Vilanterol triphenylacetate inhalation solution and preparation method thereof

Abstract

The present invention provides a solution of vilanterol triphenylacetate for inhalation, a preparation method and an application thereof, wherein the inhalation solution comprises an active substance, a solvent and an excipient. The single-dose specification of the inhalation solution is 1 ml, and the single-dose specification comprises 15 to 50 μg / mL of vilanterol triphenylacetate and / or its hydrate as an active substance; the solvent is water for sterile injection, and the excipients comprise an osmotic pressure regulator and a pH regulator, the osmotic pressure regulator has a concentration of 5 to 9 mg / ml, and the pH regulator is added to make the pH value of the inhalation solution preparation be 5.0 to 7.0. The solution of the present invention is packaged in a single dose, does not contain a preservative, is safe and convenient to use, and is used in combination with a liquid nebulizer to provide a safe, effective and stable pharmaceutical dosage form and drug delivery system for inhalation of vilanterol triphenylacetate.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a vilanterol triphenylacetate inhalation solution and a preparation method thereof. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by airflow limitation that is not fully reversible. It has a large number of patients and a high mortality rate. According to the data from the World Health Organization (WHO), there are currently 600 million people suffering from this disease worldwide, and it will become the third leading cause of death in the world by 2020. In China, there are more than 43 million patients, 1.28 million of whom die from this disease each year, with a mortality rate of 17.6%, which has exceeded the mortality rate and number of deaths from coronary heart disease. On average, 2.5 people die from it every minute.

[0003] According to the 2013 Chinese Medical Association Guidelines for the Diagnosis and Treatment of COPD, the treatment drugs include: bronchodilators, glucocorticoids, phosphodiesterase-4 (PDE-4) and other drugs. Bronchodilators are the main treatment measures for controlling COPD symptoms. They can relax bronchial smooth muscles, dilate bronchi, and relieve airflow limitation. Short-term on-demand use can relieve symptoms, and long-term regular use can prevent and alleviate symptoms and increase exercise endurance.

[0004] Vilanterol is a highly selective, long-acting β2 receptor agonist with 24h activity. Studies have found that Vilanterol can activate the intracellular adenylate cyclase system, inhibit smooth muscle contraction, and relieve smooth muscle spasm.

[0005] The currently approved Vilanterol inhalation preparations are all compound preparations, including Anoro Umeclidinium / vilanterol inhalation powder for long-term maintenance treatment of chronic obstructive pulmonary disease, bronchitis, and emphysema; Breo Fluticasone furoate / vilanterol inhalation powder is used to treat reversible obstructive airway disease in adults over 18 years old. The vilanterol single powder developed by GlaxoSmithKline is in Phase III clinical trials and has not yet been launched on the market; in addition, the powder needs to rely on the patient's large inspiratory flow rate to start atomization, and the patient cannot achieve drug delivery under normal breathing conditions, so it is not suitable for children, the elderly and other patients who have difficulty breathing actively.

[0006] In summary, the vilanterol preparations disclosed in the prior art have certain defects. Therefore, it is an urgent problem to be solved by those skilled in the art to develop a vilanterol preparation suitable for infants and young children without autonomous inhalation ability and patients with active breathing difficulties, which can directly act on the lesion site, is non-irritating, has a simple preparation process, and has good stability. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides a vilanterol triphenylacetate inhalation solution and a preparation method and application thereof. The present invention aims to solve the deficiencies in the prior art to a certain extent and provides the following technical solutions:

[0008] In a first aspect, the present invention provides a vilanterol triphenylacetate solution for inhalation, comprising an active substance, a solvent and an excipient.

[0009] The active substance contained in the single-dose specification of the inhalation solution is vilanterol triphenylacetate and / or its hydrate in an amount of 15 to 50 μg / mL, preferably 25 to 40 μg / mL;

[0010] The single dose specification of the inhalation solution is 1 to 5 ml, preferably, the single dose specification is 1 ml;

[0011] The solvent is sterile water for injection;

[0012] The auxiliary materials include an osmotic pressure regulator and a pH regulator;

[0013] The concentration of the osmotic pressure regulator is 5 to 9 mg / ml;

[0014] The pH regulator is added in an amount such that the pH value of the inhalation solution is 5.0 to 7.0;

[0015] The osmotic pressure regulator may be selected from one or more of sodium chloride, magnesium chloride, potassium chloride and calcium chloride, preferably sodium chloride;

[0016] The pH adjuster is a buffer combination, which can be selected from one or more of citric acid-sodium citrate, acetic acid-sodium acetate, disodium bicarbonate-potassium dihydrogen phosphate, lactic acid-sodium lactate, tartaric acid-sodium tartrate, preferably citric acid-sodium citrate.

[0017] In a second aspect, the present invention also provides a method for preparing a vilanterol triphenylacetate inhalation solution, comprising the following steps:

[0018] Step 1: Take 60% to 80% of the total amount of solvent required to prepare the solution at 70 to 80°C;

[0019] Step 2: Weigh vilanterol triphenylacetate and / or its hydrate, osmotic pressure regulator, and pH regulator into the solvent of step 1, and stir until they are completely dissolved;

[0020] Step 3: Add the solvent to the full amount and stir to mix evenly;

[0021] Step 4: Use 0.45 μm filter membrane for primary filtration and 0.22 μm filter membrane for fine filtration, both are sterile filtration, and fill into 1 ml ampoule.

[0022] On the other hand: the present invention provides an inhalation system for atomizing a vilanterol triphenylacetate solution and administering it to human respiratory tract, comprising a vilanterol triphenylacetate solution for inhalation and a liquid atomizer;

[0023] After the vilanterol triphenylacetate solution is atomized,

[0024] The delivery rate of active ingredient is >5.5 μg / min,

[0025] Its aerodynamic mass median diameter (MMAD) is between 3 and 5 μm.

[0026] The effective deposition rate of fine particle ions (FPF) is >60%.

[0027] Beneficial Effects

[0028] 1. Compared with other dosage forms, the drug reaches the target organ directly, avoiding the first-pass effect of the liver and the damage and degradation of the gastrointestinal tract. At the same time, due to targeted delivery, the drug concentration is reduced, which reduces the damage to systemic organs, especially the liver and kidneys, and makes the medication safer. Compared with existing dry powder inhalers, it is more suitable for the elderly, children and patients who have no autonomous inhalation ability and active breathing difficulties.

[0029] 2. Through creative screening, a pH buffer system combination was selected to solve the technical problem of the instability of the pure aqueous solution of vilanterol triphenylacetate, so that the various test indicators of the preparation did not change significantly after long-term storage, ensuring the safety and stability of the product.

[0030] 3. The use of single-dose small packages can avoid the disadvantages of repeated measurement and repeated dilution of multi-dose large-package solutions, which is prone to breeding microorganisms. The production process is simple and can be mass-produced on an industrial scale. DETAILED DESCRIPTION

[0031] In order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can be implemented equally without certain specific details. The following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Any equivalent replacement in this area carried out according to the content of the present invention belongs to the protection scope of the present invention.

[0032] Hereinafter, each component constituting the vilanterol triphenylacetate solution for inhalation of the present invention will be described.

[0033]

Vilanterol triphenylacetate and / or its hydrate

[0034] The vilanterol triphenylacetate solution-type inhalation preparation of this embodiment contains 15 to 50 μg / mL, preferably 25 to 40 μg / mL, of vilanterol triphenylacetate and / or its hydrate, all calculated as vilanterol.

[0035] When the content of the vilanterol triphenylacetate solution for inhalation of the present invention is within the above range, it is used for maintenance treatment of adult asthma and chronic obstructive pulmonary disease (COPD) patients.

[0036] [Osmotic pressure regulator]

[0037] The inventors screened many isotonic regulators such as sodium chloride, magnesium chloride, potassium chloride, calcium chloride, glucose, etc. Glucose was not selected because it has poor thermal stability and its solution becomes acidic after degradation, and it is easy to react with vilanterol triphenylacetate, which affects the product quality.

[0038] The concentration of the osmotic pressure regulator is 5 to 9 mg / ml, which can make the osmotic pressure of the vilanterol triphenylacetate inhalation solution preparation reach isotonicity, reduce the irritation to the mucous membrane during use, and help the product exert its medicinal effect.

[0039]

pH adjuster

[0040] Study on the stability of vilanterol triphenylacetate aqueous solution at different pH values

[0041] The pH value was adjusted by using 0.1M hydrochloric acid and / or sodium hydroxide to prepare aqueous solutions of vilanterol triphenylacetate at different pH values, and the stability of the vilanterol triphenylacetate solution at different pH values ​​after 24 hours was investigated. The results are shown in Table 1:

[0042] Table 1 Stability test results of vilanterol triphenylacetate aqueous solution

[0043]

[0044] As shown in the table above, when the vilanterol triphenylacetate solution is adjusted to different pH values ​​by hydrochloric acid or sodium hydroxide, oily substances appear in the solution when the pH value is below 4.0 after 24 hours at room temperature, and precipitation occurs in the solution when the pH value is above 8.0. When the pH value is between 5.0 and 7.0, the solution is a colorless clear liquid, but after 24 hours of storage, the pH value of the solution fluctuates greatly.

[0045] In summary, solubility and stability become a pair of major contradictions in the preparation process of vilanterol triphenylacetate solution, so it is considered to add a buffer system to the solution preparation prescription of the present invention. For this purpose, the inventors have devoted a lot of creative work to screen a combination of numerous pharmaceutical excipients and buffer regulators of the liquid system so that the solution preparation prescription can simultaneously meet the requirements of solubility and stability.

[0046] Hereinafter, the present invention will be described in detail with reference to examples, but the protection scope of the present invention is not limited thereto.

[0047] Example 1

[0048] Prescription composition

[0049] name composition Vilanterol triphenylacetate 25mg (based on vilanterol) Sodium chloride 9g Citric acid 0.05g Sodium Citrate 1g Add water for injection to 1000ml

[0050] Preparation method:

[0051] Add 500 ml of water for injection into the dispenser, control the water temperature to 75°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use a 0.45μm filter membrane for primary filtration and a 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0052] Example 2

[0053] Prescription composition

[0054]

[0055]

[0056] Preparation method:

[0057] Add 800 ml of water for injection into the dispenser, control the water temperature to 75°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use 0.45μm filter membrane for primary filtration and 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0058] Example 3

[0059] Prescription composition

[0060] name composition Vilanterol triphenylacetate 30mg (based on vilanterol) Sodium chloride 8g Citric acid 0.05g Sodium Citrate 0.85g Add water for injection to 1000ml

[0061] Add 500 ml of water for injection into the dispenser, control the water temperature at 80°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use a 0.45μm filter membrane for primary filtration and a 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0062] Example 4

[0063] Prescription composition

[0064] name composition Vilanterol triphenylacetate 40mg (based on vilanterol) Sodium chloride 9g Citric acid 0.05g Sodium Citrate 0.70g Add water for injection to 1000ml

[0065] Preparation method:

[0066] Add 500 ml of water for injection into the dispenser, control the water temperature at 80°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use a 0.45μm filter membrane for primary filtration and a 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0067] Example 5

[0068] Prescription composition

[0069] name composition Vilanterol triphenylacetate 40mg (based on vilanterol) Sodium chloride 8g tartaric acid 0.07g Sodium tartrate 0.12g Add water for injection to 1000ml

[0070] Preparation method:

[0071] Add 500 ml of water for injection into the dispenser, control the water temperature at 80°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use a 0.45μm filter membrane for primary filtration and a 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0072] Example 6

[0073] Prescription composition

[0074] name composition Vilanterol triphenylacetate 25mg (based on vilanterol) Sodium chloride 5g Sodium bicarbonate 0.03g Sodium dihydrogen phosphate 0.08g Add water for injection to 1000ml

[0075] Preparation method:

[0076] Add 500 ml of water for injection into the dispenser, control the water temperature to 70°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use a 0.45μm filter membrane for primary filtration and a 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0077] Example 7

[0078] Prescription composition

[0079] name composition Vilanterol triphenylacetate 25mg (based on vilanterol) Sodium chloride 8g Citric acid 0.03g Sodium Citrate 1.25g Add water for injection to 1000ml

[0080] Preparation method:

[0081] Add 800 ml of water for injection into the dispenser, control the water temperature to 75°C, add the raw and excipients into the water for injection, stir until they are completely dissolved, add water for injection to the full amount, stir to mix evenly; use 0.45μm filter membrane for primary filtration and 0.22μm filter membrane for fine filtration, both are sterile filtration, and package and seal in ampoules.

[0082] Example 8 Prescription pH Screening Test

[0083] Samples were prepared using the basic formula in Example 1, the dosages of citric acid and sodium citrate were adjusted, and the stability of the preparations under different pH conditions was investigated. The results are shown in Table 2:

[0084] Table 2 Results of the influencing factors of pH screening test for 10 days

[0085]

[0086] As can be seen from the above table, by comparing the solution of vilanterol triphenylacetate for inhalation before and after being placed at room temperature for 10 days, it was found that when the pH value of the solution was between 5 and 7, the solution was still a colorless clear liquid after being placed at room temperature for 10 days, and the pH value was within a small fluctuation range, indicating that the solution had good stability.

[0087] Example 9 Investigation of different liquid preparation temperatures

[0088] Referring to the prescription and preparation method of Example 1, four preparation temperatures of 30, 60, 70, and 80°C were investigated, and after stirring and keeping warm for 5 hours, the samples were tested for related substances. The results are shown in Table 3:

[0089] Table 3 Investigation results of different liquid preparation temperatures

[0090]

[0091] Through experimental phenomena, we know that the dissolution rate is slow at 30℃, and stirring for 180 minutes cannot dissolve all the samples. Stirring at 60℃ for 180 minutes can dissolve all the samples. Stirring at 70℃ and 80℃ for 120 minutes can dissolve all the samples. Combined with the above table, it can be seen that there is no obvious difference in the related substances of the drug solution after 5 hours of heat preservation when preparing the solution at different temperatures, but the preparation time can be greatly shortened at a preparation temperature of 70-80℃.

[0092] Experimental Example 10 Stability test of vilanterol triphenylacetate inhalation solution

[0093] The specific determination method of vilanterol triphenylacetate content and related substances is as follows:

[0094] Use octadecylsilane bonded silica gel as filler (Agilent Poroshell 120EC-C18150mm*4.6mm, 4μm or chromatographic column with equivalent performance); acetonitrile-water (15:85, containing 0.1% trifluoroacetic acid) as mobile phase A, acetonitrile-water (80:20, containing 0.1% trifluoroacetic acid) as mobile phase B, column temperature is 40℃; flow rate is 0.8ml / min; detection wavelength is 220nm, the theoretical plate number calculated based on the vilanterol peak should be not less than 6000, and gradient elution is performed according to the table below.

[0095]

[0096]

[0097] Study on the stability of vilanterol triphenylacetate inhalation solution

[0098] According to Examples 1-7 of the present application, samples of vilanterol inhalation solution were prepared, and samples were placed at the same time to determine the factors affecting stability. The results of the determination are shown in Table 4:

[0099] Table 4 Stability test data of samples in various examples

[0100]

[0101] It can be seen from the stability test results of each embodiment that under the prescription composition and preparation process conditions protected by the present invention, the pH value of the prepared vilanterol inhalation solution can still be maintained at 5 to 7 after being placed for 3 months, and the total amount of related substances in the solution is <1.5%, indicating good stability.

[0102] Example 11 Nebulization Performance Measurement-Delivery Rate and Total Delivery

[0103] Using a Bairui nebulizer (compressed air atomization), the vilanterol inhalation solutions of Examples 1 to 5 were placed in a weighed nebulizer, accurately weighed, and then atomized until no mist was released. The nebulizer was accurately weighed again to calculate the delivery rate, total delivery amount, aerosol loss, nebulizer cup residue, equilibrium recovery rate, and output drug amount. The results are shown in Table 5:

[0104] Table 5 Delivery rate-delivery total amount measurement data of each example

[0105]

[0106] Note: Each group of samples was tested 10 times in parallel.

[0107] It can be seen from the above table that the total amount of atomization delivery of the prepared samples according to the set parameters is high, and the residual amount in the atomization cup is low, which meets the requirements.

[0108] Example 12 Atomization Performance Determination - Fine Particle Dosage

[0109] Using a Bairui nebulizer (compressed air atomization), the vilanterol inhalation solutions of Examples 1 to 5 above were taken respectively and placed in the nebulizer. The FPF% and MMAD values ​​of the examples were measured by NGI at a set airflow pressure (5 bar) and a set flow rate (15±0.75 L / min). The measurement results are shown in Table 6:

[0110] Table 6 Micro-ion dose measurement data of each example

[0111]

[0112]

[0113] Note: Each group of samples was tested in parallel 3 times.

[0114] It can be seen from the above table that the prepared samples have a nebulized fine particle dose FPF%>60% according to the set parameters, and the particle distribution is between 3 and 5μm, which meets the requirements of nebulized inhalation solution.

[0115] The present invention is described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method and core idea of ​​the present invention. It should be pointed out that for ordinary technicians in this field, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A vilanterol triphenylacetate solution for inhalation, characterized in that: The active substance comprises 15 to 50 μg / mL of vilanterol triphenylacetate and / or its hydrate, solvent and excipients; The solvent is water for sterile injection, and the excipients include an osmotic pressure regulator and a pH regulator; The pH regulator is added in an amount such that the pH value of the inhalation solution is 5.0 to 7.0; The pH adjuster is a buffer combination, which can be selected from citric acid-sodium citrate or tartaric acid-sodium tartrate.

2. The vilanterol triphenylacetate solution for inhalation according to claim 1, characterized in that: The active substance is 25-40 μg / mL of vilanterol triphenylacetate and / or its hydrate.

3. The vilanterol triphenylacetate solution for inhalation according to claim 1, characterized in that: The single dose specification of the inhalation solution is 1 to 5 ml.

4. The vilanterol triphenylacetate solution for inhalation according to claim 3, characterized in that: The single dose size is 1 ml.

5. The vilanterol triphenylacetate solution for inhalation according to claim 1, characterized in that: The concentration of the osmotic pressure regulator is 5 to 9 mg / ml.

6. The vilanterol triphenylacetate solution for inhalation according to claim 1, characterized in that: The osmotic pressure regulator can be selected from one or more of sodium chloride, magnesium chloride, potassium chloride and calcium chloride.

7. The vilanterol triphenylacetate solution for inhalation according to claim 6, characterized in that: The osmotic pressure regulator is sodium chloride.

8. The method for preparing the vilanterol triphenylacetate solution for inhalation according to any one of claims 1 to 7, characterized in that: The following steps are involved: Step 1: Take 60% to 80% of the total amount of solvent required to prepare the solution at 70 to 80°C; Step 2: Weigh vilanterol triphenylacetate and / or its hydrate, isotonic agent, and pH adjuster into the solvent of step 1, and stir until they are completely dissolved; Step 3: Add the solvent to the full amount and stir to mix evenly; Step 4: Use 0.45 μm filter membrane for primary filtration and 0.22 μm filter membrane for fine filtration, both are sterile filtration, and fill into 1 ml ampoule.

9. An inhalation system for atomizing a vilanterol triphenylacetate solution and administering it to human respiratory tract, comprising the vilanterol triphenylacetate solution for inhalation according to any one of claims 1 to 7 and a liquid nebulizer; after the vilanterol triphenylacetate solution is atomized, the delivery rate of the active ingredient is >5.5 μg / min, the aerodynamic mass median diameter (MMAD) thereof is between 3 and 5 μm, and the fine particle ion effective deposition rate (FPF) is >60%.

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