CN113134000B - Pharmaceutical composition containing relaxing smooth muscle - Google Patents

Pharmaceutical composition containing relaxing smooth muscle Download PDF

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CN113134000B
CN113134000B CN202010066284.XA CN202010066284A CN113134000B CN 113134000 B CN113134000 B CN 113134000B CN 202010066284 A CN202010066284 A CN 202010066284A CN 113134000 B CN113134000 B CN 113134000B
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terbutaline
pharmaceutical composition
ambrisentan
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copd
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CN113134000A (en
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李锦良
白洁
张磊
于多
王滨燕
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Shenzhen Ausa Pharmaceutical Co ltd
Shenzhen Changqing Medical Science Research Institute
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Shenzhen Changqing Medical Science Research Institute
Shenzhen Ausa Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Aiming at chronic obstructive pulmonary disease, the application provides a safer and more effective pharmaceutical composition containing relaxed smooth muscle, which consists of terbutaline, ambrisentan and proper amount of auxiliary materials with medicinal dosage. The application has the advantages that: the pharmaceutical composition can not only relieve asthma, relieve airway spasm and obstruction, but also prevent and treat pulmonary arterial hypertension secondary to chronic obstructive pulmonary disease. In addition, the pharmaceutical composition can also facilitate the patients to take medicine and improve compliance.

Description

Pharmaceutical composition containing relaxing smooth muscle
Technical Field
The application provides a pharmaceutical composition for treating chronic obstructive pulmonary disease, which consists of terbutaline and ambrisentan; the application belongs to the field of pharmacy.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a common disease of the respiratory system, including chronic bronchitis, bronchial asthma and obstructive emphysema, which can further develop into pulmonary heart disease and respiratory failure. COPD has high mortality rate, is the fourth leading cause of death of human beings, and has the morbidity rate of 9-10% of people over 40 years old worldwide.
COPD is a pathogenesis associated with an abnormal inflammatory response of the airways to noxious gases or particles, often accompanied by respiratory tract infections, and the pathological manifestations are characterized by chronic inflammatory properties of the small airways, lung parenchyma and pulmonary blood vessels. COPD is prone to chronic hypoxia and CO due to obstruction of expiratory ventilation 2 While chronic hypoxia for a long period causes extensive contraction of pulmonary vessels, hyperplasia of vascular intima, fibrosis, reduction of pulmonary blood flow, exacerbation of hypoxia, and formation of malignant circulation. In the acute onset of COPD, capillary endothelial injury is caused by infection, hypoxia, acidosis, etc., and ET-1 is released to cause further pulmonary vascular diseasesContraction aggravates the imbalance of the lung ventilation and blood flow ratio, affecting the respiratory function of the lung. There are a number of inflammatory mediators and cytokines involved in the pathogenesis of COPD, with ET-1 having important regulatory roles in pulmonary circulation and airway reactivity. ET-1 has a strong ability to pro-vasoconstrict and smooth muscle cell proliferation. ET and its receptors are widely distributed in the respiratory system and play an important role in regulating pulmonary ventilation and pulmonary circulation, and its abnormal expression may play an important role in regulating COPD occurrence and development.
The ET family consists of 3 vasoactive peptide (ET-1, ET-2, ET-3) members, of which ET-1 has the strongest vasoconstrictor effect among the 3 ET subtypes. The 2 main receptors of ET are ETA and ETB, wherein the ETA receptor is mainly combined with ET-1 and ET-2 and distributed in muscle cells; ETB receptor has strong affinity with 3 ET, and is distributed in endothelial cells, epithelial cells, endocrine cells, nerve cells, etc. Studies have shown that the use of ET invertase inhibitors, ET receptor antagonists, are effective in treating pulmonary hypertension, salt-sensitive hypertension, etc.
Pulmonary Hypertension (PH) is a complication of COPD that develops into a late stage and further into pulmonary heart disease, leading to a rapid increase in the risk of patient mortality. The pathogenesis of pulmonary hypertension may include pulmonary vasoconstriction due to hypoxia, vascular deformation due to pulmonary hyperventilation, and damage to the pulmonary tissue structure with concomitant vascular injury due to emphysema.
Terbutaline is beta 2 The receptor agonist has the effects of relieving smooth muscle spasm and dilating bronchus, has high selectivity to bronchus smooth muscle, can relieve asthma and airway obstruction of COPD patients, has little excitation effect on heart and no central effect, can be used for treating bronchial asthma, asthmatic bronchitis, obstructive emphysema and other pulmonary diseases accompanied with bronchospasm, and is especially suitable for COPD patients accompanied with hypertension and coronary heart disease.
Ambrisentan is a new generation endothelin receptor antagonist capable of selectively binding to ETA (ki=0.011 nM), more than 4000 times greater affinity than ETB. This high selectivity allows ambrisentan to strongly inhibit the vasoconstrictor effect of ETA, while not affecting the vasodilator effect of ETB too much.
Disclosure of Invention
The application aims to provide a pharmaceutical composition containing smooth muscle relaxation, which is safer and more effective in treatment for Chronic Obstructive Pulmonary Disease (COPD).
In order to achieve the above purpose, the present application adopts the following technical scheme:
a safer and more effective pharmaceutical composition for treating COPD comprises the following components:
(1) A pharmaceutically acceptable dose of terbutaline;
(2) A pharmaceutically acceptable dose of ambrisentan;
(3) A pharmaceutically acceptable carrier.
In the present application, the pharmaceutically acceptable dosage of terbutaline is selected from 1.25-5mg, preferably 1.25-2.5mg. In the pharmaceutical composition provided by the application, terbutaline can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The terbutaline provided by the application is taken as a medicinal component, and the existence forms of salts, esters, active metabolites, medicinal precursors and the like of terbutaline are also within the scope of the application. The pharmaceutical dosage of terbutaline in the form of salts, esters, active metabolites or pharmaceutical precursors can be converted accordingly.
In the present application, the pharmaceutically acceptable dosage of ambrisentan is selected from the group consisting of 2.5-10mg, preferably 2.5-5mg. In the pharmaceutical composition provided by the application, ambrisentan can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The ambrisentan provided by the application is used as a medicinal component, and the existence forms of salts, esters, active metabolites, medicinal precursors and the like of the ambrisentan are also within the scope of the application. The pharmaceutically acceptable dosage in the form of salts, esters, active metabolites or pharmaceutically acceptable precursors of ambrisentan can be converted accordingly.
As a preferred embodiment, the pharmaceutical composition provided by the application comprises 1.25mg terbutaline and 2.5mg ambrisentan.
In the present application, the pharmaceutically acceptable dosage of the active ingredient of the composition means a dosage range in which the pharmaceutically active ingredient of the drug is combined with other pharmaceutically active ingredients in the composition to exert the drug effect of the composition. The preferred dosage is a preferred pharmaceutical dosage of the active ingredient of the composition, the preferred dosage having a better potency than the pharmaceutical dosage. Typically, the pharmaceutical dosage of the active ingredient of the composition includes an optimal dosage or optimal dosage range that maximizes the efficacy of the composition, which would benefit the patient even more.
The pharmaceutical composition also contains pharmaceutically acceptable carriers which can be prepared into common oral preparations, including common tablets, common capsules, granules and the like, and the pharmaceutically acceptable carriers comprise excipients and auxiliary agents which are helpful for preparing active compounds into pharmaceutical preparations when preparing tablets, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite and the like, and the composition of one or more substances belongs to the common general knowledge in the field.
The pharmaceutical compositions of the present application may also be used interchangeably in the form of a "combination kit". The "combination kit" is a box-like container into which a plurality of dosage forms of the pharmaceutical combination, together with instructions for administration thereof, are placed. The combined medicine box is more suitable for individual medicine application.
The pharmaceutical composition provided by the application has the beneficial effects that the two active ingredients have synergetic pharmacological effects: terbutaline can relax smooth muscle of bronchus, dilate bronchus and relieve airflow limitation; ambrisentan can reduce pulmonary artery pressure. The terbutaline and ambrisentan are combined, so that the evolution of COPD to pulmonary arterial hypertension can be prevented on the basis of spasmolysis and asthma relieving, and the clinical benefit of the terbutaline is far greater than Shan Yongte terbutaline, so that the terbutaline and ambrisentan are better combination drug products. The combination of terbutaline with ambrisentan also allows to reduce the amount of terbutaline and thus the side effects of the latter. The composition of the present application is therefore compatible with existing beta 2 The receptor agonist terbutaline is a better medicament for treating COPD than terbutaline, and is particularly suitable for treating COPD with pulmonary hypertension or preventing the conversion of COPD to pulmonary hypertension.
The application is further described in connection with the following detailed description, which is not intended to be limiting, but is set forth to cover all equivalent embodiments in the art according to the teachings of the present application.
Detailed Description
Examples 1-2: preparation of terbutaline/ambrisentan tablet (1000 tablets)
The preparation process comprises the following steps:
mixing terbutaline and ambrisentan, adding carboxymethyl starch sodium and dodecyl sodium sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, making into soft material with appropriate amount of 10% povidone ethanol solution, granulating, drying, grading, mixing granule with water content of about 3% and appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablet.
Examples 3-4: preparation of terbutaline/ambrisentan capsule (1000 capsules)
Formulation composition Example 3 Example 4
Terbutaline 1.25g 5g
Ambrisentan 2.5g 10g
Lactose and lactose 60g 66g
Microcrystalline cellulose 85g 90g
Sodium dodecyl sulfate 8g 8g
Croscarmellose sodium 4.5g 3.6g
5% hypromellose solution Proper amount of Proper amount of
Magnesium stearate 2g 2g
The preparation process comprises the following steps:
sieving carboxymethyl starch sodium with 100 mesh sieve, and sieving lactose and microcrystalline cellulose with 80 mesh sieve; mixing the raw materials with croscarmellose sodium and sodium dodecyl sulfate, adding microcrystalline cellulose and lactose, granulating with 5% hypromellose solution, drying at 50-60deg.C for 2 hr, mixing the obtained mixture with magnesium stearate, and encapsulating with No. 1 capsule. Making into 1000 granule.
Examples 5 to 6: preparation of terbutaline/ambrisentan granule (1000 bags)
The preparation process comprises the following steps:
(1) Weighing the prescription amount of terbutaline/ambrisentan, sieving with a 100-mesh sieve, and uniformly mixing for later use according to an equivalent incremental method;
(2) Sieving other adjuvants with 100 mesh sieve respectively;
(3) Weighing lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame with a prescription amount, uniformly mixing the lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame with the mixed raw materials by an equal-amount incremental method, and uniformly mixing the lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame with the same amount incremental method;
(4) Adding a proper amount of adhesive to prepare a soft material, granulating by a 24-mesh sieve, and drying at 40-45 ℃;
(5) Sieving with 20 mesh sieve, and sieving with 80 mesh sieve to remove fine powder;
(6) Adding proper amount of magnesium stearate into the dry granules, mixing uniformly, measuring the content of the magnesium stearate, and bagging.
Example 7: effect of terbutaline + ambrisentan treatment on COPD rats
52 healthy SPF-grade SD rats weighing 180+ -20 g and male and female halves. 10 rats were used as a normal control group, and the rest was subjected to COPD model production.
The rats to be molded were placed in a transparent box (volume 300L) with small holes for ventilation, 8 cigarettes were lit each day, and the smoke was introduced into the box via an external catheter for 12 weeks. And (3) placing the normal control group in a smokeless environment for feeding, and after the experiment is finished, taking 2 pathological sections, and observing by using a light mirror to prompt successful modeling of the COPD model.
And 3d after the molding is finished, dividing the rat successfully molded into a model group, a terbutaline group, an ambrisentan group and a terbutaline/ambrisentan group. The terbutaline group, the ambrisentan group and the terbutaline/ambrisentan group start to treat after successful molding, and the dosage concentrations are respectively 0.125mg/kg, 0.25mg/kg and 0.125/0.25mg/kg, and the administration is carried out by gastric lavage according to the volume of 1ml per 100g of body weight for 8 weeks.
After the end of the experiment, the rats were anesthetized with 3% sodium pentobarbital for intraperitoneal injection, the neck and pleuroperitoneal cavity were exposed, the right main bronchi were isolated and ligated, and left lung bronchoalveolar lavage was performed via the left main bronchi. The lavage was repeated 3 times with 4ml of physiological saline, bronchoalveolar lavage fluid (BALF) was collected, the total number of cells was counted, and PLA2, IL-8 and TNF-alpha factors were measured.
The statistical method comprises the following steps:
1. test data resultsAnd (3) representing. The comparison between groups adopts t test, P<0.05 has significant statistical differences, P<0.01 has very significant statistical differences.
2. In order to prove the scientificity of the pharmaceutical composition provided by the application, the two components of the pharmaceutical composition are reasonably compatible, can exert a synergistic effect by combining with each other, and are not the superposition of the simple pharmacological actions of the two medicines, and the experimental result is analyzed by adopting a golden average Q value method. The golden average Q value method is also called a probability addition method, and according to the pharmacological actions of the combination of two medicaments and the pharmacological actions of the single use of the two medicaments in a dose-response curve area, the golden average Q value method is calculated by the following calculation formula: q=e A+B /(E A +E B -E A *E B ) In the formula, the numerator represents the actual measurement combination effect, and the denominator represents the expected combination effect (in order to meet the analysis of the pharmacological action relation of the components and the composition, the pharmacological actions of the components and the composition are converted into the effect capable of intuitively representing the pharmacological action intensity, and the calculation formula is as follows: ei=1-Pi/P Model group Pi is the pharmacological index of each component, P Model group Pharmacological index of model group), Q is the ratio of the two: when Q is less than 0.85, the combination of the two drugs is considered to be antagonistic, when Q is less than 1.15 and greater than 0.85, the combination is considered to be additive, and when Q is greater than 1.15, the combination is considered to be synergistic.
Table 1: bronchoalveolar lavage fluid cell count results
Note that: t-test, compared with the normal group, △△ p is less than 0.01; in comparison with the set of models, ** P＜0.01， * p is less than 0.05; the composition was compared to the ambrisentan group, ## p <0.01, compared with terbutaline group, □ P＜0.05。
table 2: effect analysis of bronchoalveolar lavage fluid cell count results
Compared with the normal group, the model group has the advantages that the white blood cells, the neutrophils and the lymphocytes of the rats are all increased, the mononuclear-macrophages are decreased, and obvious differences exist, which indicates that the modeling is successful. The 0.125mg/kg terbutaline group reduces the white blood cell number of COPD rats, and compared with the model group, the difference is significant; 0.125mg/kg terbutaline group has no significant change to the effect of COPD rat mononuclear-macrophages, neutrophils and lymphocytes; the ambrisentan group at 0.25mg/kg had no significant change in the effects on leukocytes, mononuclear-macrophages, neutrophils and lymphocytes of COPD rats. The terbutaline/ambrisentan group significantly reduced COPD rat leukocytes, neutrophils, lymphocytes, with significant statistical differences, P <0.01 or P <0.05, compared to the model group. The analysis of the white blood cells, the neutrophils and the lymphocytes of the rats of the terbutaline/ambrisentan group by using a golden average Q value method, wherein the Q values are respectively 1.22, 1.77 and 2.83 and are respectively more than 1.15, which shows that the terbutaline and ambrisentan generate unexpected synergistic effect after being combined.
Table 3: total count of rat bronchoalveolar lavage fluid cells from each group
Note that: t-test, compared with the normal group, △ p is less than 0.05; in comparison with the set of models, * p is less than 0.05; the composition was compared to the ambrisentan group, # p <0.05, compared with terbutaline group, □□ P＜0.01。
table 4: effect analysis of total number of rat bronchoalveolar lavage fluid cells from each group
Compared with the normal group, the model group rats have raised PLA2 and IL-8, and have obvious differences, which indicates that the modeling is successful. The 0.125mg/kg terbutaline group and the 0.25mg/kg ambrisentan group had no significant change in the effect on COPD rat PLA 2. The terbutaline/ambrisentan group can significantly reduce PLA2 and IL-8 in rats with COPD, and the difference is significant compared with the model group. The experimental results show that terbutaline and ambrisentan can obviously improve the lung inflammation characteristics of rats with COPD models, and the combined effect is obviously better than that of single-drug application (P <0.05 or P < 0.01). The analysis of the PLA2 and IL-8 of the terbutaline/ambrisentan group rats by using the golden average Q value method, the Q values are respectively 1.22 and 1.46 and are respectively more than 1.15, which shows that the terbutaline and ambrisentan generate unexpected synergistic effect after being combined.
The research results show that the pharmaceutical composition provided by the application has a synergistic effect in the aspect of treating chronic obstructive pulmonary disease, and the application provides a medicament with a curative effect obviously superior to beta for treating chronic obstructive pulmonary disease 2 Pharmaceutical compositions of receptor agonists.
Example 8: clinical observations of terbutaline in combination with ambrisentan for the treatment of COPD
46 patients meeting the COPD diagnostic criteria were enrolled, each half of a man and a woman, aged 50-75 years. All patients were bled on an empty stomach in the early morning before dosing, plasma hs-CRP, ET-1 levels were measured, radial artery bled for blood-gas analysis, PO was measured 2 And PCO 2 And the like. The pulmonary function instrument detects the pulmonary function of a subject and records the indexes of VC, FEV/FVC and the like of the patient in detail. The patients were then randomized into study groups, 23 cases each, which were treated with terbutaline + ambrisentan (1.25 mg +2.5 mg), and control groups, which were treated with terbutaline (1.25 mg) alone, for a treatment period of 4 weeks, once daily, one at a time. The above index was measured in the same manner after the treatment.
Table 5: treatment of hs-CRP, ET-1 effects on COPD patients with the composition of the application
P <0.05, P <0.01 compared to terbutaline group.
After both groups of treatments, the patient has reduced hs-CRP, but compared with terbutaline alone, terbutaline plus ambrisentan has more obvious effect of reducing hs-CRP and obvious difference (P < 0.01), which proves that the composition can more effectively reduce inflammatory reaction caused by hs-CRP. The blood plasma ET-1 (endothelin) has the function of shrinking blood vessels, and the capillary vessel endothelial injury is caused by factors such as infection, hypoxia and the like in the dosage form attack period and the remission period of COPD patients, and the ET-1 can be released to cause further contraction of pulmonary vessels, thereby affecting respiratory functions. After two groups of treatments, the ET-1 of the patient is reduced, but compared with the terbutaline alone, the terbutaline and ambrisentan have more obvious effect of reducing the ET-1, and have obvious difference (P < 0.01), so that the composition can effectively reduce the gas collecting tube contraction reaction caused by the ET-1 and effectively relax the airway.
Table 6: the treatment of the composition of the application compares the lung function parameters and blood gas analysis of patients
In comparison with the pre-packet comparison, # P<0.05, ## P<0.01, compared to terbutaline group, P<0.05,**P<0.01。
Lung capacity (VC): maximum inspiration is followed by maximum expiration, the maximum amount of gas that can be expired (vc=tv+irv+erv). One second forced expiratory volume (FEV 1) and FEV1% (FEV 1/FVC): during rapid expiration with effort after deep inhalation, the volume of expired air in the first second time is called FEV1, and is clinically evaluated by the ratio of one second effort expiration volume to forced vital capacity (FEV 1%). PaO (PaO) 2 Blood oxygen partial pressure refers to the tension (or pressure) created by oxygen molecules in blood. PaCO2: partial pressure of arterial blood carbon dioxide
Compared with Shan Yongte butaline, the combined administration group of the application has obviously improved pulmonary capacity VC after the combined treatment of terbutaline and ambrisentan (P)<0.01)，FEV/FVC、PO 2 Obviously raise (P)<0.01)，PCO 2 Obviously reduce (P)<0.01 These all show that the addition of ambrisentan has the synergistic effect of improving airway obstruction, can significantly improve lung function for the treatment of COPD, and greatly improves the treatment effect.

Claims (4)

1. A pharmaceutical composition for treating chronic obstructive pulmonary disease comprises the following components:
(1) 1.25mg terbutaline;
(2) 2.5mg ambrisentan;
(3) A pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated into oral formulations, including tablets, capsules, granules.
3. Use of a pharmaceutical composition according to claim 1 or 2 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.
4. Use of a pharmaceutical composition according to claim 1 or 2 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease combined with pulmonary hypertension.
CN202010066284.XA 2020-01-20 2020-01-20 Pharmaceutical composition containing relaxing smooth muscle Active CN113134000B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101530618A (en) * 2009-04-13 2009-09-16 莫始平 Pharmaceutical composition for the treatment of chronic obstructive pulmonary disease and bronchial asthma
CN108567787A (en) * 2017-03-10 2018-09-25 辛衍雪 A kind of pharmaceutical composition for treating chronic obstructive pulmonary disease

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7550133B2 (en) * 2002-11-26 2009-06-23 Alexza Pharmaceuticals, Inc. Respiratory drug condensation aerosols and methods of making and using them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101530618A (en) * 2009-04-13 2009-09-16 莫始平 Pharmaceutical composition for the treatment of chronic obstructive pulmonary disease and bronchial asthma
CN108567787A (en) * 2017-03-10 2018-09-25 辛衍雪 A kind of pharmaceutical composition for treating chronic obstructive pulmonary disease

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