WO2023138478A1 - 一种治疗鼻炎的溶液型鼻喷雾剂及制备方法 - Google Patents

一种治疗鼻炎的溶液型鼻喷雾剂及制备方法 Download PDF

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WO2023138478A1
WO2023138478A1 PCT/CN2023/071983 CN2023071983W WO2023138478A1 WO 2023138478 A1 WO2023138478 A1 WO 2023138478A1 CN 2023071983 W CN2023071983 W CN 2023071983W WO 2023138478 A1 WO2023138478 A1 WO 2023138478A1
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nasal spray
compound
formula
rhinitis
nasal
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PCT/CN2023/071983
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English (en)
French (fr)
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陈小平
温守明
高泽军
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北京硕佰医药科技有限责任公司
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Priority to CN202380016956.8A priority Critical patent/CN118555954A/zh
Publication of WO2023138478A1 publication Critical patent/WO2023138478A1/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
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the invention relates to a nasal spray in the technical field of pharmaceutical preparations, in particular to a solution-type nasal spray for treating various rhinitis and cold-associated rhinitis and a preparation method thereof.
  • Rhinitis includes acute rhinitis such as cold-associated rhinitis and chronic rhinitis. Chronic rhinitis is classified into allergic rhinitis (AR) and non-allergic rhinitis (NAR) according to allergens, and is divided into seasonal rhinitis and perennial rhinitis according to the time of onset. Rhinitis is a common respiratory disease, among which AR is one of the most common diseases in adults, and its incidence rate shows a trend of increasing significantly. Typical symptoms of rhinitis are sneezing, runny nose, nasal itching and nasal congestion.
  • Drugs currently used to treat rhinitis mainly include glucocorticoids, antihistamines, and anticholinergics, and nasal sprays are the first choice for preparations.
  • Glucocorticoids and antihistamines have certain effects on runny nose, nasal congestion, sneezing, and nasal itching. Among them, glucocorticoids are slow to take effect and generally take more than 2 weeks to obtain a good curative effect.
  • the curative effect on AR with negative eosinocytes is not significant.
  • the curative effect of oral and intranasal administration of antihistamines on NAR is uncertain, and both steroids and antihistamines have certain side effects.
  • the anticholinergic drug ipratropium bromide (IPR) nasal spray can treat rhinitis symptoms such as cold-associated rhinitis, AR, NAR, etc., and can be used for short-term or long-term treatment. Its advantages are quick onset and few side effects. It can be used as an urgently needed drug for symptomatic treatment, but the action time is short. It needs to be administered 3-4 times or more every day, and the patient's compliance is poor. Long-acting anticholinergic drugs (LAMA) that have been on the market are not suitable for the treatment of rhinitis because they have no selectivity to the M receptor subtype.
  • LAMA Long-acting anticholinergic drugs
  • the compound of formula I has strong selectivity to the M receptor subtype and is an ideal LAMA for the treatment of rhinitis. It is characterized in that it has a strong and long-lasting effect on the M3 receptor, and a very weak and short-lasting effect on the M2 receptor. It is intended to be used for the treatment of symptoms such as runny nose and nasal itching caused by various rhinitis. After years of research, the pharmacological effects of the compound of formula I have been fully proved.
  • the nasal spray of the present invention achieves good stability, improves drug concentration, and eliminates irritation; the nasal spray of the present invention has the characteristic of faster onset of action compared with the nasal spray of the prior art, and produces unexpected effects.
  • the invention provides a nasal spray for treating acute and chronic rhinitis, which is in the form of clear and uniform solution.
  • the nasal spray comprises a compound of formula I, water, a cosolvent, a bacteriostat, a pH regulator, and an osmotic pressure regulator NaCl.
  • Active ingredient formula I compound in the present invention has following structure:
  • M - is a suitable organic or inorganic pharmaceutical anion, which can be selected from but not limited to bromide, fluoride, chloride, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenylacetate, triphenylacetate, o-hydroxybenzoate, para -Hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate, or p-toluenesulfonate.
  • the compound of formula I has two chiral centers, so there are four optical isomers, namely (2R, 3R), (2S, 3R), (2R, 3S) and (2S, 3S) configuration compounds.
  • the compound of formula I described in the present invention also includes one or more of the above isomers, or their mixtures and racemates, such as (2S/3S, 2R/3R) racemates, which are all within the scope of the present invention.
  • the representative compound of the compound of formula I is compound 1, the molecular formula is C 29 H 40 BrNO 3 , the molecular weight is 530.54, and its structure is as follows:
  • M - is a pharmaceutically acceptable anion
  • the preparation of the compound is known in the prior art, refer to the patent document with publication number WO2015007073.
  • the co-solvent includes one or more mixtures of ethanol, glycerin, and glycols, wherein the glycols include but are not limited to ethylene glycol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, etc.
  • the bacteriostatic agent is benzalkonium chloride or benzalkonium bromide; the structure of benzalkonium chloride and benzalkonium bromide is shown in formula II, X is Cl and is benzalkonium chloride, X is Br and is benzalkonium bromide, and n is between 1 and 18.
  • X is Cl and is benzalkonium chloride
  • X is Br and is benzalkonium bromide
  • n is between 1 and 18.
  • the content of the compound of formula I is 0.01-1% by weight, preferably 0.02-0.5%; the content of co-solvent is 0-10% by weight, preferably 0-5%; the content of the antibacterial agent in the nasal spray is 0.001-0.05% by weight, preferably 0.005-0.02%.
  • the content of the osmotic pressure regulator NaCl in the nasal spray is 0.45-2.25% by weight, preferably 0.45-1.35%.
  • the pH of the nasal spray is 4.5-8, preferably 5-7.
  • the nasal spray of the present invention can further increase the drug content, increase the stability, reduce the stimulating effect, and have a quick effect.
  • the whole animal anti-rhinitis test adopts the ovalbumin (OVA)-induced guinea pig allergic rhinitis model to observe the effect and onset time of the compound of formula I on the symptoms of allergic rhinitis model; adopts guinea pig nasal administration for 30 days continuously, observes the stimulating effect of formula I compound nasal spray pH, NaCl content and cosolvent on nasal mucosa.
  • OVA ovalbumin
  • the nasal spray of the present invention can be used to treat various rhinitis, including acute rhinitis such as cold-associated rhinitis and chronic rhinitis.
  • Chronic rhinitis is classified into allergic rhinitis (AR) and non-allergic rhinitis (NAR) according to allergens, and into seasonal rhinitis and perennial rhinitis according to the time of onset.
  • AR allergic rhinitis
  • NAR non-allergic rhinitis
  • the typical symptoms of cold-associated rhinitis and AR are runny nose and nasal itching.
  • Another object of the present invention is to provide a preparation method of nasal spray, comprising the steps of dissolving the compound of formula I or its optical isomer and racemate, cosolvent, bacteriostat, NaCl, etc. in water, adjusting to a suitable pH with acid, salt or alkali, filling the finished product in a glass or plastic bottle and adding a nozzle and a protective cap.
  • the filling method belongs to the conventional technology in the field, and is recorded in textbooks in the field, and these textbooks can be incorporated into the present invention as a reference.
  • Compound 10 (2R,3S)-3-[(2-cyclopentyl-2-hydroxy-2-phenyl)ethoxy]-1-(3-phenoxypropyl)-1-azabicyclo[2,2,2]octylium hydrogensulfate.
  • the drug solution of Examples 1-14 is a clear liquid, which is filtered through a 0.22 ⁇ m or 0.45 ⁇ m microporous membrane, and determined by HPLC, the drug content in the filtrate is the same as that of the solution before filtration.
  • Preparation of reference substance solution for content determination Precisely weigh an appropriate amount of the corresponding compound of formula I as a reference substance for different compound nasal sprays, add mobile phase to dissolve, and prepare a solution containing 0.02 ⁇ g per 1 ml as a reference solution, and dilute the sample with mobile phase to a solution containing 2 ⁇ g per 1 ml.
  • the enantiomer When the enantiomer is used as an impurity, it has the same retention time as the main drug, so it must be separated by a chiral column, and the results are less than 0.02% of the main drug (unpublished); the acid radical, bromine and solvent peak Rf values are about 0.13 to 0.2 min; The maximum detected impurity Rf value is about 0.53, and the content is less than 0.01%; the above components are well separated.
  • the impurities and optical isomers introduced by the raw material drug in the preparation are all trace amounts, and there is no obvious change during the long-term storage of the preparation and the long-term sample retention process, and are controlled as special known impurities. Impurities produced during the production and storage of preparations, including degradation products of bacteriostats and extracts from inner packaging, are controlled as unknown impurities.
  • Table 1 the impurity content (%) of different formula I compound and preparation production 0 days Table 1 shows that the total impurity control of different compounds of formula I is very good.
  • Table 2 shows the stability in the range of pH 4 to 8.
  • the increase of total impurities in 24 hours under high temperature conditions of 60°C in the range of pH 5 to 7 is very small, especially at pH 6.2.
  • the solubility of the formula I compound in pure water is about 0.25%, but it is easy to drop below 0.2% during the placement process.
  • the analysis thinks that the liquid medicine near the saturation concentration may be absorbed by the inner packaging (glass bottle, plastic bottle or nozzle).
  • ethanol, glycerin, isopropanol, ethylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800 or the mixture of these alcohols can effectively increase the solubility, the concentration of co-solvent can be increased to 3%, the drug content can be increased to 0.5%, the concentration of co-solvent can be increased to 5%, the drug content can be increased to more than 1%, the solution is very stable with the addition of co-solvent, enough to meet the needs of various uses of nasal spray.
  • Sensitization and challenge Day 1, 3, 5, 7, 14, 21 sensitization, intraperitoneal injection of OVA + aluminum hydroxide gel; Day 28-34 challenge, intranasal administration of OVA solution, once a day, a total of 7 days.
  • Guinea pig D34 was administered 30 minutes after challenge, with a total volume of 20 ⁇ l/300 g body weight, and the same amount was administered in the left and right nostrils.
  • Index detection mainly to observe the effect of the test drug on nasal mucosal inflammation. On Day 34, administration was given 30 minutes after challenge, and the number of nose scratches of guinea pigs in each time period of 0-10 minutes, 10-20 minutes, 20-30 minutes, 30-40 minutes, 40-50 minutes, and 50-60 minutes after drug administration was observed and statistically analyzed.
  • Table 5 shows that different pH nasal sprays of the present invention have obvious inhibitory effect on the nasal itching of the guinea pig rhinitis model caused by OVA, and the pH has a significant impact on the onset time.
  • the pH value is less than 5 (4 and 4.5) or greater than 7 (7.5 and 8) after 20 minutes after administration, the obvious curative effect can be achieved (*p ⁇ 0.05); , 7) can achieve significant curative effect (*p ⁇ 0.05).
  • the guinea pigs were grouped by random method, male and female, 8 in each group, divided into a control group and a test drug group.
  • the control group was given 0.9% NaCl solution by nasal drops; the test drug group was tested with different pH, different NaCl concentrations, and different cosolvent types.
  • Table 8 shows: when the NaCl content deviates from 0.90% to 2.70%, repeated administration for 30 days, twice a day, there is an obvious stimulating effect, p ⁇ 0.05; the greater the NaCl content deviates from the value of 0.9%, the more obvious the guinea pig long-term administration is on the irritation of the nasal mucosa; the range of 0.45% ⁇ NaCl content ⁇ 2.25% has no significant difference in the stimulation effect on the nasal mucosa compared with the control group (p>0.05).
  • solubilizer of selection test drug nasal spray is ethanol (content is 5%, 10%, 15%), ethylene glycol 200 (content is 5%, 10%, 15%) and the mixture of ethylene glycol 200 and ethanol 1:1 (content is 5%, 10%, 15%); main ingredient is compound 1, and content is 0.5%; 9:
  • Table 9 shows: the cosolvent will not produce obvious irritating effect at a concentration of less than 5%; as the concentration of cosolvent increases, the irritation tends to increase; when the content of various cosolvents exceeds 10%, repeated administration for 30 days, twice a day, has obvious irritating effect, and p ⁇ 0.05.

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Abstract

本发明公开了一种含3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐或其衍生物的溶液型鼻喷雾剂及其制备方法，其组分中含有主药、溶剂、助溶剂、抑菌剂、pH调节剂和渗透压调节剂。该鼻喷雾剂稳定性好，药效学试验结果显示起效快，刺激性小，可用于各种鼻炎和感冒伴随性鼻炎的治疗。

Description

一种治疗鼻炎的溶液型鼻喷雾剂及制备方法 技术领域
本发明涉及药物制剂技术领域一种鼻喷雾剂，特别涉及一种治疗各种鼻炎和感冒伴随性鼻炎的溶液型鼻喷雾剂及其制备方法。
背景技术
鼻炎包括急性鼻炎如感冒伴随性鼻炎、慢性鼻炎。慢性鼻炎按变应原分类为变应性鼻炎(AR)和非变应性鼻炎(NAR)，按发病时间分类分为季节性鼻炎和常年性鼻炎。鼻炎是常见的呼吸系统疾病，其中，AR是成年人中最常见的疾病之一，且发病率呈现明显增加的趋势。鼻炎的典型症状为喷嚏、流涕、鼻痒和鼻塞等。
目前用于治疗鼻炎的药物主要包括糖皮质激素、抗组胺药和抗胆碱药等，制剂以鼻喷雾剂为首选。糖皮质激素、抗组胺药对流涕、鼻塞、喷嚏、鼻痒均有一定作用，其中糖皮质激素起效较慢，一般需要2周以上才获得好的疗效，对伊红细胞阴性的AR疗效不显著；另外，抗组胺类口服和鼻内给药对NAR疗效不确定，且激素和抗组胺药都有一定的副作用。
抗胆碱药异丙托溴铵(IPR)鼻喷雾剂可治疗感冒伴随性鼻炎、AR、NAR等的鼻炎症状，可短期或长期治疗，其优点是起效快，副作用少，可以作为对症治疗的急需用药，但作用时间短，每天需给药3-4次甚至更多，病人依从性差。已经上市的长效抗胆碱药(LAMA)由于对M受体亚型没有选择性，并不适合用于鼻炎的治疗，式I化合物对M受体亚型有很强的选择性，是理想的治疗鼻炎的LAMA，特点是对M3受体的作用强而且持久，对M2的作用非常弱并且持续时间很短，拟用于治疗各种鼻炎引起的流涕、鼻痒等症状。经过多年的研究，充分证明了式I化合物的药理作用。本发明的鼻喷雾剂经过处方和工艺创新与现有技术比较，达到了稳定性好，提高药物浓度，消除刺激作用的目的；本发明鼻喷雾剂与现有技术鼻喷雾剂比较具有起效更快的作用特点，产生了令人意想不到的效果。
发明内容
本发明提供了一种可用于治疗急、慢性鼻炎的鼻喷雾剂，其为澄明均匀的溶液形式。鼻喷雾剂包含式I化合物、水、助溶剂、抑菌剂、pH调节剂、渗透压调节剂NaCl。
本发明中的活性成分式I化合物具有如下结构：
M-为适宜的有机或无机药用阴离子，可以选自但不限于溴离子、氟离子、氯离子、碘离子、硝酸根、硫酸根、磷酸根、甲酸根、乙酸根、三氟乙酸根、丙酸根、丁酸根、乳酸根、柠檬酸根、酒石酸根、苹果酸根、马来酸根、琥珀酸根、苯甲酸根、对氯苯甲酸根、二苯基乙酸根、三苯基乙酸根、邻-羟基苯甲酸根、对-羟基苯甲酸根、1-羟基萘-2-甲酸根、3-羟基萘-2-甲酸根、甲磺酸根或对甲苯磺酸根。式I化合物具有两个手性中心，因此存在四种光学异构体，即(2R，3R)、(2S，3R)、(2R，3S)和(2S，3S)构型的化合物。本发明中所述的式I化合物，也包含以上这些异构体中的一种或多种，或者它们的混合物及外消旋体，如(2S/3S，2R/3R)外消旋体，这些均在本发明的范围之内。
式I化合物的代表化合物是化合物1，分子式为C29H40BrNO3，分子量为530.54，其结构如下：
M-为可药用阴离子，化合物的制备是现有技术中已知的，参见公开号为WO2015007073的专利文献。
本发明的鼻喷雾剂中，所述的助溶剂包括乙醇、甘油、二醇类中的一种或一种以上的混合物，其中的二醇类包括但不限于乙二醇、丙二醇、聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇800等。
本发明的鼻喷雾剂中，所述的抑菌剂为苯扎氯铵或苯扎溴铵；苯扎氯铵和苯扎溴铵结构见式II，X为Cl为苯扎氯铵，X为Br为苯扎溴铵，n在1～18之间，商品有单一分子的纯品也有不同分子的混合物，文献显示抑菌作用没有明显差别。
本发明的鼻喷雾剂中，所述式I化合物含量按重量百分比为0.01～1％，优选为0.02～0.5％；助溶剂含量按重量百分比为0～10％，优选0～5％；鼻喷雾剂中的抑菌剂含量按重量百分比为0.001～0.05％，优选0.005～0.02％。鼻喷雾剂中的渗透压调节剂NaCl含量按重量百分比为0.45～2.25％，优选0.45～1.35％。鼻喷雾剂的pH为4.5～8，优选pH为5～7。
本发明的鼻喷雾剂与现有技术比较所发明的鼻喷雾剂可以进一步提高药物含量，稳定性增加、减少刺激作用，起效快。动物整体抗鼻炎试验采用卵白蛋白(OVA)诱导的豚鼠过敏性鼻炎模型观察了式I化合物对过敏性鼻炎模型症状的作用及起效时间；采用豚鼠鼻部连续给药30日，观察了式I化合物鼻喷雾剂pH、NaCl含量和助溶剂对鼻黏膜的刺激作用。本发明的鼻喷雾剂可用于治疗各种鼻炎，包括急性鼻炎如感冒伴随性鼻炎和慢性鼻炎。慢性鼻炎按变应原分类为变应性鼻炎(AR)和非变应性鼻炎(NAR)，按发病时间分类分为季节性鼻炎和常年性鼻炎，感冒伴随性鼻炎和AR典型症状为流涕、鼻痒等症状。
本发明的另一目的是提供一种鼻喷雾剂的制备方法，包括将式I化合物或其光学异构体及消旋体、助溶剂、抑菌剂、NaCl等用水溶解后，用酸、盐或碱调节至合适的pH，成品灌装于玻璃或塑料瓶中并加喷头和保护帽的步骤。灌装的方法属于本领域常规技术，记载于本领域教科书内，这些教科书均可引入本发明作为参考。
具体实施方式
以下通过具体实施方式对本发明进行进一步说明。这里需要指出的是，下面的具体实施方式仅用来说明本发明，本领域技术人员在理解本发明精神的前提下，可以根据本技术领域的现有技术和公知知识对本发明进行相应变换，这些技术方案均落入本发明的范围之内。
参见公开号为WO2015007073的专利文献合成的化合物如下：
化合物1：溴化(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐；
化合物2：(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓富马酸(1：1)盐；
化合物3：(2R,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓甲磺酸盐；
化合物4：溴化(2R,3S),(2S,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐；
化合物5：氯化(2R,3S),(2S,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐；
化合物6：溴化-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓盐；
化合物7：(2R,3R)，(2S,3S)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-氮杂双环[2，2，2]辛鎓磷酸二氢盐；
化合物8：(2S,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-氯化-1-氮杂双环[2，2，2]辛鎓马来酸(1：1)盐；
化合物9：(2S,3R)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓酒石酸(1：1)盐；
化合物10：(2R,3S)-3-[(2-环戊基-2-羟基-2-苯基)乙氧基]-1-(3-苯氧丙基)-1-氮杂双环[2，2，2]辛鎓硫酸氢盐。
实施例1
规格：每喷140μl，含化合物1 20μg
实施例2
规格：每喷140μl，含化合物1 80μg
实施例3
规格：每喷140μl，含化合物1 240μg
实施例4
规格：每喷90μl，含化合物1 80μg
实施例5
规格：每喷140μl，含化合物2 80μg
实施例6
规格：每喷140μl，含化合物3 240μg
实施例7
规格：每喷140μl，含化合物4 240μg
实施例8
规格：每喷140μl，含化合物5 700μg
实施例9
规格：每喷140μl，含化合物6 240μg
实施例10
规格：每喷140μl，含化合物6 420μg
实施例11
规格：每喷140μl，含化合物7 220μg
实施例12
规格：每喷90μl，含化合物8 135μg
实施例13
规格：每喷90μl，含化合物9 900μg
实施例14
规格：每喷90μl，含化合物10 450μg
实验例1样品中药物含量和有关物质的测定
(1)方法
实施例1-14的药物溶液为澄明液体，将该液体经过0.22μm或0.45μm微孔滤膜过滤，经过HPLC测定，滤液中药物含量与过滤前的溶液相同。
HPLC含量测定方法的色谱条件如下：
含量测定对照品溶液配制：不同化合物鼻喷雾剂精密称取对应的式I化合物适量作为对照品，加流动相溶解，配制而成每1ml含0.02μg溶液作为对照品溶液，样品用流动相稀释成每1ml含2μg的溶液。式I化合物的各种光学异构体出峰保留时间分布为：RR或SS构型保留时间约为15min(Rf＝1)，两者重合；(2R，3S)(3S，2R)构型保留时间Rf值约1.07，非对映异构体作为杂质时与主药分离良好。对映异构体作为杂质时与主药保留时间一致，必须用手性柱进行分离，结果含量均小于主药的0.02％(未发表)；酸根、溴和溶剂峰Rf值约为0.13～0.2min之间；苯扎氯铵(或溴铵)见式II，实施例使用结构n＝2，保留时间Rf值约3，其降解产物Rf值约为1.27；浸出物的Rf值约2.2；原料合成过程带入可检测出的最大杂质Rf值约0.53，含量小于0.01％；以上各种成分分离良好。制剂中原料药带入的杂质和光学异构体均为微量，在制剂长期放置和长期留样过程中也没有明显变化，作为特殊已知杂质控制。制剂生产过程和放置过程产生的杂质包含抑菌剂降解产物和内包装浸出物等作为未知杂质加以控制。
(2)结果
①不同式I化合物和制剂0天杂质见表1：
表1、不同式I化合物和制剂生产0天的杂质含量(％)

表1显示不同的式I化合物总杂控制都非常良好。“*”：主药成分；“-”：指杂质是主药的一部
分或杂质中含有主药
②式I化合物在不同pH条件下的稳定性研究
化合物1、2、5、6、9、10水溶液在不同pH、60℃条件下，采用实验例1的方法，测定各实施例的总杂，结果见表2：
表2、式I化合物在不同pH水溶液中储存在60℃条件下24h总杂结果

*式I化合物1溶液获得的最稳定pH
表2显示在pH为4～8范围内的稳定性，pH为5～7范围内60℃高温条件下24h总杂增加幅度很小，尤其pH6.2时增加最小；大于7或小于5时，60℃高温条件下10天总杂增加较为明显。
③实施例鼻喷雾剂在高温、强光照射和加速条件下的稳定性研究
在高温(50℃)、加速条件下(40℃/75％RH)样品，采用实验例1的方法，测定各实施例的有关物质，结果见表3～4。
表3、实施例鼻喷雾剂高温试验有关物质结果(储存在50℃)
表4、实施例鼻喷雾剂加速试验有关物质结果(储存在40℃/75％RH)
结论：实施例鼻喷雾剂在50℃条件下5、10天和在40℃/75％RH加速条件下放置6个月，总的有关物质在正放条件下增加较少或不明显。但在pH小于5或大于7的条件下倒放总杂增加明显。
④化合物浓度对鼻喷雾剂放置过程中的稳定性影响和助溶剂的作用
在试验中发现式I化合物在纯水中的溶解度约为0.25％，但在放置的过程中很容易降为0.2％以下，分析认为可能是接近饱和浓度的药液被内包装(玻璃瓶、塑料瓶或喷头)吸附所致，经过选择，发现乙醇、甘油、异丙醇、乙二醇、聚乙二醇200、聚乙二醇400、聚乙二醇 600、聚乙二醇800或这些醇的混合物可以有效增加溶解度，助溶剂浓度增加至3％，药物含量可增加至0.5％，助溶剂浓度增加至5％，药物含量可增加至1％以上，加了助溶剂溶液很稳定，足以满足鼻喷雾剂各种用途的需求。
实验例2、pH对卵清蛋白(OVA)诱导的豚鼠过敏性鼻炎模型鼻部挠鼻症状的治疗作用和起效时间
(1)方法
致敏与激发：Day1、3、5、7、14、21致敏，腹腔注射OVA+氢氧化铝凝胶；Day28～34激发，滴鼻给予OVA溶液，每天1次，共计7天。
分组与给药：将豚鼠随机分组，每组8只，雌雄各半，分别为空白对照(Control)组、模型(Model)组、给药组的pH为4、4.5、5、5.5、6、6.5、7、7.5、8，其它成分同实施例2。豚鼠D34激发后30min给药,总容积为20μl/300g体重，左右鼻孔给药量相同。
指标检测：主要观察受试药物对鼻腔黏膜炎症的影响。Day34，激发后30min给药，观察药后0～10min、10～20min、20～30min、30～40min、40～50min、50～60min各时间段内豚鼠挠鼻的次数，进行统计分析。
(2)结果
①抑制OVA引起豚鼠过敏性鼻炎症状的作用结果见表5：
表5、对OVA诱导的过敏性鼻炎模型豚鼠鼻部挠鼻的影响(x±SEM)

统计学：one way ANOVA，与Control组比较：###p<0.001；与Model比较：*p<0.05
表5显示，本发明不同pH鼻喷雾剂对OVA引起的豚鼠鼻炎模型的鼻痒有明显的抑制作用，并且pH对起效时间有显著的影响，当pH值小于5(4和4.5)或大于7(7.5和8)给药后20min后才能达到明显的疗效(*p<0.05)；当pH值为5和7之间给药后20min以内(pH为5、5.5)甚至10min内(pH为6、6.5、7)就能达到显著的疗效(*p<0.05)。
实验例3、鼻喷雾剂的pH、NaCl含量、助溶剂滴鼻给药对豚鼠鼻黏膜的刺激作用
(1)方法
采用随机法分组，把豚鼠分组，雌雄各半，每组8只，分为对照组和试药组，对照组滴鼻给予0.9％NaCl溶液；试药组分别对不同pH、不同NaCl浓度、不同助溶剂种类进行试验，动物的给药容积为20μl/300g体重，左右鼻孔给药量相同，每日2次，连续给药30日。
H&E染色鼻黏膜炎症病理学分级评分标准见表6：
表6、H&E染色鼻黏膜炎症病理学分级评分标准
(2)结果
①pH的影响：选择试验药鼻喷雾剂的pH为4、4.5、5、5.5、6、6.5、7、7.5和8，其它成分同实施例2，不同pH对豚鼠鼻黏膜的刺激作用见表7：
表7、不同pH对豚鼠鼻黏膜的刺激作用(x±SEM)

统计学：x±SEM，n＝8，one way ANOVA，与Control组比较：*p<0.05。
表7显示：当pH＝4，反复给药30日，每日2次，有一定的刺激作用，p<0.05；pH值≦4.5或≧7.5，豚鼠长期给药对鼻黏膜有刺激作用的趋势，但P值大于0.05；pH在5～7之间豚鼠长期给药对鼻黏膜没有明显的刺激作用或趋势。
②NaCl含量的影响：试验药鼻喷雾剂的NaCl含量为0％、0.45％、0.9％、1.35％、1.8％、2.25％和2.70％，其它成分同实施例2，不同NaCl含量对豚鼠鼻黏膜的刺激作用见表8：
表8、不同NaCl浓度对豚鼠鼻黏膜的刺激作用(x±SEM)

统计学：x±SEM，n＝8，one way ANOVA，与Control组比较：*p<0.05。
表8显示：当NaCl含量偏离0.90％达到2.70％，反复给药30日，每日2次，有明显的刺激作用，p<0.05；NaCl含量偏离0.9％值越大，豚鼠长期给药对鼻黏膜刺激作用的趋势越明显；0.45％≦NaCl含量≦2.25％范围对鼻黏膜的刺激作用与对照组比较没有明显的差异 (p>0.05)。
③助溶剂的影响：选择试验药鼻喷雾剂的助溶剂为乙醇(含量为5％、10％、15％)、乙二醇200(含量为含量为5％、10％、15％)和乙二醇200与乙醇1：1的混合物(含量为含量为5％、10％、15％)；主药为化合物1，含量为0.5％；其它成分同实施例2，不同含量的助溶剂对豚鼠鼻黏膜的刺激作用见表9：
表9、不同含量的助溶剂对豚鼠鼻黏膜的刺激作用(x±SEM)

统计学：x±SEM，n＝8，one way ANOVA，与Control组比较：*p<0.05。
表9显示：助溶剂在小于5％的浓度下不会产生明显的刺激作用；随着助溶剂的浓度增加，刺激性有增加的趋势；当各种助溶剂的含量超过10％，反复给药30日，每日2次，有明显的刺激作用，且p<0.05。

Claims (12)

  1. 一种含有式I化合物、水、助溶剂、抑菌剂、pH调节剂和NaCl的鼻喷雾剂，其pH为4.5-8，
    M-为有机或无机阴离子。
  2. 根据权利要求1所述鼻喷雾剂，式I化合物中M-选自溴离子、氟离子、氯离子、碘离子、硝酸根、硫酸根、磷酸根、甲酸根、乙酸根、三氟乙酸根、丙酸根、丁酸根、乳酸根、柠檬酸根、酒石酸根、苹果酸根、马来酸根、琥珀酸根、苯甲酸根、对氯苯甲酸根、二苯基乙酸根、三苯基乙酸根、邻-羟基苯甲酸根、对-羟基苯甲酸根、1-羟基萘-2-甲酸根、3-羟基萘-2-甲酸根、甲磺酸根或对甲苯磺酸根。
  3. 根据权利要求2所述鼻喷雾剂，式I化合物中M-为溴离子。
  4. 根据以上任一项权利要求的鼻喷雾剂，其式I化合物含量按重量百分比为0.01～1％，优选0.02～0.5％。
  5. 根据权利要求1-3中任一项的鼻喷雾剂，其助溶剂选自乙醇、甘油、丙二醇、乙二醇200、乙二醇300、乙二醇400、乙二醇600、乙二醇800的一种或一种以上的混合物。
  6. 根据权利要求5所述的鼻喷雾剂，其助溶剂含量按重量百分比为0～10％，优选0～5％。
  7. 根据权利要求1-3中任一项的鼻喷雾剂，其抑菌剂为苯扎氯氨或苯扎溴铵。
  8. 根据权利要求1-3中任一项的鼻喷雾剂，其抑菌剂含量按重量百分比为0.001～0.05％，优选0.005～0.02％。
  9. 根据权利要求1-3中任一项的鼻喷雾剂，所述pH调节剂选自HCl、H3PO4、H2SO4、乳酸、柠檬酸、酒石酸、苹果酸、马来酸、琥珀酸、苯甲酸中一种或一种以上的混合物、前述除HCl外酸的钠盐、NaOH。
  10. 根据权利要求1的鼻喷雾剂，pH为5～7。
  11. 根据权利要求1的鼻喷雾剂，NaCl含量按重量百分比为0.45～2.25％，优选0.45～1.35％。
  12. 根据权利要求1-3中任一项的鼻喷雾剂的制备方法，其是将式I化合物溶于水或溶于助溶剂后溶于水，加入抑菌剂和渗透压调节剂NaCl溶解，调节pH后灌装制备而成。
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WO2015007073A1 (zh) * 2013-07-13 2015-01-22 北京市丰硕维康技术开发有限责任公司 奎宁类化合物、其光学异构体及其制备方法和医药用途
WO2021218833A1 (zh) * 2020-04-26 2021-11-04 北京硕佰医药科技有限责任公司 一种m受体拮抗剂的晶体、制备方法及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015007073A1 (zh) * 2013-07-13 2015-01-22 北京市丰硕维康技术开发有限责任公司 奎宁类化合物、其光学异构体及其制备方法和医药用途
WO2021218833A1 (zh) * 2020-04-26 2021-11-04 北京硕佰医药科技有限责任公司 一种m受体拮抗剂的晶体、制备方法及其应用

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