Inhalation type pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides an inhalation type pharmaceutical composition as well as a preparation method and application thereof. The inhalation type pharmaceutical composition comprises an active component, a pH regulator and a solvent, the active component is penehyclidine or a pharmaceutically acceptable salt thereof; the preparation method comprises the following steps: (a) taking 80-90% of a solvent in prescription dosage, and regulating the pH value to 4.5-5.5 by using a pH regulator; (b) adding the active ingredients according to the prescription dosage, stirring and dissolving uniformly, and adding the solvent to the total dosage to obtain a liquid medicine; and (c) degerming, filtering and encapsulating to obtain the inhalation type pharmaceutical composition. The penehyclidine hydrochloride injection is improved into an inhalation solution, the administration route and dosage form are changed, and indications are newly increased. Therefore, the clinical requirements of postoperative pulmonary complications in the perioperative period or airway management in the perioperative period, especially for patients with high airway risk, are met.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an inhalation-type pharmaceutical composition and a preparation method and use thereof. Background Art

[0002] Perioperative airway management refers to airway management from 5-7 days before surgery to 7-12 days after surgery. It emphasizes lung function assessment and lung rehabilitation training before surgery; emphasizes the rational use of anesthetic drugs and lung protective ventilation strategies during surgery; and strengthens airway management, pain management, drainage tube management, and cough assessment and treatment after surgery.

[0003] Commonly used drugs for airway management include anti-infective drugs, glucocorticoids, bronchodilators, and mucolytics. In clinical practice, the rate of intraoperative bronchospasm is reduced by preventive inhalation of anticholinergic drugs (bronchodilators). Because anticholinergic drugs can act on central and peripheral postganglionic cholinergic receptors, they can prevent stimulation during intubation and slow heart rate caused by vagal reflex induced by intraoperative traction, counteract bradycardia caused by various anesthetic drugs, relieve tension of various smooth muscles, relax tracheobronchial tubes, and inhibit glandular secretion. Commonly used anticholinergic drugs (M receptor antagonists) include atropine, scopolamine, glycopyrrolate, ipratropium bromide, tiotropium bromide, and penehyclidine hydrochloride. The products already on the market (for example, atropine injection, scopolamine capsules, scopolamine injection, ipratropium bromide aerosol, tiotropium bromide inhalation powder, glycopyrrolate aerosol, glycopyrrolate powder, glycopyrrolate injection, glycopyrrolate tablets and penehyclidine hydrochloride injection, etc.) cannot meet the clinical needs of perioperative airway management due to their mechanism of action and dosage form, especially those of patients with perioperative and postoperative pulmonary complications.

[0004] Penehyclidine hydrochloride is a new type of selective anticholinergic drug with selective cholinergic receptor antagonism. It selectively acts on M1 and M3 receptors, but has a weak or insignificant effect on M2 receptors. It does not act on cardiac M2 receptors, does not increase myocardial oxygen consumption, and can inhibit heart rate variability, reduce the incidence of arrhythmias in patients, does not cause acetylcholine negative feedback regulation disorders, does not cause excessive acetylcholine release, and does not induce bronchospasm. Compared with atropine, a commonly used anticholinergic drug at home and abroad, penehyclidine hydrochloride has advantages in many aspects, such as small or mild toxic and side effects, small effective dose, long duration of action, strong and comprehensive anticholinergic effects, and can effectively avoid adverse reactions such as tachycardia caused by atropine, etc., and has a long drug effect and fewer adverse reactions. The marketed preparation is penehyclidine hydrochloride injection, which is mainly administered by intramuscular injection and is used for 1) administration before anesthesia to inhibit the secretion of salivary glands and airway glands; 2) for emergency treatment of organophosphorus poisoning (pesticides) and maintenance of atropine in the late stage of poisoning or after cholinesterase aging. In recent years, clinical research and application have found that penehyclidine hydrochloride can inhibit the contraction of airway smooth muscle and dilate bronchi, and has the effect of preventing and treating perioperative pulmonary complications. In addition, there are cases of off-label use in clinical practice. At the same time, expert consensus recommends its nebulized inhalation administration for perioperative airway management. However, no inhalation-related varieties are currently on the market.

[0005] In the prior art, patent document CN101234108A discloses a pharmaceutical composition containing (3S, 2'R)-3-(2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy)quinuclidine hydrochloride as an active ingredient, and its use in the preparation of drugs for treating chronic obstructive pulmonary disease, shock diseases, urinary incontinence diseases, and pre-anesthetic auxiliary medication. It is mentioned that the pharmaceutical composition is a liquid preparation that can be administered by inhalation, and specific examples are sprays and aerosols. Patent document CN1568984A discloses sprays and aerosols containing penehyclidine for the prevention and treatment of respiratory diseases. CN101474178A relates to the use of penehyclidine hydrochloride in the preparation of drugs for treating cardiogenic shock diseases. In the examples, it is disclosed that penehyclidine hydrochloride is directly mixed with water or a propellant to prepare a spray and an aerosol. CN101601672A provides a new medical use of penehyclidine hydrochloride, mainly involving the application of penehyclidine hydrochloride as a dental surgery drug for oral topical administration, and penehyclidine hydrochloride can be prepared as a spray or a solution. Since penehyclidine hydrochloride is dissolved in water, after high-temperature sterilization or long-term storage, there are problems such as increased pH value, increased content of related substances (impurities), and decreased content of penehyclidine hydrochloride, and no related products are on the market.

[0006] In order to solve the above problems, the preparation method of penehyclidine hydrochloride injection disclosed in patent CN102525910B adopts the method of acidifying and heat-treating the commercially available medicinal ampoule or glass vial, and then pouring the penehyclidine hydrochloride liquid into it and sterilizing it to prepare penehyclidine hydrochloride injection; but in the actual production process, this method of acidifying and pre-treating the commercially available medicinal ampoule or glass vial is cumbersome to operate. CN112716889B relates to a preparation method of penehyclidine hydrochloride injection, comprising: adjusting the pH of the penehyclidine hydrochloride liquid, filtering it once until the pH value is stable, filtering it twice until it is filled, and then sterilizing it at high temperature. However, both of them are intravenously injected, which has poor compliance for elderly or child patients. Among multiple expert consensuses, the "Guidelines for Perioperative Airway Management in Thoracic Surgery in China (2020 Edition)", "Guangdong Provincial Expert Consensus on the Use of Anticholinergic Drugs Before Anesthesia (2021 Edition)", and "Expert Consensus on the Use of Penehyclidine Hydrochloride for Perioperative Airway Management" all recommend the use of penehyclidine hydrochloride in perioperative airway management. The recommended method of use is: Patients entering the intensive care unit after surgery can inhale penehyclidine hydrochloride by nebulization to prevent pulmonary complications. Each time, 0.5 mg of penehyclidine hydrochloride is diluted to 6 ml with normal saline, 2 times / day, for 3 consecutive days. There are certain risks in using it beyond the instructions, and the dosage during the dilution process is inaccurate and the operation steps are complicated. Therefore, it is necessary to develop an inhaled pharmaceutical composition to solve the problems existing in existing clinical applications. Summary of the invention

[0007] Based on the deficiencies of the prior art, the purpose of the present invention is to provide an inhalation pharmaceutical composition, which aims to improve the penehyclidine hydrochloride injection into an inhalation solution, change the administration route and dosage form, and add new indications to meet the clinical needs of preventing perioperative and postoperative pulmonary complications or perioperative airway management, especially those with high airway risk.

[0008] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] In one aspect, the present invention provides an inhalation pharmaceutical composition comprising an active ingredient, a pH regulator and a solvent; the active ingredient is penehyclidine or a pharmaceutically acceptable salt thereof.

[0010] Furthermore, the pharmaceutically acceptable salt of penehyclidine is penehyclidine hydrochloride or penehyclidine sulfate.

[0011] Furthermore, in the inhaled pharmaceutical composition, the concentration of penehyclidine hydrochloride is 0.01 to 2 mg / mL, preferably, the concentration is 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 mg / mL.

[0012] Furthermore, the pH regulator is selected from an inorganic acid aqueous solution, an organic acid aqueous solution or an alkaline solution. Furthermore, the concentration of the pH regulator is 0.01 to 0.5 mol / L, preferably 0.05 to 0.15 mol / L.

[0013] Furthermore, the inorganic acid is selected from hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[0014] Further, the organic acid is selected from acetic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, ascorbic acid, fumaric acid, maleic acid, malic acid, amino acid, tartaric acid, etc. Further, the organic acid can be citric acid: the content is 0.0039-27.7 mg / mL; or ascorbic acid: the content is 0.0045-5.0 mg / mL. By using a pH regulator, the quality and stability of the prepared penehyclidine hydrochloride inhalation pharmaceutical composition product are guaranteed, and compared with the prior art, the preparation process is stable and simplified.

[0015] Further, the alkali is selected from sodium dihydrogen phosphate, sodium carbonate, sodium hydroxide, sodium bicarbonate, etc. Further, the concentration of the alkali solution is 0.01 to 0.5 mol / L, preferably 0.05 to 0.15 mol / L.

[0016] Furthermore, the pH value of the inhalation pharmaceutical composition is 2.5 to 6.5, preferably 4.5 to 6.5, 4.5 to 5.5 or 4.7 to 4.9. By controlling the pH value of the penehyclidine hydrochloride solution, the product quality and stability of the penehyclidine hydrochloride inhalation pharmaceutical composition are ensured.

[0017] Furthermore, the solvent is selected from water (such as sterile water for injection, purified water), ethanol, ethylene glycol, glycerol, ether, cyclohexane, etc. The toxic and side effects of the solvent used should meet the requirements.

[0018] Furthermore, the inhalation pharmaceutical composition may further include an osmotic pressure regulator. Further, the osmotic pressure regulator is selected from sodium chloride, glycerol, mannitol, sorbitol, boric acid, glucose, borax, etc. Further, the concentration of the osmotic pressure regulator is 0.01 to 0.5 mol / L, preferably 0.05 to 0.15 mol / L.

[0019] Furthermore, in the inhalation pharmaceutical composition, the mass percentage of the active ingredient, the pH regulator and the osmotic pressure regulator is independently 0.001-5%, and the active ingredient and the pH regulator are independently preferably 0.001%, 0.0015%, 0.002%, 0.0025%, 0.003%, 0.0035%, 0.004%, 0.0045%, 0.005%, 0.0055%, 0.006%, 0.0065%, 0.007%, 0.0075%, 0.008%, 0.0085%, 0.009%, 0.0095%, ...96%, 0.0097%, 0.0098%, 0.0099%, 0.0100%, 0.0111%, 0.0120%, 0.0130%, 0.0140%, 0.0150%, 0.0160%, 0.0170%, 0.0180%, 0.0190%, 0.0210%, 0.0220%, 0.0230%, 0.0240%, 0.0250%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.105%, 0.11%, 0.115%, 0.12%, 0.125%, 0.13%, 0.135%, 0.14%, 0.145%, 0.15%, 0.155%, 0.16%, 0.165%, 0.17%, 0. .175%, 0.18%, 0.185%, 0.19%, 0.195%, 0.2%, 0.205%, 0.21%, 0.215%, 0.22%, 0.225%, 0.23%, 0.235%, 0.24%, 0.245%, 0.25%, 0.255%, 0.26%, 0.265%, 0.27%, 0.275%, 0.28%, 0.285%, 0.29%, 0.295%, 0.3%, 0.305%, 0.31%, 0.315%, 0.32%, 0.325%, 0.33%, 0.335%, 0.34%, 0.345%, 0.35%, 0.355%, 0.36%, 0.365%, 0.37%, 0.375%, 0.38%, 0.385%, 0.39%, 0.395%, 0.4%, 0.405%, 0.41%, 0.415%, 0.42%, 0.425%, 0.43%, 0.435%, 0.44%, 0.445%, 0.45%, 0.455%, 0.46%, 0.465%, 0.47%, 0.475%, 0.48%, 0.485%, 0.49%, 0.495% or 0.5%. Furthermore, the mass percentage of the osmotic pressure regulator is 0.1-5%, preferably 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 3%, 4% or 5%.

[0020] Further, the pharmaceutical composition according to the present invention can be in the following dosage forms: sprays such as but not limited to sprays for oral sprays, nasal sprays, topical skin sprays, etc.; aerosols such as but not limited to aerosols for lung inhalation, aerosols for topical skin, etc.; inhalants such as but not limited to inhalation solutions, etc.; powder sprays such as but not limited to powder sprays for oral sprays, powder sprays for nasal sprays, powder sprays for topical skin, etc. The inhalation pharmaceutical composition provided in the present application has a fast onset of action, which is equivalent to intravenous injection. The inhalation pharmaceutical composition acts on the lungs, which have a large surface area, and is absorbed by lung epithelial cells or respiratory mucosa and directly enters the blood circulation; first-pass elimination can be avoided; especially as an inhalation solution.

[0021] The term "inhaler" refers to a true solution in which the drug and excipients contained therein are miscible with each other. For solution-type inhalers suitable for atomization, some basic properties are usually required to be met, including: 1) sterile medium; 2) low viscosity liquid, low surface tension; 3) moderate pH; 4) the ability to form droplets with an average diameter of less than 5μm or less than 3μm; 5) the prescription is relatively stable to the nebulizer; 6) does not contain irritating preservatives and stabilizers. Particle size and dosage form are the main factors affecting the effect of inhaled preparations, among which particle size is one of the main factors. The delivery of drugs by inhalation can deposit drugs in different parts of the respiratory tract, such as the throat, trachea, bronchi and alveoli. Generally, the smaller the particle size, the longer the particles remain suspended in the air, and the drug can be delivered to deeper parts of the respiratory tract.

[0022] In another aspect, the present invention provides a method for preparing an inhalable pharmaceutical composition, the method comprising the following steps:

[0023] (a) taking 80-90% of the prescribed amount of solvent and adjusting the pH to 2.5-6.5 with a pH adjuster;

[0024] (b) adding the prescribed amount of active ingredient, stirring to dissolve evenly, and adding solvent to the full amount to obtain a drug solution;

[0025] (c) sterilizing, filtering and filling to obtain the inhalation pharmaceutical composition.

[0026] Furthermore, the inhalable pharmaceutical composition is filled using a blow-fill-seal (BFS) aseptic filling technology, and the packaging material is selected from one or more of low-density polyethylene (LDPE) particles, polypropylene (PP) particles, and polyester (PET) particles.

[0027] Furthermore, during the preparation process of step (b), a pH adjuster is added to adjust and maintain the pH at 2.5 to 6.5.

[0028] Furthermore, the filling refers to filling the filtered liquid medicine with a plastic bottle blow-fill-seal (BFS) integrated machine. By using a blow-fill-seal integrated machine to form, fill and seal plastic bottles, aseptic filling of the filtered liquid medicine is achieved, ensuring good aseptic stability of the inhalation drug composition, low probability of cross contamination, low production cost and management cost, which has obvious advantages over the existing filling and sterilization methods.

[0029] Furthermore, the filling specification is 6mL / vial.

[0030] Furthermore, the filling refers to filling the filtered medicinal solution into a borosilicate glass bottle.

[0031] Furthermore, the sterilization filtration uses a 0.45 μm polyethersulfone filter or a PP material filter membrane.

[0032] In another aspect, the present invention provides an inhaled pharmaceutical composition for perioperative airway management or for preventing perioperative and postoperative pulmonary complications. Further, the airway may be one or more of the airways of the nose, throat, trachea, esophagus and main bronchus.

[0033] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0034] 1: The inhalation pharmaceutical composition provided by the present invention overcomes the defect that the existing dosage forms cannot meet the clinical application, and organic acid is added to the prescription to maintain the stability of penehyclidine ether.

[0035] 2: Compared with the prior art which uses acidification pretreatment of ampoules or glass vials to ensure product quality, and the cyclic filtration treatment of two filter elements with different pore sizes connected in series, the preparation process of the inhalation pharmaceutical composition provided by the present invention adopts a single sterilization filtration process, which not only avoids the influence of high temperature on the stability of the drug solution in the conventional high-temperature sterilization process, but also reduces the process difficulty; the blow-fill-seal aseptic filling technology is adopted to reduce the microbial contamination of the drug solution and improve the safety of the preparation.

[0036] 3: Compared with the complicated acidification pretreatment process in the prior art, the inhalation pharmaceutical composition provided by the present invention adopts the combined use of two pH regulators, which effectively ensures the stability of the drug solution while reducing the process difficulty; the obtained filtrate is filled in borosilicate glass bottles, which not only reduces the microbial contamination of the drug solution, but also reduces the process difficulty.

[0037] 4: The present invention is formulated into a standard preparation used in clinical applications, which reduces the preparation steps during clinical use and improves the accuracy of drug administration; the inhalation drug composition provided by the present invention is simple to operate, ensures the uniformity and stability of the inhalation drug composition, and at the same time has better product quality and stability, thereby improving patient compliance with medication.

[0038] 5: The inhalation pharmaceutical composition prepared by the method of the present invention has stable quality, is suitable for industrial production, and can be quality monitored. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0040] Preparation Example 1

[0041] A penehyclidine hydrochloride inhalation solution, the preparation process is as follows:

[0042] ① Weighing: Weigh the penehyclidine hydrochloride raw material according to the prescribed amount and set aside.

[0043] ② Preparation of solution: Weigh 80% to 90% of the prescribed amount of purified water, and adjust the pH value to between 4.5 and 5.5 with a pH adjuster; add penehyclidine hydrochloride, stir to dissolve evenly, and measure the pH value of the solution (if the pH value is not between 4.5 and 5.5, adjust the pH value to 4.5 to 5.5 with tartaric acid solution); add purified water and make up to the full volume.

[0044] ③Sterile filtration: Sterile filter the prepared drug solution using a 0.45 μm polyethersulfone filter.

[0045] ④Filling: Fill the filtered liquid medicine with a plastic bottle blowing, filling and sealing (BFS) integrated machine, with a filling specification of 6ml / tube.

[0046] ⑤ Packaging: labeling, outer packaging.

[0047] Example 1

[0048] Prescription quantity: Penehyclidine hydrochloride: 0.5 mg, 0.1 mol / L tartaric acid solution: adjust the pH to 4.5, and adjust the solution to 6 mL with purified water.

[0049] The preparation process was carried out with reference to the steps of Preparation Example 1.

[0050] Embodiments 2 to 7

[0051] The difference from Example 1 is: 0.1 mol / L pH adjuster: adjust the pH to 4.5, and the pH adjuster changes as shown in Table 1:

[0052] Example 2 3 4 5 6 7 Penehyclidine hydrochloride 0.5mg 0.49mg 0.53mg 0.5mg 0.51mg 0.52mg pH Adjusters hydrochloric acid sulfuric acid acetic acid Citric acid ascorbic acid lactic acid Purified water Up to 6ml Up to 6ml Up to 6ml Up to 6ml Up to 6ml Up to 6ml

[0053] Examples 8-12

[0054] The difference from Example 1 is that: 0.1 mol / L tartaric acid solution: pH is adjusted as shown in Table 2:

[0055] Example 8 9 10 11 12 Penehyclidine hydrochloride 0.5mg 0.49mg 0.53mg 0.52mg 0.51mg tartaric acid solution Adjust pH to 4.7 Adjust pH to 4.8 Adjust pH to 4.9 Adjust pH to 5.0 Adjust pH to 5.5 Purified water Up to 6ml Up to 6ml Up to 6ml Up to 6ml Up to 6ml

[0056] Embodiments 13 to 17

[0057] The difference from Example 1 is that: the pH adjusting agent is a 0.1 mol / L solution: the pH is adjusted to 5, filtered through a PP filter membrane and then filled into a borosilicate glass bottle, as shown in Table 3 below:

[0058]

[0059] Comparative Example 1

[0060] The difference from Example 1 is that during the preparation process, the prepared drug solution is sterilized at 121° C. for 30 min.

[0061] Comparative Example 2

[0062] 0.5 mg of penehyclidine hydrochloride was diluted to 6 ml with normal saline and filled into a vial.

[0063] Comparative Example 3

[0064] Patent CN102525910B discloses penehyclidine hydrochloride injection.

[0065] Comparative Example 4

[0066] Patent CN112716889B discloses penehyclidine hydrochloride injection.

[0067] Test 1:

[0068] The content and related substances of the inhalation drug composition before and after sterilization are compared as shown in Table 3:

[0069]

[0070] Results: High temperature sterilization process reduced the content of active ingredient penehyclidine hydrochloride and increased the content of related substances.

[0071] Test 2:

[0072] Accelerated test conditions: The test sample is placed in a clean container and subjected to an accelerated test (60°C ± 2°C, RH 75% ± 5%). The detection of impurities is shown in Table 4 below:

[0073]

[0074]

[0075] From the comparison of stability data in the above table, it can be seen that the product quality and stability prepared by the preparation method of the inhalation pharmaceutical composition provided by the present invention are good. After being placed at 60°C for 30 days, the content of related substances is less than 0.3%. During long-term placement, the content of active ingredients can be stably maintained. Compared with Comparative Example 2, the product is obviously uniform and stable. Compared with the use of inorganic acids as pH regulators, the stability of the inhalation pharmaceutical composition prepared by the organic acid as the pH regulator in this application is better. Compared with the products and product packaging prepared by the prior art using complex processes, the inhalation pharmaceutical composition prepared in this application adopts simple sterilization and filtration, and then directly uses the blowing, filling and sealing integrated technology to achieve filling, ensuring better stability of the product and ensuring the quality of the product. From the stability data in the above table, it can be seen that the use of a composite pH regulator combined with an osmotic pressure regulator to prepare an inhalation solution can also achieve excellent stability of the composition, and the difficulty of the preparation process is reduced.

[0076] Experiment 3 Effects of inhaled solution on postoperative pulmonary complications model in COPD rats

[0077] The purpose of this experiment is to investigate the efficacy of the inhalation solution prepared in this application in preventing long-term anesthesia + endotracheal intubation surgery + infection factors (small-dose Pseudomonas aeruginosa infection) and reducing pulmonary complications in model rats with underlying diseases (COPD) after inhalation of the inhalation solution.

[0078] 1 Modeling, grouping and drug administration

[0079] 152 SPF male SD rats that passed the quarantine were divided into a normal control group (13 rats) and a model group (139 rats). The rats in the model group were subjected to repeated fumigation combined with tracheal instillation of lipopolysaccharide to replicate the obstructive pulmonary disease model. The model rats were placed in a fumigation box, and cigarettes were burned at a speed of 5 min / stick using an automatic smoking machine, and the smoke from the combustion was passed into the fumigation box. The fumigation was performed for 1 hour each time, once a day, for 8 consecutive weeks. At the same time, 0.2 mL / rat of 1 mg / mL lipopolysaccharide (LPS) solution was injected into the trachea, once every 2 weeks. The same method was used to inject an equal volume of 0.9% sodium chloride injection into the airway of the normal control group rats. Before administration, 3 rats were randomly selected from the normal control group and the model group, and lung function and lung tissue pathology examinations were performed to determine the successful replication of the model.

[0080] After modeling, 136 model rats were selected and randomly divided into a model control group (10 rats), a penehyclidine hydrochloride injection group (90 μg / kg, 48 rats), an ipratropium bromide solution group for inhalation (180 μg / kg, 10 rats), and low, medium, and high dose groups of the inhalation solution of Example 13 of the present application (45 μg / kg, 90 μg / kg, 180 μg / kg, 10, 48, and 10, respectively); among them, the penehyclidine hydrochloride injection group and the medium dose group of the inhalation solution of Example 13 of the present application (38 rats / group) were taken as pharmacokinetic satellite groups, which were used for plasma and lung tissue drug concentration detection, respectively. The animals in the low, medium and high dose groups of the inhalation solution of Example 13 of the present application continuously inhaled the inhalation solution of the corresponding concentration, respectively, the animals in the penehyclidine hydrochloride injection group were given 9 μg / mL of penehyclidine hydrochloride injection by intramuscular injection at 10 mL / kg, the animals in the inhalation ipratropium bromide solution group inhaled the inhalation solution of Example 13 of the present application at the corresponding concentration, and the animals in the normal control group and the model control group were given the inhalation solution (solvent group) by oral and nasal inhalation, and the administration was continued for 7 days. 1 hour after the first administration, the animals in each group were anesthetized by intraperitoneal injection of 1.2 mL / kg of Shutai 50, and after anesthesia, the animals in each group were intubated (infiltrated with a small dose of Pseudomonas aeruginosa, the concentration is to be determined, determined according to model exploration), and anesthesia was continued for 12 hours.

[0081] 2. Detection indicators

[0082] 2.1 Pulmonary function test

[0083] On the day after the last administration, the animals in each group were anesthetized by intraperitoneal injection of 1.2 mL / kg of Shutai 50 and then fixed in the body recorder in a supine position. The airway resistance (Penh), lung compliance (Cpyn), tidal volume (VT), forced vital capacity (FVC), forced expiratory volume in 0.2 seconds (FEV) of the rats in each group were measured by a small animal pulmonary function tester. 200 ).

[0084] 2.2 Blood gas analysis

[0085] On the day after the last administration, arterial blood was collected from the abdominal aorta of the animals in each group after anesthesia, and the arterial carbon dioxide partial pressure (PaCO2) and arterial oxygen partial pressure (PaO2) of the animals were measured using a BG-800 blood gas electrolyte analyzer.

[0086] 2.3 Bacterial load in lung tissue

[0087] On the day after the last administration, the animals in each group were anesthetized and blood was collected, and then bled from the abdominal aorta and euthanized. The right lung was dissected and the lung tissue was weighed and homogenized with 0.9% sodium chloride injection at a ratio of 1:9. Pathogenic microorganisms were cultured, and the colony morphology was observed and counted. The bacterial count was based on the microbial counting method of the 2020 edition of the "Chinese Pharmacopoeia".

[0088] 2.4 Lung tissue pathology

[0089] On the day after the last administration, the animals in each group were anesthetized and blood was collected by bleeding from the abdominal aorta. The left lung was removed by dissection and fixed in 10% neutral formalin, embedded in paraffin, sliced, and stained with HE. The pathological changes of bronchial and lung tissues were observed under a light microscope.

[0090] 2.5PK detection

[0091] The pharmacokinetic satellite group (pentaethyl chloride injection group, MZ-01 inhalation solution medium dose group) collected blood samples before and 12 time points after administration on the day of administration. Blood was collected from the jugular vein, 0.1 mL / time point, placed in an EDTA-K2 anticoagulant EP tube, and centrifuged at 4°C, 4000g for 5 minutes to obtain plasma, 8 animals / time point; animals were dissected at 5 time points after the last administration, and alveolar lavage fluid, lung tissue, nasopharynx (including nasal concha), larynx (including epiglottis), main trachea and bronchi), as well as brain, heart, liver, spleen, and kidney were collected. The drug concentration in plasma and tissue was detected, and t was calculated. max , AUC, etc.

[0092] 3. Data Processing and Statistical Analysis

[0093] The significant figures of the test data were rounded off and statistical analysis was performed in accordance with SOP regulations. The statistical software used was SPSS23.0. The measurement data were expressed as mean ± standard deviation, and the Leven's test method was used to test normality and homogeneity of variance. The statistical results were tested with α = 0.05 as the test limit, where P ≤ 0.05 indicated statistical significance, and P ≤ 0.01 indicated that the difference tested was very significant.

[0094] 4. Conclusion

[0095] It is found through experiments that the inhalation pharmaceutical composition prepared by the present invention has a suitable pH range, good solution compliance, and can effectively reduce lung complications clinically.

[0096] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. An inhalation pharmaceutical composition, characterized in that: The invention comprises an active ingredient, a pH regulator and a solvent; the active ingredient is penehyclidine or a pharmaceutically acceptable salt thereof; Furthermore, the pharmaceutically acceptable salt of penehyclidine is penehyclidine hydrochloride or penehyclidine sulfate.

2. The inhalation pharmaceutical composition according to claim 1, characterized in that: In the inhalation pharmaceutical composition, the concentration of penehyclidine hydrochloride is 0.01 to 2 mg / mL; The mass percentage of the active ingredient is 0.001-5%, and the mass percentage of the pH adjuster is 0.001-5%.

3. The inhalation pharmaceutical composition according to claim 1, characterized in that: The pH regulator is selected from an inorganic acid aqueous solution, an organic acid aqueous solution or an alkaline solution; the concentration of the pH regulator is 0.01-0.5 mol / L; and the pH value of the inhalation pharmaceutical composition is 4.5-5.

5.

4. The inhalation pharmaceutical composition according to claim 3, characterized in that: The inorganic acid is selected from hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid; The organic acid is selected from acetic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, ascorbic acid, fumaric acid, maleic acid, malic acid, amino acid or tartaric acid; The base is selected from sodium dihydrogen phosphate, sodium carbonate, sodium hydroxide or sodium bicarbonate.

5. The inhalation pharmaceutical composition according to claim 1, characterized in that: The solvent is selected from water, ethanol, ethylene glycol, glycerol, ether or cyclohexane; and the inhalation pharmaceutical composition is a solution preparation for inhalation.

6. The inhalation pharmaceutical composition according to claim 1, characterized in that: The inhalation pharmaceutical composition may further include an osmotic pressure regulator, the mass percentage of which is 0.1 to 5%; further, the osmotic pressure regulator is selected from sodium chloride, glycerol, mannitol, sorbitol, boric acid, glucose or borax; further, the concentration of the osmotic pressure regulator is 0.01 to 0.5 mol / L.

7. A method for preparing an inhalable pharmaceutical composition, the method comprising the following steps: (a) taking 80-90% of the prescribed amount of solvent and adjusting the pH to 4.5-5.5 with a pH adjuster; (b) adding the prescribed amount of active ingredient, stirring to dissolve evenly, and adding solvent to the full amount to obtain a drug solution; (c) sterilizing, filtering and filling to obtain the inhalation pharmaceutical composition.

8. The preparation method according to claim 7, characterized in that: The filtered liquid medicine in step (c) is filled with a plastic bottle blowing, filling and sealing machine to obtain an inhalable pharmaceutical composition; or the filtered liquid medicine is directly filled into a borosilicate glass bottle.

9. The preparation method according to claim 8, characterized in that: The material of the plastic bottle is selected from one or more of low-density polyethylene particles, polypropylene particles, and polyester particles; the sterilization filtration adopts a 0.45 μm polyethersulfone filter or a PP material filter membrane.

10. Use of the inhalation pharmaceutical composition according to any one of claims 1 to 6 or the inhalation pharmaceutical composition prepared by the method according to any one of claims 7 to 9 in preparing a drug for preventing perioperative and postoperative pulmonary complications.

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