CN107569474A - Preparation method of carrier used in a pharmaceutical composition in the form of inhalable dry powder - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to a method for preparing a carrier for use in an inhalable dry powder pharmaceutical composition. The preparation method of the present invention comprises mixing magnesium stearate with lactose particles in a ball mill to prepare the carrier. The resulting carrier does not suffer from particle grinding and crushing. Compared to carriers obtained by directly mixing magnesium stearate with lactose particles, and compared to carriers prepared using a high-shear mixing granulator, the method not only significantly increases the effective deposition rate of drugs in the lungs of inhalable powder aerosols, but also significantly reduces the degradation of certain drugs, thereby improving drug stability.

Description

Preparation method of carrier used in a pharmaceutical composition in the form of inhalable dry powder

technical field

The invention belongs to the technical field of medicine, and relates to a preparation method of a carrier used in an inhalable dry powder pharmaceutical composition, in particular to a preparation method of a carrier used in an inhalable powder aerosol.

Background technique

Inhalation powder, also known as dry powder inhaler (DPI), is a new dosage form developed on the basis of quantitative inhalation aerosol and the knowledge of powder engineering. It is a micronized drug alone or mixed with a carrier. , through a special drug delivery device, through the active inhalation of the patient, the drug is atomized into an aerosol and then enters the respiratory tract to exert a local or systemic effect.

The physiological structure of the lungs determines that the size of the drug particles entering the lungs needs to be strictly controlled. According to the requirements of the 2015 edition of the "Chinese Pharmacopoeia" Four General Rules 0111 Inhalation Preparations "The particle size of raw materials in inhalation preparations should usually be controlled below 10 μm, of which Most of them should be below 5 μm”, so in the formulation research of inhalation powder and aerosol, the micronization of the drug and the particle size range of the drug should be strictly required. Due to the high surface free energy of the drug after micronization, the particles are easy to aggregate into agglomerates, have high adhesion and poor fluidity, and cannot be effectively inhaled and administered. Therefore, in the formulation design of inhalation powders, some carriers are often added, which can be used as diluents to adsorb drug particles and improve the powder properties of dry powders. The most commonly used carriers are carbohydrates such as lactose and mannitol, among which lactose is the only dry powder inhaler carrier approved by the FDA. When the patient inhales, the shear force generated by air turbulence separates the drug from the carrier. Particles smaller than 5 μm can enter the lower respiratory tract, while large particle carriers or drugs fall into the mouth and throat.

Lactose is combined with drug particles through van der Waals force, electrostatic adsorption force, and capillary force. These forces directly affect the desorption ability of the drug and lactose, and then affect the deposition and distribution of the effective part of the drug in the respiratory tract. The carrier makes it easier for the drug to desorb with the carrier during the nebulization process, which can effectively improve the effective deposition rate of the drug in the lungs. This step is very important and critical. In addition, stability is very important for inhalation powders, and the development of stable inhalation powders is one of the primary goals of those skilled in the art.

CN102858326A discloses that magnesium stearate can change the surface properties of carrier particles, and a high-shear mixing granulator based on friction behavior is used to coat magnesium stearate on lactose particles to prepare carriers. The key of the present invention is to prepare the carrier by using a ball mill, which is beneficial in improving the effective deposition rate of the drug in the lung and improving the stability of the drug, and significantly improves the performance of the drug preparation.

Contents of the invention

In one aspect, the present invention provides a method for preparing a carrier used in a pharmaceutical composition in the form of inhalable dry powder, the method comprising: mixing magnesium stearate and lactose granules in a ball mill.

Wherein the d(v0.5) of the lactose granules is 5-800 microns, preferably 20-500 microns, more preferably 30-200 microns, most preferably 35-150 microns; in some embodiments of the present invention, the lactose granules The d(v0.5) is 50-100 microns.

wherein the d (v0.9) of the lactose particles is 10-1000 microns, preferably 30-600 microns, more preferably 80-300 microns, most preferably 100-180 microns; in some embodiments of the present invention, lactose The particles have a d(v0.9) of 120-160 microns.

In some embodiments of the present invention, the particle size distribution of the lactose particles is as follows: d(v0.1) is 5-15 microns, d(v0.5) is 50-100 microns, d(v0.9) is 120- 160 microns.

Wherein the lactose is selected from α-lactose or β-lactose or a solvate thereof, preferably α-lactose or a solvate thereof, most preferably α-lactose monohydrate.

Wherein the weight of magnesium stearate is 0.05%-1.5% of carrier, preferably 0.1-1.0%; In some embodiments of the present invention, the weight of magnesium stearate can be 0.1-0.5%, 0.1-0.3% of carrier %, 0.3-1.0%, 0.3-0.5% or 0.5-1.0%; in some specific embodiments of the present invention, the weight of the magnesium stearate is 0.1%, 0.3%, 0.5% or 1% of the carrier.

Wherein the rotation speed of the container of the ball mill is 15-960rpm, preferably 60-600rpm, more preferably 120-530rpm, most preferably 240-500rpm; in some embodiments of the present invention, the rotation speed of the container of the ball mill is 480rpm .

Wherein ball mill can select suitable grinding medium according to needs, and the material of described grinding medium comprises metal and nonmetal, is preferably nonmetal, and the shape of grinding medium can be spherical or quasi-spherical, and in some specific embodiments of the present invention, grinding The medium is an agate ball.

Wherein the grinding medium can be selected with an appropriate size according to needs, for example, when the grinding medium is spherical, the diameter of the grinding medium is not greater than 2 cm, preferably not greater than 1 cm.

Preferably, the ball mill is a planetary ball mill; in some embodiments of the present invention, the planetary ball mill is a QM-3SP4 planetary ball mill or a QM-1SP4 planetary ball mill.

Wherein the rotation speed of the container of the planetary ball mill is 30-600rpm, preferably 120-530rpm, more preferably 240-500rpm, in some specific embodiments of the present invention, the rotation speed of the planetary ball mill is 480rpm.

The revolution speed of the container of the planetary ball mill is 15-240rpm, preferably 60-265rpm, more preferably 120-250rpm, and in some specific embodiments of the present invention, the revolution speed of the planetary ball mill is 240rpm.

In other specific embodiments of the present invention, the rotational speed ratio of the planetary ball mill's rotation to revolution is 2:1.

Wherein the mixing time is not more than 360 minutes, preferably 5-120 minutes, more preferably 30-90 minutes, and in some specific embodiments of the present invention, the mixing time is 60 minutes.

Wherein the pharmaceutical composition comprises a carrier and one or more active ingredients.

Wherein the carrier is such that after the carrier and the active ingredient are mixed, the pulmonary deposition rate of the active ingredient is not less than 30%.

Wherein at least one active ingredient is selected from β2-agonists, muscarinic antagonists or corticosteroids, preferably, at least one active ingredient is selected from β2-agonists; in some embodiments of the present invention, the pharmaceutical combination The composition comprises a carrier and more than one active ingredient, wherein at least one active ingredient is selected from a β2-agonist, and at least another active ingredient is selected from a muscarinic antagonist or a corticosteroid.

It should be understood that the active ingredient may also be other drugs suitable for preparation into a pharmaceutical composition in the form of inhalable dry powder, such as some anti-inflammatory drugs or drugs for treating chronic obstructive pulmonary disease, chronic bronchitis, emphysema or asthma.

Wherein the β2-agonist is selected from terbutaline, vilanterol (vilanterol), ripterol, albuterol, salmeterol, formoterol, camoterol, miviterol, indacaterol, Odaterol, fenoterol, clenbuterol, bambuterol, bromoxaterol, epinephrine, isoproterenol or hysonaline or their salt and/or solvate forms, preferably vitamin Lanbuterol or a salt and/or solvate form thereof, most preferably vilanterol triphenylacetate or a solvate form thereof.

Wherein the muscarinic antagonist is selected from tiotropium bromide, umeclidinium bromide (umeclidinium bromide), ipratropium bromide, oxygentropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salts and/or solvents Compound form, preferably umeclidinium bromide or its salt and/or solvate form.

Wherein the corticosteroid is selected from the group consisting of rofluconide, flunisolide budesonide, ciclesonide, mometasone and its esters (ie furoate), fluticasone and its esters (ie propionate and furoate ), beclomethasone and its esters (ie propionate), loteprednol or triamcinolone acetonide or their salts and/or solvate forms, preferably fluticasone furoate.

Wherein the pharmaceutical composition in the form of inhalable dry powder is an inhalable powder mist.

In another aspect, the present invention provides a carrier for a pharmaceutical composition in the form of inhalable dry powder, said carrier comprising magnesium stearate and lactose granules, said carrier passing the pharmaceutical composition in the form of inhalable dry powder as described above in the present invention The preparation method of the carrier used in the composition is prepared.

Wherein the pharmaceutical composition comprises a carrier and one or more active ingredients.

Wherein at least one active ingredient is selected from β2-agonists, muscarinic antagonists or corticosteroids, preferably, at least one active ingredient is selected from β2-agonists; in some embodiments of the present invention, the pharmaceutical combination The composition comprises a carrier and more than one active ingredient, wherein at least one active ingredient is selected from a β2-agonist, and at least another active ingredient is selected from a muscarinic antagonist or a corticosteroid.

Wherein the β2-agonist is selected from terbutaline, vilanterol (vilanterol), ripterol, albuterol, salmeterol, formoterol, camoterol, miviterol, indacaterol, Odaterol, fenoterol, clenbuterol, bambuterol, bromoxaterol, epinephrine, isoproterenol or hysonaline or their salt and/or solvate forms, preferably vitamin Lanbuterol or a salt and/or solvate form thereof, most preferably vilanterol triphenylacetate or a solvate form thereof.

Wherein the muscarinic antagonist is selected from tiotropium bromide, umeclidinium bromide (umeclidinium bromide), ipratropium bromide, oxygentropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salts and/or solvents Compound form, preferably umeclidinium bromide or its salt and/or solvate form.

Wherein the corticosteroid is selected from the group consisting of rofluconide, flunisolide budesonide, ciclesonide, mometasone and its esters (ie furoate), fluticasone and its esters (ie propionate and furoate ), beclomethasone and its esters (ie propionate), loteprednol or triamcinolone acetonide or their salts and/or solvate forms, preferably fluticasone furoate.

Wherein the carrier is such that after the carrier and the active ingredient are mixed, the pulmonary deposition rate of the active ingredient is not less than 30%.

Wherein the pharmaceutical composition in the form of inhalable dry powder is an inhalable powder mist.

In yet another aspect, the present invention provides a pharmaceutical composition in the form of an inhalable dry powder, the pharmaceutical composition comprising a carrier and one or more active ingredients, wherein the carrier is inhalable as described above in the present invention. The method for preparing the carrier used in the pharmaceutical composition in the form of dry powder is prepared.

Wherein at least one active ingredient is selected from β2-agonists, muscarinic antagonists or corticosteroids, preferably, at least one active ingredient is selected from β2-agonists; in some embodiments of the present invention, the pharmaceutical combination The composition comprises a carrier and more than one active ingredient, wherein at least one active ingredient is selected from a β2-agonist, and at least another active ingredient is selected from a muscarinic antagonist or a corticosteroid.

Wherein the β2-agonist is selected from terbutaline, vilanterol (vilanterol), ripterol, albuterol, salmeterol, formoterol, camoterol, miviterol, indacaterol, Odaterol, fenoterol, clenbuterol, bambuterol, bromoxaterol, epinephrine, isoproterenol or hysonaline or their salt and/or solvate forms, preferably vitamin Lanbuterol or a salt and/or solvate form thereof, most preferably vilanterol triphenylacetate or a solvate form thereof.

Wherein the muscarinic antagonist is selected from tiotropium bromide, umeclidinium bromide (umeclidinium bromide), ipratropium bromide, oxygentropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salts and/or solvents Compound form, preferably umeclidinium bromide or its salt and/or solvate form.

Wherein the corticosteroid is selected from the group consisting of rofluconide, flunisolide budesonide, ciclesonide, mometasone and its esters (ie furoate), fluticasone and its esters (ie propionate and furoate ), beclomethasone and its esters (ie propionate), loteprednol or triamcinolone acetonide or their salts and/or solvate forms, preferably fluticasone furoate.

The pharmaceutical composition described therein is the same as the pharmaceutical composition described in the preparation method of the carrier used in the pharmaceutical composition in the form of inhalable dry powder as described above in the present invention.

Wherein the carrier is such that after the carrier and the active ingredient are mixed, the pulmonary deposition rate of the active ingredient is not less than 30%.

Wherein the pharmaceutical composition in the form of inhalable dry powder is an inhalable powder mist.

In yet another aspect, the present invention provides a method for preparing a pharmaceutical composition in the form of an inhalable dry powder, the method comprising mixing a carrier with one or more than one active ingredient, and the carrier is formulated as described above in the present invention. The preparation method of the carrier used in the pharmaceutical composition in the form of inhalable dry powder is prepared.

Wherein at least one active ingredient is selected from β2-agonists, muscarinic antagonists or corticosteroids, preferably, at least one active ingredient is selected from β2-agonists; in some embodiments of the present invention, the pharmaceutical combination The composition comprises a carrier and more than one active ingredient, wherein at least one active ingredient is selected from a β2-agonist, and at least another active ingredient is selected from a muscarinic antagonist or a corticosteroid.

When there are more than one active ingredient, the carrier may be mixed with each active ingredient separately, and then mixed.

Wherein the β2-agonist is selected from terbutaline, vilanterol (vilanterol), ripterol, albuterol, salmeterol, formoterol, camoterol, miviterol, indacaterol, Odaterol, fenoterol, clenbuterol, bambuterol, bromoxaterol, epinephrine, isoproterenol or hysonaline or their salt and/or solvate forms, preferably vitamin Lanbuterol or a salt and/or solvate form thereof, most preferably vilanterol triphenylacetate or a solvate form thereof.

Wherein the muscarinic antagonist is selected from tiotropium bromide, umeclidinium bromide (umeclidinium bromide), ipratropium bromide, oxygentropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salts and/or solvents Compound form, preferably umeclidinium bromide or its salt and/or solvate form.

Wherein the corticosteroid is selected from the group consisting of rofluconide, flunisolide budesonide, ciclesonide, mometasone and its esters (ie furoate), fluticasone and its esters (ie propionate and furoate ), beclomethasone and its esters (ie propionate), loteprednol or triamcinolone acetonide or their salts and/or solvate forms, preferably fluticasone furoate.

The pharmaceutical composition described therein is the same as the pharmaceutical composition described in the preparation method of the carrier used in the pharmaceutical composition in the form of inhalable dry powder as described above in the present invention.

Wherein the carrier is such that after the carrier and the active ingredient are mixed, the pulmonary deposition rate of the active ingredient is not less than 30%.

Wherein the pharmaceutical composition in the form of inhalable dry powder is an inhalable powder mist.

In another aspect, the present invention provides a use of the carrier used in the pharmaceutical composition in the form of inhalable dry powder of the present invention for preparing the pharmaceutical composition in the form of inhalable dry powder.

In another aspect, the present invention provides a use of the pharmaceutical composition in the form of inhalable dry powder of the present invention in the preparation of medicines for treating and/or preventing respiratory diseases, wherein respiratory diseases include but not limited to chronic obstructive pulmonary disease, Chronic bronchitis, emphysema, or asthma.

In another aspect, the present invention provides a method for treating and/or preventing diseases in mammals (such as humans), the method comprising administering to mammals (such as humans) a therapeutically effective amount of the pharmaceutical composition in the form of inhalable dry powder of the present invention, Wherein the disease is selected from respiratory diseases, including but not limited to chronic obstructive pulmonary disease, chronic bronchitis, emphysema or asthma.

The carrier prepared by the present invention will not appear the phenomenon of particle grinding and crushing, compared with the carrier obtained by directly using magnesium stearate mixed with lactose granules, and compared with the carrier phase prepared by a high-shear mixing granulator Ratio, not only can significantly improve the effective deposition rate of the drug inhaled powder in the lungs, but also can significantly reduce the degradation of some drugs (such as vilanterol), improve the chemical stability of the drug; the carrier of the present invention also It has the advantages of good fluidity, low compressibility, low hygroscopicity, good air permeability, etc., and is easy to prepare and easy to operate, and is especially suitable for preparing inhalation powder aerosol.

definition

The terms "drug," "active ingredient," "active" and "active substance" are synonymous unless otherwise indicated.

The term "ball mill" refers to a device with a grinding medium and a rotatable container, including but not limited to a planetary ball mill. Before the ball mill is operated, the grinding medium and the carrier are placed in the container together. When the container is rotated, the grinding medium is in the container. The carrier is impacted and ground to thoroughly mix the carrier. The "grinding medium" described herein refers to the energy carrier that collides and grinds the carrier in the container to make the carrier fully mixed. It can be separated from the container. The typical shape of the grinding medium includes spherical, spherical (such as elliptical) ), but can also be other shapes (such as rods, round truncated balls, short round rods, etc.), and the materials of the grinding media include metals (such as steel, iron, alloys, etc.) and non-metals (such as glass, plastic, agate , zircon, rock, ceramics, etc.), examples of grinding media include glass balls, plastic beads, steel balls, agate balls, zirconia beads, zirconium silicate beads, etc.; the material of the rotatable container includes metal (such as stainless steel) and non- Metal (such as agate, ceramic, nylon, polyurethane, PTFE, zirconia, hard alloy, etc.).

The term "planetary ball mill" refers to a device having a rotatable disc, a rotatable container (for example, 2 or 4 containers) and a grinding medium. Placed on the disk in order, when the disk is in revolution motion, the container is in rotation motion on its revolution track, the container and the disk rotate at the same time, the speed of rotation is greater than the speed of revolution, for example, the ratio of rotation to revolution is 2:1 .

The term "high-shear mixing granulator" means a device fitted with paddle-shaped mixing elements in which the carrier is accelerated by the paddle and mixed intensively by friction with the vessel wall, e.g. the high-shear mixing granulator used in the present invention The force mixing granulator is heysun process equipment (Shanghai Huishen Engineering Equipment Co., Ltd.), model M1.

The term "rpm" refers to a unit of rotational speed, and rpm is an abbreviation of revolutions per minute, which means a rotational speed per minute, for example, 480 rpm means 480 revolutions per minute.

The term "pulmonary deposition rate of the active ingredient" refers to the percentage of active ingredient particles that can reach deep lungs of a patient with an inhaled formulation.

The term "aerosol distribution", that is, the dose of fine particles, is an important parameter for evaluating the quality of inhaled preparations. It refers to the percentage of the dose of fine drug particles inhaled into powder aerosols to the labeled amount, which can be measured by in vitro devices (see "People's Republic of China Pharmacopoeia" 2015 edition of the fourth part "0951 Determination of the aerodynamic properties of fine particles of inhalation preparations"), the value can reflect the deposition rate of active ingredients in the lungs, for example, when the gas flow rate reaches 60L/min, the distribution of mist particles The rate at grades 2-7 is comparable to the lung deposition rate of the active ingredient.

The term "w/w" refers to a weight ratio, for example, in a carrier containing magnesium stearate, 0.3% w/w magnesium stearate means that the weight of magnesium stearate is 0.3% of the carrier.

Generally, the particle size of the particles is quantified by measuring the characteristic equivalent spherical diameter (called volume diameter) by laser diffraction, for example, by a laser particle size tester.

In the present invention, the particle size distribution is represented by the volume diameter (VD).

The term "d(v0.5)" refers to the particle size corresponding to when the cumulative particle size distribution percentage reaches 50%, which is called the volume median diameter (volum median diameter), and its physical meaning is that the particles with a particle size larger than it account for 50% %, particles smaller than it also account for 50%.

The term "d(v0.1)" refers to the particle size corresponding to when the cumulative particle size distribution percentage reaches 10%. Its physical meaning is that the particles with a particle size larger than it account for 90%, and the particles smaller than it account for 10%.

The term "d(v0.9)" refers to the corresponding particle size when the cumulative particle size distribution percentage reaches 90%. Its physical meaning is that the particles with a particle size larger than it account for 10% and the particles smaller than it account for 90%.

Detailed ways

The purpose of the following specific examples is to enable those skilled in the art to understand and implement the present invention more clearly. They should not be considered as limiting the scope of the invention, but only illustrative and typical of the invention.

Embodiment 1 Planetary ball mill prepares carrier

Commercially available alpha-lactose monohydrate, type: 200, specifications: d (v0.1) is 5-15 microns, d (v0.5) is 50-100 microns, d (v0.9) is 120-160 microns.

1. Preparation of carrier a1

Mix 1.2kg of α-lactose monohydrate, 1.2g of magnesium stearate (0.1% w/w) and an appropriate amount of agate balls (diameter not greater than 1cm), mix them evenly and divide them into 4 parts on average, and place them in 4 rotatable In the agate ball mill jar, process by QM-3SP4 planetary ball mill (manufactured by Nanjing University Instrument Factory), the processing parameters are: rotation speed (autorotation speed): 480rpm, and last for 60 minutes to obtain the carrier a1.

2. Preparation of carrier a2

According to the preparation method of the above-mentioned carrier a1, the 0.1% w/w magnesium stearate was replaced by 0.3% w/w magnesium stearate to obtain the carrier a2.

3. Preparation of carrier a3

According to the preparation method of the above-mentioned carrier a1, the 0.1% w/w magnesium stearate was replaced by 0.5% w/w magnesium stearate to obtain the carrier a3.

4. Preparation of carrier a4

According to the preparation method of the above-mentioned carrier a1, 0.1% w/w magnesium stearate was replaced by 1.0% w/w magnesium stearate to obtain the carrier a4.

Comparative study with HELOS-OASIS laser particle size analyzer (Sympatec GmbH) 200 and the particle size distribution of carriers a1, a2, a3, a4. The test method is as follows: take an appropriate amount of the sample to be tested so that the optical concentration of the sample is in the range of 2% to 15%, use dry method, RODOS dispersion system, R4 lens (0.5-350μm) test, the dispersion pressure is 3.0bar, and the sample measurement time is 5s, collect volume/mass distribution particle size, the results are shown in Table 1.

Table 1 Particle size distribution results

carrier number sample d(v0.1) d (v0.5) d (v0.9) LH200 10.93 70.70 129.49 a1 LH200+0.1%MS 9.48 70.86 127.53 a2 LH200+0.3%MS 10.07 71.53 127.56 a3 LH200+0.5%MS 10.54 72.60 128.93 a4 LH200+1.0%MS 10.99 73.85 129.58

Embodiment 2 physical mixing preparation carrier

Commercially available alpha-lactose monohydrate, type: 200, specifications: d (v0.1) is 5-15 microns, d (v0.5) is 50-100 microns, d (v0.9) is 120-160 microns.

1. Preparation of carrier b1

50 g of α-lactose monohydrate and 0.05 g of magnesium stearate (0.1% w/w) were passed through an 80-mesh sieve 5 times for mixing to obtain the carrier b1.

2. Preparation of carrier b2

According to the preparation method of the above-mentioned carrier b1, the 0.1% w/w magnesium stearate was replaced by 0.3% w/w magnesium stearate to obtain the carrier b2.

3. Preparation of carrier b3

According to the preparation method of the above-mentioned carrier b1, the 0.1% w/w magnesium stearate was replaced by 0.5% w/w magnesium stearate to obtain the carrier b3.

4. Preparation of carrier b4

According to the preparation method of the above-mentioned carrier b1, the 0.1% w/w magnesium stearate was replaced by 1.0% w/w magnesium stearate to obtain the carrier b4.

Embodiment 3 High-shear force mixing granulator prepares carrier

Commercially available alpha-lactose monohydrate, type: 200, specifications: d (v0.1) is 5-15 microns, d (v0.5) is 50-100 microns, d (v0.9) is 120-160 microns.

1. Preparation of carrier c1

α-Lactose monohydrate (400g) and magnesium stearate 0.4g (0.1%w/w) were placed in a high-shear mixing granulator (heysun process equipment, Shanghai Huishen Engineering Equipment Co., Ltd., model M1 ), the processing parameters are as follows: the rotation speed is 1000rpm, and lasts for 10min to obtain the carrier c1.

2. Preparation of carrier c2

According to the preparation method of the above-mentioned carrier c1, the 0.1% w/w magnesium stearate was replaced by 0.3% w/w magnesium stearate to obtain the carrier c2.

3. Preparation of carrier c3

According to the preparation method of the above-mentioned carrier c1, the 0.1% w/w magnesium stearate was replaced with 0.5% w/w magnesium stearate to obtain the carrier c3.

4. Preparation of carrier c4

According to the preparation method of the above-mentioned carrier c1, the 0.1% w/w magnesium stearate was replaced with 1.0% w/w magnesium stearate to obtain the carrier c4.

The preparation of embodiment 4 vilanterol inhalation powder spray

Pass 0.16g of vilanterol triphenylacetic acid after jet milling (detected by laser particle size analyzer: d(v0.5)≤5μm, d(v0.9)≤9μm) and 50g of carrier a1 through an 80-mesh sieve and mix for 5 The second time, obtained vilanterol triphenylacetic acid inhalation powder 1-A1.

According to the same process as above, the carrier a1 is replaced with the carrier a2, a3, a4, b1, b2, b3, b4, c1, c2, c3 and c4 respectively, and the vilanterol triphenylacetic acid inhalation powder spray 1- A2, 1-A3, 1-A4, 1-B1, 1-B2, 1-B3, 1-B4, 1-C1, 1-C2, 1-C3, and 1-C4.

Vilanterol Triphenylacetate Inhalation Powder 1-A1, 1-A2, 1-A3, 1-A4, 1-B1, 1-B2, 1-B3, 1-B4, 1-C1, 1-C2 , 1-C3 and 1-C4 formulation formulations are shown in Table 2:

Table 2 Prescription of vilanterol triphenylacetic acid inhalation powder

The preparation of embodiment 5 umeclidinium bromide vilanterol inhalation powder spray

Pass 0.16g of vilanterol triphenylacetic acid after jet milling (detected by laser particle size analyzer: d(v0.5)≤5μm, d(v0.9)≤9μm) and 25g of carrier a1 through an 80-mesh sieve and mix for 5 Second, the obtained vilanterol triphenylacetic acid partial intermediate X. Uumeclidinium bromide (detected by laser particle size analyzer: d(v0.5)≤5 μm, d(v0.9)≤9 μm) after 0.297g airflow pulverization is crossed 80 mesh sieves and mixed 5 times together with 25g carrier a1, obtains The umeclidinium bromide partial intermediate Y. Pass X and Y together through an 80-mesh sieve 5 times. Obtain Uclidinium Vilanterol Inhalation Powder 2-A1.

According to the same process as above, the carrier a1 is replaced with the carrier a2, a3, a4, b1, b2, b3, b4, c1, c2, c3 and c4 respectively, and the corresponding umeclidinium bromide vilanterol inhalation powder 2 is respectively obtained -A2, 2-A3, 2-A4, 2-B1, 2-B2, 2-B3, 2-B4, 2-C1, 2-C2, 2-C3 and 2-C4.

Umeclidinium bromide vilanterol inhalation powder 2-A1, 2-A2, 2-A3, 2-A4, 2-B1, 2-B2, 2-B3, 2-B4, 2-C1, 2- The formulation formulations of C2, 2-C3 and 2-C4 are as shown in Table 3:

Table 3 Prescription of umeclidinium bromide vilanterol inhalation powder

Example 6 Preparation of fluticasone furoate vilanterol inhalation powder

Pass 0.16g of vilanterol triphenylacetic acid after jet milling (detected by laser particle size analyzer: d(v0.5)≤5μm, d(v0.9)≤9μm) and 25g of carrier a1 through an 80-mesh sieve and mix for 5 Second, the obtained vilanterol triphenylacetic acid partial intermediate X. Mix 0.4 g of fluticasone furoate after jet milling (detected by laser particle size analyzer: d(v0.5)≤5 μm, d(v0.9)≤9 μm) and 25 g of carrier a1 through an 80-mesh sieve and mix 5 times to obtain Partial intermediate Y of fluticasone furoate. Pass X and Y together through an 80-mesh sieve 5 times. Obtain fluticasone furoate vilanterol inhalation powder 3-A1.

According to the same process as above, the carrier a1 is replaced with the carrier a2, a3, a4, b1, b2, b3, b4, c1, c2, c3 and c4 respectively, and the corresponding fluticasone furoate vilanterol inhalation powder 3- A2, 3-A3, 3-A4, 3-B1, 3-B2, 3-B3, 3-B4, 3-C1, 3-C2, 3-C3, and 3-C4.

Fluticasone Vilanterol Furoate Inhalation Powder 3-A1, 3-A2, 3-A3, 3-A4, 3-B1, 3-B2, 3-B3, 3-B4, 3-C1, 3-C2 , 3-C3 and 3-C4 formulation formulations are shown in Table 4:

Table 4 Prescription of fluticasone furoate vilanterol inhalation powder

Example 7 Fine Particle Dosimetry

Fine particle dose determination method:

According to Chinese Pharmacopoeia 2015 Edition Four General Rules 0951 device 3 (next generation impactor, NGI), method 2 connection device. Add 15ml of receiving solution to the central collection cup of the pre-separator, fasten the device, check the airtightness, and adjust the flow rate after the airtightness is qualified. Turn on the vacuum pump, connect the flowmeter to the L-shaped connecting pipe, and adjust the flow control valve so that the stable flow through the system reaches 60±5% L/min. Under the test flow rate, the pressure ratio (P ₃ /P ₂ ) before and after the flow control valve should be ≤0.5.

Take off the flow meter and start the measurement. Take this product, keep the suction device level, turn on the vacuum pump, pull the switch to the open position once, suck for 4±5% seconds, repeat the above operation 10 times, turn off the vacuum pump, remove the device, and wash the 2-7 level collection with the receiving solution plate, combined lotion, constant volume, shake well, filter, take the subsequent filtrate as the test solution, and detect it with high performance liquid chromatography. The test results of some samples are shown in Table 5-7.

Table 5 Test results of vilanterol inhalation powder aerosol

Table 6 Test results of umeclidinium bromide vilanterol inhalation powder aerosol

Table 7 Test results of fluticasone furoate vilanterol inhalation powder

Embodiment 8 triphenylacetic acid vilanterol stability

For fluticasone vilanterol furoate inhalation powder 3-A1 and 3-B4, the experiment was carried out with reference to the "Pharmacopoeia of the People's Republic of China" 2010 Edition, Appendix XIX C Stability Experiment Guidelines for Raw Materials and Pharmaceutical Preparations, listed in the following table After standing at 40°C for 10 days, the purity and impurities of vilanterol triphenylacetate in the sample were detected by HPLC and the results are shown in Table 8.

Table 8 The purity of vilanterol triphenylacetate and the results of changes in impurities

Note 1: The increase value of the total impurity content refers to the increase value of the total impurity content relative to the 0 day

Note 2: The total impurities and purity in the above table are the test results for vilanterol alone

The results showed that using the carrier prepared by ball mill to prepare inhalation powder aerosol can significantly improve the chemical stability of vilanterol in the product.

Claims (10)

1. a kind of preparation method of the carrier used in pharmaceutical composition of inhalable dry powder form, including：By magnesium stearate and breast Sugared particle is mixed in ball mill, and the wherein d (v0.5) of lactose granule is the weight of 5-800 microns, wherein magnesium stearate For the 0.05%-1.5% of carrier.

2. the rotation rotating speed of the container of the preparation method of claim 1, wherein ball mill is 15-960rpm.

3. the material of the abrasive media of the preparation method of claim 1, wherein ball mill is metal and nonmetallic.

4. the preparation method of claim 1, wherein described pharmaceutical composition include carrier and one or more than one kinds of activity Composition.

5. the preparation method of claim 4, wherein active component at least one are selected from β 2- activators, muscarinic antagonist or skin Matter steroids.

6. the carrier used in a kind of pharmaceutical composition of inhalable dry powder form, the carrier includes magnesium stearate and lactose Grain, the carrier are prepared by the preparation method described in claim any one of 1-5.

7. a kind of pharmaceutical composition of inhalable dry powder form, described pharmaceutical composition includes carrier and one or more Active component, wherein the carrier is prepared by the preparation method described in claim any one of 1-5.

8. the pharmaceutical composition of claim 7, wherein active component it is at least one selected from β 2- activators, muscarinic antagonist or Corticosteroid.

9. a kind of preparation method of the pharmaceutical composition of inhalable dry powder form, methods described is included carrier and a kind of or one kind Active component mixing above, the carrier are prepared by the preparation method described in claim any one of 1-5.

10. purposes of the claim 7-8 pharmaceutical composition in the medicine for preparing treatment and/or prevention respiratory disease, Wherein respiratory disease includes but is not limited to chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema or asthma.