From medicine to concept, the next step in asthma treatment

Asthma is a common chronic respiratory disease characterized by airway inflammation that involves a variety of cells (such as eosinophils, mast cells, T lymphocytes, neutrophils, airway epithelial cells, etc.

Therefore, the goal of clinical treatment and management of asthma is to focus on the control of clinical symptoms on the one hand, including alleviating symptoms, reducing the use of alleviating drugs, increasing mobility, and improving lung function.

Based on the above treatment goals and clinical treatment scenarios, commonly used asthma drugs can be divided into three categories

The first category is control drugs, which mainly make the clinical symptoms of asthma can be maintained and controlled daily through anti-inflammatory effects, and they need to be maintained and used daily for a long time

At present, the number of asthma patients in the world is about 300 million people (about 5% of the global population) with asthma [1]

Current status of asthma control in China: overall poor

In recent years, with the widespread promotion of standardized diagnosis and treatment of asthma, the overall control rate of asthma patients in China has increased significantly, but it is still lower than that in developed countries [4]

Poor asthma control is usually related to some patients' insensitivity to glucocorticoid therapy, poor use of inhalation devices, and poor compliance with treatment

For example, researchers have found the same inflammatory factors in the large and small airways of asthma patients, and the eosinophilic inflammatory changes in the small airways are more serious [9-10]; inflammation of the small airways causes the tube wall to thicken and cause the lumen to narrow.

From the perspective of population characteristics, smoking, airflow limitation (FVC<80% predicted value), and long-term disease (with asthma for more than 10 years) are all high-risk patients with small airway dysfunction

Control of small airway inflammation: need ultra-fine drug particles

Small airway dysfunction is closely related to poor asthma control and poor clinical outcomes, but it is the most neglected factor in clinical treatment because the detection methods for small airway diseases are limited and the "gold standard" is lacking

In ventilation and lung function tests, the main indicators reflecting small airway function are FEF 50% (expiratory flow rate when expiring 50% vital capacity), FEF 75% (expiratory flow rate when expiring 75% vital capacity), FEF 25%～75% (The average flow when exhaling 25% to 75% of the vital capacity, also known as the maximum mid-expiratory flow (MMEF)), when two of these three indicators are lower than the LLN (lower limit of normal, about 65% of the predicted value), It can be judged as small airway dysfunction [14]

Under the premise that asthma control factors and evaluation indicators are clear, the development and application of asthma drugs should also be more targeted, such as allowing drug particles to effectively enter all large and small airways, especially small airways, so as to more comprehensively control the progression of inflammation

The deposition area of ​​different sizes of drug particles in the lungs

A randomized, placebo-controlled trial of 12 asthmatic patients demonstrated that ultrafine particles with a median total aerodynamic diameter of 1.

Particle size and sediment distribution

The 2020 version of the Bronchial Asthma Prevention and Control Guide compiled by the Asthma Group of the Respiratory Branch of the Chinese Medical Association also recognizes that ultrafine particle aerosols have a higher lung deposition rate, and clearly pointed out that the lung deposition rate of dry powder inhalers is higher than that of standard particle quantitative aerosols.

Sufficient clinical evidence: ultrafine particles significantly improve asthma control

Ultrafine particles can effectively control airway inflammation and significantly improve asthma control, which is also supported by clinical evidence

An open-label, single-dose, parallel grouping study included 8 healthy volunteers, 8 patients with persistent asthma, and 8 patients with stable chronic obstructive pulmonary disease (COPD).

Reflected in curative effect, compared with ordinary particles of fluticasone/salmeterol (FP/S), ultrafine particles of BDP/F significantly improve forced vital capacity (FVC)
.
For example, in an international multi-center, randomized double-blind, double-arm parallel grouping, phase III controlled study, 228 moderate to severe asthma patients randomly received ultrafine particles of BDP/F 100/6μg or FP/S 125/25μg, 2 per day Times, 2 puffs each time, a total of 12 weeks of treatment
.
The results showed that the morning peak expiratory flow (PEF), the primary endpoint of the two groups of patients, increased significantly, and there were no significant differences in the daytime and nighttime symptom scores and the frequency of acute exacerbations of asthma
.
But in terms of FVC, the BDP/F improvement effect is better, with a statistically significant difference [21]
.

In terms of clinical outcome, ultrafine particles of BDP/F can significantly increase the rate of complete asthma control and reduce emergency response compared with ordinary particles of budesonide/formoterol (BUD/F) and fluticasone/salmeterol (FP/S).
The amount of drugs and hormones used
.

For example, in a 12-month prospective PRISMA study, a total of 1,017 patients with uncontrolled or partially controlled asthma were included, of which 569 received ICS/LABA compound metered-dose inhalation treatment
.
The results showed that compared with the ordinary particles of BUD/F, the proportion of patients with complete control of asthma who received ultrafine particles of BDP/F treatment was significantly higher (P=0.
032) [22]
.

In a real-world cross-regional study code-named Müller, 111 patients with moderate to severe persistent asthma received ICS/LABA maintenance treatment
.
The results show that, compared with ordinary particles of ICS/LABA (BUD/F and FP/S), ultrafine particles of BDP/F significantly improve the rate of asthma control (57% vs 36%)
.
In addition, the daytime symptoms and the use of emergency drugs in the ultrafine particle BDP/F group were significantly reduced
.
And BDP/F can achieve better asthma control under the condition of lower average daily treatment hormones (BDP/F: BUD/F: FP/S= 321μg: 715μg: 720μg) [23]
.

Another real-world retrospective study also proved this.
Compared with FP-SAL (fluticasone propionate salmeterol), the use of ultra-fine particle BDP/F can significantly reduce the daily therapeutic dose of hormones by about 130μg/day
.
In addition, in the overall control of asthma, treatment compliance and SABA dosage, the ultrafine particles of BDP/F all showed significant differences [24]
.

The ultrafine particle administration of beclomethasone dipropionate formoterol aerosol (BDP/F) is achieved through a pressure metered dose inhaler (pMDI)
.
On the one hand, it adopts the patented technology of "superfine slow fog" (Modulite®), adding co-solvents and non-volatile components to effectively adjust the size of BDP/F aerosol particles, and the median particle size of the prepared particles is only 1.
4-1.
5μm[ 25]
.
At the same time, changing the nozzle diameter and shape of aerosols makes the duration of aerosols 3 times longer than that of traditional aerosols, the speed of mist is slowed, and it is easier for patients to achieve press-inhalation coordination [26]
.
On the other hand, the pressure metered-dose inhaler does not depend on the inspiratory flow rate, and is also suitable for patients with poor lung function and unable to effectively inhale dry powder
.

Concluding remarks

Asthma and chronic obstructive pulmonary disease (COPD) are the two most common chronic respiratory diseases, affecting many people around the world
.
Because of the need for long-term medication, it will have a greater impact on the patient's physical and mental health and quality of life
.
From the perspective of the industry’s strategy for developing therapeutic drugs for these two chronic respiratory diseases, on the one hand, the drug treatment mechanism is constantly upgrading, except for the continuous introduction of ICS/LAMA/LABA triple therapy from ICS single therapy to LAMA/LABA dual therapy.
In addition to the drug combination with better control effect for severe patients, breakthroughs have been made in more innovative drug targets (IL-5/IL-5R, IL-4/IL-4R); on the other hand, it is based on respiratory diseases The pathological characteristics and treatment scenarios of the disease, the continuous optimization of the delivery technology of inhaled drugs, the continuous upgrade from ordinary particle aerosols to dry powder inhalants, ultra-fine slow fog aerosols, etc.
, so that the drugs can reach the large and small airways more effectively, and the air can be controlled more comprehensively.
Inflammation of the tract, realize the co-treatment of the large and small airways, gradually improve the effect of asthma control, and improve the long-term clinical results
.

The upgrading of asthma and COPD treatments is the result of the joint promotion of the world's leading companies in respiratory diseases
.
China has currently approved a number of asthma/COPD treatment drugs for the market, including the triple Budi Gefu inhalation aerosol, and the flutimex veena device in the past two years, keeping pace with foreign advanced technology
.
Casey Pharmaceuticals also submitted a domestic marketing application for beclomethasone dipropionate/formoterol fumarate/glycopyrrolate aerosol in China in October 2020, using beclomethasone formoterol aerosol.
With the same inhalation device and technology, the ICS/LABA/LAMA/ drugs of the three mechanisms can reach the small and large airways more effectively in the form of ultra-fine particles, and control airway inflammation more deeply, which is beneficial to improve the long-term outcome of patients[ 27]
.
These innovative triple therapies will also provide Chinese patients with asthma/COPD with richer treatment options and help achieve the goal of "Healthy China 2030"
.

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