WO2023087345A1 - 一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法 - Google Patents

一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法 Download PDF

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WO2023087345A1
WO2023087345A1 PCT/CN2021/132791 CN2021132791W WO2023087345A1 WO 2023087345 A1 WO2023087345 A1 WO 2023087345A1 CN 2021132791 W CN2021132791 W CN 2021132791W WO 2023087345 A1 WO2023087345 A1 WO 2023087345A1
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treprostinil
salt
aerosol
treatment
drug
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PCT/CN2021/132791
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English (en)
French (fr)
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李小羿
戴向荣
殷雷
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兆科药业（广州）有限公司
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Publication of WO2023087345A1 publication Critical patent/WO2023087345A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to an atomization method of treprostinil aerosol inhalation used for treating pulmonary hypertension.
  • Pulmonary hypertension is a type of malignant pulmonary vascular disease characterized by vascular remodeling of small pulmonary arteries, often due to progressive increase in pulmonary vascular resistance, which eventually leads to right heart failure and death in patients.
  • Treprostinil is a targeted therapeutic drug for pulmonary arterial hypertension. It belongs to prostacyclin analogs. Its pharmacological effects are similar to those of endogenous prostacyclin. It has direct vasodilation and platelet aggregation inhibitory effects on the pulmonary and systemic arterial vascular beds. .
  • Treprostinil currently developed and marketed preparations include subcutaneous or intravenous injections (Remodulin, 20ml: 20mg), slow-release tablets (Orenitram, 0.125mg/0.25mg), and inhalants (Tyvaso, 1.74mg/2.9ml), these three preparations, injections have long-term pain or reaction at the infusion site, resulting in erythema, hardening or rash, etc.
  • Inhalation administration refers to the administration method in which one or more drugs enter the lungs deep in the respiratory tract through a special drug delivery device to exert local or systemic effects.
  • Inhalation preparations mainly include inhalation aerosols, inhalation powder aerosols and liquid preparations for nebulizers.
  • Liquid Technologies invented a treprostinil dry powder inhaler, which belongs to inhalation powder spray, and made 25 micrograms of treprostinil into a dry particle dose Contained in capsules, it is inhaled by the patient through a dry powder inhaler.
  • the aerosol inhaler Tyvaso needs to use a specific product that is large in size and inconvenient to carry.
  • the atomization device because the atomization device needs to be used four times a day when it is awake after adding the liquid medicine, and it needs to be used once every four hours. When using it, an external power supply is required, and the device must not be placed flat or dumped during the day's use or standby. The atomized water needs to be replaced every day, and the cleaning and sterilization operations are carried out regularly. Therefore, it is very inconvenient for patients to use the aerosol inhalation Tyvaso daily, which affects their quality of life and work.
  • the particle size of the drug particles in the dry powder inhaler and inhalation powder aerosol is small (1-5 ⁇ m), and because of the strong interaction force (van der Waals force, electrostatic force and capillary force) between the particles, the aggregation of the particles is strong, During the storage process, it is easy to agglomerate, which will cause the particle size to change and affect the efficacy of the drug. Therefore, it is usually necessary to use carrier particles to prevent the agglomeration of the drug powder.
  • the drug powder is mixed so that the drug powder is adsorbed on the surface of the carrier particles. When in use, the drug powder is separated from the carrier particles during the inhalation process of the patient, and enters the lungs of the human body and deposits them.
  • Sodium disulfide, 92.44% trehalose dihydrate, 2% polysorbate 80, 4% L leucine, 0.27% sodium citrate dihydrate and 0.23% sodium chloride using macromolecular polysaccharides with large particle size
  • the compound trehalose is mixed with treprostinil sodium micropowder as a carrier to make treprostinil inhalation, but in the process of inhalation and use of patients, large particle excipients are very easy to attach to the throat, resulting in foreign body sensation and affecting the patient's Inhalation experience, for patients with sensitive pharynx, it is more likely to cause stress cough, cough up the drug inhaled into the lungs, and then reduce the efficacy of the drug.
  • the patent application number is 202110996422.9.
  • the device includes interconnected drug cartridges and transmitters, and self-medication can be performed at any time through the drug delivery control device, which can quickly relieve pain and is easy to operate and flexible.
  • the medicine box of this invention controls the heating of different foils by sequentially welding different foils to the conductive posts at both ends of the foil connector, and electrically connects the conductive posts to the conductive holes, effectively controlling the heating of different foils. medication.
  • the present invention provides a method for producing treprostinil aerosol inhalation for treating pulmonary hypertension, which is convenient for daily carrying and use by patients, and at the same time increases medication compliance of patients.
  • the present invention provides an atomization method for treprostinil aerosol inhalation for the treatment of pulmonary hypertension.
  • the present invention utilizes the principle of forming an aerosol under the high temperature state of the medicine, and coats treprostinil on the medicine
  • the gaseous Treprostinil is formed by heating to quickly condense to form an aerosol, which is inhaled into the lungs through the air path and directly acts on the receptors in the pulmonary artery blood vessels, which is similar to the aerosol inhalation agent Tyvaso described in US Patent 10076505
  • Tyvaso described in US Patent 10076505
  • the present invention mainly solves the above-mentioned technical problems through the following technical solutions.
  • the inventors have found through experiments that solid treprostinil and its salts will rapidly gasify to form aerosols with stable quality under high temperature conditions within 500°C, and utilize the heteroatoms contained in treprostinil molecules, which can be combined with stainless steel surfaces
  • the phenomenon of strong synergy between the polar end groups and adhesion on the stainless steel foil is designed to design the present invention.
  • the present invention provides a kind of nebulization method that is used for the treatment of the treprostinil aerosol inhalation of pulmonary hypertension, comprises the following steps:
  • step (1) treprostinil or its salt is prepared as a solution, sprayed evenly on the heating sheet of the drug inhaler, and dried;
  • step (2) the patient inhales air and activates the drug inhaler for heating
  • step (3) the temperature rises rapidly to 100-500° C., and the treprostinil vaporizes rapidly, forms an aerosol in contact with the passing air, and enters the lungs of the patient along with the air, where it is deposited on the alveoli to exert its drug effect.
  • the treprostinil salt is selected from treprostinil sodium salt, calcium salt, diethanolamine salt, triethanolamine salt, L-arginine salt, lysine salt, meglucosamine One of amine salts, ammonium salts, and choline salts.
  • the dose of treprostinil or its salt is calculated as treprostinil, and the spraying amount is 1.2-1000 ⁇ g/cm 2 .
  • treprostinil or its salt is dissolved in acetone, methanol, absolute ethanol, ethyl acetate, ethyl formate, isopropanol, n-butanol, triethylamine and water Spray in one or more mixtures.
  • step (2) when the patient's inhaled gas flow rate is 15-60L/min, the air flow rate through the heating sheet is adjusted to be 0.2L/min-20L/min.
  • the heating is started by giving a current pulse of 0.1 second to 2 seconds and a voltage intensity of 0.1 volts to 10 volts to the heating sheet of the drug inhaler.
  • a delivery dose is 2 ⁇ g to 90 ⁇ g calculated as treprostinil.
  • the delivered treprostinil aerodynamic diameter MMAD is between 0.5-5 ⁇ m, and the effective deposition rate FPF of fine particles is between 60%-99%.
  • the positive progress effect of the present invention is:
  • the treprostinil aerosol inhalation of the present invention can directly act on the diseased part of the respiratory system without absorption after administration, binds to the receptors in the pulmonary arteries and blood vessels to play a role, and has a rapid onset of action, and because it directly acts on the target point, it can
  • the drug dosage is small, the metabolism is rapid, and the drug distribution to other organs of the human body is low. Compared with injections and sustained-release tablets, it has obvious advantages in adverse reactions.
  • a kind of nebulization method for the treprostinil aerosol inhalation that is used for the treatment of pulmonary arterial hypertension comprises the following steps:
  • step (1) treprostinil or its salt is prepared as a solution, sprayed evenly on the heating sheet of the drug inhaler, and dried;
  • step (2) the patient inhales air and activates the drug inhaler for heating
  • step (3) the temperature rises rapidly to 100-500° C., and the treprostinil vaporizes rapidly, forms an aerosol in contact with the passing air, and enters the lungs of the patient along with the air, where it is deposited on the alveoli to exert its drug effect.
  • Treprostinil aerosol inhalation of the present invention is a kind of selective pulmonary vasodilator, because the precapillary resistance vessel is surrounded by alveoli, the anatomical characteristics of alveolar-capillary adjoining decision medicine can produce effect by inhalation mode, after inhalation
  • the local alveolar concentration is high, and it directly acts on the sphincter and smooth muscle cells of the precapillary resistance vessels through diffusion, so it has a targeted therapeutic effect that cannot be compared with other methods.
  • the present invention utilizes the principle of aerosol formation under the high-temperature state of the medicine, coats treprostinil on the metal foil, forms gaseous treprostinil by heating, rapidly condenses to form an aerosol, inhales the lungs through the air path, and directly acts on the pulmonary artery blood vessels receptors in .
  • the generating device of treprostinil aerosol inhalation is based on the drug inhalation device disclosed in the patent 202110996422.9, preferably treprostinil or its salt is prepared as a solution and evenly sprayed on the metal foil of the drug inhaler Slice arrays and dry.
  • Described proprostinil or its salt solution is that treprostinil or its salt is dissolved in acetone, methanol, dehydrated alcohol, ethyl acetate, ethyl formate, isopropanol, n-butanol, triethylamine and water Spraying in one or more mixed liquids, preferably one or more mixed liquids of acetone, methanol, absolute ethanol and water.
  • the treprostinil salt is selected from treprostinil sodium salt, calcium salt, diethanolamine salt, triethanolamine salt, L-arginine salt, lysine salt, meglumine salt, ammonium salt, bile A kind of in the alkali salt;
  • the present invention preferably sprays Treprostinil or Treprostinil diethanolamine salt on the metal foil array of drug inhaler;
  • the amount of spraying is 1.2-1000 ⁇ g/cm 2 in terms of prostanier, preferably 20-380 ⁇ g/cm 2 , more preferably 100-200 ⁇ g/cm 2 .
  • the present invention has no special limitation on the source of treprostinil or its salt, and commercially available products can be used.
  • the heating of the drug inhaler is generated by a current pulse, the duration of the current pulse is 0.2 seconds to 0.6 seconds, and the voltage intensity is 0.1 volts to 10 volts, so that the metal foil is rapidly heated to 100-500 ° C, preferably heating the metal foil
  • the sheet causes the temperature to rise rapidly to 250-350°C, more preferably 300°C.
  • the inventors have found through experiments that solid treprostinil and its salts can be rapidly vaporized to form an aerosol with stable quality under high temperature conditions within 500°C.
  • the airflow split control is used to adjust the airflow flow rate passing through the metal foil to 0.2L/min-20L/min, so that the treprostinil aerosol enters with the airflow.
  • the airflow split control is used to adjust the airflow flow rate passing through the metal foil to 0.2L/min-20L/min, so that the treprostinil aerosol enters with the airflow.
  • the preferred adjustment of the air flow rate through the metal foil is 1L/min-8L/min, more preferably 5L/min; a delivered dose is 2 ⁇ g to 90 ⁇ g in terms of Treprostinil, which can achieve the drug effect, preferably 5 ⁇ g to 50 ⁇ g , more preferably 10 ⁇ g to 30 ⁇ g, most preferably 20 ⁇ g.
  • the delivered treprostinil aerodynamic diameter MMAD is between 0.5-5 ⁇ m, and the particle size distribution of the drug powder is a key factor affecting the inhalation efficiency of the inhalant. Most of the particles larger than this range are deposited in the upper respiratory tract. Particles in this range are easily exhaled or adhere to the oral cavity.
  • the effective deposition rate FPF of fine particles is between 60% and 99%.
  • the effective deposition rate FPF of fine particles is calculated by measuring the ratio of the content of fine particles of 0-5.0 ⁇ m to the content of main ingredients per dose.
  • the particle size is 0.5-5 ⁇ m Particles in between can be deposited in the lungs, therefore, the larger the index, the greater the proportion of drug deposition in the lungs.
  • the preferred delivery treprostinil aerodynamic diameter MMAD is between 1-3 ⁇ m, and the effective deposition rate FPF of fine particles is between 90%-99%.
  • the heating controller in the inhalation system When in use, the patient inhales air, and the heating controller in the inhalation system will give the foil a pulse current of 3 volts for 0.3 seconds to rapidly heat the foil to 300°C and vaporize treprostinil to form an aerosol, which can be inhaled
  • the airflow diversion controller in the device controls the airflow above the foil to be 2-7L/min, and about 6 ⁇ g of treprostinil aerosol is brought into the human body.
  • treprostinil diethanolamine salt Accurately weigh 300 mg of treprostinil diethanolamine salt, put it in a volumetric flask, add 10 ml of absolute ethanol, and shake to dissolve.
  • the drug solution was coated on the foil array of the drug inhaler with a coating amount of 90 ⁇ g/cm 2 and dried.
  • the heating controller in the inhalation system will give the foil a pulse current of 4.5 volts for 0.5 seconds to rapidly heat the foil to 250°C and vaporize treprostinil diethanolamine salt to form gas.
  • the airflow splitter controller in the inhaler controls the airflow above the foil to be 2-7L/min, and about 15 ⁇ g of treprostinil diethanolamine salt aerosol is brought into the human body.
  • the aerosol system uses a suitable rubber interface to connect with the DUSA tube equipped with a filter membrane to ensure that the connection is sealed. Spray the sample into the DUSA tube once, add methanol and sodium hydroxide solution with a pipette gun, vortex for 30s, and sonicate for 10min. The supernatant was taken as the test solution, and the operation was repeated 10 times. It was measured by high performance liquid chromatography, and the average delivered dose and standard deviation were calculated. The results are shown in Table 1.
  • the treprostinil diethanolamine aerosol that the treprostinil aerosol that embodiment 1 is made and embodiment 2 is made is carried out particle size characterization
  • use NGI (The next generation impactor) device collects aerosols and collects 10 emitted aerosols per test to evaluate the aerodynamic droplet size distribution.
  • the results of the drug concentration in plasma showed that the drug concentration of the aerosol inhalation in the systemic plasma was significantly lower than that of the tablet gavage group, and the peak time of the drug was faster than that of the tablet gavage group, indicating that the aerosol inhalation After the drug enters the body, it has a low impact on other organs in the whole body.
  • the drug concentration of the aerosol inhalation in the lung tissue is slightly higher than that of the tablet, but Cmax can reach more than 2 times of the Cmax of the gavage group, indicating that treprostinil After inhalation, aerosol inhalation can quickly reach a higher concentration in the lung tissue and take effect.

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Abstract

一种用于雾化治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的制备方法。利用药物高温状态下形成气溶胶原理，将曲前列尼尔涂布于药物吸入器的加热片上，通过加热形成气态曲前列尼尔迅速凝结形成气溶胶，通过气路吸入肺部，直接作用于肺动脉血管中的受体，起效迅速，直接作用至靶点，用药量少、快速代谢，分布至人体其他器官药量低。

Description

一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法 技术领域
本发明属于药物制剂领域，特别涉及一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法。
背景技术
肺动脉高压是一类小肺动脉血管重构为特征的恶性肺血管疾病，往往由于肺血管阻力进行性升高并最终导致患者右心衰竭至死亡。曲前列尼尔为肺动脉高压的靶向性治疗药物，属于前列环素类似物，其药理作用与内源性前列环素相似，对肺和全身动脉血管床起直接血管扩张作用和血小板聚集抑制作用。
目前曲前列尼尔开发上市的制剂有皮下或静脉注射剂(瑞莫杜林，20ml:20mg)，缓释片剂(Orenitram，0.125mg/0.25mg)，通过超声波脉冲雾化的吸入剂(Tyvaso，1.74mg/2.9ml)，此三种制剂，注射剂在输注部位有长期疼痛或反应，产生红斑、硬化或皮疹等，缓释片使用过程中，会出现因血管扩张导致的血压降低、头疼、咳嗽、晕厥以及加重颊肌痉挛(口腔开合困难)等前列环素药理学特性相关的不良反应，影响患者的日常生活，并且无论静脉还是口服曲前列尼尔治疗肺动脉高压，还均存在药物分布不均匀导致通气血流比值失调，加重低氧血症的问题。
吸入给药是指一种或一种以上的药物经特殊的给药装置，进入呼吸道深处的肺部，发挥局部或全身作用的给药方式。吸入制剂主要包括吸入气雾剂、吸入粉雾剂和供雾化器用的液体制剂3大类。
根据美国专利US Patent 10076505“Inhalation formulations of treprostinil”，联合治疗公司(United Therapeutics Corporation)开发了一种曲前列尼尔吸入系统TYVASO，其属于供雾化器用的液体制剂，通过雾化器将曲前列尼尔液体药物制剂转化为雾状形态，并吸入人体肺部，达到药物治疗作用。根据美国专利US Patent 10898494“Dry powder treprostinil for the treatment ofpulmonary hypertension”，Liquid Technologies公司发明了一种曲前列尼尔干粉吸入剂，属于吸入粉雾剂，将25微克曲前列环素制成干颗粒剂量包含 在胶囊中，通过干粉吸入器吸入患者体内。
由于肺动脉高压病属于慢性病，高发期一般在20～40岁，接受治疗的中轻度患者仍可正常外出活动与工作，气雾吸入剂Tyvaso根据产品要求，需要使用体积较大、携带不便的特定雾化装置，由于雾化设备加入药液后一天清醒时需使用四次，每四小时使用一次，使用时需要外接电源，并在一天的使用或备用过程中设备不得平放、倾倒，同时每日需更换用雾化水，定期进行清洁灭菌操作，因此患者日常使用气雾吸入剂Tyvaso十分不便，影响其生活工作质量。
干粉吸入剂、吸入粉雾剂中药物粒子的粒径较小(1～5μm)，因粒子间存在较强相互作用力(范德华力、静电力和毛细管力)使粒子之间的聚集性强，储存过程中极易结团而导致粒径改变并影响药效，因此通常需要使用载体颗粒以阻碍药粉的结团现象，一般加入粒径为70～100μm的载体颗粒，与粒径0.5～7μm的药物微粉混合，使药物微粉吸附于载体颗粒表面，使用时，患者吸入过程中药物微粉与载体颗粒分开，进入人体肺部并沉积，如专利US Patent 10076505中描述的处方为“1.06％曲前列尼尔钠、92.44％海藻糖二水合物、2％聚山梨醇酯80、4％L亮氨酸、0.27％二水柠檬酸钠和0.23％氯化钠”，使用大粒径的大分子多糖类化合物海藻糖为作为载体与曲前列尼尔钠微粉混合，制成曲前列尼尔吸入剂，但在患者吸入使用过程中，大颗粒辅料极易附着于咽喉处，产生异物感，影响患者的吸入感受，对于咽部敏感患者，更容易引起应激性咳嗽，把吸入肺部的药物咳出，进而降低药效。
本专利申请人前期发明了一种药物吸入装置，专利申请号为202110996422.9，该装置包括相互连接的药匣和发射器，通过药物发送管控装置随时进行自行给药，快速缓解疼痛，操作简单，灵活方便，安全性强；该发明的药匣，通过将不同箔片依次焊接于箔片连接件两端的导电柱上，并将导电柱与导电孔电连接，控制对不同的箔片加热，有效控制给药。基于此装置，本发明提供了一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的产生方法，患者方便日常携带及使用，同时增加了患者用药依从性。
发明内容
有鉴于此，本发明提供了一种用于治疗肺动脉高压的曲前列尼尔气溶胶 吸入剂的雾化方法，本发明利用药物高温状态下形成气溶胶原理，将曲前列尼尔涂布于药物吸入器的加热片上，通过加热形成气态曲前列尼尔迅速凝结形成气溶胶，通过气路吸入肺部，直接作用于肺动脉血管中的受体，与US Patent 10076505所描述的气雾吸入剂Tyvaso相比，具有相同药效的同时，克服了其使用过程中依靠大型雾化设备的缺点，使患者方便日常携带及使用，与专利US Patent 10898494描述的干粉吸入剂相比，处方中仅有原料药成分，吸入过程中不会产生因大颗粒辅料黏附于咽喉处而产生的刺激性，增加了患者的用药依从性。
本发明主要是通过以下技术方案解决上述技术问题。
发明人通过实验发现固态曲前列尼尔及其盐在500℃以内的高温条件下，会迅速气化形成质量稳定的气溶胶，并利用曲前列尼尔分子中含有杂原子，可与不锈钢表面上极性端基之间产生强协同作用，粘附在不锈钢箔片上的现象，设计本发明。
本发明提供了一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，包括以下步骤：
步骤(1)，将曲前列尼尔或其盐配制为溶液后均匀地喷涂于药物吸入器的加热片上，干燥；
步骤(2)，患者吸入空气，启动药物吸入器进行加热；
步骤(3)，温度迅速升至100～500℃，曲前列尼尔迅速蒸发汽化，与通过气流接触形成气溶胶，并随气流进入患者肺部，沉积在肺泡上发挥药效。
优选的，步骤(1)中，所述曲前列尼尔盐选自曲前列尼尔钠盐、钙盐、二乙醇胺盐、三乙醇胺盐、L-精氨酸盐、赖氨酸盐、葡甲胺盐、铵盐、胆碱盐中的一种。
优选的，步骤(1)中，曲前列尼尔或其盐的剂量以曲前列尼尔计，喷涂量为1.2～1000μg/cm 2。
优选的，步骤(1)中，将曲前列尼尔或其盐溶于丙酮、甲醇、无水乙醇、乙酸乙酯、甲酸乙酯、异丙醇、正丁醇、三乙胺和水中的一种或多种混合液中进行喷涂。
优选的，步骤(2)中，患者吸入气流量为15-60L/min时，调节通过加 热片的气流流速为0.2L/min-20L/min。
优选的，步骤(2)中，所述加热是通过给予药物吸入器的加热片0.1秒至2秒的电流脉冲，0.1伏至10伏的电压强度启动的。
优选的，步骤(3)中，加热蒸发后，一次递送剂量以曲前列尼尔计为2μg至90μg。
优选的，步骤(3)中，递送的曲前列尼尔空气流动力学直径MMAD在0.5-5μm之间，细微粒子有效沉积率FPF在60％-99％之间。
与现有技术相比，本发明的积极进步效果在于：
本发明的曲前列尼尔气溶胶吸入剂给药后不经过吸收可直接作用于呼吸系统病变部位，与肺动脉血管中的受体结合发挥作用，起效迅速，并且因直接作用至靶点，所以用药量少、快速代谢，分布至人体其他器官药量低，相比注射剂、缓释片剂不良反应优势明显。
与气雾吸入剂相比，具有相同药效的同时，克服了其使用过程中依靠大型雾化设备的缺点，使患者方便日常携带及使用，与干粉吸入剂相比，处方中仅有原料药成分，吸入过程中不会产生因大颗粒辅料黏附于咽喉处而产生的刺激性，增加了患者的用药依从性。
具体实施方式
一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，包括以下步骤：
步骤(1)，将曲前列尼尔或其盐配制为溶液后均匀地喷涂于药物吸入器的加热片上，干燥；
步骤(2)，患者吸入空气，启动药物吸入器进行加热；
步骤(3)，温度迅速升至100～500℃，曲前列尼尔迅速蒸发汽化，与通过气流接触形成气溶胶，并随气流进入患者肺部，沉积在肺泡上发挥药效。
本发明的曲前列尼尔气溶胶吸入剂是一种选择性肺血管扩张药，由于毛细血管前阻力血管被肺泡包围，肺泡-毛细血管毗邻的解剖特点决定药物可通过吸入方式产生作用，吸入后肺泡局部浓度较高，通过弥散直接作用于毛细血管前阻力血管的括约肌和平滑肌细胞，因而具有其他途径无法比拟的靶向治疗作用。本发明利用药物高温状态下形成气溶胶原理，将曲前列尼尔涂 布于金属箔片上，通过加热形成气态曲前列尼尔迅速凝结形成气溶胶，通过气路吸入肺部，直接作用于肺动脉血管中的受体。
本发明中，曲前列尼尔气溶胶吸入剂的发生装置以专利202110996422.9中公开的药物吸入装置为基础，优选将曲前列尼尔或其盐配制为溶液后均匀地喷涂于药物吸入器的金属箔片阵列上，干燥。所述前列尼尔或其盐溶液为将曲前列尼尔或其盐溶于丙酮、甲醇、无水乙醇、乙酸乙酯、甲酸乙酯、异丙醇、正丁醇、三乙胺和水中的一种或多种混合液中进行喷涂，优选丙酮、甲醇、无水乙醇和水中的一种或多种混合液。其中，所述曲前列尼尔盐选自曲前列尼尔钠盐、钙盐、二乙醇胺盐、三乙醇胺盐、L-精氨酸盐、赖氨酸盐、葡甲胺盐、铵盐、胆碱盐中的一种；本发明优选将曲前列尼尔或曲前列尼尔二乙醇胺盐喷涂于药物吸入器的金属箔片阵列上；箔片上涂布曲前列尼尔或其盐的剂量以曲前列尼尔计，喷涂量为1.2～1000μg/cm 2，优选的喷涂量为20～380μg/cm 2，更优选为100～200μg/cm 2。本发明对曲前列尼尔或其盐的来源没有特殊限定，采用市售产品即可。
本发明中，药物吸入器加热是通过电流脉冲产生的，电流脉冲持续时间0.2秒至0.6秒，电压强度为0.1伏至10伏，使金属箔片迅速升温至100～500℃，优选加热金属箔片使温度迅速升至250～350℃，更优选为300℃。发明人通过实验发现固态曲前列尼尔及其盐在500℃以内的高温条件下，会迅速气化形成质量稳定的气溶胶。
本发明中，当患者吸入气流量为15-60L/min时，使用气流分流控制，调节通过金属箔片的气流流速为0.2L/min-20L/min，使曲前列尼尔气溶胶随气流进入体内，经试验发现，通过加热片的气流速度在此范围内，可获得稳定的气溶胶粒径分布。优选的调节通过金属箔片的气流流速为1L/min-8L/min，更优选为5L/min；一次递送剂量以曲前列尼尔计为2μg至90μg，可达到药效，优选为5μg至50μg，更优选为10μg至30μg，最优选为20μg。
本发明中，递送的曲前列尼尔空气流动力学直径MMAD在0.5-5μm之间，药物粉末的粒径分布是影响吸入剂吸入效率的关键因素，大于此范围的粒子大多沉积在上呼吸道，小于此范围的粒子则很容易被呼出或粘附在口腔。细微粒子有效沉积率FPF在60％-99％之间，细微粒子有效沉积率FPF 是通测定0～5.0μm细颗粒的含量占每剂量主药含量的比值计算而得，粒径在0.5-5μm之间的颗粒可沉积在肺部，因此，此指标越大，反映药物沉积在肺部的占比越多。优选的递送曲前列尼尔空气流动力学直径MMAD在1-3μm之间，细微粒子有效沉积率FPF在90％-99％之间。
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例对本发明进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。
实施例1
精密称取曲前列尼尔120mg置容量瓶中，加入甲醇10ml，振摇使溶解。使用高精度超声雾化涂覆机，将药液涂覆于药物吸入器的箔片阵列上，涂覆量为30μg/cm 2，干燥。使用时，患者吸入空气，吸入系统中的加热控制器将给箔片以0.3秒3伏的脉冲电流，以将箔片迅速加热至300℃并将曲前列尼尔进行气化形成气溶胶，吸入器中的气流分流控制器控制通过箔片上方气流为2-7L/min，将曲前列尼尔气溶胶约6μg带入人体。
实施例2
精密称取曲前列尼尔二乙醇胺盐300mg置容量瓶中，加入无水乙醇10ml，振摇使溶解。使用高精度超声雾化涂覆机，将药液涂覆于药物吸入器的箔片阵列上，涂覆量为90μg/cm 2，干燥。使用时，患者吸入空气，吸入系统中的加热控制器将给箔片以0.5秒4.5伏的脉冲电流，以将箔片迅速加热至250℃并将曲前列尼尔二乙醇胺盐进行气化形成气溶胶，吸入器中的气流分流控制器控制通过箔片上方气流为2-7L/min，将曲前列尼尔二乙醇胺盐气溶胶约15μg带入人体。
实施例3递送剂量测定
根据中国药典递送剂量均一性要求，采用DUSA管(dosage unit sampling apparatus，单位剂量取样装置)法，对实施例1制成的曲前列尼尔气溶胶与实施例2制成的曲前列尼尔二乙醇胺气溶胶的递送剂量进行测定。
气溶胶系统吸气口连接好DUSA管，开启真空泵，调节流量计节流阀使流量达到28.3L/min(±5％)。气溶胶系统采用合适的橡胶接口与装有滤膜的 DUSA管相连，以保证连接处密封，向DUSA管内喷射样品一次，用移液枪加入甲醇，氢氧化钠溶液，涡旋30s，超声10min，取上清液作为供试品溶液，重复操作10次，采用高效液相色谱法进行测定，计算平均递送剂量及标准偏差，结果见表1。
表1曲前列尼尔气溶胶系统递送剂量测定
Figure PCTCN2021132791-appb-000001
实施例4气溶胶微细粒子空气动力学特性测定。
根据中国药典四部《0951吸入制剂微细粒子空气动力学特性测定法》，对实施例1制成的曲前列尼尔气溶胶与实施例2制成的曲前列尼尔二乙醇胺气溶胶进行粒度表征，使用吸入系统中的加热控制器进行气溶胶发射，以吸入气流为30L/min±1.5L/min，空气温度为25℃±5℃，相对湿度为50.0％±5％的条件下，使用NGI(next generation impactor)装置对气溶胶进行收集，每次测试收集10次发射的气溶胶，评估空气动力学液滴尺寸分布。
下表总结了上述气溶胶表征实验的结果(n＝5)：
表2曲前列尼尔气溶胶系统微细粒子空气动力学表征
Figure PCTCN2021132791-appb-000002
实施例5
曲前列尼尔气溶胶吸入给药与经口给药对比，在大鼠中的血药浓度以及在大鼠肺组织中的分布情况
取12只SD大鼠(200g±20g)，曲前列尼尔片剂灌胃组6只，给药剂量600μg/只；曲前列尼尔气溶胶吸入剂(实施例1)组：6只，将药物直接输送到麻醉、通气的大鼠肺部中，给药剂量1.2μg/只。分别在10min，30min，1h， 2h，4h，6h使用LC-MS测定血浆曲前列尼尔药物浓度，根据药物浓度计算0至6小时的药时曲线下面积AUC0-6h、最大血药浓度Cmax、血药达峰时间Tmax，结果见表3。
另取48只SD大鼠(200g±20g)，曲前列尼尔片剂组24只，给药剂量600μg/只；曲前列尼尔气溶胶吸入组：24只，给药剂量1.2μg/只。分别在10min，30min，1h，2h，4h，6h，每组解剖大鼠4只，使用LC-MS测定肺组织药物浓度，根据药物浓度计算0至6小时药时曲线下面积AUC0-6h、最大血药浓度Cmax、血药达峰时间Tmax，结果见表3。
表3曲前列尼尔气溶胶大鼠吸入给药与经口给药全血与肺中血药浓度对比
Figure PCTCN2021132791-appb-000003
如表3所示，血浆中的药物浓度结果显示，气溶胶吸入剂在全身血浆中的药物浓度显著低于片剂灌胃组，药物达峰时间快于片剂灌胃组，说明气溶胶吸入剂进入体内后对全身其他器官影响低。同时如表3所示的肺组织中的药物浓度结果，气溶胶吸入剂在肺组织中的药物浓度稍高于片剂，但Cmax可以达到灌胃组Cmax的2倍以上，说明曲前列尼尔气溶胶吸入剂吸入后可以快速在肺组织达到较高浓度而起效。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (8)

  1. 一种用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，包括以下步骤：
    步骤(1)，将曲前列尼尔或其盐配制为溶液后均匀地喷涂于药物吸入器的加热片上，干燥；
    步骤(2)，患者吸入空气，启动药物吸入器进行加热；
    步骤(3)，温度迅速升至100～500℃，曲前列尼尔迅速蒸发汽化，与通过气流接触形成气溶胶，并随气流进入患者肺部，沉积在肺泡上发挥药效。
  2. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(1)中，所述曲前列尼尔盐选自曲前列尼尔钠盐、钙盐、二乙醇胺盐、三乙醇胺盐、L-精氨酸盐、赖氨酸盐、葡甲胺盐、铵盐、胆碱盐中的一种。
  3. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(1)中，曲前列尼尔或其盐的剂量以曲前列尼尔计，喷涂量为1.2～1000μg/cm 2。
  4. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(1)中，将曲前列尼尔或其盐溶于丙酮、甲醇、无水乙醇、乙酸乙酯、甲酸乙酯、异丙醇、正丁醇、三乙胺和水中的一种或多种混合液中进行喷涂。
  5. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(2)中，患者吸入气流量为15-60L/min时，调节通过加热片的气流流速为0.2L/min-20L/min。
  6. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(2)中，所述加热是通过给予药物吸入器的加热片0.1秒至2秒的电流脉冲，0.1伏至10伏的电压强度启动的。
  7. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(3)中，加热蒸发后，一次递送剂量以曲前列尼尔计为2μg至90μg。
  8. 根据权利要求1所述的用于治疗肺动脉高压的曲前列尼尔气溶胶吸入剂的雾化方法，其特征在于，步骤(3)中，递送的曲前列尼尔空气流动 力学直径MMAD在0.5-5μm之间，细微粒子有效沉积率FPF在60％-99％之间。
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