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CN116077471A - Powder aerosol composition for inhalation and preparation method and application thereof - Google Patents

Powder aerosol composition for inhalation and preparation method and application thereof Download PDF

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CN116077471A
CN116077471A CN202111314732.4A CN202111314732A CN116077471A CN 116077471 A CN116077471 A CN 116077471A CN 202111314732 A CN202111314732 A CN 202111314732A CN 116077471 A CN116077471 A CN 116077471A
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powder
inhalation
carrier
lactose
composition
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杜狄峥
罗国军
谭中华
张艳
沈涛
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Shanghai Chenbang Pharmaceutical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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Abstract

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a powder aerosol pharmaceutical composition for inhalation, and a preparation method and application thereof. The powder aerosol composition comprises an active substance and a carrier; the active substances are budesonide, formoterol or pharmaceutically acceptable salts thereof, and a long-acting or super-long-acting muscarinic antagonist drug or pharmaceutically acceptable salts thereof. The powder aerosol pharmaceutical composition for inhalation has good stability of active drugs; the powder fog agent composition product is simple and convenient to operate, convenient for patients to use and convenient to carry; the medicine is stable and uniform; the powder spray composition can realize multi-dose drug administration, has low drug residue rate in the device, and realizes better clinical symptom relief and maintenance treatment effect.

Description

Powder aerosol composition for inhalation and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a powder aerosol pharmaceutical composition for inhalation, and a preparation method and application thereof.
Background
The drug is directly delivered to the lung of a human body through an inhalation mode, is a preferred mode for treating Asthma (Asthama) and chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD), and the used drug is usually a bronchodilator and an adrenocortical hormone, and the inhalation administration has the advantages of quick response, low toxic and side effects, no liver first pass effect and the like.
The existing inhalant administration preparations comprise aerosol, aerosol inhalation liquid preparations, soft aerosol and powder aerosol, wherein the powder aerosol is environment-friendly, small in size, convenient for patients to carry, relatively less in medicine waste and the like due to the fact that the powder aerosol does not contain a propellant, and gradually becomes the most competitive preparation product in a plurality of inhalant preparation products in developed countries and regions. Powder mists are a combination formulation product of a pharmaceutically active ingredient and a medical device (inhaler). Existing powder aerosol inhalation devices on the market can be divided into single doses (the formulation powder is contained in a single capsule, blister or reservoir), single doses (containing multiple blisters) which are reusable, and multiple doses (the powder is contained in a reservoir).
International guidelines for asthma and COPD recommend methods of progressive treatment with exacerbation of the disease state, including the use of drugs with no sign of failureA combination of drug classes with or complementary mechanism of action. Various combinations of products are currently known, such as salmeterol-triamcinolone inhalation powder mist "Shu Lidie
Figure BDA0003343268940000011
"(multiple dose vesicle type powder fog agent), budesonide formoterol powder inhalant" Xinbike all protects +.>
Figure BDA0003343268940000012
"(Multi-dose reservoir type powder spray) Fluticavine inhalation powder spray" Quanzhenle>
Figure BDA0003343268940000013
"(multiple dose vesicle type powder spray), indacaterol bromoammonium mometasone furoate inhalation powder spray ++>
Figure BDA0003343268940000014
(Single dose capsule type powder fog agent) and Budigafil inhalation aerosol
Figure BDA0003343268940000015
(inhalation of aerosols).
The inhalation performance of a powder spray is highly dependent on interactions between the drug delivery device and the formulation components, such as inter-particle cohesion (drug/drug) and adhesion (drug/carrier), which must be large enough to maintain the physical stability of the formulation during storage and use, but yet allow for the Xu Yaowu to be effectively separated from the carrier or drug agglomerates prior to or during inhalation. The multi-dose reservoir type powder fog agent is used for dispensing medicines in a fixed dose when a patient uses the product, and when a plurality of active ingredients are combined together, specific polar/nonpolar areas on the surfaces of components, carriers and impurities are complex. In addition, the drugs in powder aerosol products are usually prepared into micron-sized particles suitable for entering the lung through jet milling, but the particles are easy to cohere due to the high specific surface area, so that accurate quantification and dispersion are difficult. It is therefore generally considered that in the course of developing products by those skilled in the art, separate storage of the different active ingredients should be employed andinhalation drug delivery is achieved either by way of a pre-dispensed dose or by way of an aerosol, for example,
Figure BDA0003343268940000021
each vesicle contains a precisely-quantitative drug, the vesicles are covered on an aluminum foil to form a sheet strip, the sheet strip is tightly curled in a device, the vesicles have a moisture-proof effect, and different active components of a compound exist in different chambers, however, the vesicle type inhalation product preparation form is required to realize effective and precise-dose drug pulmonary delivery and moisture-proof treatment, has large industrial manufacturing difficulty and high equipment requirement, leads to expensive production cost of the product, and increases the burden of long-term drug administration of patients;
Figure BDA0003343268940000022
The delivery of three pharmaceutical active ingredient combination inhalation formulations is achieved by means of a pressurized metered dose inhalation aerosol (pMDI), however, most inhalation aerosols do not deliver too large an amount of drug per actuation, are not suitable for certain active ingredients, and the amount of lung deposition of pMDI is generally low and the method of correctly using the device is highly demanding for the patient.
As is known to those skilled in the art, when a multi-component active drug is formulated as an inhalation powder spray, the powder deagglomeration process depends on whether the drug particles are subjected to external forces greater than the inter-particle adhesion and cohesion, which may involve a number of mechanisms including turbulence, vibration and mechanical collisions with the inner surfaces of the device. At the same time, the inhalation powder must have certain flowability properties, which are important for the process, precise dosing and uniformity of the released dose (DDCU). The formulation must be capable of producing sufficiently small particles of the drug to be delivered to the lungs under the influence of the patient's inhalation flow. Particle size, surface morphology, ratio of drug to carrier, nature of the pharmaceutically active ingredient, powder handling process, etc. all affect dispersion of the powder formulation and ultimately drug delivery. For example, some studies have shown that lactose with a small roughness increases the amount of drug deagglomerated from the carrier surface, but there are also studies showing that the wrinkled surface contributes to deagglomeration of the drug, which suggests that the drug delivery process of multicomponent inhalation powders is related to a number of factors.
In summary, pulmonary delivery of drugs is a relatively complex technique, since the methods of use of different inhalers affect patient compliance, the particle size of the drug needs to be controlled within a certain range, the pulmonary defense mechanism prevents small particles from depositing in the lungs and from being removed immediately after the deposition of the particles, and thus the choice of the pharmaceutically active ingredient and the structure of the inhalation device bring about a good and bad final therapeutic effect of the pharmaceutical formulation product.
It is therefore highly desirable to provide a multi-component combination therapy in a single product that reduces bronchitis, bronchoconstriction and bronchial secretions to achieve better clinical symptomatic relief and maintenance of therapeutic efficacy, while providing a combination formulation product that provides more convenient, economical, environmentally friendly, safer use by the powder aerosol inhaler to the patient for pulmonary delivery, accurate dosage dispensing, etc. of the combined active ingredients.
Disclosure of Invention
In the invention, the technical personnel find that for the multi-component reservoir type inhalation powder aerosol with better clinical treatment effect, the more the drug components in the inhaler are, the more the interaction among powder particles is complicated due to the self properties of materials with different drug activities; in addition, the multicomponent drug requires more carriers (the carriers can improve the fluidity of the powder and assist the dispersion of the drug to prevent aggregation thereof) due to the increased content, but when the carrier ratio is too high, drug deagglomeration is more difficult and drug delivery meeting the quality requirements cannot be achieved. Therefore, the invention provides a pharmaceutical composition with better clinical effect, the content of the active ingredients of the pharmaceutical composition is higher than that of the active ingredients of the known composition products of the same type on the market at present, and the better drug delivery effect and quality stability are realized through a certain drug and carrier prescription and preparation process.
In view of the above, the present invention provides an inhalation powder aerosol composition comprising three active ingredients, in particular a depot inhalation powder aerosol composition.
The technical scheme of the invention is as follows:
the invention provides an inhalation powder spray composition, which comprises budesonide, formoterol or pharmaceutically acceptable salt thereof, and a long-acting or super-long-acting muscarinic antagonist drug or pharmaceutically acceptable salt thereof as active substances, lactose as a carrier; wherein the pharmaceutically active ingredient is subjected to micronization treatment and is mixed with a carrier, and the pharmaceutically active ingredient and the carrier exist in a multi-dose reservoir type dry powder inhaler in the form of dry powder.
In the inhalation powder aerosol composition of the invention, further, the particle size characteristic d50=1.5-3.5 μm and d90 is less than or equal to 5 μm of the active substance.
In the inhalation powder aerosol composition, the long-acting or ultra-long-acting muscarinic antagonist drug is preferably glycopyrrolate (Glycopyrrolate bromide), aclidinium bromide (Aclidinium bromide), ubenimex bromide (Umeclidinium bromide), tiotropium bromide (Tiotropium bromide), and revenaxin (revenacin) or pharmaceutically acceptable salts thereof.
Further, the composition may further comprise other excipients, such as lactose for inhalation, or a mixture of lactose for inhalation and magnesium stearate.
The inhalation powder aerosol composition of the present invention preferably contains no other excipients or additives other than budesonide, formoterol or a salt thereof, a long-acting or ultra-long acting muscarinic antagonist drug, carrier lactose.
The inhalation powder aerosol composition of the invention is a long-acting or ultra-long-acting muscarinic antagonist medicament, more preferably glycopyrrolate, aclidinium bromide, tiotropium bromide.
Furthermore, in the pharmaceutical composition of the invention, the budesonide content in each drug is 100-400 mcg, preferably 200-400mcg; the content of formoterol is 6-12 mcg (calculated as formoterol fumarate dihydrate), and the content of aclidinium bromide is 100-400 mcg, preferably 200-400mcg (calculated as aclidinium bromide); the content ratio of carrier lactose in the pharmaceutical composition is 93% -99%, preferably 94% -98%, and more preferably 96% -97%.
Further, the carrier lactose of the composition is
Figure BDA0003343268940000041
100 or->
Figure BDA0003343268940000042
SV010 or
Figure BDA0003343268940000043
70 or->
Figure BDA0003343268940000044
120, the particle size distribution is characterized by d10=35-160 μm, d50=95-250 μm, d90=160-340 μm.
The inhalation powder spray composition provided by the invention can be used for preparing powder spray combined preparation products by the following processes for three medicinal active ingredients:
(1) Micronizing the medicine: the particle size characteristics d50=1.5-3.5 μm and d90 is less than or equal to 5 μm of the micronized medicine;
(2) Carrier treatment: sieving and premixing lactose;
(3) Other special treatments: the active ingredients generated after micronizing the active drugs are subjected to modulation treatment, the temperature condition of the modulation equipment is 25-60 ℃, preferably 25-40 ℃, the humidity condition is 50-92.5 RH, preferably 50-75RH, and the amorphous content of the active ingredients is reduced;
(4) Mixing: mixing the three active ingredients and the carrier using a high shear mixing device or a three dimensional mixing device or a combination of both;
(5) And (3) filling: the powder formulation is metered into the inhalation device using a metering device. And after filling, the preparation treatment can be carried out, the temperature condition of the preparation equipment is 25-60 ℃, the humidity condition range is 50-92.5 RH, the energy input by mixing and filling is reduced, and the influence on aerodynamic parameters of the initial time for preparing the sample is avoided.
The invention also provides application of the powder aerosol composition for inhalation in preparation of medicines for treating chronic obstructive pulmonary disease and asthma.
In the invention, the content proportion of carrier lactose in the pharmaceutical composition, lactose type and particle size distribution characteristics have great influence on the quality of the pharmaceutical preparation. The carrier lactose is safe to human bodies, has stable self-properties, can improve the fluidity of the pharmaceutical preparation as a carrier, and adjusts the interaction force (van der Waals force at contact points, capillary force generated due to the existence of water, electrostatic force and mechanical crosslinking caused by surface roughness) between three pharmaceutical active ingredients and different particles. The surface of carrier particles has high-energy or active sites, and drug particles can be preferentially adsorbed on the sites, and different lactose particle sizes, amorphous contents, surface roughness and the like can influence the inhalation behavior of the preparation.
The combination of the three active ingredients has better clinical effect than the two active ingredients; the technology of pulmonary delivery of the three active ingredients of the present invention by using a reservoir type powder aerosol inhaler is not reported at present. Details such as lactose content ratio, lactose type, processing parameters and the like in the preparation have great influence on product stability and drug pulmonary delivery indexes, for example, the stability of too low or too high lactose content is not as good as the ratio of the preparation.
The technical scheme of the invention also provides a dry powder inhaler loaded with the powder aerosol composition for inhalation, wherein the dry powder inhaler is a reservoir type dry powder inhaler;
the dry powder inhaler is a reservoir type dry powder inhaler;
the reservoir type dry powder inhaler is provided with a reservoir or a powder storage container for storing powder aerosol compositions and is used for storing at least two powder aerosol compositions and carriers;
when the powder inhaler is used each time, the reservoir or the powder storage container sequentially or simultaneously conveys at least two powder aerosol compositions and carriers to a rotary mixing cavity of the dry powder inhaler;
under the drive of the air flow, the dry powder is stably, uniformly and accurately delivered to the lung system of a patient through the flow channel and the suction nozzle after the at least two powder fog agent compositions and the carrier are mixed, so that the drug delivery function is realized. Compared with the prior art, the invention has the advantages that:
1. the powder aerosol composition for inhalation provided by the invention has good stability of active medicaments;
2. the powder aerosol composition for inhalation provided by the invention is simple and convenient to operate, convenient for patients to use and convenient to carry;
3. the powder fog agent composition for inhalation provided by the invention has stable and uniform drug release;
4. the powder aerosol composition can realize multi-dose drug administration, and has low residual rate of the drug in the device;
5. the powder fog agent composition for inhalation provided by the invention realizes better clinical symptom relief and maintenance treatment effects for the combined treatment drug.
Drawings
FIG. 1 is a graph showing the distribution of the weight per suction of the powder aerosol compositions prepared in examples 1 to 4 and comparative examples 1 to 4;
FIG. 2 is an aerodynamic particle size distribution diagram of the powder aerosol composition prepared in example 2;
FIG. 3 is a graph of delivered dose uniformity of the powder aerosol composition prepared in example 2;
FIG. 4 is a graph showing the ISM trend of the powder aerosol composition prepared in example 3;
fig. 5 is a DDU trend graph of the stability of the powder aerosol composition prepared in example 3.
Detailed Description
Example 1
Powder aerosol composition formulation for inhalation: 100mcg budesonide and 6mcg formoterol and 200mcg aclidinium bromide powder aerosol composition
The preparation method of the powder fog agent composition for inhalation comprises the following steps:
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 ＝1.5-3.5μm，d 90 A bulk drug of less than or equal to 5 um;
(2) Weighing:
micronized budesonideSelecting d 50 =2.5 μm:500mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：1000mg；
Carrier lactose
Figure BDA0003343268940000061
100 37.5g；
(3) Mixing:
18.75g will be
Figure BDA0003343268940000062
100 adding into a high shear mixer for premixing for 2min; adding 500mg of budesonide, 30mg of formoterol and 1000mg of aclidinium bromide into a mixer; will remain 18.75 g->
Figure BDA0003343268940000063
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; the mixing is ended.
(4) And (3) filling:
the powder is dosed into the inhaler and equilibrated at 25 ℃ and 50% rh for 1-4 weeks, preferably 2 weeks.
The technical scheme of the invention also provides a dry powder inhaler containing the powder aerosol composition for inhalation, wherein the dry powder inhaler is a reservoir type dry powder inhaler;
the reservoir type dry powder inhaler is provided with a reservoir or a powder storage container for storing powder aerosol compositions and is used for respectively storing at least two powder aerosol compositions and carriers;
when the powder inhaler is used each time, the reservoir or the powder storage container sequentially or simultaneously conveys at least two powder aerosol compositions and carriers to a rotary mixing cavity of the dry powder inhaler;
under the drive of the air flow, the dry powder is stably, uniformly and accurately delivered to the lung system of a patient through the flow channel and the suction nozzle after the at least two powder fog agent compositions and the carrier are mixed, so that the drug delivery function is realized.
At ordinary times, the reservoir dry powder inhaler stores the drug and its carrier in the inhaler.
Further, the dry powder inhaler also includes a counter that displays the remaining dose.
Because of the structure and function of the dry powder inhaler, it is disclosed in the patent documents of the issued or published US9750901B2, ZL2011101567684, ZL2011101567701, ZL2015103735659, ZL2015103736064, ZL2015103736098, ZL2015103742667, CN2015103736083, CN2015103736863, ZL2017109468595, ZL2017109475705, CN2019108182621, CN2019108182693, etc., the basic structure and specific method of use of the reservoir type dry powder inhaler will not be described herein (hereinafter).
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
Example 2
Powder aerosol composition formulation for inhalation: 200mcg budesonide and 6mcg formoterol and 400mcg aclidinium bromide powder fog agent composition
The preparation method of the powder fog agent composition for inhalation comprises the following steps:
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 ＝1.5-3.5μm，d 90 A bulk drug of less than or equal to 5 um;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:1000mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：2000mg；
Carrier lactose
Figure BDA0003343268940000071
100 25g; carrier lactose->
Figure BDA0003343268940000072
70 50g
(3) Mixing 1:
will be 12.5g
Figure BDA0003343268940000073
100 adding into a high shear mixer for premixing for 2min; adding 1000mg of budesonide and 30mg of formoterol into a mixer; will remain 12.5 g->
Figure BDA0003343268940000074
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; mixing 1 is ended.
Mixing 2:
25g will be
Figure BDA0003343268940000075
70 adding the mixture into a high shear mixer for premixing for 2min; 2000mg of aclidinium bromide was added to the mixer; will remain 25 g->
Figure BDA0003343268940000076
70 adding into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; mixing 2 is ended. />
(4) And (3) filling:
a dry powder inhaler of the reservoir type described in example 1 was used.
Mix 1 powder is dosed into the inhaler first dry powder reservoir, mix 2 powder is dosed into the inhaler second dry powder reservoir, and powder is dosed into the inhaler and equilibrated at 25 ℃,75% rh for 1-4 weeks, preferably 2 weeks.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
Example 3
Powder aerosol composition formulation for inhalation: 400mcg budesonide and 12mcg formoterol and 400mcg aclidinium bromide powder fog agent composition
The preparation method of the powder fog agent composition for inhalation comprises the following steps:
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 ＝1.5-3.5μm，d 90 A bulk drug of less than or equal to 5 um;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:2000mg; micronizing formoterol preferably d 50 =2.5 μm:60mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：2000mg；
Carrier lactose
Figure BDA0003343268940000081
100 50g; carrier lactose->
Figure BDA0003343268940000082
7050g
(3) Mixing 1:
25g will be
Figure BDA0003343268940000083
100 adding into a high shear mixer for premixing for 2min; adding 2000mg of budesonide and 60mg of formoterol into a mixer; will remain 25 g->
Figure BDA0003343268940000084
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; mixing 1 is ended.
Mixing 2:
25g will be
Figure BDA0003343268940000085
70 adding the mixture into a high shear mixer for premixing for 2min; 2000mg of aclidinium bromide was added to the mixer; will remain 25 g->
Figure BDA0003343268940000086
70 adding into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; mixing 2 is ended.
(4) And (3) filling:
a dry powder inhaler of the reservoir type described in example 1 was used.
Mix 1 powder is dosed into a first dry powder reservoir of the inhaler (first dry powder reservoir for short), mix 2 powder is dosed into a second dry powder reservoir of the inhaler, and the powder is dosed into the inhaler and equilibrated for 1-4 weeks, preferably 2 weeks, at 25 ℃,92.5% rh.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
Example 4
Powder aerosol composition formulation for inhalation: 200mcg budesonide and 6mcg formoterol and 63mcg glycopyrrolate powder mist composition
The preparation method of the powder fog agent composition for inhalation comprises the following steps:
(1) Micronizing:
micronizing budesonide, formoterol and glycopyrrolate under set parameters to obtain particle size distribution d 50 ＝1.5-3.5μm，d 90 A bulk drug of less than or equal to 5 um;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:1000mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized glycopyrronium bromide is preferably d 50 ＝2.5μm：315mg；
Carrier lactose
Figure BDA0003343268940000091
100 37.5g；
(3) Mixing:
18.75g will be
Figure BDA0003343268940000092
100 adding into a high shear mixer for premixing for 2min; adding 1000mg of budesonide, 30mg of formoterol and 315mg of glycopyrrolate into a mixer; will remain 18.75 g->
Figure BDA0003343268940000093
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; the mixing is ended.
(4) And (3) filling:
the powder is dosed into the inhaler and equilibrated at 40 ℃ for 1-4 weeks, preferably 2 weeks, at 50% rh.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
The procedure is as in example 1.
Example 5
The rats model for Chronic Obstructive Pulmonary Disease (COPD) were subjected to inhalation test using examples 1, 2, 3 and 4, and after the test was completed, the lung function was measured, and the effects of the intervention on the lung function of animals were compared with those of inhaled blank auxiliary materials or positive control drugs.
1) Rat COPD model:
the method of fragrance smoking and injecting lipopolysaccharide into the airway is used for establishing a rat COPD model. 60 SD rats were taken and aged for 12 weeks and weighing 200+ -20 g, and COPD molding was performed.
On day 14, rats were anesthetized with 10% chloral hydrate (0.3 mg/100 g) and were fixed on the rat plates after anesthesia, the throats were exposed, the tracheal catheter was replaced with a intravenous trocar, 0.2ml (1 mg/ml) of Lipopolysaccharide (LPS) was instilled into the rat trachea, and the rats were rotated vertically for 10s-20s after instillation to distribute LPS as evenly as possible in their lungs.
Rats were concentrated in three batches per day in homemade glass sealed boxes (box size 80 x 60 x 50 cm) 3 The upper part is provided with a vent hole with the diameter of 1.2 cm) which continuously sucks the cigarette smoke for 60 minutes (10 times a day and twice a day). The molding was completed for 4 weeks.
2) Group administration
The test animals are randomly divided into 6 groups, namely a blank group (a blank auxiliary material inhalation group) and a positive control group
Figure BDA0003343268940000102
Figure BDA0003343268940000103
200mcg of budesonide+6 mcg of formoterol), test group A (inhalation example 1), test group B (inhalation example 2), test group C (inhalation example 3), test group D (inhalation example 4), 10 per group.
The rats are placed in a closed device of an animal breathing machine for controlled ventilation, and three groups of rats respectively inhale corresponding medicaments. Inhalation was performed twice a day for a total of 8 weeks.
3) Test results
After being inhaled and administrated for 8 weeks, a rat with COPD is subjected to cervical skin shearing by a sterile surgical scissors, a trachea cannula is carried out by a 50ml syringe needle (with the diameter of about 3 mm) after the trachea is exposed, one end of the trachea cannula is connected with a three-way pipe after the trachea cannula is fixed, and the animal respiratory function instrument is connected with the animal respiratory function instrument, and respiratory function parameters of the rat are detected, wherein the respiratory function parameters comprise a Forced Expiratory Volume (FEV) of 0.3 seconds 0.3 ) Forced Vital Capacity (FVC), peak Expiratory Flow (PEF).
TABLE 1 rat pulmonary function test results
Figure BDA0003343268940000101
Note that: a p is less than 0.05 compared with the blank group; b p is less than 0.05 compared with the positive control group.
The results of the study are shown in Table 1, and compared with the blank adjuvant group, the positive control group
Figure BDA0003343268940000104
FEV of rats in each of the test groups A-D (examples 1-4) 0.3 、FVC、FEV 0.3 FVC, PEF are both significantly increased (P<O.05); in contrast, FEV of test group B, test group C, test group D compared with the positive control group 0.3 Significantly elevated FVC, PEF (P<O.05), whereas test group a had no significant differences (P>O.05). Test group B, test group C, and test group D were statistically analyzed by ANOVA with no significant differences between the three groups (P>O.05)。
The test results show that the preparation of the COPD of the example 1, the example 2, the example 3 and the example 4 can obviously improve the pulmonary ventilation function of the rats after being inhaled for 8 weeks, and can be used for improving the COPD symptoms. Wherein, example 1 and control group
Figure BDA0003343268940000111
The effect was comparable (trend better than control group but no significant difference), while example 2, example 3, example 4 improved rat lung ventilation significantly better than +.>
Figure BDA0003343268940000112
Figure BDA0003343268940000113
Comparative example 1 (lower limit lactose formulation)
The formula comprises the following components: 200mcg budesonide and 6mcg formoterol and 400mcg aclidinium bromide powder fog agent composition
The preparation process comprises the following steps:
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 Bulk drug=1.5-3.5 μm;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:1000mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：2000mg；
Carrier lactose
Figure BDA0003343268940000114
10050g；
(3) Mixing:
25g will be
Figure BDA0003343268940000115
100 adding into a high shear mixer for premixing for 2min; adding 1000mg of budesonide, 30mg of formoterol and 2000mg of aclidinium bromide into a mixer; will remain 25 g->
Figure BDA0003343268940000116
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; the mixing is ended.
(4) And (3) filling:
the powder is dosed into the inhaler and equilibrated at 60 ℃ and 60% rh for 1-4 weeks, preferably 2 weeks.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
The procedure is as in example 1.
Comparative example 2 (upper limit ratio lactose formulation)
The formula comprises the following components: 200mcg budesonide and 6mcg formoterol and 400mcg aclidinium bromide powder fog agent composition
The preparation process comprises the following steps:
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 Bulk drug=1.5-3.5 μm;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:1000mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：2000mg；
Carrier lactose
Figure BDA0003343268940000121
100150g；
(3) Mixing 1:
75g is added
Figure BDA0003343268940000122
100 adding into a high shear mixer for premixing for 2min; adding 1000mg of budesonide, 30mg of formoterol and 2000mg of aclidinium bromide into a mixer; will leave 75 g->
Figure BDA0003343268940000123
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; the mixing is ended.
(4) And (3) filling:
the powder is dosed into the inhaler and equilibrated at 60 c, 75% rh for 1-4 weeks, preferably 2 weeks.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
The procedure is as in example 1.
Comparative example 3 (Low ratio lactose formulation)
The formula comprises the following components: 200mcg budesonide and 6mcg formoterol and 400mcg aclidinium bromide powder fog agent composition
Preparation process
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 Bulk drug=1.5-3.5 μm;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:1000mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：2000mg；
Carrier lactose
Figure BDA0003343268940000124
10035g；
(3) Mixing:
will be 17.5g
Figure BDA0003343268940000125
100 adding into a high shear mixer for premixing for 2min; adding 1000mg of budesonide, 30mg of formoterol and 2000mg of aclidinium bromide into a mixer; will leave 17.5 g->
Figure BDA0003343268940000126
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; the mixing is ended.
(4) And (3) filling:
the powder is dosed into the inhaler and equilibrated at 60 ℃ and 60% rh for 1-4 weeks, preferably 2 weeks.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
The procedure is as in example 1.
Comparative example 4 (high lactose formulation)
The formula comprises the following components: 200mcg budesonide and 6mcg formoterol and 400mcg aclidinium bromide powder fog agent composition
Preparation process
(1) Micronizing:
micronizing budesonide, formoterol and aclidinium bromide under set parameters to obtain particle size distribution d 50 Bulk drug=1.5-3.5 μm;
(2) Weighing:
micronized budesonide preferably d 50 =2.5 μm:1000mg; micronizing formoterol preferably d 50 =2.5 μm:30mg; micronized aclidinium bromide preferably d 50 ＝2.5μm：2000mg；
Carrier lactose
Figure BDA0003343268940000132
100300g；
(3) Mixing:
150g of
Figure BDA0003343268940000133
100 adding into a high shear mixer for premixing for 2min; adding 1000mg of budesonide, 30mg of formoterol and 2000mg of aclidinium bromide into a mixer; will remain 150 g->
Figure BDA0003343268940000134
100 is added into a mixer; all materials are mixed for 5min at low speed and 10min at medium speed; the mixing is ended.
(4) And (3) filling:
the powder is dosed into the inhaler and equilibrated at 60 ℃ and 60% rh for 1-4 weeks, preferably 2 weeks.
(5) And (3) detection:
the samples were examined for aerodynamic related properties in the laboratory.
The procedure is as in example 1.
Comparative example 5
Examples 1, 2, 3, 4, and 4, the prescriptions are summarized as follows:
Figure BDA0003343268940000131
Figure BDA0003343268940000141
the weighing experiments per suction were performed on example 1, example 2, example 3, example 4, comparative example 1, comparative example 2, comparative example 3, comparative example 4, and the comparative results are as follows:
Figure BDA0003343268940000142
Figure BDA0003343268940000151
a per-suction weight profile (see fig. 1).
Conclusion 1: comparative example 1 lactose proportion 94% is near the lower limit and the average value per weight of absorbed is 85.4%, it is known that lactose proportion low flowability is affected, resulting in a lower average value.
Conclusion 2: comparative example 2 lactose ratio 98% is near the upper limit and the average of weight per inhalation is 88.8%, it is known that a high lactose ratio with a single dose would be too high to be completely aspirated by one inhalation.
Conclusion 3: comparative example 3 has a low lactose ratio, a low percentage by weight per inhalation, and comparative example 4 has a high lactose ratio, a low percentage by weight per inhalation.
Conclusion 4: the ratio of lactose and the weight of single suction can be controlled to improve the sucking quantity per suction to keep high ratio and stable.
Noun interpretation
Aerodynamic Particle Size Distribution (APSD): the inhalation preparation is externally simulated by a cascade impactor method, and the distribution of the aerosol in different levels under the action of the airflow can reflect the actual inhalation process to a certain extent. The aerodynamic particle size distribution of the inhaled powder aerosol will determine the possible deposition positions of the aerosol fine particles after inhalation; if the fine particles are too large, they may get stuck in the back of the throat; the fine particles are too small and are exhaled instead of being deposited in the body.
Delivery Dose Uniformity (DDU): the dose released from the device is the delivered dose; the degree of difference between the delivered dose and the average value measured for multiple times is the delivered dose uniformity.
Example 6
Results of pharmaceutical formulation Performance index test on the powder spray composition prepared in example 2
(inhalation performance index: delivered dose uniformity, aerodynamic particle size distribution) delivered dose uniformity table:
Figure BDA0003343268940000152
Figure BDA0003343268940000161
the aerodynamic particle size distribution is shown in figure 2.
Figure BDA0003343268940000162
The delivered dose uniformity graph is shown in figure 3.
Example 7
Results of pharmaceutical quality inhalation performance index test for the powder aerosol composition prepared in example 3
(stability index)
Figure BDA0003343268940000163
The stability diagrams are shown in fig. 4 and 5.

Claims (15)

1. A powder aerosol composition for inhalation, characterized by: the powder aerosol composition comprises an active substance and a carrier; the active substances are budesonide, formoterol or pharmaceutically acceptable salts thereof, and a long-acting or super-long-acting muscarinic antagonist drug or pharmaceutically acceptable salts thereof.
2. A powder for inhalation according to claim 1, wherein: the particle size of the active substance is characterized in that d50=1.5-3.5 mu m and d90 is less than or equal to 5 mu m.
3. A powder for inhalation according to claim 1, wherein: the long-acting or super-long-acting muscarinic antagonist drug is glycopyrrolate, aclidinium bromide, ubenimex, tiotropium bromide, and the like or pharmaceutically acceptable salts thereof.
4. A powder for inhalation according to claim 1, wherein: the long-acting or super-long-acting muscarinic antagonist drug is glycopyrrolate, aclidinium bromide, tiotropium bromide or a pharmaceutically acceptable salt thereof.
5. A powder for inhalation according to claim 1, wherein: the content of budesonide in each drug absorbed by the powder fog agent composition is 100-400 mcg, the content of formoterol fumarate Ji Fumo tertiol dihydrate is 6-12 mcg, and the content of aclidinium bromide calculated by aclidinium bromide is 100-400 mcg.
6. A powder for inhalation according to claim 1, wherein: the carrier in the powder aerosol composition is lactose.
7. A powder for inhalation according to claim 6, wherein: the content ratio of the carrier lactose in the powder fog agent composition is 94% -98%, preferably 96% -97%.
8. A powder for inhalation according to claim 6, whereinThe method comprises the following steps: the lactose carrier of the composition is
Figure FDA0003343268930000011
100 or->
Figure FDA0003343268930000012
SV010 or->
Figure FDA0003343268930000013
70 or->
Figure FDA0003343268930000014
120。
9. A powder for inhalation according to claim 6, wherein: the carrier lactose particle size distribution of the composition is characterized by d10=35-160 μm, d50=95-250 μm, d90=160-340 μm.
10. A powder for inhalation according to claim 1, wherein: the powder aerosol composition also comprises other pharmaceutically acceptable auxiliary materials.
11. A powder for inhalation according to claim 10, wherein: the auxiliary material is lactose for inhalation or a mixture of lactose for inhalation and magnesium stearate.
12. A process for the preparation of a powder for inhalation according to any one of claims 1 to 11, characterized in that: the method comprises the following steps:
(1) Micronizing active substance medicine: the particle size characteristics d50=1.5-3.5 μm and d90 is less than or equal to 5 μm of the micronized medicine;
(2) Carrier treatment: sieving and premixing lactose;
(3) Other special treatments: the active ingredients generated after micronizing the active drugs are subjected to modulation treatment, the temperature condition of the modulation equipment is 25-60 ℃, preferably 25-40 ℃, the humidity condition is 50-92.5 RH, preferably 50-75RH, and the amorphous content of the active ingredients is reduced;
(4) Mixing: mixing the three active ingredients and the carrier using a high shear mixing device or a three dimensional mixing device or a combination of both;
(5) And (3) filling: the powder formulation is metered into the inhalation device using a metering device.
13. Use of the powder aerosol composition for inhalation according to any one of claims 1 to 11 in a reservoir dry powder inhaler.
14. A dry powder inhaler loaded with the powder aerosol composition for inhalation according to any one of claims 1 to 11, characterized in that:
the dry powder inhaler is a reservoir type dry powder inhaler;
the reservoir type dry powder inhaler is provided with a reservoir or a powder storage container for storing powder aerosol compositions and is used for storing at least two powder aerosol compositions and carriers;
when the powder inhaler is used each time, the reservoir or the powder storage container sequentially or simultaneously conveys at least two powder aerosol compositions and carriers to a rotary mixing cavity of the dry powder inhaler;
under the drive of the air flow, the dry powder is stably, uniformly and accurately delivered to the lung system of a patient through the flow channel and the suction nozzle after the at least two powder fog agent compositions and the carrier are mixed, so that the drug delivery function is realized.
15. Use of a powder for inhalation as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease and asthma.
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