WO2022218310A1 - 气溶胶形成基质以及气溶胶生成系统 - Google Patents

气溶胶形成基质以及气溶胶生成系统 Download PDF

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WO2022218310A1
WO2022218310A1 PCT/CN2022/086384 CN2022086384W WO2022218310A1 WO 2022218310 A1 WO2022218310 A1 WO 2022218310A1 CN 2022086384 W CN2022086384 W CN 2022086384W WO 2022218310 A1 WO2022218310 A1 WO 2022218310A1
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aerosol
forming substrate
yohimbine
glycol
oil
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PCT/CN2022/086384
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English (en)
French (fr)
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卢禁
徐中立
李永海
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深圳市合元科技有限公司
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Priority to EP22787532.5A priority Critical patent/EP4324455A1/en
Priority to US18/554,479 priority patent/US20240207252A1/en
Publication of WO2022218310A1 publication Critical patent/WO2022218310A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A24B15/302—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances by natural substances obtained from animals or plants
    • A24B15/303—Plant extracts other than tobacco
    • 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
    • A24B15/36—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring
    • A24B15/38—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring having only nitrogen as hetero atom
    • A24B15/385—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring having only nitrogen as hetero atom in a five-membered ring
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24F—SMOKERS' REQUISITES; MATCH BOXES; SIMULATED SMOKING DEVICES
    • A24F40/00—Electrically operated smoking devices; Component parts thereof; Manufacture thereof; Maintenance or testing thereof; Charging means specially adapted therefor
    • A24F40/10—Devices using liquid inhalable precursors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
    • A61M11/041—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters
    • A61M11/042—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised using heaters electrical

Definitions

  • the present application belongs to the technical field of atomization, and relates to an aerosol-forming substrate and an aerosol-generating system.
  • Yohimbine is an alkaloid of natural origin. The ingredient was first extracted from the bark of the Rubiaceae Corunant Yohimbine tree in West Africa. The chemical formula of yohimbine is methyl 17 ⁇ -hydroxyyohenane-16 ⁇ -carboxylate, and the molecular formula is C21H26N2O3.
  • Literature research has found that yohimbine has a wide range of pharmacological effects and has been developed for clinical treatment of arteriosclerosis, rheumatism and other diseases. Among them, the most obvious pharmacological effect is for the treatment of male sexual dysfunction.
  • the vaporizable material may contain botanicals and/or nutritional products, such as: yohimbine; in certain embodiments, the vaporizable material
  • the material can be dissolved at least 50% by weight in any suitable carrier solvent, such as glycols (eg, propylene glycol and vegetable glycerin), ethylene glycol, dipropylene glycol, trimethylene glycol, ethanol, and combinations thereof .
  • the problem with this disclosed solution is that, on the one hand, the solubility of yohimbine in the carrier solvent is poor, at least 50% (by weight) of yohimbine cannot be completely dissolved; whether the vaporizable material containing this weight can be vaporized and The effect on the electronic vaporizer device cannot be verified from this literature; even if it can be vaporized, the conversion rate is very low; on the other hand, the vaporizable material containing at least 50% (by weight) yohimbine, (even if The conversion rate is very low) for the user, the dose is very large, far exceeding the dose of oral or injection administered in current clinical trials, and the safety cannot be guaranteed.
  • the first aspect of the present application aims to provide an aerosol-forming substrate with less impact on the electronic atomization device, high conversion rate and guaranteed safety, so
  • the aerosol-forming substrate comprises yohimbine or a pharmaceutically acceptable salt of yohimbine or yohimbine hydrate;
  • the mass percentage of yohimbine or a pharmaceutically acceptable salt of yohimbine or yohimbine hydrate is 0.1%-10%, preferably 0.1%-8%, and further Preferably it is 0.1%-6%, More preferably, it is 0.1%-5%, More preferably, it is 0.5%-5%, More preferably, it is 1%-5%, More preferably, it is 2%-5%.
  • the pharmaceutically acceptable salt is selected from at least one of the following:
  • Hydrochloride Hydrobromide, Benzoate, Hydrofluoride, Sulfate, Nitrate, Phosphate, Formate, Acetate, Propionate, Oxalate, Malonate, Succinate acid salt, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, mesylate, ethanesulfonate, besylate, aspartate acid, glutamate.
  • pharmaceutically acceptable salts include benzoates.
  • the aerosol-forming substrate further comprises a solvent selected from at least one of the following:
  • the solvent includes propylene glycol
  • the mass percentage of propylene glycol in the aerosol-forming substrate is 20%-60%, preferably 20%-50%, more preferably 20%-45%, further Preferably it is 25%-45%, More preferably, it is 30%-45%, More preferably, it is 35%-45%.
  • the solvent includes glycerol
  • the mass percentage of glycerin in the aerosol-forming substrate is 10-60%, preferably 10%-50%, more preferably 10%-40%, further preferably It is 20%-40%, More preferably, it is 30%-40%.
  • the mass ratio of propylene glycol to glycerol is greater than 1, preferably 1.1-4:1, more preferably 2-4:1.
  • the aerosol-forming substrate further includes a fragrance.
  • the flavoring agent in the aerosol-forming matrix is added according to the conventional amount required for flavoring, and the mass percentage is 1-20%, preferably 5%-20%, more preferably 10%-20%, further preferably 15%- 20%.
  • the fragrance is selected from at least one of the following:
  • the aerosol-forming matrix is free of nicotine and/or nicotine salts.
  • a second aspect of the present application provides an aerosol generating system, the aerosol generating system comprising an electronic atomization device and the aerosol-forming substrate; the electronic atomizing device is configured to perform the aerosol-forming process on the aerosol-forming substrate. Heated atomization to generate an aerosol.
  • the aerosol-forming substrate containing yohimbine or a pharmaceutically acceptable salt of yohimbine or yohimbine hydrate provided by the present application no carbonization occurs after repeated heating by an electronic atomization device, and the conversion of yohimbine The rate is relatively high, which is close to the dose of oral or injection in current clinical trials, and the safety can be guaranteed.
  • Fig. 1 is the HPLC detection result schematic diagram provided by the embodiment of the application.
  • FIG. 2 is a schematic diagram of an atomizer in an electronic atomization device before a carbonization experiment provided by an embodiment of the present application;
  • FIG. 3 is a schematic diagram of an atomizer in an electronic atomization device after a carbonization experiment provided by an embodiment of the present application.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 1 of the present application provides an aerosol-forming substrate, wherein the aerosol-forming substrate includes yohimbine or a pharmaceutically acceptable salt of yohimbine or yohimbine hydrate;
  • the mass percentage of yohimbine or a pharmaceutically acceptable salt of yohimbine or yohimbine hydrate is 0.1%-10%, preferably 0.1%-8%, and further Preferably it is 0.1%-6%, More preferably, it is 0.1%-5%, More preferably, it is 0.5%-5%, More preferably, it is 1%-5%, More preferably, it is 2%-5%.
  • the pharmaceutically acceptable salt is selected from at least one of the following:
  • Hydrochloride Hydrobromide, Benzoate, Hydrofluoride, Sulfate, Nitrate, Phosphate, Formate, Acetate, Propionate, Oxalate, Malonate, Succinate acid salt, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, mesylate, ethanesulfonate, besylate, aspartate acid, glutamate.
  • pharmaceutically acceptable salts include benzoates.
  • the aerosol-forming substrate further comprises a solvent selected from at least one of the following:
  • the propylene glycol includes 1,2-propanediol, 1,3-propanediol;
  • the butanediol includes 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,2-butanediol, 3-Butanediol;
  • pentanediol includes 1,2-pentanediol, 1,4-pentanediol, 2,4-pentanediol, 1,5-pentanediol;
  • hexanediol includes 1,2- Hexanediol, 1,6-hexanediol, 2,5-hexanediol.
  • the solvent includes propylene glycol
  • the mass percentage of propylene glycol in the aerosol-forming substrate is 20%-60%, preferably 20%-50%, more preferably 20%-45%, further Preferably it is 25%-45%, More preferably, it is 30%-45%, More preferably, it is 35%-45%.
  • the solvent includes glycerol
  • the mass percentage of glycerin in the aerosol-forming substrate is 10-60%, preferably 10%-50%, more preferably 10%-40%, further preferably It is 20%-40%, More preferably, it is 30%-40%.
  • the mass ratio of propylene glycol to glycerol is greater than 1, preferably 1.1-4:1, more preferably 2-4:1.
  • the aerosol-forming substrate further includes a fragrance
  • the mass percentage of the fragrance in the aerosol-forming substrate is 1-20%, preferably 5%-20%, more preferably 10% -20%, more preferably 15%-20%.
  • the fragrance agent is selected from at least one of the following:
  • flavoring agent is not limited to the substances listed above, and all flavoring agents complying with the FEMA code and the CAS code can be applied.
  • the aerosol-forming matrix is free of nicotine and/or nicotine salts.
  • an electronic atomization device with a ceramic structure atomizer is used for heating (heating for 3 s every 27 s), and the number of heating (or suction) times is 400 times.
  • the aerosol-forming substrate of this embodiment is composed of 1.5% yohimbine, 40% propylene glycol, 37% glycerin, and 20% flavoring agent.
  • FIG 2 it is a schematic diagram of the atomizer before the electronic atomization device heats the aerosol to form a matrix; as shown in Figure 3, it is a schematic diagram of the atomizer after the electronic atomization device heats the aerosol to form a matrix.
  • the naked eye it can be seen that the atomizer has no gelatinization and carbon deposition. During the experiment, the experimenter did not detect any odor when smoking.
  • the TPM of each time was about 5-6mg.
  • commercially available yohimbine tablets (Oral) is 5.4 mg each time, assuming its bioavailability is 50%, it is about 2.7 mg each time. Therefore, the user's intake of 10 puffs through the electronic atomization device is about 2.4 mg (the bioavailability of the atomized intake method is much higher than that of the oral method), which is close to the dose of the current clinical trial using the oral method. Security can be guaranteed.
  • Example 1 The aerosol-forming matrix was composed of 10wt% yohimbine, 40wt% propylene glycol, 37wt% glycerin, and the balance was fragrance.
  • Example 2 The aerosol-forming matrix was composed of 8 wt % of yohimbine, 40 wt % of propylene glycol, 37 wt % of glycerin, and the balance was fragrance.
  • Example 3 The aerosol-forming matrix was composed of 6 wt % of yohimbine, 40 wt % of propylene glycol, 37 wt % of glycerin, and the balance was fragrance.
  • Example 4 The aerosol-forming matrix was composed of 4 wt % of yohimbine, 40 wt % of propylene glycol, 37 wt % of glycerin, and the balance was fragrance.
  • Example 5 The aerosol-forming matrix was composed of 3wt% yohimbine, 40wt% propylene glycol, 37wt% glycerin, and the balance was fragrance.
  • Example 6 The aerosol-forming matrix was composed of 1.5 wt % of yohimbine, 40 wt % of propylene glycol, 37 wt % of glycerin, and the balance was fragrance.
  • Example 7 The aerosol-forming matrix was composed of 0.5 wt % of yohimbine, 40 wt % of propylene glycol, 37 wt % of glycerin, and the balance was fragrance.
  • Example 8 The aerosol-forming matrix was composed of 0.1 wt % of yohimbine, 40 wt % of propylene glycol, 37 wt % of glycerin, and the balance was fragrance.
  • Example 9 The aerosol-forming matrix was selected as 3wt% yohimbine, and the solvent was selected as a mixture of propylene glycol and glycerol with a mass ratio of about 7:3.
  • Example 10 The aerosol-forming matrix was selected as 3wt% yohimbine, and the solvent was selected as a mixture of propylene glycol and glycerol with a mass ratio of about 3:7.
  • Example 11 The aerosol-forming substrate was selected as 3wt% of yohimbine's pharmaceutically acceptable benzoate, and the solvent was selected as a mixture of glycerol and propylene glycol with a mass ratio of about 1:1.
  • the pharmaceutically acceptable benzoate of yohimbine can be prepared by mixing yohimbine alkaloids with benzoic acid.
  • Example 12 The aerosol-forming substrate was selected as 3 wt % of the pharmaceutically acceptable hydrochloride of yohimbine, and the solvent was selected as a mixture of glycerol and propylene glycol with a mass ratio of about 1:1.
  • the pharmaceutically acceptable hydrochloride of yohimbine can be separated and purified from the bark of Rubiaceae Corunant Yohimbine tree, and can also be obtained by existing chemical synthesis methods, and can also be purchased from the market.
  • Example 1-Example 12 were sucked with a smoking machine according to international standards, the aerosols from the aerosol-forming matrix were collected with a Cambridge filter, and then extracted with an organic solvent, filtered, and analyzed by HPLC for calculation.
  • the calculation method of the conversion rate is: weighing the difference m_0 of the weight before and after the Cambridge filter (that is, the weight of the collected aerosol), taking the same mass of aerosol to form the matrix m 1 , extracting with the same volume V of organic solvent, and then taking The extract is fed into HPLC. According to the ratio of the chromatographic peak area A 1 and the concentration C 1 of the aerosol-forming matrix in HPLC, multiply by the chromatographic peak area A 0 of the aerosol, and then divide by the aerosol concentration C 0 , which is the conversion Rate.
  • the specific calculation formula is as follows:
  • electronic atomizing device 1 adopts an atomizer with a cotton core structure
  • electronic atomizing device 2 adopts an atomizer with a ceramic structure
  • electronic atomizing device 3 adopts a cotton-wrap ceramic structure.
  • the atomizers with the above structures can be known from the prior art, and will not be repeated here.
  • Example 1-Example 8 with the increase of the content of yohimbine in the aerosol-forming matrix, the conversion rate (average value) showed a downward trend; when the content of yohimbine in the aerosol-forming matrix reached 10% , the conversion (average) is about 34%.
  • Example 5 Example 9-Example 10, the content of propylene glycol in the solvent has a greater influence on the conversion rate; when the mass ratio of propylene glycol and glycerol is 7:3, the conversion rate (average value) can reach 67% , higher than the conversion rate of Example 5 or Example 10.
  • Example 5 Example 11-Example 12, the pharmaceutically acceptable salts of yohimbine, the conversion rate (average value) is generally higher, and the conversion rate of Example 11 or Example 12 is higher than the embodiment The conversion rate of Example 5; wherein, the pharmaceutically acceptable benzoate of yohimbine, the conversion rate (average value) can reach 66%.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • the second embodiment of the present application provides an aerosol generation system, including an electronic atomization device and the aerosol-forming substrate described in the first embodiment;
  • the electronic atomization device is configured to heat and atomize the aerosol-forming substrate to generate an aerosol.

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Abstract

本发明提供了一种气溶胶形成基质以及气溶胶生成系统，所述气溶胶形成基质包括育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物；以气溶胶形成基质的总质量计，育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物的质量百分比为0.1％-10％。本发明提供的气溶胶形成基质，采用电子雾化装置多次加热后没有碳化现象发生，育亨宾的转化率较高，与目前临床试验采用口服或者注射给药的剂量接近，安全性能够得到保障。

Description

气溶胶形成基质以及气溶胶生成系统
相关申请的交叉参考
本申请要求于2021年4月12日提交中国专利局，申请号为202110398742.4，名称为“气溶胶形成基质以及气溶胶生成系统”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本本申请属于雾化技术领域，涉及一种气溶胶形成基质以及气溶胶生成系统。
背景技术
育亨宾(Yohimbine)是一种天然来源的生物碱。该成分最早是从西非Rubiaceae Corunant Yohimbine树的树皮中提取出来。育亨宾的化学式为17α-羟基育亨烷-16α-羧酸甲酯，分子式为C21H26N2O3。
文献调研发现，育亨宾具有较为广泛的药理作用，已开发用于临床上治疗动脉硬化、风湿病等疾病。其中药理作用最为明显的是用于治疗男性性功能障碍。
目前，大部分临床试验采用口服或者注射给药。有研究证明育亨宾为一室代谢模型。单次口服给药体内代谢迅速，Tmax和t1/2均小于1h。由于口服生物利用度非常低，并且差异明显，平均值从22.3％-33％。因此，有必要开发吸入给药途径提高生物利用度。
发明人在实现本申请的过程中发现：申请公布号为CN112155255A的专利文献公开了，可蒸发材料可以含有植物药和/或营养品，例如：育亨宾；在某些实施方案中，可蒸发材料可在任何合适的载体溶剂中溶解至少50％(按重量计)，所述溶剂例如二醇(例如丙二醇和植物甘油)、 乙二醇、二丙二醇、三亚甲基二醇、乙醇及其组合。
该公开方案存在的问题是，一方面，育亨宾在载体溶剂中的溶解性较差，至少50％(按重量计)育亨宾不能完全溶解；含有该重量的可蒸发材料是否可以蒸发以及对电子蒸发器装置的影响，从该文献中无法得到验证；即使可以蒸发，其转化率也是非常低；另一方面，含有至少50％(按重量计)育亨宾的可蒸发材料，(即使转化率非常低的情形)对于用户来说剂量非常大，远超目前临床试验采用口服或者注射给药的剂量，安全性无法得到保障。
发明内容
基于发明人在实现本申请的过程中的发现，本申请第一方面旨在提供一种对电子雾化装置的影响较小、转化率较高且安全性能够得到保障的气溶胶形成基质，所述气溶胶形成基质包括育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物；
以气溶胶形成基质的总质量计，育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物的质量百分比为0.1％-10％，优选的为0.1％-8％，进一步优选为0.1％-6％，进一步优选为0.1％-5％，进一步优选为0.5％-5％，进一步优选为1％-5％，进一步优选为2％-5％。
在一些实施方案中，在药学上可接受的盐选自以下至少之一：
盐酸盐、氢溴酸盐、苯甲酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、天冬氨酸盐、谷氨酸盐。
在一些实施方案中，在药学上可接受的盐包括苯甲酸盐。
在一些实施方案中，所述气溶胶形成基质还包括溶剂，所述溶剂选 自以下至少之一：
丙二醇，丁二醇，戊二醇，己二醇，1,2,4-丁三醇，一缩二丙二醇，二甘醇，三甘醇，聚乙二醇200，聚乙二醇400，三醋酸甘油酯，甘油，二丙二醇缩醚，乙醇，水，柠檬酸三乙酯，辛癸酸甘油酯，异丙醇，甜橙油，柠檬油，薄荷油，棕榈油，花生油，玉米油，色拉油，木糖醇，山梨醇，赤藓醇。
在一些实施方案中，所述溶剂包括丙二醇，且所述气溶胶形成基质中丙二醇的质量百分比为20％-60％，优选的为20％-50％，进一步优选为20％-45％，进一步优选为25％-45％，进一步优选为30％-45％，进一步优选为35％-45％。
在一些实施方案中，所述溶剂包括甘油，且所述气溶胶形成基质中甘油的质量百分比为10-60％，优选的为10％-50％，进一步优选为10％-40％，进一步优选为20％-40％，进一步优选为30％-40％。
在一些实施方案中，丙二醇与甘油的质量比大于1，优选的为1.1-4:1，进一步优选为2-4:1。
在一些实施方案中，所述气溶胶形成基质还包括香味剂。
所述气溶胶形成基质中香味剂依据调香需要的常规量添加，质量百分比为1-20％，优选的为5％-20％，进一步优选为10％-20％，进一步优选为15％-20％。所述香味剂选自以下至少之一：
橙花醇、反2-己烯醇、芳樟醇、苯甲醇、1-己醇、叶醇、alpha-松油醇、香茅醇、beta-苯乙醇、氧化芳樟醇、香叶醇、异戊醇、辛醇、己醇、癸醇、肉桂醇、庚醇、丁香酚、麦芽酚、乙基麦芽酚、百里香酚、异丁香酚、2-甲基丁酸、苹果酸、正戊酸、正己酸、食用乙酸、正辛酸、草莓酸、丁酸、柠檬酸、丙酸、3-甲基戊酸、异戊酸、乙酸异戊酯、甲酸戊酯、甲酸香叶酯、甲酸丁酯、甲酸苄酯、甲酸叶醇酯、丙位癸内酯、 丁位壬内酯、丙位辛内酯、丙位庚内酯、丙位十一内酯、丁位十二内酯、苯甲醛、草莓醛、肉桂醛、糠醛、柠檬醛、乙醛、3-甲硫基丙醛、天然3-巯基-2-甲基戊醛、异丁醛、反-2-辛烯醛、反-2-壬烯醛、反-2-癸烯醛、反,反-2,4-庚二烯醛、2,5-二甲基吡嗪、2-乙酰基呋喃、2-乙基-3(5或6)-二甲基吡嗪、2,3,5,6-四甲基吡嗪、2,3,5-三甲基吡嗪、2-乙酰基吡嗪、苯乙酮、beta-紫罗兰酮、突厥烯酮2号(芬美意)、丁二酮、甲位紫罗兰酮、乙偶姻(乙酰基甲基原醇)、乙偶姻(乙酰基甲基原醇)、甲基庚烯酮、香兰素、乙基香兰素、二氢香豆素、覆盆子酮、大茴香醚、甲基柏木醚、甲基-2-甲基-3-呋喃基二硫醚、冬青油、丁香花蕾油、十倍甜橙油、玫瑰木油、香叶油、苦杏仁油、丁香罗勒油、乙基香兰素、二氢香豆素、覆盆子酮、浓馥香兰素、吐鲁浸膏、秘鲁浸膏、橡木提取物、浓咖啡超临界萃取提取物(水溶)、可可提取物、咖啡酊、独活酊、香兰提取物、香草提取物、赖百当浸膏、鸢尾油或浸膏、茉莉浸膏、树苔浸膏(琥珀香)、罗望子提取物、津巴布韦烟提取物、烟草精油、白肋烟提取物、烤烟净油A、烤烟头香提取物、晒烟头香提取物。
在一些实施方案中，所述气溶胶形成基质不含有尼古丁和/或尼古丁盐。
本申请第二方面提供一种气溶胶生成系统，所述气溶胶生成系统包括电子雾化装置以及所述的气溶胶形成基质；所述电子雾化装置被配置为对所述气溶胶形成基质进行加热雾化以生成气溶胶。
本申请提供的含有育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物的气溶胶形成基质，采用电子雾化装置多次加热后没有碳化现象发生，育亨宾的转化率较高，与目前临床试验采用口服或者注射给药的剂量接近，安全性能够得到保障。
附图说明
图1是本申请实施方式提供的HPLC检测结果示意图；
图2是本申请实施方式提供的碳化实验前的电子雾化装置中的雾化器示意图；
图3是本申请实施方式提供的碳化实验后的电子雾化装置中的雾化器示意图。
具体实施方式
本申请将结合以下实施例作进一步描述。
实施方式一：
本申请实施方式一提供一种气溶胶形成基质，所述气溶胶形成基质包括育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物；
以气溶胶形成基质的总质量计，育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物的质量百分比为0.1％-10％，优选的为0.1％-8％，进一步优选为0.1％-6％，进一步优选为0.1％-5％，进一步优选为0.5％-5％，进一步优选为1％-5％，进一步优选为2％-5％。
在一些实施方案中，在药学上可接受的盐选自以下至少之一：
盐酸盐、氢溴酸盐、苯甲酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、天冬氨酸盐、谷氨酸盐。
在一些实施方案中，在药学上可接受的盐包括苯甲酸盐。
在一些实施方案中，所述气溶胶形成基质还包括溶剂，所述溶剂选自以下至少之一：
丙二醇，丁二醇，戊二醇，己二醇，1,2,4-丁三醇，一缩二丙二醇， 二甘醇，三甘醇，聚乙二醇200，聚乙二醇400，三醋酸甘油酯，甘油，二丙二醇缩醚，乙醇，水，柠檬酸三乙酯，辛癸酸甘油酯，异丙醇，甜橙油，柠檬油，薄荷油，棕榈油，花生油，玉米油，色拉油，木糖醇，山梨醇，赤藓醇。
在该实施方案中，丙二醇包括1,2-丙二醇，1,3-丙二醇；丁二醇包括1,2-丁二醇、1,3-丁二醇、1,4-丁二醇、2,3-丁二醇；戊二醇包括1,2-戊二醇、1,4-戊二醇、2,4-戊二醇、1,5-戊二醇；己二醇包括1,2-己二醇、1,6-己二醇、2,5-己二醇。
在一些实施方案中，所述溶剂包括丙二醇，且所述气溶胶形成基质中丙二醇的质量百分比为20％-60％，优选的为20％-50％，进一步优选为20％-45％，进一步优选为25％-45％，进一步优选为30％-45％，进一步优选为35％-45％。
在一些实施方案中，所述溶剂包括甘油，且所述气溶胶形成基质中甘油的质量百分比为10-60％，优选的为10％-50％，进一步优选为10％-40％，进一步优选为20％-40％，进一步优选为30％-40％。
在一些实施方案中，丙二醇与甘油的质量比大于1，优选的为1.1-4:1，进一步优选为2-4:1。
在一些实施方案中，所述气溶胶形成基质还包括香味剂，且所述气溶胶形成基质中香味剂的质量百分比为1-20％，优选的为5％-20％，进一步优选为10％-20％，进一步优选为15％-20％。
在一些实施方案中，所述香味剂选自以下至少之一：
橙花醇、反2-己烯醇、芳樟醇、苯甲醇、1-己醇、叶醇、a l pha-松油醇、香茅醇、beta-苯乙醇、氧化芳樟醇、香叶醇、异戊醇、辛醇、己醇、癸醇、肉桂醇、庚醇、丁香酚、麦芽酚、乙基麦芽酚、百里香酚、异丁香酚、2-甲基丁酸、苹果酸、正戊酸、正己酸、食用乙酸、正辛酸、 草莓酸、丁酸、柠檬酸、丙酸、3-甲基戊酸、异戊酸、乙酸异戊酯、甲酸戊酯、甲酸香叶酯、甲酸丁酯、甲酸苄酯、甲酸叶醇酯、丙位癸内酯、丁位壬内酯、丙位辛内酯、丙位庚内酯、丙位十一内酯、丁位十二内酯、苯甲醛、草莓醛、肉桂醛、糠醛、柠檬醛、乙醛、3-甲硫基丙醛、天然3-巯基-2-甲基戊醛、异丁醛、反-2-辛烯醛、反-2-壬烯醛、反-2-癸烯醛、反,反-2,4-庚二烯醛、2,5-二甲基吡嗪、2-乙酰基呋喃、2-乙基-3(5或6)-二甲基吡嗪、2,3,5,6-四甲基吡嗪、2,3,5-三甲基吡嗪、2-乙酰基吡嗪、苯乙酮、beta-紫罗兰酮、突厥烯酮2号(芬美意)、丁二酮、甲位紫罗兰酮、乙偶姻(乙酰基甲基原醇)、乙偶姻(乙酰基甲基原醇)、甲基庚烯酮、香兰素、乙基香兰素、二氢香豆素、覆盆子酮、大茴香醚、甲基柏木醚、甲基-2-甲基-3-呋喃基二硫醚、冬青油、丁香花蕾油、十倍甜橙油、玫瑰木油、香叶油、苦杏仁油、丁香罗勒油、乙基香兰素、二氢香豆素、覆盆子酮、浓馥香兰素、吐鲁浸膏、秘鲁浸膏、橡木提取物、浓咖啡超临界萃取提取物(水溶)、可可提取物、咖啡酊、独活酊、香兰提取物、香草提取物、赖百当浸膏、鸢尾油或浸膏、茉莉浸膏、树苔浸膏(琥珀香)、罗望子提取物、津巴布韦烟提取物、烟草精油、白肋烟提取物、烤烟净油A、烤烟头香提取物、晒烟头香提取物。
需要说明的是，香味剂并不限于以上所列出的物质，符合FEMA编码、CAS编码的香味剂都可以适用。
在一些实施方案中，所述气溶胶形成基质不含有尼古丁和/或尼古丁盐。
一、HPLC检测：
按照如下表格所示的项目和参数，对具有育亨宾的样品以及无育亨宾的样品分别进行HPLC检测，检测结果可参考图1所示。图中的数据1 为具有育亨宾的样品的色谱示意图，数据2为无育亨宾的样品的色谱示意图。
项目 参数
色谱柱 InertSustain C18,4.6x250mm,3.5um
流动相 乙腈-水＝40：60
检测波长 278nm
流速 1.0ml/min
柱温 40℃
二、碳化实验
对本实施例的气溶胶形成基质，采用具有陶瓷结构雾化器的电子雾化装置进行加热(每间隔27s加热3s)，加热(或者抽吸)次数为400次。其中，本实施例的气溶胶形成基质组成为育亨宾1.5％，丙二醇40％，甘油37％，香味剂20％。
如图2所示，为电子雾化装置加热气溶胶形成基质前的雾化器示意图；如图3所示，为电子雾化装置加热气溶胶形成基质后的雾化器示意图。用肉眼观察，可以看出雾化器没有糊化、积碳。实验人员在实验过程中，抽吸时也没有察觉到异味。
实验过程中，每一次的TPM大约为5-6mg，以育亨宾4％为例，每一次的育亨宾含量大约为0.24mg；通过查找相关资料可以得知，市售的育亨宾片(口服)为每次5.4mg，假设其生物利用度为50％，则每次约为2.7mg。因此，用户通过电子雾化装置抽吸10次的摄入量大约为2.4mg(雾化摄入方式的生物利用度要远远高于口服方式)，与目前临床试验采用口服方式的剂量接近，安全性能够得到保障。
三、转化率实验
实验测试方法：
实施例1：气溶胶形成基质组成为育亨宾10wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例2：气溶胶形成基质组成为育亨宾8wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例3：气溶胶形成基质组成为育亨宾6wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例4：气溶胶形成基质组成为育亨宾4wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例5：气溶胶形成基质组成为育亨宾3wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例6：气溶胶形成基质组成为育亨宾1.5wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例7：气溶胶形成基质组成为育亨宾0.5wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例8：气溶胶形成基质组成为育亨宾0.1wt％，丙二醇40wt％，甘油37wt％，余量为香味剂。
实施例9：气溶胶形成基质选取育亨宾3wt％，溶剂选择质量比约为7：3的丙二醇和甘油的混合物。
实施例10：气溶胶形成基质选取育亨宾3wt％，溶剂选择质量比约为3：7的丙二醇和甘油的混合物。
实施例11：气溶胶形成基质选用育亨宾在药学上可接受的苯甲酸盐3wt％，溶剂选择质量比约为1：1的甘油和丙二醇的混合物。其中，育 亨宾在药学上可接受的苯甲酸盐，可通过育亨宾生物碱与苯甲酸混合制备得到。
实施例12：气溶胶形成基质选用育亨宾在药学上可接受的盐酸盐3wt％，溶剂选择质量比约为1：1的甘油和丙二醇的混合物。其中，育亨宾在药学上可接受的盐酸盐可从Rubiaceae Corunant Yohimbine树的树皮中分离纯化制备得到，也可以通过现有的化学合成方法得到，还可以从市场上购买得到。
用抽烟机按照国际标准分别对实施例1-实施例12进行抽吸，用剑桥滤片收集气溶胶形成基质雾化出来的气溶胶，然后使用有机溶剂进行萃取，过滤，进HPLC分析，计算。
其中，转化率的计算方式为：称量剑桥滤片的前后重量差异m_0(即收集气溶胶的重量)，取相同质量的气溶胶形成基质m 1，用相同体积V的有机溶剂萃取，然后取萃取液进HPLC，根据气溶胶形成基质在HPLC中的色谱峰面积A 1和浓度C 1之比，乘以气溶胶的色谱峰面积A 0，再除以气溶胶的浓度C 0，即为转化率。具体的计算公式如下：
Figure PCTCN2022086384-appb-000001
其中C 0＝m 0/v；C 1＝m 1/v。
其中，育亨宾在药学上可接受的盐的计算与上类似。
其中，采用不同的电子雾化装置进行抽吸，电子雾化装置1采用棉芯结构的雾化器，电子雾化装置2采用陶瓷结构的雾化器，电子雾化装置3采用棉包陶瓷结构的雾化器。上述结构的雾化器均可从现有技术中得知，在此不作赘述。
其中，涉及到的国际标准可参考：
CORESTA RECOMMENDED METHOD № 81，Afnor standardization XP D90-300-3，International Standard ISO 20768:2018 and PD CEN/TR 17236:2018。
Figure PCTCN2022086384-appb-000002
实验测试结果：采用不同的电子雾化装置进行抽吸，并分别计算其对应的转化率(k1-k3)；依据不同电子雾化装置对应的转化率，计算其转化率的平均值。结果如下表格所示：
Figure PCTCN2022086384-appb-000003
Figure PCTCN2022086384-appb-000004
从上述实验测试结果可以看出：
1)实施例1-实施例8，随着气溶胶形成基质中育亨宾的含量的提升，转化率(平均值)呈下降趋势；当气溶胶形成基质中育亨宾的含量达到10％时，转化率(平均值)约为34％。
2)实施例5、实施例9-实施例10，溶剂中丙二醇的含量对转化率的影响较大；当丙二醇与甘油的质量比为7:3时，转化率(平均值)可达到67％，高于实施例5或者实施例10的转化率。
3)实施例5、实施例11-实施例12，育亨宾在药学上可接受的盐，转化率(平均值)普遍较高，实施例11或者实施例12的转化率均要高于实施例5的转化率；其中，育亨宾在药学上可接受的苯甲酸盐，转化率(平均值)可达到66％。
实施方式二：
本申请实施方式二提供一种气溶胶生成系统，包括电子雾化装置以及实施方式一所述的气溶胶形成基质；
所述电子雾化装置被配置为对所述气溶胶形成基质进行加热雾化以生成气溶胶。
本书面描述使用实例来公开本申请，包括最佳模式，且还使本领域技术人员能够制造和使用本申请。本申请的可授予专利的范围由权利要求书限定，且可以包括本领域技术人员想到的其它实例。如果这种其它 实例具有不异于权利要求书的字面语言的结构元素，或者如果这种其它实例包括与权利要求书的字面语言无实质性差异的等效结构元素，则这种其它实例旨在处于权利要求书的范围之内。在不会造成不一致的程度下，通过参考将本文中参考的所有引用之处并入本文中。

Claims (10)

  1. 一种气溶胶形成基质，其特征在于，所述气溶胶形成基质包括育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物；
    以气溶胶形成基质的总质量计，育亨宾或者育亨宾在药学上可接受的盐或者育亨宾水合物的质量百分比为0.1％-10％，优选的为0.1％-8％，进一步优选为0.1％-6％，进一步优选为0.1％-5％，进一步优选为0.5％-5％，进一步优选为1％-5％，进一步优选为2％-5％。
  2. 根据权利要求1所述的气溶胶形成基质，其特征在于，在药学上可接受的盐选自以下至少之一：
    盐酸盐、氢溴酸盐、苯甲酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、天冬氨酸盐、谷氨酸盐。
  3. 根据权利要求2所述的气溶胶形成基质，其特征在于，在药学上可接受的盐包括苯甲酸盐。
  4. 根据权利要求1-3任一所述的气溶胶形成基质，其特征在于，所述气溶胶形成基质还包括溶剂，所述溶剂选自以下至少之一：
    丙二醇，丁二醇，戊二醇，己二醇，1,2,4-丁三醇，一缩二丙二醇，二甘醇，三甘醇，聚乙二醇200，聚乙二醇400，三醋酸甘油酯，甘油，二丙二醇缩醚，乙醇，水，柠檬酸三乙酯，辛癸酸甘油酯，异丙醇，甜橙油，柠檬油，薄荷油，棕榈油，花生油，玉米油，色拉油，木糖醇，山梨醇，赤藓醇。
  5. 根据权利要求4所述的气溶胶形成基质，其特征在于，所述溶剂包括丙二醇，且所述气溶胶形成基质中丙二醇的质量百分比为20％-60％，优选的为20％-50％，进一步优选为20％-45％，进一步优选为25％-45％，进一步优选为30％-45％，进一步优选为35％-45％。
  6. 根据权利要求5所述的气溶胶形成基质，其特征在于，所述溶剂包括甘油，且所述气溶胶形成基质中甘油的质量百分比为10-60％，优 选的为10％-50％，进一步优选为10％-40％，进一步优选为20％-40％，进一步优选为30％-40％。
  7. 根据权利要求6所述的气溶胶形成基质，其特征在于，丙二醇与甘油的质量比大于1，优选的为1.1-4:1，进一步优选为2-4:1。
  8. 根据权利要求1-7任一所述的气溶胶形成基质，其特征在于，所述气溶胶形成基质还包括香味剂。
  9. 根据权利要求1-8任一所述的气溶胶形成基质，其特征在于，所述气溶胶形成基质不含有尼古丁和/或尼古丁盐。
  10. 一种气溶胶生成系统，其特征在于，所述气溶胶生成系统包括电子雾化装置以及权利要求1-9任一所述的气溶胶形成基质；
    所述电子雾化装置被配置为对所述气溶胶形成基质进行雾化以生成气溶胶。
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