求項本身中未明確出現之限制而界定。Therefore, although the invention is described in detail herein in terms of one or more embodiments, it is to be understood that this disclosure is illustrative and exemplary of the invention and is merely to provide the invention complete and based upon which to achieve the purpose of revealing the content. The detailed disclosure of one or more embodiments herein is not intended to and should not be construed as limiting the scope of the patented invention in any claim based on the patent granted herein, the scope of which should be determined by the application The patent scope claims and their equivalents are defined. It is not intended that the scope of the patented invention is defined by reading in any claim of the patented scope of the application the limitations found herein but not expressly appearing in the claim itself.

因此，例如，本文中所描述之各種過程或方法之步驟的任何一或多個順序及／或時間次序為說明性而非限制性的。因此，應理解，儘管各種過程或方法之步驟可按順序或時間次序展示及描述，但在未指示之情況下，任何如此過程或方法之步驟不限於以任何特定順序或次序執行。實際上，如此過程或方法中之步驟一般可以各種不同順序及次序執行而仍落入本發明之範圍內。因此，以下者為意欲的：受專利保護的發明之範圍由所授予之一或多個申請專利範圍請求項界定而非由本文中所闡述之描述界定。Thus, for example, any order and/or chronological order of the steps of various processes or methods described herein are illustrative and not restrictive. Thus, it should be understood that although the steps of various processes or methods may be shown and described in a sequential or chronological order, the steps of any such process or method are not limited to being performed in any particular order or sequence, unless indicated. Indeed, the steps of such a process or method may generally be performed in a variety of different orders and sequences while remaining within the scope of the present disclosure. Accordingly, it is intended that the scope of the patented invention is defined by one or more of the patented scope claims issued and not by the description set forth herein.

另外，很重要地，應注意，各個本文中所使用之術語均指一般技術人員基於本文中如此術語之使用情境會理解如此術語所意謂者。在一般技術人員基於本文中使用之某術語之使用情境所理解的如此術語之意義以任何方式不同於任何如此術語之特定詞典定義之情況下，以下者為意欲的：應以一般技術人員所理解之該術語之意義為準。Additionally, it is important to note that each term used herein refers to what one of ordinary skill would understand such term to mean based on the context in which such term is used herein. To the extent that the meaning of a term as understood by one of ordinary skill herein based on the context in which such term is used differs in any way from the specific dictionary definition of any such term, it is intended that: the meaning of the term shall prevail.

關於任何包括先決條件步驟之方法申請專利範圍請求項，如此方法需要滿足該先決條件且執行該步驟至少一次，但在執行所請方法期間未必每次皆需要執行該步驟。The claim is claimed for any method that includes a prerequisite step, such that the method needs to satisfy the prerequisite and perform the step at least once, but not necessarily every time during the execution of the claimed method.

此外，很重要地，應注意，如本文所用，「包含（comprising）」為開放式的，只要此類術語之後的內容並非排他性的。另外，「一（a）」及「一（an）」各自通常指示「至少一個（at least one）」，但並不排除複數個，除非使用情境另外指示。因此，對「具有一蘋果之野餐籃（a picnic basket having an apple）」的提及與「包含一蘋果之野餐籃（a picnic basket comprising an apple）」及「包括一蘋果之野餐籃（a picnic basket including an apple）」相同，其中之每一者等同地描述「具有至少一個蘋果之野餐籃（a picnic basket having at least one apple）」以及「具有多個蘋果之野餐籃（a picnic basket having apples）」；該野餐籃進一步可含有除蘋果之外的一或多個其他物品。相比之下，對「具有單個蘋果之野餐籃（a picnic basket having a single apple）」的提及描述「僅具有一個蘋果之野餐籃（a picnic basket having only one apple）」；該野餐籃進一步可含有除蘋果之外的一或多個其他物品。相比之下，「由蘋果組成之野餐籃（a picnic basket consisting of an apple）」僅具有其中所含有的單個物品，亦即一個蘋果；該野餐籃不含其他物品。Furthermore, it is important to note that, as used herein, "comprising" is open ended so long as what follows such term is not exclusive. In addition, "a (a)" and "an (an)" each generally indicate "at least one", but do not exclude a plurality unless the context of use dictates otherwise. Hence the reference to "a picnic basket having an apple" is the same as "a picnic basket comprising an apple" and "a picnic basket having an apple" basket including an apple", each of which equally describes "a picnic basket having at least one apple" and "a picnic basket having apples" )”; the picnic basket may further contain one or more items other than apples. In contrast, references to "a picnic basket having a single apple" describe "a picnic basket having only one apple"; the picnic basket has further May contain one or more other items other than apples. In contrast, "a picnic basket consisting of an apple" has only the single item contained in it, an apple; the picnic basket contains no other items.

當在本文中用於連接物品清單時，「或（or）」指示「物品中之至少一者（at least one of the items）」，但並不排除該清單中之複數個物品。因此，對「具有奶酪或餅乾之野餐籃（a picnic basket having cheese or crackers）」的提及描述「具有奶酪而不具有餅乾之野餐籃（a picnic basket having cheese without crackers）」、「具有餅乾而不具有奶酪之野餐籃（a picnic basket having crackers without cheese）」及「具有奶酪及餅乾兩者之野餐籃（a picnic basket having both cheese and crackers）」；該野餐籃進一步可含有除奶酪及餅乾之外的一或多個其他物品。When used herein to concatenate lists of items, "or" indicates "at least one of the items," but does not exclude multiple items in the list. Thus, references to "a picnic basket having cheese or crackers" describe "a picnic basket having cheese without crackers", "a picnic basket having cheese without crackers", "a picnic basket having cheese or crackers" "a picnic basket having crackers without cheese" and "a picnic basket having both cheese and crackers"; the picnic basket may further contain one or more other items.

當在本文中用於連接物品清單時，「及（and）」指示「該清單中之所有物品（all of the items of the list）」。因此，對「具有奶酪及餅乾之野餐籃（a picnic basket having cheese and crackers）」的提及描述「具有奶酪之野餐籃，其中該野餐籃進一步具有餅乾（a picnic basket having cheese, wherein the picnic basket further has crackers）」，以及描述「具有餅乾之野餐籃，其中該野餐籃進一步具有奶酪（a picnic basket having crackers, wherein the picnic basket further has cheese）」；該野餐籃進一步可含有除奶酪及餅乾之外的一或多個其他物品。When used herein in connection with a list of items, "and" means "all of the items of the list". Thus, the reference to "a picnic basket having cheese and crackers" describes "a picnic basket having cheese and crackers, wherein the picnic basket has cheese, wherein the picnic basket further has crackers" and the description "a picnic basket having crackers, wherein the picnic basket further has cheese"; the picnic basket may further contain other than cheese and crackers one or more other items.

片語「至少一個」後接由「及」連接之物品清單指示該清單中的一物品但並不需該清單中之每個物品。因此，「蘋果及橙子中之至少一者（at least one of an apple and an orange）」涵蓋以下相互排他性情境：存在蘋果但無橙子；存在橙子但無蘋果；及存在蘋果及橙子兩者。在此等情境中，若存在蘋果，則可存在多於一個蘋果，且若存在橙子，則可存在多於一個橙子。另外，片語「一或多個（one or more）」後接由「及」連接之物品清單等效於「至少一個」後接由「及」連接之物品清單。The phrase "at least one" followed by a list of items connected by "and" indicates an item in the list but does not require every item in the list. Thus, "at least one of an apple and an orange" covers the following mutually exclusive situations: the presence of apples but no oranges; the presence of oranges but no apples; and the presence of both apples and oranges. In these scenarios, if an apple is present, there may be more than one apple, and if an orange is present, there may be more than one orange. Additionally, the phrase "one or more" followed by a list of items linked by an "and" is equivalent to a list of items linked by an "and" followed by "at least one".

現參看圖式，接下來描述根據本發明之一或多個態樣及特徵的一或多個較佳實施方式。一或多個較佳實施方式之以下描述在本質上僅為例示性的且決不意欲限制本發明、其實施方式或用途。Referring now to the drawings, one or more preferred embodiments in accordance with one or more aspects and features of the present invention are described next. The following description of one or more preferred embodiments is merely exemplary in nature and is in no way intended to limit the invention, its implementations, or uses.

圖1A-1C分別為非質子化菸鹼、單質子化菸鹼、及二質子化菸鹼之結構式。呈圖1A中所描繪之其非質子化（或「游離鹼（free-base）」）形式時，菸鹼係pK a值為8.0之弱鹼。如圖1A中所展示，菸鹼之非質子化形式包括兩個展現鹼性特性之氮原子。藉由向兩個氮原子中之一者添加一個質子，非質子化形式變為單質子化形式，其描繪於圖1B中。向兩個氮原子中之另一者添加另一質子將單質子化形式轉化為二質子化形式，其描繪於圖1C中。在單質子化及二質子化形式中，菸鹼之揮發性低於非質子化形式。 1A-1C are the structural formulas of aprotonated nicotine, monoprotonated nicotine, and diprotonated nicotine, respectively. In its unprotonated (or "free-base") form depicted in Figure 1A, nicotine is a weak base with a pKa value of 8.0. As shown in Figure 1A, the aprotonated form of nicotine includes two nitrogen atoms that exhibit basic properties. By adding a proton to one of the two nitrogen atoms, the unprotonated form becomes the monoprotonated form, which is depicted in Figure IB. The addition of another proton to the other of the two nitrogen atoms converts the monoprotonated form to the diprotonated form, which is depicted in Figure 1C. In the monoprotonated and diprotonated forms, nicotine is less volatile than the aprotonated form.

圖1D為說明溶液中pH與圖1A-1C之各物種之相對分率之間的關係的圖形表示。如圖1D中所示，溶液中之非質子化形式之相對優勢傾向於在8之pH附近轉而向質子化形式偏移。在大約3.5至大約8範圍內的中度酸性至輕微鹼性pH值下，單質子化形式為溶液中之主要物種。且在大約3.5及更低之pH值下，二質子化形式為溶液中之主要物種。就此而言，經考慮，溶液中可將酸添加至非質子化菸鹼中以調整pH且增加質子化菸鹼物種，包括單質子化及二質子化物種兩者之比率。Figure ID is a graphical representation illustrating the relationship between pH in solution and the relative fraction of each species of Figures 1A-1C. As shown in Figure ID, the relative dominance of the aprotonated form in solution tends to shift towards the protonated form around a pH of 8. At moderately acidic to slightly basic pH values ranging from about 3.5 to about 8, the monoprotonated form is the predominant species in solution. And at pH values of about 3.5 and lower, the diprotonated form is the predominant species in solution. In this regard, it is contemplated that acid may be added to the unprotonated nicotine in solution to adjust the pH and increase the ratio of protonated nicotine species, including both monoprotonated and diprotonated species.

圖2為說明總菸鹼濃度與總菸鹼之非質子化分率之間的關係及該關係可如何影響感官體驗的圖形表示。瞭解菸鹼作為鹼性化合物，呈非質子化形式時在較高菸鹼濃度下產生刺激性感官體驗。如圖2中所說明，當相對於溶液中存在之菸鹼之總量而言，非質子化菸鹼之分率減少時，感官體驗之刺激性可得到緩和。Figure 2 is a graphical representation illustrating the relationship between total nicotine concentration and the aprotonated fraction of total nicotine and how this relationship can affect sensory experience. Understand that nicotine is a basic compound that produces a stimulating sensory experience at higher nicotine concentrations in its unprotonated form. As illustrated in Figure 2, when the fraction of aprotonated nicotine is reduced relative to the total amount of nicotine present in the solution, the irritation of the sensory experience can be moderated.

圖3為說明含薄荷醇調配物隨總菸鹼濃度而變的刺激性量測結果的圖形表示。經考慮，由菸鹼吸入引起之刺激性感官體驗可藉由在溶液中包括薄荷醇而進一步緩和。如圖3中所描繪，大約3.5%之薄荷醇濃度可在較高菸鹼濃度（諸如在18 mg/mL或更高之菸鹼濃度）下減少刺激性（irritation/harshness）感官效果。此刺激性效果之緩和可與薄荷醇之其他有利特徵，包括強烈清涼感覺及強烈整體強度（strong overall intensity）結合。Figure 3 is a graphical representation illustrating the results of irritancy measurements for menthol-containing formulations as a function of total nicotine concentration. It is contemplated that the irritating sensory experience caused by nicotine inhalation may be further moderated by including menthol in the solution. As depicted in Figure 3, a menthol concentration of approximately 3.5% can reduce the irritation/harshness sensory effect at higher nicotine concentrations, such as at 18 mg/mL or higher nicotine concentrations. The mitigation of this irritating effect can be combined with other beneficial characteristics of menthol, including a strong cooling sensation and strong overall intensity.

參考圖2及圖3，經考慮，可氣溶膠化且可吸入水性調配物之整體感官吸引力可藉由考慮因素總菸鹼量、非質子化菸鹼相對於總菸鹼量之比率及薄荷醇中之一或多者影響。Referring to Figures 2 and 3, it is considered that the overall sensory appeal of an aerosolizable and inhalable aqueous formulation can be determined by considering the factors total nicotine, ratio of aprotonated nicotine to total nicotine, and mint. one or more of the alcohols.

在一些考慮實施方式中，用於使用電子裝置氣溶膠化與吸入之水性調配物包括在水性溶液中之大約20 mg/mL的總菸鹼濃度。為在此類調配物中實現所要的非質子化菸鹼:質子化菸鹼（包括單質子化及二質子化形式）比率，可添加酸直至相對於總菸鹼量達成大約0.2至大約0.35之非質子化分率。進一步參考圖2，此類調配物之相關區域由 A標記的圖形表示部分反映，且 B標記之部分為較佳的。當鑒於圖1D之圖形表示進行考慮時，用於達成大約0.2至大約0.35之非質子化分率的目標pH在6至8範圍之間。舉例而言，包括大約0.3非質子化分率之物種可能需要大約7.5之目標pH，其在圖1D中用 C標記的線描繪。另外，經考慮調配物中可包括薄荷醇以增強感官體驗且減少刺激性。 In some contemplated embodiments, the aqueous formulation for aerosolization and inhalation using an electronic device includes a total nicotine concentration in an aqueous solution of about 20 mg/mL. To achieve the desired ratio of aprotonated nicotine:protonated nicotine (including both monoprotonated and diprotonated forms) in such formulations, acid may be added until a ratio of about 0.2 to about 0.35 is achieved relative to the total nicotine amount. Aprotonated fraction. With further reference to Figure 2, the relevant regions of such formulations are reflected in the graphical representation portion marked A , and the portion marked B is preferred. The target pH for achieving an aprotonation fraction of about 0.2 to about 0.35 ranged between 6 and 8 when considered in view of the graphical representation of Figure ID. For example, a species including an aprotonated fraction of about 0.3 may require a target pH of about 7.5, which is depicted by the line marked with C in Figure ID. Additionally, it is contemplated that menthol may be included in the formulation to enhance the sensory experience and reduce irritation.

在其他考慮實施方式中，用於使用電子裝置氣溶膠化與吸入之水性調配物包括鹽水組分、菸鹼組分、酸組分、及視需要薄荷醇組分及乙醇組分中之一或兩者。此類調配物之各組分的考慮質量百分比範圍包括：溶液之大約30質量%至大約99.998質量%的鹽水組分；溶液之大約0.001質量%至大約5質量%的菸鹼組分；溶液之大約0.001質量%至大約25質量%的酸組分；溶液之0質量%至大約15質量%的薄荷醇組分；及溶液之0質量%至大約25質量%的乙醇組分。In other contemplated embodiments, the aqueous formulation for aerosolization and inhalation using an electronic device includes a saline component, a nicotine component, an acid component, and optionally one of a menthol component and an ethanol component, or both. Considered mass percentage ranges for the components of such formulations include: about 30% to about 99.998% by mass of the brine component of the solution; about 0.001% to about 5% by mass of the nicotine component of the solution; About 0.001% to about 25% by mass of the acid component; 0% to about 15% by mass of the menthol component of the solution; and 0% to about 25% by mass of the ethanol component of the solution.

經考慮鹽水組分為類似或接近常規生理溶液之安全水性溶液。用作水性調配物中之鹽水組分的鹽水之一個較佳形式為等張鹽水，諸如0.9% NaCl鹽水溶液。經進一步考慮可使用低張或高張鹽水。就此而言，鹽水溶液可在大約0.001%至大約7.5% NaCl鹽水溶液範圍內。在又其他考慮實施方式中，使用水代替鹽水組分。Saline components are considered to be safe aqueous solutions similar to or close to conventional physiological solutions. One preferred form of saline for use as the saline component in aqueous formulations is isotonic saline, such as a 0.9% NaCl saline solution. Hypotonic or hypertonic saline may be used with further consideration. In this regard, the saline solution may range from about 0.001% to about 7.5% NaCl saline solution. In yet other contemplated embodiments, water is used in place of the brine component.

酸組分用於減少非質子化菸鹼相對於總菸鹼量之分率。在水性調配物中用作酸組分之一種較佳的酸為乳酸。其他考慮酸包括但不限於苯甲酸、蘋果酸、酒石酸、水楊酸、乙醯丙酸、及鹽酸。The acid component is used to reduce the fraction of aprotonated nicotine relative to the total amount of nicotine. A preferred acid for use as the acid component in aqueous formulations is lactic acid. Other contemplated acids include, but are not limited to, benzoic acid, malic acid, tartaric acid, salicylic acid, acetylpropionic acid, and hydrochloric acid.

如上文所論述，薄荷醇可視需要包括於水性調配物中以增強感官體驗且減少刺激性。除薄荷醇之外（或代替薄荷醇），同樣考慮其他調味劑及組分。As discussed above, menthol can be optionally included in aqueous formulations to enhance the sensory experience and reduce irritation. In addition to (or in place of) menthol, other flavors and components are also contemplated.

經考慮乙醇可視需要包括於水性調配物中作為界面活性劑或共溶劑。其他考慮共溶劑包括但不限於丙二醇及丙三醇。It is contemplated that ethanol may optionally be included in aqueous formulations as a surfactant or co-solvent. Other contemplated co-solvents include, but are not limited to, propylene glycol and glycerol.

一種根據上述特徵之特定考慮調配物包括：溶液之大約93.486質量%的0.9% NaCl鹽水組分；溶液之大約2質量%的菸鹼組分；溶液之大約4.477質量%的乳酸組分；及溶液之大約0.037質量%的薄荷醇組分。One specific consideration formulation according to the above features comprises: about 93.486 mass % of the solution of a 0.9% NaCl saline component; about 2 mass % of the solution of a nicotine component; about 4.477 mass % of the solution of a lactic acid component; and about 0.037% by mass of the menthol component.

圖4為說明根據本發明之一或多個態樣的水性調配物之製備方法 100的流程圖，該調配物包括鹽水組分、菸鹼組分、及酸組分。在第一步驟 105中，將菸鹼組分與酸組分組合以形成菸鹼鹽混合物。在酸組分包括乳酸之實施方式中，將菸鹼組分與酸組分組合以形成菸鹼乳酸鹽混合物。在第二步驟 110中，將菸鹼鹽混合物與鹽水溶液組合以產生用於使用電子裝置氣溶膠化與吸入之目標調配物。 4 is a flow chart illustrating a method 100 of making an aqueous formulation including a saline component, a nicotine component, and an acid component according to one or more aspects of the present invention. In a first step 105 , the nicotine component is combined with the acid component to form a nicotine salt mixture. In embodiments where the acid component includes lactic acid, the nicotine component is combined with the acid component to form a nicotine lactate mixture. In a second step 110 , the nicotine salt mixture is combined with a saline solution to produce a target formulation for aerosolization and inhalation using an electronic device.

圖5為說明根據本發明之一或多個態樣的水性調配物之製備方法 200的流程圖，該調配物包括鹽水組分、菸鹼組分、酸組分、及薄荷醇組分。在第一步驟 205中，將菸鹼組分與酸組分組合以形成菸鹼鹽混合物。在酸組分包括乳酸之實施方式中，將菸鹼組分與酸組分組合以形成菸鹼乳酸鹽混合物。在第二步驟 210中，分開地，將薄荷醇組分與鹽水組分組合以形成薄荷醇／鹽水混合物。隨後，在第三步驟 215中，將來自第一步驟 205之菸鹼鹽混合物與來自第二步驟 210之薄荷醇／鹽水混合物組合以產生用於使用電子裝置氣溶膠化與吸入之目標調配物。 5 is a flowchart illustrating a method 200 of making an aqueous formulation including a saline component, a nicotine component, an acid component, and a menthol component according to one or more aspects of the present invention. In a first step 205 , the nicotine component is combined with the acid component to form a nicotine salt mixture. In embodiments where the acid component includes lactic acid, the nicotine component is combined with the acid component to form a nicotine lactate mixture. In a second step 210 , separately, the menthol component is combined with the brine component to form a menthol/saline mixture. Then, in a third step 215 , the nicotine salt mixture from the first step 205 is combined with the menthol/saline mixture from the second step 210 to produce a target formulation for aerosolization and inhalation using electronic devices.

圖6為說明根據本發明之一或多個態樣的水性調配物之製備方法 300的流程圖，該調配物包括鹽水組分、菸鹼組分、酸組分、薄荷醇組分、及乙醇組分。在第一步驟 305中，將菸鹼組分與酸組分組合以形成菸鹼鹽混合物。在酸組分包括乳酸之實施方式中，將菸鹼組分與酸組分組合以形成菸鹼乳酸鹽混合物。在第二步驟 310中，分開地，將薄荷醇組分與乙醇組分組合以形成薄荷醇／乙醇混合物。如上文所論述，經考慮可包括乙醇組分作為界面活性劑或共溶劑。就此而言，應注意，添加至溶液中超出薄荷醇溶解限度之組分可能需要界面活性劑。就此而言，經考慮使用界面活性劑使得超出溶解限度之組分能夠經由形成乳液被包括於混合物中。界面活性劑分子相互連接以形成能夠囊封在其他情況下不溶性的組分之結構。在第三步驟 315中，將來自第二步驟 310之薄荷醇／乙醇混合物與鹽水組分組合以產生薄荷醇／乙醇／鹽水混合物。隨後，在第四步驟 320中，將來自第一步驟 305之菸鹼鹽混合物與來自第三步驟 315之薄荷醇／乙醇／鹽水混合物組合以產生用於使用電子裝置氣溶膠化與吸入之目標調配物。 6 is a flow chart illustrating a method 300 of making an aqueous formulation including a saline component, a nicotine component, an acid component, a menthol component, and ethanol according to one or more aspects of the present invention components. In a first step 305 , the nicotine component is combined with the acid component to form a nicotine salt mixture. In embodiments where the acid component includes lactic acid, the nicotine component is combined with the acid component to form a nicotine lactate mixture. In a second step 310 , separately, the menthol component is combined with the ethanol component to form a menthol/ethanol mixture. As discussed above, it is contemplated that an ethanol component may be included as a surfactant or co-solvent. In this regard, it should be noted that components added to the solution beyond the menthol solubility limit may require surfactants. In this regard, the use of surfactants is contemplated to enable components beyond the solubility limit to be included in the mixture via formation of an emulsion. Surfactant molecules are interconnected to form structures capable of encapsulating otherwise insoluble components. In a third step 315 , the menthol/ethanol mixture from the second step 310 is combined with the brine component to produce a menthol/ethanol/brine mixture. Then, in a fourth step 320 , the nicotine salt mixture from the first step 305 is combined with the menthol/ethanol/saline mixture from the third step 315 to generate a target formulation for aerosolization and inhalation using electronic devices thing.

在又其他考慮實施方式中，用於使用電子裝置氣溶膠化與吸入之水性調配物包括鹽水組分、菸鹼組分、酸組分、及視需要薄荷醇組分、乙醇組分、及界面活性劑組分中之任一者或任何組合。此類調配物之各組分的考慮質量百分比範圍包括：溶液之大約35質量%至大約99.998質量%的鹽水組分；溶液之大約0.001質量%至大約5質量%的菸鹼組分；溶液之大約0.001質量%至大約25質量%的酸組分；溶液之0質量%至大約15質量%的薄荷醇組分；溶液之0質量%至大約10質量%的乙醇組分；及溶液之0質量%至大約10質量%的界面活性劑組分。In yet other contemplated embodiments, aqueous formulations for aerosolization and inhalation using electronic devices include a saline component, a nicotine component, an acid component, and optionally a menthol component, an ethanol component, and an interface Any one or any combination of active agent components. Considered mass percentage ranges for the components of such formulations include: about 35% to about 99.998% by mass of the saline component of the solution; about 0.001% to about 5% by mass of the nicotine component of the solution; About 0.001% to about 25% by mass of the acid component; 0% to about 15% by mass of the menthol component of the solution; 0% to about 10% by mass of the ethanol component of the solution; and 0% by mass of the solution % to about 10% by mass of the surfactant component.

經考慮鹽水組分為類似或接近常規生理溶液之安全水性溶液。用作水性調配物中之鹽水組分的鹽水之一個較佳形式為等張鹽水，諸如0.9% NaCl鹽水溶液。經進一步考慮可使用低張或高張鹽水。就此而言，鹽水溶液可在大約0.001%至大約7.5% NaCl鹽水溶液範圍內。在又其他考慮實施方式中，使用水代替鹽水組分。Saline components are considered to be safe aqueous solutions similar to or close to conventional physiological solutions. One preferred form of saline for use as the saline component in aqueous formulations is isotonic saline, such as a 0.9% NaCl saline solution. Hypotonic or hypertonic saline may be used with further consideration. In this regard, the saline solution may range from about 0.001% to about 7.5% NaCl saline solution. In yet other contemplated embodiments, water is used in place of the brine component.

酸組分用於減少非質子化菸鹼相對於總菸鹼量之分率。在水性調配物中用作酸組分之一種較佳的酸為乳酸。其他考慮酸包括但不限於苯甲酸、蘋果酸、酒石酸、水楊酸、乙醯丙酸及鹽酸。The acid component is used to reduce the fraction of aprotonated nicotine relative to the total amount of nicotine. A preferred acid for use as the acid component in aqueous formulations is lactic acid. Other contemplated acids include, but are not limited to, benzoic acid, malic acid, tartaric acid, salicylic acid, acetopropionic acid, and hydrochloric acid.

如上文所論述，薄荷醇可視需要包括於水性調配物中以增強感官體驗且減少刺激性。除薄荷醇之外（或代替薄荷醇），同樣考慮其他調味劑及組分。As discussed above, menthol can be optionally included in aqueous formulations to enhance the sensory experience and reduce irritation. In addition to (or in place of) menthol, other flavors and components are also contemplated.

經考慮乙醇可視需要包括於水性調配物中作為界面活性劑或共溶劑。其他考慮共溶劑包括但不限於丙二醇及丙三醇。It is contemplated that ethanol may optionally be included in aqueous formulations as a surfactant or co-solvent. Other contemplated co-solvents include, but are not limited to, propylene glycol and glycerol.

界面活性劑組分可有助於降低該界面活性劑組分溶解於之溶液之表面張力。界面活性劑分子在溶液中可聚集在一起以形成微胞或脂質體結構以囊封溶液中之目標成分或組分。就此而言，可形成乳液或奈米乳液以使得在其他情況下不溶性的組分可由界面活性劑囊封且保持為混合物之一部分。在至少一些實施方式中，經考慮微流控方法（使用微流控機器）可用於經由界定微通道中之液體流的相互作用形成奈米乳液。關於作為用於藉由吸入將特定成分或組分經肺遞送至肺泡肺之囊封劑的界面活性劑的額外論述，參考同在申請且共同轉讓之美國專利申請案序列號17/075,679，其以引用的方式併入本文中。The surfactant component can help reduce the surface tension of the solution in which the surfactant component is dissolved. Surfactant molecules can aggregate together in solution to form micelle or liposome structures to encapsulate target components or components in solution. In this regard, an emulsion or nanoemulsion can be formed so that otherwise insoluble components can be encapsulated by the surfactant and remain part of the mixture. In at least some embodiments, it is contemplated that a microfluidic approach (using a microfluidic machine) can be used to form nanoemulsions via the interaction of liquid flows that define microchannels. For additional discussion of surfactants as encapsulating agents for pulmonary delivery of certain ingredients or components to the alveolar lung by inhalation, reference is made to co-pending and commonly assigned US Patent Application Serial No. 17/075,679, which Incorporated herein by reference.

經考慮用於根據本發明之一或多個態樣之水性調配物中的界面活性劑可包括但不限於：高純度聚氧乙烯山梨糖醇酐單油酸酯（亦由其商標名SUPER REFINED®聚山梨醇酯80已知）；聚氧乙烯山梨糖醇酐單油酸酯；（亦由其商標名TWEEN®聚山梨醇酯80已知）；聚氧乙烯山梨糖醇酐單硬脂酸酯（亦由其商標名TWEEN®聚山梨醇酯60已知）；聚氧乙烯山梨糖醇酐單棕櫚酸酯（亦由其商標名TWEEN®聚山梨醇酯40已知）；聚氧乙烯山梨糖醇酐單月桂酸酯（亦由其商標名TWEEN®聚山梨醇酯20已知）；卵磷脂；二棕櫚醯基磷脂醯膽鹼（dipalmitoylphosphatidylcholine，DPPC）；1,2-二硬脂醯基- sn-甘油-3-磷酸膽鹼（1,2-distearoyl- sn-glycero-3-phosphocholine，DSPC）；山梨糖醇酐單硬脂酸酯（亦由其商標名SPAN 60已知）；山梨糖醇酐單棕櫚酸酯（亦由其商標名SPAN 40已知）；及泊洛沙姆（諸如泊洛沙姆188或泊洛沙姆447）。經進一步考慮根據本發明之一或多個態樣的水性調配物可包括單一界面活性劑或可包括多種界面活性劑。 Surfactants contemplated for use in aqueous formulations according to one or more aspects of the present invention may include, but are not limited to: high purity polyoxyethylene sorbitan monooleate (also known by its trade name SUPER REFINED) ® polysorbate 80); polyoxyethylene sorbitan monooleate; (also known by its trade name TWEEN® polysorbate 80); polyoxyethylene sorbitan monostearate ester (also known by its trade name TWEEN® polysorbate 60); polyoxyethylene sorbitan monopalmitate (also known by its trade name TWEEN® polysorbate 40); polyoxyethylene sorbitan Anhydrosugar monolaurate (also known by its trade name TWEEN® polysorbate 20); lecithin; dipalmitoylphosphatidylcholine (DPPC); 1,2-distearyl - sn -glycero-3-phosphocholine (1,2-distearoyl- sn -glycero-3-phosphocholine, DSPC); sorbitan monostearate (also known by its trade name SPAN 60); sorbitan Anhydrosugar monopalmitate (also known by its trade name SPAN 40); and Poloxamers (such as Poloxamer 188 or Poloxamer 447). It is further contemplated that aqueous formulations according to one or more aspects of the present invention may include a single surfactant or may include multiple surfactants.

一種根據上述特徵之特定考慮調配物包括：溶液之大約91.291質量%的0.9% NaCl鹽水組分；溶液之大約2.001質量%的菸鹼組分；溶液之大約4.479質量%的乳酸組分；溶液之大約2.229質量%的薄荷醇組分；溶液之大約1.758質量%的乙醇組分；及溶液之大約2.377質量%的TWEEN®聚山梨醇酯80界面活性劑組分。One particular consideration formulation according to the above features comprises: approximately 91.291 mass % of the solution of a 0.9% NaCl saline component; approximately 2.001 mass % of the solution of a nicotine component; approximately 4.479 mass % of the solution of a lactic acid component; About 2.229% by mass of the menthol component; about 1.758% by mass of the ethanol component of the solution; and about 2.377% by mass of the TWEEN® polysorbate 80 surfactant component of the solution.

圖7為說明根據本發明之一或多個態樣的水性調配物之製備方法 400的流程圖，該調配物包括鹽水組分、菸鹼組分、酸組分、薄荷醇組分、乙醇組分、及界面活性劑組分。在第一步驟 405中，將菸鹼組分與酸組分組合以形成菸鹼鹽混合物。在酸組分包括乳酸之實施方式中，將菸鹼組分與酸組分組合以形成菸鹼乳酸鹽混合物。隨後，在第二步驟 410中，將來自第一步驟 405之菸鹼鹽混合物與鹽水組分組合以產生菸鹼鹽／鹽水混合物。在第三步驟 415中，分開地，將薄荷醇組分、乙醇組分、及界面活性劑組分組合以形成薄荷醇／乙醇／界面活性劑混合物。在考慮實施方式中，界面活性劑組分包括TWEEN®聚山梨醇酯80。另外，如上文所論述，經考慮可包括乙醇組分作為界面活性劑或共溶劑。就此而言，應注意，添加至溶液中超出薄荷醇溶解限度之組分可能需要界面活性劑。隨後，在第四步驟 420中，將來自第二步驟 410之菸鹼鹽／鹽水混合物與來自第三步驟 415之薄荷醇／乙醇／界面活性劑混合物組合以產生用於使用電子裝置氣溶膠化與吸入之目標調配物。當界面活性劑，諸如TWEEN®聚山梨醇酯80用於水性調配物中時，製備步驟之順序可有助於防止組分在組分混合期間沈澱為固體。特定言之，當薄荷醇及界面活性劑均用於水性調配物中時，將分開組合之組分混合在一起以產生目標調配物時，將菸鹼組分及酸組分與薄荷醇組分及界面活性劑組分分開組合有助於防止薄荷醇自系統中沈澱出。 7 is a flow chart illustrating a method 400 of making an aqueous formulation including a saline component, a nicotine component, an acid component, a menthol component, an ethanol component, according to one or more aspects of the present invention components, and surfactant components. In a first step 405 , the nicotine component is combined with the acid component to form a nicotine salt mixture. In embodiments where the acid component includes lactic acid, the nicotine component is combined with the acid component to form a nicotine lactate mixture. Then, in a second step 410 , the nicotine salt mixture from the first step 405 is combined with the brine components to produce a nicotine salt/brine mixture. In a third step 415 , separately, the menthol component, the ethanol component, and the surfactant component are combined to form a menthol/ethanol/surfactant mixture. In contemplated embodiments, the surfactant component includes TWEEN® polysorbate 80. Additionally, as discussed above, it is contemplated that an ethanol component may be included as a surfactant or co-solvent. In this regard, it should be noted that components added to the solution beyond the menthol solubility limit may require surfactants. Then, in a fourth step 420 , the nicotine salt/saline mixture from the second step 410 is combined with the menthol/ethanol/surfactant mixture from the third step 415 to produce a mixture for aerosolization and Inhaled target formulation. When surfactants, such as TWEEN® polysorbate 80, are used in aqueous formulations, the sequence of preparation steps can help prevent the components from settling as solids during mixing of the components. Specifically, when both menthol and surfactant are used in aqueous formulations, the nicotine and acid components are combined with the menthol component when the separately combined components are mixed together to produce the target formulation. and surfactant components in separate combinations to help prevent menthol from precipitating out of the system.

如上文所論述，pH水準量測可用於幫助瞭解不同菸鹼物種在溶液中之分率。pH水準亦可充當在氣溶膠化與吸入水性調配物時的總體感官體驗的衡量標準。在考慮實施方式中，向使用者提供合意的感官體驗之目標pH範圍將水性調配物之量測pH定為大約2至大約7。在至少一些實施方式中，在大約2至大約5範圍內之目標pH值為較佳的。此外，在至少一些實施方式中，大約3.38之目標pH值反映尤其令人愉快的感官體驗，其緩和可在較高菸鹼濃度下產生的刺激性。As discussed above, pH level measurements can be used to help understand the fraction of different nicotine species in solution. The pH level can also serve as a measure of the overall sensory experience when aerosolizing and inhaling aqueous formulations. In contemplated embodiments, the target pH range to provide a user with a desirable sensory experience places the measured pH of the aqueous formulation at about 2 to about 7. In at least some embodiments, a target pH in the range of about 2 to about 5 is preferred. Furthermore, in at least some embodiments, a target pH value of about 3.38 reflects a particularly pleasant sensory experience that moderates irritation that can occur at higher nicotine concentrations.

基於以上描述，所屬技術領域中具有通常知識者可輕易理解到本發明具有廣泛的實用性及應用性。除本文中特定描述者之外的許多本發明之實施方式及調整方案以及許多變體、修改及等效安排基於本發明及其以上描述會是明顯的或被本發明及其以上描述合理地暗示，而不會脫離本發明之實質或範圍。因此，儘管本文中已以一或多個較佳實施方式詳細地描述本發明，但應理解，此揭示內容對本發明而言為僅為說明性的及例示性的且僅僅出於提供本發明之完整且可據以實現的揭示內容之目的而產生。以上揭示內容並不意欲被視為限制本發明或以其他方式排除任何如此其他實施方式、調整方案、變體、修改或等效安排，本發明僅由隨附申請專利範圍及其等效者限制。Based on the above description, those skilled in the art can easily understand that the present invention has wide practicability and applicability. Many embodiments and adaptations of the invention other than those specifically described herein, as well as many variations, modifications and equivalent arrangements would be apparent from or reasonably implied by the invention and the foregoing description thereof , without departing from the spirit or scope of the present invention. Therefore, while the present invention has been described in detail herein in terms of one or more preferred embodiments, it is to be understood that this disclosure is illustrative and exemplary of the present invention only and for the purpose of providing the present invention only. Complete and achievable for the purposes of the disclosure. The above disclosure is not intended to be construed as limiting the invention or otherwise excluding any such other embodiments, adaptations, variations, modifications or equivalent arrangements, the invention being limited only by the scope of the appended claims and their equivalents .

現將參考隨附圖式詳細地描述本發明之一或多個較佳實施方式，在圖式中相同元件用相同符號指示，且其中，One or more preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, in which like elements are designated by like symbols, and wherein,

[圖1A-1C]分別為非質子化菸鹼、單質子化菸鹼、及二質子化菸鹼之結構式；[FIG. 1A-1C] are the structural formulas of aprotonated nicotine, monoprotonated nicotine, and diprotonated nicotine, respectively;

[圖1D]為說明溶液中pH與圖1A-1C之各物種之相對分率之間的關係的圖形表示；[FIG. 1D] is a graphical representation illustrating the relationship between pH in solution and the relative fraction of each species of FIGS. 1A-1C;

[圖2]為說明總菸鹼濃度與總菸鹼之非質子化分率之間的關係及該關係可如何影響感官體驗的圖形表示；[FIG. 2] is a graphical representation illustrating the relationship between total nicotine concentration and the aprotonated fraction of total nicotine and how this relationship can affect sensory experience;

[圖3]為說明含薄荷醇調配物隨總菸鹼濃度而變的刺激性量測結果的圖形表示；[FIG. 3] is a graphical representation illustrating irritant measurements of menthol-containing formulations as a function of total nicotine concentration;

[圖4]為說明根據本發明之一或多個態樣的水性調配物之製備方法的流程圖，該調配物包括鹽水組分、菸鹼組分、及酸組分；[FIG. 4] is a flowchart illustrating a method for preparing an aqueous formulation according to one or more aspects of the present invention, the formulation including a saline component, a nicotine component, and an acid component;

[圖5]為說明根據本發明之一或多個態樣的水性調配物之製備方法的流程圖，該調配物包括鹽水組分、菸鹼組分、酸組分、及薄荷醇組分；[FIG. 5] is a flowchart illustrating a method for preparing an aqueous formulation according to one or more aspects of the present invention, the formulation including a saline component, a nicotine component, an acid component, and a menthol component;

[圖6]為說明根據本發明之一或多個態樣的水性調配物之製備方法的流程圖，該調配物包括鹽水組分、菸鹼組分、酸組分、薄荷醇組分、及乙醇組分；及[FIG. 6] is a flow chart illustrating a method of preparing an aqueous formulation according to one or more aspects of the present invention, the formulation including a saline component, a nicotine component, an acid component, a menthol component, and Ethanol components; and

[圖7]為說明根據本發明之一或多個態樣的水性調配物之製備方法的流程圖，該調配物包括鹽水組分、菸鹼組分、酸組分、薄荷醇組分、乙醇組分、及界面活性劑組分。[FIG. 7] is a flow chart illustrating a method for preparing an aqueous formulation according to one or more aspects of the present invention, the formulation including a saline component, a nicotine component, an acid component, a menthol component, ethanol components, and surfactant components.

Claims (20)

一種用於使用電子裝置氣溶膠化與吸入之水性調配物，該調配物包含： 鹽水組分； 酸組分，其中該酸組分包括乳酸；及 菸鹼組分。 An aqueous formulation for aerosolization and inhalation using an electronic device, the formulation comprising: Brine components; an acid component, wherein the acid component comprises lactic acid; and Nicotine component. 如請求項1之水性調配物，其中該鹽水組分包括0.9% NaCl鹽水溶液。The aqueous formulation of claim 1, wherein the saline component comprises a 0.9% NaCl saline solution. 如請求項1之水性調配物，其中該鹽水組分為該調配物之大約30質量%至大約99.998質量%。The aqueous formulation of claim 1, wherein the brine component is from about 30% to about 99.998% by mass of the formulation. 如請求項1之水性調配物，其中該酸組分進一步包括苯甲酸、蘋果酸、酒石酸、水楊酸、乙醯丙酸、及鹽酸中之一或多者。The aqueous formulation of claim 1, wherein the acid component further comprises one or more of benzoic acid, malic acid, tartaric acid, salicylic acid, acetylpropionic acid, and hydrochloric acid. 如請求項1之水性調配物，其中該酸組分為該調配物之大約0.001質量%至大約25質量%。The aqueous formulation of claim 1, wherein the acid component is about 0.001% to about 25% by mass of the formulation. 如請求項1之水性調配物，其中該菸鹼組分包括呈質子化形式之菸鹼及呈非質子化形式之菸鹼。The aqueous formulation of claim 1, wherein the nicotine component comprises nicotine in protonated form and nicotine in unprotonated form. 如請求項1之水性調配物，其中該菸鹼組分為該調配物之大約0.001質量%至大約5質量%。The aqueous formulation of claim 1, wherein the nicotine component is about 0.001% to about 5% by mass of the formulation. 如請求項1之水性調配物，其中該水性調配物之pH值量測在大約2與大約5之間。The aqueous formulation of claim 1, wherein the pH of the aqueous formulation is measured between about 2 and about 5. 如請求項1之水性調配物，其中該水性調配物之該pH值量測為大約3.38。The aqueous formulation of claim 1, wherein the pH of the aqueous formulation measures about 3.38. 如請求項1之水性調配物，其進一步包含薄荷醇組分。The aqueous formulation of claim 1, further comprising a menthol component. 如請求項10之水性調配物，其中該薄荷醇組分為該調配物之大約0.001質量%至大約15質量%。The aqueous formulation of claim 10, wherein the menthol component is about 0.001% to about 15% by mass of the formulation. 如請求項10之水性調配物，其進一步包含乙醇組分。The aqueous formulation of claim 10, further comprising an ethanol component. 如請求項12之水性調配物，其中該乙醇組分為該調配物之大約0.001質量%至大約10質量%。The aqueous formulation of claim 12, wherein the ethanol component is about 0.001% to about 10% by mass of the formulation. 如請求項10之水性調配物，其進一步包含界面活性劑組分，其中該界面活性劑組分包括一或多種不同界面活性劑。The aqueous formulation of claim 10, further comprising a surfactant component, wherein the surfactant component includes one or more different surfactants. 如請求項14之水性調配物，其中該界面活性劑組分包括聚氧乙烯山梨糖醇酐單油酸酯、聚氧乙烯山梨糖醇酐單硬脂酸酯、聚氧乙烯山梨糖醇酐單月桂酸酯、卵磷脂及泊洛沙姆（poloxamer）中之一或多者。The aqueous formulation of claim 14, wherein the surfactant component comprises polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monostearate One or more of laurate, lecithin and poloxamer. 如請求項14之水性調配物，其中該界面活性劑組分為該調配物之大約0.001質量%至大約10質量%。The aqueous formulation of claim 14, wherein the surfactant component is from about 0.001% to about 10% by mass of the formulation. 如請求項10之水性調配物，其進一步包含乙醇組分及界面活性劑組分。The aqueous formulation of claim 10, further comprising an ethanol component and a surfactant component. 一種製備用於使用電子裝置氣溶膠化與吸入之水性調配物的方法，其包含： 將菸鹼組分與酸組分混合以形成第一混合物； 分開地，將薄荷醇組分與鹽水組分混合以形成第二混合物；及 將該第一混合物與該第二混合物混合以形成目標水性調配物。 A method of preparing an aqueous formulation for aerosolization and inhalation using an electronic device, comprising: mixing the nicotine component and the acid component to form a first mixture; Separately, combining the menthol component and the brine component to form a second mixture; and The first mixture is mixed with the second mixture to form the target aqueous formulation. 一種製備用於使用電子裝置氣溶膠化與吸入之水性調配物的方法，其包含： （a）    將菸鹼組分與酸組分混合以形成第一混合物； （b）    分開地，將薄荷醇組分與乙醇組分混合以形成第二混合物； （c）    將鹽水組分與該第二混合物混合以形成第三混合物；及 （d）    將該第一混合物與該第三混合物混合以形成目標水性調配物。 A method of preparing an aqueous formulation for aerosolization and inhalation using an electronic device, comprising: (a) mixing the nicotine component and the acid component to form a first mixture; (b) separately, mixing the menthol component with the ethanol component to form a second mixture; (c) mixing the brine components with the second mixture to form a third mixture; and (d) mixing the first mixture with the third mixture to form the target aqueous formulation. 一種製備用於使用電子裝置氣溶膠化與吸入之水性調配物的方法，其包含： （a）    將菸鹼組分與酸組分混合以形成第一混合物； （b）    將鹽水組分與該第一混合物混合以形成第二混合物； （c）    分開地，將薄荷醇組分、乙醇組分、與界面活性劑組分混合以形成第三混合物；及 （d）    將該第二混合物與該第三混合物混合以形成目標水性調配物。 A method of preparing an aqueous formulation for aerosolization and inhalation using an electronic device, comprising: (a) mixing the nicotine component and the acid component to form a first mixture; (b) mixing the brine components with the first mixture to form a second mixture; (c) separately, combining the menthol component, the ethanol component, and the surfactant component to form a third mixture; and (d) mixing the second mixture with the third mixture to form the target aqueous formulation.
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