Rafenasin inhalation solution and preparation method thereof

Abstract

The invention provides a refenasin inhalation solution and a preparation method thereof. The refenasin inhalation solution comprises an active component refenasin, a pH buffer agent, an osmotic pressure regulator and a stabilizer. The stability of the rafenasin inhalation solution under ultrasonic atomization can be remarkably improved, the storage stability is good, and the effect of the better lung deposition rate is achieved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a refenacin inhalation solution and a preparation method. BACKGROUND

[0002] Aerosol inhalation therapy is a direct drug delivery method targeting the respiratory tract and lungs, and is an important treatment for respiratory diseases.

[0003] Aerosol inhalation therapy is a treatment method in which a drug solution is atomized into aerosol particles with a particle size of 0.01-10 μm by using an aerosol inhalation device, and then inhaled into the airway and deposited in the lungs, thereby exerting a disease prevention and treatment effect. It has the advantages of high local drug concentration and few systemic adverse reactions, and is an important means for treating asthma, bronchitis and other respiratory diseases, and relieving acute and chronic respiratory symptoms such as coughing and expectoration.

[0004] Aerosol inhalation is based on air dynamics and particle physics. First, the drug solution is atomized into aerosol particles, and then delivered to the trachea, bronchus and alveoli. Aerosol is a dispersed system in which solid particles or liquid droplets are suspended in a gas. When the aerosol particles are inhaled into the lungs, they contact the respiratory mucosa through mechanisms such as inert impaction, gravitational sedimentation and Brownian motion, and are deposited in the respiratory tract and lungs.

[0005] The drug deposition site is related to the size and speed of the aerosol particles. Larger aerosol particles (particle size > 10 μm) are mainly deposited in the nose and / or oropharynx, aerosol particles with a particle size of 5-10 μm are mainly deposited in the proximal conductive airway of the lower respiratory tract, and aerosol particles with a particle size of 1-5 μm can reach and deposit in the peripheral lung.

[0006] Aerosol inhalation delivers drugs directly to the respiratory mucosa and alveoli, and quickly locates them. Compared with systemic administration, it can avoid damage by the gastrointestinal tract and the first-pass effect of the liver, and has high local tissue drug concentration and fewer systemic adverse reactions. The effective aerosol particle size refers to the diameter of the aerosol particles with therapeutic value that can be deposited in the airway and lungs, and is preferably 3-5 μm.

[0007] In terms of affecting the effectiveness of aerosol inhalation therapy, the main drug factors are: ① particle size: the distribution of inhaled drugs in the lungs depends on the aerodynamic particle size, which is influenced by physical particle size, crystal form, shape, density, etc.; ② molecular weight, oil / water partition coefficient, esterification: the absorption of drugs in the lungs after aerosol inhalation is passive diffusion, so the rate and efficiency of absorption are related to the molecular weight and liposolubility of the drug; ③ receptor affinity and pharmacological activity: the combination of drugs with lung receptors produces beneficial effects, while the combination with lung receptors produces harmful effects.

[0008] Inhalation solution is a liquid preparation for nebulizer, which refers to a solution, suspension and emulsion for aerosol inhalation produced by continuous nebulization. Through continuous nebulization, liquid is converted into aerosol by high-pressure gas, ultrasonic vibration or other methods, so that the inhaled dose can be deposited in the lungs at a certain rate and appropriate particle size. Compared with injection and oral administration, the advantages of drug delivery are rapid and efficient.

[0009] Roflumilast is a long-acting muscarinic antagonist, which is mainly administered by inhalation. It can significantly improve lung function, reduce the clinical symptoms of COPD, and prevent further deterioration of the disease. In 2018, FDA approved roflumilast for maintenance therapy in patients with chronic obstructive pulmonary disease (COPD).

[0010] The current marketed product is roflumilast solution for inhalation, with the trade name Yupelri, and the specification is 3ml:175ug. Each time it needs to be continuously nebulized for 8 minutes, and the lung deposition rate is only 10%~20%.

[0011] Patent CN11763848A discloses an inhalation spray of roflumilast, which takes roflumilast trihydrate as the active ingredient, including solvent, osmotic pressure regulator and preservative. The formula contains preservative, which may cause damage to the epidermis. Patent CN117205186A discloses a roflumilast inhalation spray and its preparation method. The formula does not add an osmotic pressure regulator. SUMMARY

[0012] Based on the prior art, the present application uses glucose as an osmotic pressure regulator, and roflumilast inhalation solution is prepared in combination with the stabilizer trehalose / maltose. The content of 3-5um effective mist particle size is more than 50%, and the stability is good, which has a better lung deposition rate effect. DETAILED DESCRIPTION

[0013] In the following examples, the experimental methods are described, and if not specifically stated, they are all conventional methods. The reagents and materials can be obtained from commercial channels if not specifically stated.

[0014] Example 1: Selection of stabilizer

[0015] Table 1. Composition of formula 1

[0016] Active ingredient Rapacuronium bromide 0.15g pH buffer Citric acid / sodium citrate 1.00g Osmotic pressure regulator Sodium chloride 7.20g Stabilizer Trehalose 1.50g Solvent Water for injection 1000ml

[0017] Table 2. Composition of formula 2

[0018]

[0019]

[0020] Table 3. Composition of formula 3

[0021] Active ingredient Rapacuronium bromide 0.15g pH buffer Citric acid / sodium citrate 1.00g Osmotic pressure regulator Disodium hydrogen phosphate dihydrate 7.20g Stabilizer Lactose 1.50g Solvent Water for injection 1000ml

[0022] Table 4. Composition of Formula 4

[0023] Active ingredient Rapacuronium bromide 0.15g pH buffer Citric acid / sodium citrate 1.00g Osmotic pressure regulator Glucose 7.20g Stabilizer Trehalose 1.50g Solvent Water for injection 1000ml

[0024] Table 5. Composition of Formula 5

[0025] Active ingredient Rapacuronium bromide 0.15g pH buffer Citric acid / sodium citrate 1.00g Osmotic pressure regulator Glucose 7.20g Stabilizer Maltose 1.50g Solvent Water for injection 1000ml

[0026] Table 6. Composition of Formula 6

[0027] Active ingredient Rapacuronium bromide 0.15g pH buffer Citric acid / sodium citrate 1.00g Osmotic pressure regulator Sodium chloride 7.20g Stabilizer / 0 Solvent Water for injection 1000ml

[0028] Table 7. Composition of Formula 7

[0029]

[0030]

[0031] Weigh each material according to Formulas 1-7, stir, and adjust the pH to between 4.5-5.5; sample and test the liquid medicine after passing through a three-stage series of polyether sulfone cartridge filters, and after passing the test, seal, sterilize.

[0032] Example 2 Determination of Osmolality

[0033] Take the products made according to Formulas 1-7, and determine the osmolality according to the method (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0632). The osmolalities are all between 270-350 mOsmol / kg, meeting the product qualification requirements.

[0034] Example 3 Determination of Nebulization Performance

[0035] Determination of Fine Particle Dose Inhalation Preparations Fine Particle Aerodynamic Characteristics (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0951) was determined.

[0036] Precisely measure 2 ml of each of Formulas 1-7, use Device 3, the gas flow rate is 15 L / min (±5%), and nebulize for 2 min. Collect the deposition amounts in the L-shaped connecting tube pre-separator (including the mouthpiece adapter) and each level with water as the blank receiving solution. Dilute the L-shaped connecting tube pre-separator (including the mouthpiece adapter) by 100 times, and dilute the 1st level, 2nd level, 3rd level, 4th level, 5th level, 6th level, 7th level, MOC level, and filter paper by 50 times as the test solution.

[0037] Table 8. Nebulization performance determination results of Formulas 1-7

[0038] Product Delivered dose (mg) FPD (mg) FPF (%) MMAD (μm) Formulation 1 1.760 0.892 50.689 4.718 Formulation 2 1.533 0.800 52.217 4.560 Formulation 3 1.800 0.916 50.862 4.699 Formulation 4 1.561 0.828 53.068 4.512 Formulation 5 1.769 0.932 52.701 4.552 Formulation 6 1.563 0.785 50.253 4.767 Formulation 7 1.645 0.851 51.739 4.588

[0039] Example 4 Stability Test

[0040] The total impurity content of the products prepared from Formulations 1-7 was determined after ultrasonic nebulization for 90 min.

[0041] Table 9. Results of stability test of Formulations 1-7

[0042]

[0043]

[0044] It can be seen from the above that the stability of the inhalation solution of rufinamide prepared with glucose as an osmotic pressure regulator and in combination with the stabilizer trehalose / maltose is better under ultrasonic nebulization conditions.

Claims

1. A refennaxine inhalation solution, characterized in that, The inhalation solution comprises refennaxine, a pH buffer, an osmotic pressure regulator, a stabilizer, and a solvent, wherein the pH buffer is citric acid / sodium citrate.

2. The revannacin inhalation solution according to claim 1, characterized in that, The mass ratio of the stabilizer to refennaxine is 10:

1. Preferably, the stabilizer can be one of trehalose and maltose.

3. The revannacin inhalation solution according to claim 1, characterized in that, The mass ratio of the osmotic pressure regulator to revanasin is 48:

1. Preferably, the osmotic pressure regulator is glucose.

Images