Pharmaceutical composition for treating COPD (chronic obstructive pulmonary disease) and preparation method thereof

Abstract

The invention provides a pharmaceutical composition, the pharmaceutical composition comprises active pharmaceutical ingredients, i.e., umequat or a salt thereof, vilanterol or a salt thereof, a pharmaceutically acceptable carrier and an inhalation device, and provides a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in treatment of respiratory system diseases, such as asthma and COPD (chronic obstructive pulmonary disease).

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a pharmaceutical composition of umeclidinium or its salt, vilanterol or its salt and a preparation process thereof. The present invention also relates to the use of the pharmaceutical composition in the treatment of respiratory diseases, such as asthma and COPD. Background Art

[0002] COPD is a common, preventable and treatable heterogeneous disease. It is a chronic respiratory disease characterized by persistent airflow limitation. The most common respiratory symptoms include dyspnea, cough and sputum. The WHO predicts that COPD will become the third leading cause of death in the world by 2030.

[0003] COPD is a preventable and treatable disease characterized by airflow limitation that is not completely reversible. Airflow obstruction is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by smoking. Although COPD affects the lungs, it also produces significant systemic effects.

[0004] Currently, there are several recommended treatment categories for COPD, among which bronchodilators such as β2-agonists and anticholinergics are the main drugs for symptom management of mild and moderate diseases. They are prescribed as needed for mild COPD and as maintenance therapy for moderate COPD. However, for moderate to severe patients, recent clinical studies have shown that the combination of LABA+LAMA is more advantageous than bronchodilators alone in reducing acute exacerbations, improving lung function, and reducing all-cause mortality.

[0005] Umeclidinium is a long-acting muscarinic receptor antagonist (also called an anticholinergic). It is a quinine

[0006] Cyclic derivative with activity against multiple muscarinic receptor subtypes. Umeclidinium exerts its bronchodilator activity by competitively inhibiting the binding of acetylcholine to muscarinic receptors on airway smooth muscle. It exhibits slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in preclinical models.

[0007] Vilanterol is a selective, long-acting β2-adrenergic receptor agonist (β2-adrenergic agonist). The pharmacological effects of β2-adrenergic agonists, including vilanterol, are at least partially attributed to their stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3',5'-monophosphate adenosine (cyclic AMP). Increased cyclic AMP levels lead to relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity reactions in cells, especially mast cells.

[0008] These two compounds have valuable pharmacological properties. Umeclidinium and vilanterol can be used in the treatment of asthma.

[0009] or chronic obstructive pulmonary disease (including chronic bronchitis and emphysema).

[0010] At present, there are some LABA and LAMA combinations on the market, such as the combination of salmeterol and tiotropium bromide. However, existing inhalation preparations still face many challenges in terms of drug stability, dosage accuracy, delivery efficiency, and patient convenience. For example, the physicochemical properties of different drugs may lead to decreased preparation uniformity or insufficient storage stability; differences in inhalation devices can also affect the pressure drop value and lung deposition rate of the drug. In addition, the prior art has not fully addressed how to reduce the deposition of drugs in non-targeted areas while delivering high doses, thereby reducing the risk of side effects. Therefore, it is urgent to develop a LABA+LAMA pharmaceutical composition with better uniformity, fluidity, and lung deposition efficiency. Summary of the invention

[0011] The object of the present invention is to provide a pharmaceutical composition for treating chronic obstructive pulmonary disease (COPD) and a preparation method thereof, characterized in that the active ingredients include vilanterol triphenylacetate and umeclidinium bromide, the active ingredients are present in the pharmaceutical composition at a ratio of 1:1 to 7:1, and glycine / lactose monohydrate of different particle sizes are selected as carriers. Glycine is a white crystalline powder, odorless, sweet, and easily soluble in water. Among the 20 basic amino acids that constitute protein, glycine is the only amino acid whose R side chain is a hydrogen atom, and it is also the only amino acid that does not contain chiral carbon atoms and is not optically active. It has low hygroscopicity, and the hydrogen atoms in its side chain are relatively stable. Lactose monohydrate is usually a white or almost white crystalline powder, odorless, and sweet. Lactose monohydrate generates less static electricity, which can reduce the agglomeration phenomenon caused by electrostatic action between micropowder particles, so that the drug particles can be more evenly dispersed around the carrier. Glycine / lactose monohydrate is used as a carrier, which has high safety and stable quality, and is conducive to improving the dispersibility and lung deposition efficiency of the preparation to ensure the efficacy.

[0012] The technical solution adopted by the present invention is as follows:

[0013] The present invention provides a pharmaceutical composition, which comprises a preparation and a device. The preparation comprises an active pharmaceutical ingredient, and the active pharmaceutical ingredient comprises a combination of umeclidinium or its salt, vilanterol or its salt, preferably umeclidinium bromide and vilanterol triphenylacetate; the preparation further comprises a pharmaceutically acceptable carrier; and the device is a powder mist inhalation device disclosed in CN219423486U.

[0014] The pharmaceutically acceptable carrier of the present invention is selected from one or more commonly used sugars or amino acids, wherein the sugars include arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starch, dextran or mannitol; the amino acids include glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine, preferably lactose monohydrate or glycine, characterized in that the particle size of the fine powder is controlled at D90≤20μm, and the particle size of the coarse powder is controlled within 40-100μm.

[0015] The active ingredients of the pharmaceutical composition of the present invention, vilanterol triphenylacetate and umeclidinium bromide, are in a ratio of 1: 1 to 7: 1, and the particle size D90 of the active ingredients is ≤10um.

[0016] The method for preparing the pharmaceutical composition of the present invention comprises the following steps:

[0017] Step 1) Synthesis of vilanterol triphenylacetate: using phenylacetic acid as a starting material, phenylacetic acid is reacted with a chlorinating agent (such as thionyl chloride) to generate phenylacetyl chloride, which is then reacted with phenol to generate triphenylacetic acid; externally purchased vilanterol is reacted with triphenylacetic acid in a suitable solvent (such as ethanol, isopropanol) to generate vilanterol triphenylacetate.

[0018] Step 2) Micronization of umeclidinium bromide: Control the humidity of the operating environment to 25-45%, preferably 30%, and micronize the mixture by air flow crushing, high-speed grinding, or ball milling.

[0019] Step 3) Micronization of vilanterol triphenylacetate: Control the humidity of the operating environment to 25-45%, preferably 30%, and micronize the product by air flow milling, high-speed grinding, or ball milling.

[0020] Step 4) Preparation of a pharmaceutically acceptable carrier: Control the humidity of the operating environment to 25-45%, preferably 30%, pass the pharmaceutically acceptable carrier crystals that cannot pass through an 80-mesh sieve through a hammer mill equipped with a 0.2 mm screen, and grind to obtain a pharmaceutically acceptable carrier powder; place the pharmaceutically acceptable carrier powder in an ultrasonic vibration sieve equipped with a 90 um screen, and ultrasonically screen to obtain a pharmaceutically acceptable carrier fine powder; place the pharmaceutically acceptable carrier fine powder in an airflow mill, and grind to obtain a pharmaceutically acceptable carrier ultrafine powder.

[0021] Step 5) Detect the particle sizes of umeclidinium bromide ultrafine powder, vilanterol triphenylacetate ultrafine powder and pharmaceutically acceptable carrier ultrafine powder. If the powder passes the test, weigh the powder according to the prescribed amount for later use.

[0022] The above step can be replaced by purchasing a commercially available inhalation pharmaceutical carrier that meets the particle size control requirements.

[0023] Step 6) Controlling the humidity of the operating environment to 25-45%, preferably 30%, the umeclidinium bromide ultrafine powder, the vilanterol triphenylacetate ultrafine powder, and the pharmaceutically acceptable carrier ultrafine powder are mixed by one or more of the following methods: sieving mixing, V-shaped mixing, three-dimensional mixing, shear mixing, etc., preferably shear mixing.

[0024] The composition is mixed, and the weight ratio of vilanterol triphenylacetate: umeclidinium bromide: pharmaceutically acceptable carrier is 1:1 to 7-1000, preferably 1:2.5:550.

[0025] Step 7) The mixed composition is loaded into a gelatin hollow capsule or a hypromellose capsule by quantitative cannula filling or vacuum drum filling, preferably a hypromellose capsule, with a filling amount of 5 to 35 mg.

[0026] Step 8) The filled capsules are packaged in aluminum-plastic packaging to prepare commercially available packaging products.

[0027] The capsule content composition is administered by oral inhalation using an inhalation device and delivered to the lungs. Preferably, a powder mist inhalation device CN219423486U disclosed by Nanchang Hongyi Pharmaceutical Co., Ltd. is used. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with specific examples. The examples given are only for illustrating the present invention, rather than for limiting the scope of the present invention.

[0029] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art.

[0030] In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0031] All fine particle quantity and delivery uniformity tests were conducted using a powder mist inhalation device CN219423486U disclosed by Nanchang Hongyi Pharmaceutical Co., Ltd. unless otherwise specified.

[0032] Example 1: Synthesis of Vilanterol Triphenylacetate

[0033] Using phenylacetic acid as a starting material, phenylacetic acid reacts with thionyl chloride to generate phenylacetyl chloride, which then reacts with phenol to generate triphenylacetic acid; under room temperature, vilanterol reacts with triphenylacetic acid in ethanol to generate a crude product of triphenylacetic acid vilanterol; and triphenylacetic acid vilanterol is purified by crystallization or recrystallization.

[0034] Example 2: Micronization of Vilanterol Triphenylacetate

[0035] The vilanterol triphenylacetate prepared in Example 1 was crushed using a DecJet 30 airflow mill, connected to compressed air with a dew point temperature below -40°C, with an air source pressure greater than 12 bar, the Venturi pressure was adjusted to 11 bar, the rotary pressure was adjusted to 10 bar, and the feed rate was controlled to be 0.5 g per minute. After crushing, the mixture was collected in a drying bottle for later use.

[0036] Example 3: Micronization of Umeclidinium Bromide

[0037] Take the purchased umeclidinium bromide raw material, use DecJet 30 air flow mill, connect to compressed air with a dew point temperature below -40℃ (-41.3℃ on the meter), the air source pressure is greater than 12bar, adjust the Venturi pressure to 11bar, the rotary pressure to 10bar, control the feed rate to 0.5g per minute for grinding, and collect the powder into a drying bottle for later use.

[0038] Example 4: Preparation of glycine carrier:

[0039] Control the operating environment humidity at 35±5%;

[0040] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set to 8000 rpm, the feeding speed set to 25 rpm, and a 0.2 mm screen installed. Glycine (for injection) that could not pass through an 80-mesh screen was put into the hammer mill to obtain glycine powder (to be screened).

[0041] Use RUSSELL's Finex Separator grading screen to install a 90um screen, put in glycine micropowder (to be screened), screen and collect the material under the screen to obtain glycine micropowder.

[0042] Glycine powder was pulverized using a DecJet 100 air flow mill, connected to compressed air with a dew point temperature below -40°C (-42.1°C on the meter), with an air source pressure greater than 6 bar, the Venturi pressure was adjusted to 4 bar, the rotary pressure was 6 bar, and the feed rate was controlled to be 50 g per minute. The glycine ultrafine powder was collected and vacuum packed for later use.

[0043] Example 5: Lactose carrier preparation:

[0044] Control the operating environment humidity at 35±5%

[0045] The D10 of lactose SV001 is 139; D50 is 226; D90 is 312.

[0046] A Quadro U5c hammer mill was used, with the main cutter head crushing speed set to 8000 rpm, the feeding speed set to 25 rpm, and a 0.2 mm sieve installed. Lactose SV001 was put into the hammer mill, and the lactose SV001 powder (to be screened) was obtained.

[0047] Use RUSSELL's Finex Separator grading sieve to install a 90um sieve, put in lactose SV001 micro powder (to be sieved), sieve and collect the sieve to obtain lactose SV001 micro powder.

[0048] The lactose SV001 powder was pulverized using a DecJet 100 air flow mill, connected to compressed air with a dew point temperature below -40°C (-44.7°C on the meter), with an air source pressure greater than 6 bar. The Venturi pressure was adjusted to 4 bar, the rotary pressure was 6 bar, and the feed rate was controlled to be 50 g per minute. The lactose SV001 ultrafine powder was collected and vacuum packed for later use.

[0049] Lactose L100 is commercially available inhaled lactose, with D10 of 58, D50 of 132, and D90 of 214, vacuum packed.

[0050] Lactose L200 is commercially available inhaled lactose, with D10 of 9, D50 of 72, D90 of 149, and vacuum packaging.

[0051] Lactose L201 is commercially available inhaled lactose, with D10 of 3, D50 of 22, and D90 of 59, and is vacuum packed.

[0052] Example 6: Preparation of pharmaceutical composition formulation 1

[0053] Each 10 mg inhalation contains 22 μg of vilanterol triphenylacetate and 55 μg of umeclidinium bromide, see Table 1.

[0054] Table 1: Composition of Prescription 1

[0055] Element Single tablet dosage Total dosage per 100,000 tablets (g) Umeclidinium 55 μg 55 g Vilanterol triphenylacetate 22 μg 22 g Glycine Ultrafine Powder 9.932 mg 993.2 g total 10 mg 1000 g

[0056] Before use, the ultrafine powders of vilanterol triphenylacetate, umeclidinium bromide, and glycine were manually sieved through a 100-mesh sieve in a waterless box (the humidity of the operating environment was controlled to be ≤20%) to destroy agglomerates in the package.

[0057] The humidity of the operating environment was controlled at 30±5%, 1 / 3 of the glycine superfine powder by weight was placed in a high shear mixer and mixed at a low speed of 100 rpm for 30 seconds, vilanterol triphenylacetate, umeclidinium bromide, and 2 / 3 of the glycine superfine powder by weight were placed in the high shear mixer, the mixture was mixed at a high speed of 1500 rpm for 3 minutes, and then mixed at a low speed for 60 seconds before discharging to obtain the umeclidinium bromide and vilanterol composition.

[0058] The humidity of the operating environment was controlled at 35±5%, and the composition was loaded into a gelatin hollow capsule (manufacturer: Suzhou Capsule Co., Ltd.; specification: 3#) by Hanhui vacuum drum filling.

[0059] The filled composition was packaged by Hualian DPH380 aluminum-plastic blister packaging machine within 6 hours, with the heat sealing temperature of 130°C.

[0060] The aluminum-plastic composite is packaged into finished products by manual simulation, and the packaging environment temperature is ≤30℃.

[0061] Example 7: Preparation of Pharmaceutical Composition Formulation 2

[0062] Procedure

[0063] The steps of Example 6 were repeated, except that the dry powder inhalation preparation was prepared using vilanterol triphenylacetate, umeclidinium bromide, and lactose SV001 ultrafine powder according to Table 2 below.

[0064] Each 10mg inhalation contains 22μg of vilanterol triphenylacetate and 55μg of umeclidinium bromide.

[0065] Table 2: Composition of Prescription 2

[0066] Element Single tablet dosage Total dosage per 100,000 tablets (g) Umeclidinium 55 μg 55 g Vilanterol triphenylacetate 22 μg 22 g Glycine Ultrafine Powder 9.932 mg 993.2 g total 10 mg 1000 g

[0067] Example 8: Preparation of pharmaceutical composition formulation 3

[0068] Procedure

[0069] The steps of Example 6 were repeated, except that a dry powder inhalation preparation was prepared using vilanterol triphenylacetate, umeclidinium bromide, and lactose L100 according to Table 3 below.

[0070] Each 10mg inhalation contains 22μg of vilanterol triphenylacetate and 55μg of umeclidinium bromide.

[0071] Table 3: Composition of Prescription 3

[0072] Element Single tablet dosage Total dosage per 100,000 tablets (g) Umeclidinium 55 μg 55 g Vilanterol triphenylacetate 22 μg 22 g Lactose L100 9.932 mg 993.2 g total 10 mg 1000 g

[0073] Example 9: Preparation of Pharmaceutical Composition Formulation 4

[0074] Procedure

[0075] The steps of Example 6 were repeated, except that a dry powder inhalation preparation was prepared using vilanterol triphenylacetate, umeclidinium bromide, and lactose L200 according to Table 4 below.

[0076] Each 10mg inhalation contains 22μg of vilanterol triphenylacetate and 55μg of umeclidinium bromide.

[0077] Table 4: Composition of Prescription 4

[0078] Element Single tablet dosage Total dosage per 100,000 tablets (g) Umeclidinium 55 μg 55 g Vilanterol triphenylacetate 22 μg 22 g Lactose L200 9.932 mg 993.2 g total 10 mg 1000 g

[0079] Example 10: Preparation of Pharmaceutical Composition Formulation 5

[0080] Procedure

[0081] The steps of Example 6 were repeated, except that a dry powder inhalation preparation was prepared using vilanterol triphenylacetate, umeclidinium bromide, and lactose L201 according to Table 5 below.

[0082] Each 10mg inhalation contains 22μg of vilanterol triphenylacetate and 55μg of umeclidinium bromide.

[0083] Table 5: Composition of Prescription 5

[0084] Element Single tablet dosage Total dosage per 100,000 tablets (g) Umeclidinium 55 μg 55 g Vilanterol triphenylacetate 22 μg 22 g Lactose L201 9.932 mg 993.2 g total 10 mg 1000 g

[0085] Example 11: Fine Particle Fraction of Composition

[0086] The inhalation powder aerosol method was used using Device 3 in the "Determination of Aerodynamic Characteristics of Fine Particles of Inhalation Preparations" 0951 of the "Chinese Pharmacopoeia (2020 Edition)". The results are shown in Table 6.

[0087] Table 6: Fine particle fractions of umeclidinium bromide and vilanterol triphenylacetate

[0088] prescription Umeclidinium bromide (%) Vilanterol triphenylacetate (%) Prescription 1 36.65 23.45 Prescription 2 36.83 20.91 Prescription 3 35.76 20.23 Prescription 4 31.02 19.68 Prescription 5 32.91 22.11

[0089] Example 12: Delivery Dosage Uniformity of Compositions

[0090] The two active ingredients, umeclidinium bromide and vilanterol triphenylacetate, were tested using the inhalation powder delivery dose uniformity test method in 0111 inhalation preparations of the "Chinese Pharmacopoeia (2020 Edition)". The results are shown in Table 7.

[0091] Table 7: Tiotropium and salmeterol delivery uniformity

[0092] prescription Umeclidinium bromide (%) Vilanterol triphenylacetate (%) Prescription 1 90.2 91.8 Prescription 2 92.5 88.9 Prescription 3 89.3 90.4 Prescription 4 89.7 92.5 Prescription 5 93.1 90.1

[0093] Example 13: Stability study of the composition

[0094] Preparations 1 to 5 were tested for content determination (limit requirement: 80.0%-105.0% of the labeled amount of umeclidinium bromide, 80.0%-100.0% of the labeled amount of vilanterol triphenylacetate); delivery dose uniformity (limit requirement: 80%-120% of the labeled amount of umeclidinium bromide, 80.0%-100.0% of the labeled amount of vilanterol triphenylacetate); fine drug particle fraction FPF (%) (limit requirement: umeclidinium bromide should be no less than 10% of the labeled amount, vilanterol triphenylacetate should be no less than 10% of the labeled amount) and the results were in compliance with the regulations. The results are shown in Tables 8 and 9.

[0095] Table 8: Accelerated Stability Study Day 0

[0096]

[0097] Table 9: Accelerated stability study for 3 months

[0098]

[0099] Through the above examples, it can be found that the pharmaceutical composition prepared by the present invention has a reasonable prescription, a simple preparation process, and reduces the loss of active drugs in the production process. At the same time, glycine / lactose monohydrate is selected as a carrier, and the uniformity of the dual preparation can be improved by controlling the carrier particle size and adopting a high shear mixing method. Its content, delivery dose uniformity and percentage of fine particles can all meet the requirements. The use of a self-developed drug delivery device can further improve the emptying rate and lung deposition efficiency, providing patients with a more reliable and effective new treatment option.

Claims

1. A pharmaceutical composition, comprising a preparation and a device, wherein the preparation comprises an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient comprises a combination of umeclidinium or its salt, vilanterol or its salt, preferably umeclidinium bromide and vilanterol triphenylacetate; the preparation further comprises a pharmaceutically acceptable carrier; and the device is a powder mist inhalation device disclosed in CN219423486U.

2. The pharmaceutically acceptable carrier according to claim 1 is selected from one or more commonly used sugars or amino acids, wherein the sugars include arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starch, dextran or mannitol; the amino acids include glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine, preferably lactose monohydrate or glycine.

3. The pharmaceutical composition according to claim 1, wherein the ratio of vilanterol triphenylacetate to umeclidinium bromide is 1:1 to 7:

1.

4. The method of the pharmaceutical composition according to any one of claims 1 to 4, comprising the following steps: Step 1) synthesizing vilanterol triphenylacetate; Step 2) micronizing umeclidinium bromide and vilanterol triphenylacetate for later use; Step 3) micronizing an appropriate amount of glycine / lactose monohydrate for later use; Step 4) weighing micronized umeclidinium bromide, vilanterol triphenylacetate and glycine / lactose monohydrate according to a predetermined ratio and mixing them evenly; Step 5) The mixture is filled into capsules and packaged to produce a commercial product.

5. The pharmaceutical composition according to claim 1, characterized in that The particle size D90 of the active ingredient is ≤10 μm.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is preferably glycine or lactose monohydrate, characterized in that The particle size of fine powder is controlled within D90≤20μm, and the particle size of coarse powder is controlled within 40~100μm.

7. The method according to claim 4, characterized in that In step 4, the active ingredient is dispersed in the carrier by a specific mixing method, wherein the specific mixing method is extrusion shear mixing; the extrusion shear mixing is achieved by a device selected from a high-speed stirrer and a high-speed mixer; The speed of the cutting blade or stirring paddle of the device is 100 rpm to 1500 rpm; The gap between the blade of the stirring paddle and the wall of the equipment container is 0.5-1.0 mm.

8. The method according to claim 4 or 7, characterized in that During the micronization process, the humidity of the operating environment is controlled at 25% to 45%, preferably 30%.

9. The method according to any one of claims 4 or 7, characterized in that: The capsule content composition is administered by oral inhalation using a dry powder inhalation device and delivered to the lungs.

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