CN113134000A - Pharmaceutical composition containing relaxing smooth muscle - Google Patents
Pharmaceutical composition containing relaxing smooth muscle Download PDFInfo
- Publication number
- CN113134000A CN113134000A CN202010066284.XA CN202010066284A CN113134000A CN 113134000 A CN113134000 A CN 113134000A CN 202010066284 A CN202010066284 A CN 202010066284A CN 113134000 A CN113134000 A CN 113134000A
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- CN
- China
- Prior art keywords
- terbutaline
- pharmaceutical composition
- ambrisentan
- group
- copd
- Prior art date
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- Granted
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Classifications
-
- 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
Abstract
The invention provides a safer and more effective pharmaceutical composition containing relaxed smooth muscle for treating chronic obstructive pulmonary disease, which consists of terbutaline with medicinal dosage, ambrisentan and a proper amount of auxiliary materials. The invention has the advantages that: the pharmaceutical composition can relieve asthma, relieve airway spasm and obstruction, and prevent and treat pulmonary hypertension secondary to chronic obstructive pulmonary disease. In addition, the medicine composition can also facilitate the taking of the medicine by patients and improve the compliance.
Description
Technical Field
The invention provides a pharmaceutical composition for treating chronic obstructive pulmonary disease, which consists of terbutaline and ambrisentan; the invention 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 may further progress to cor pulmonale and respiratory failure. COPD is high in fatality rate, is the fourth leading cause of death of human beings, and the morbidity of people over 40 years old is up to 9-10 percent globally.
Pathogenesis of COPD and airway resistance to harmful gases or particlesAbnormal inflammatory responses are associated, often with respiratory tract infections, and pathological manifestations are characterized by chronic inflammation of the small airways, lung parenchyma and pulmonary vessels. COPD is prone to chronic hypoxia and CO due to respiratory obstruction2Retention, and chronic hypoxia for a long time causes extensive contraction of pulmonary vessels, intimal hyperplasia and fibrosis of blood vessels, reduction of pulmonary blood flow, aggravation of hypoxia and formation of malignant circulation. In the acute attack stage of COPD, the capillary endothelium is damaged due to infection, hypoxia, acidosis and the like, ET-1 is released to further contract pulmonary vessels, and the respiratory function of the lung is affected by the imbalance of the ratio of lung ventilation to blood flow. There are a number of inflammatory mediators and cytokines involved in the pathogenesis of COPD, of which ET-1 has a central regulatory role in the pulmonary circulation and airway responsiveness. ET-1 has a strong vasoconstrictor and smooth muscle cell proliferation promoting ability. ET and its receptors are widely distributed in the respiratory system and have important regulatory effects on lung ventilation and lung circulation, and abnormal expression of ET may play an important regulatory role in the development and progression of COPD.
The ET family is composed of 3 vasoactive peptide (ET-1, ET-2, ET-3) members, and ET-1 has the strongest vasoconstrictive action among 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; the ETB receptor has stronger affinity with 3 kinds of ET and is distributed in endothelial cells, epithelial cells, endocrine cells, nerve cells and the like. Studies show that the ET invertase inhibitor and the ET receptor antagonist can effectively treat pulmonary hypertension, salt-sensitive hypertension and the like.
Pulmonary Hypertension (PH) is a complication of the progression of COPD to late stages, and further to pulmonary heart disease, leading to a rapidly increasing risk of death for the patient. The pathogenesis of pulmonary hypertension may include pulmonary vasoconstriction due to hypoxia, vascular deformation due to pulmonary hyperventilation, and pulmonary tissue structure destruction with vascular injury due to emphysema.
Terbutaline is beta2The receptor agonist has the effects of relieving smooth muscle spasm and dilating bronchus, has high selectivity on bronchial smooth muscle, can relieve asthma and airway obstruction of COPD patients, and has little excitation effect on heart without any effectHas central function, and can be used for treating bronchial asthma, asthmatic bronchitis, obstructive emphysema and other lung diseases accompanied with bronchospasm, especially for COPD patients accompanied with hypertension and coronary heart disease.
Ambrisentan is a new generation endothelin receptor antagonist, selectively binds ETA (Ki 0.011nM) with more than 4000-fold greater affinity than ETB. This high degree of selectivity allows ambrisentan to strongly inhibit the vasoconstrictive action of ETA without much affecting the vasodilatory action of ETB.
Disclosure of Invention
The invention aims to provide a safer and more effective pharmaceutical composition containing smooth muscle relaxation for Chronic Obstructive Pulmonary Disease (COPD).
In order to achieve the purpose, the invention 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 invention, the pharmaceutically acceptable dose of terbutaline is selected from 1.25 to 5mg, preferably 1.25 to 2.5 mg. In the pharmaceutical composition provided by the invention, terbutaline may exist in the form of salts, esters, active metabolites or pharmaceutically acceptable precursors. The terbutaline provided by the invention is used as a medicine component, and the existing forms of salts, esters, active metabolites or medicinal precursors of the terbutaline are also within the protection scope of the application. The medicinal dosage of the salts, esters, active metabolites or medicinal precursors of terbutaline can be converted correspondingly.
In the present invention, the pharmaceutical dosage of ambrisentan is selected from 2.5-10mg, preferably 2.5-5 mg. In the pharmaceutical composition provided by the invention, ambrisentan can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The ambrisentan provided by the invention is used as a medicinal component, and the existing forms of the salts, esters, active metabolites or medicinal precursors of the ambrisentan are also within the protection scope of the application. The medicinal dosage of the existing forms of salts, esters, active metabolites or medicinal precursors of ambrisentan can be converted correspondingly.
Preferably, the pharmaceutical composition provided by the invention comprises 1.25mg of terbutaline and 2.5mg of ambrisentan.
In the present invention, the pharmaceutically acceptable dose of the active ingredient of the composition means a dose range in which the active ingredient of the composition exerts its pharmacological effect when combined with other active ingredients in the composition. The preferred dosage is the preferred dosage of the active ingredients of the composition, and the preferred dosage has better efficacy than the pharmaceutical dosage. Generally, the pharmaceutically acceptable dose of the active ingredient of the composition will include an optimum dose or range of optimum doses for the composition to produce the maximum effect, which will benefit the patient even more.
The pharmaceutical composition also contains pharmaceutically acceptable carriers, can be prepared into common oral preparations, including common tablets, common capsules, granules and the like, and when the pharmaceutical composition is prepared into tablets, the pharmaceutically acceptable carriers comprise excipients and adjuvants which are helpful for preparing active compounds into pharmaceutical preparations, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite and the like, and belong to the common knowledge in the field.
The pharmaceutical compositions of the present invention may also be used interchangeably in the form of "combination kits". The "combination kit" is a box-shaped container, which contains a plurality of dosage forms of the drug combination, and instructions for administration. The combined medicine box is more suitable for individual medicine.
The pharmaceutical composition provided by the invention has the beneficial effects that the two active ingredients have synergistic pharmacological effects: terbutaline can relax bronchial smooth muscle, expand bronchus, and relieve airflow limitation; ambrisentan can reduce pulmonary artery pressure. The combination of terbutaline and ambrisentan can prevent COPD from evolving to pulmonary hypertension on the basis of spasmolysis and asthma relief, and the clinical benefit is far greater than that of terbutaline which is used alone, so that the terbutaline and ambrisentan combined drug is a better combined drug product. The combination of terbutaline and ambrisentan can reduce the dosage of terbutaline, thereby reducing the dosage of terbutalineThe latter side effects. Therefore, the composition of the present invention is compared with the existing beta2The receptor agonist terbutaline is a better drug for treating COPD than terbutaline, and is particularly suitable for treating COPD with pulmonary hypertension or preventing the transformation of COPD to pulmonary hypertension.
The present invention is further described with reference to the following detailed description, which is not intended to be limiting, but rather is intended to cover all equivalent art-recognized alternatives falling within the scope of the invention.
Detailed Description
Examples 1 to 2: preparation of terbutaline/ambrisentan tablet (1000 tablets)
The preparation process comprises the following steps:
mixing terbutaline and ambrisentan, adding carboxymethyl starch sodium and sodium lauryl sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, adding appropriate amount of 10% polyvidone ethanol solution to obtain soft material, granulating, drying, grading, mixing with appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablets.
Examples 3 to 4: preparation of terbutaline/ambrisentan capsule (1000 granules)
| Formulation composition | Example 3 | Example 4 |
| Terbutaline | 1.25g | 5g |
| Ambrisentan | 2.5g | 10g |
| 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 lauryl sulfate, adding microcrystalline cellulose and lactose, mixing, granulating with 5% hypromellose solution, drying at 50-60 deg.C for 2 hr, mixing with magnesium stearate, and encapsulating with No. 1 capsule. Making into 1000 granules.
Examples 5 to 6: preparation of terbutaline/ambrisentan granules (1000 bags)
The preparation process comprises the following steps:
(1) weighing the terbutaline/ambrisentan with the prescription amount, sieving with a 100-mesh sieve, and uniformly mixing according to an equivalent incremental method for later use;
(2) sieving other adjuvants with 100 mesh sieve respectively;
(3) weighing lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame according to the prescription amount, uniformly mixing, and uniformly mixing with the mixed raw material medicines by an equivalent incremental method;
(4) adding a proper amount of adhesive to prepare a soft material, granulating by using 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 magnesium stearate into the dry granules, mixing, measuring content, and packaging.
Example 7: effect of terbutaline + ambrisentan treatment on COPD rats
Healthy SPF grade SD rats with weight of 180 + -20 g and half female and half male were obtained. 10 rats served as a normal group control group, and the rest were subjected to the fabrication of a COPD model.
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 through an external catheter for 12 weeks. And (3) feeding the normal control group in a smokeless environment, taking 2 animals arbitrarily to make pathological sections after the experiment is finished, and observing by using a light microscope to prompt that the COPD model is successfully molded.
And 3d after the molding is finished, dividing the rats 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 treatment after the successful modeling, the dosage concentration is 0.125mg/kg, 0.25mg/kg and 0.125/0.25mg/kg respectively, and the administration is carried out by intragastric administration according to the volume of 1ml per 100g body weight for 8 weeks.
After the experiment, 3% sodium pentobarbital is used for intraperitoneal injection to anaesthetize the rat, the neck and the pleuroperitoneal cavity are exposed, the right main bronchus is separated and ligated, and the left lung bronchus and alveolus are lavaged through the left main bronchus. Bronchoalveolar lavage fluid (BALF) was collected by repeating 3 lavages with 4ml of physiological saline, and the total number of cells was counted to determine PLA2, IL-8 and TNF-. alpha.factor.
The statistical method comprises the following steps:
1. the test data results are all as follows
And (4) showing. Comparison between groups by t test, P<0.05 statistically significant difference, P<0.01 had a very significant statistical difference.
2. In order to confirm the scientificity of the pharmaceutical composition provided by the invention, the two components of the pharmaceutical composition are reasonably compatible and can exert a synergistic interaction effect in combination with each other, rather than the simple superposition of pharmacological effects of the two drugs, and the experimental result is analyzed by a golden mean Q value method. The "Jinzheng average Q value" is also called probability addition method, and is calculated according to the pharmacological action of two drugs in combination and the pharmacological action of two drugs in single use in the dose-effect curve region by the following calculation formula: q ═ EA+B/(EA+EB-EA*EB) In the formula, the numerator represents the 'actually measured combined effect', the denominator represents the 'expected combined effect' (in order to satisfy the analysis of the relationship of the pharmacological actions of the components and the composition, the pharmacological actions are converted into the effect which can visually represent the strength of the pharmacological actions, and the calculation formula is as follows: Ei-1-Pi/PModel setPi is the pharmacological index of each component, PModel setIs a pharmacological index of the model group),q is the ratio of: 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: total number of bronchoalveolar lavage fluid cells results
Note: t-test, compared to 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 is less than 0.01, compared with the terbutaline group,□P＜0.05。
table 2: effect analysis of total cell count results in bronchoalveolar lavage fluid
Compared with the normal group, the white blood cells, the neutrophils and the lymphocytes of the model group of rats are all increased, the mononuclear-macrophages are reduced, and the obvious difference indicates that the model building is successful. The 0.125mg/kg terbutaline group reduces the number of white blood cells of COPD rats, and compared with the model group, the difference is significant; the 0.125mg/kg terbutaline group has no significant change on the action of mononuclear-macrophages, neutrophils and lymphocytes of COPD rats; the 0.25mg/kg ambrisentan group has no significant change on the effects of white blood cells, mononuclear-macrophages, neutrophils and lymphocytes of COPD rats. The terbutaline/ambrisentan group can obviously reduce white blood cells, neutrophils and lymphocytes of COPD rats, and has obvious statistical difference compared with a model group, wherein P is less than 0.01 or P is less than 0.05. The white blood cells, the neutrophils and the lymphocytes of the terbutaline/ambrisentan group rats are analyzed by using a golden mean Q value method, the Q values are respectively 1.22, 1.77 and 2.83, and are respectively more than 1.15, which indicates that the terbutaline and ambrisentan generate unexpected synergistic effect after being combined.
Table 3: results of total number of bronchoalveolar lavage fluid cells in each group of rats
Note: t-test, compared to 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 is less than 0.05, compared with the terbutaline group,□□P＜0.01。
table 4: effect analysis of Total cell count results in bronchoalveolar lavage fluid of rats in each group
Compared with the normal group, the rats PLA2 and IL-8 in the model group are increased and have significant difference, 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 of COPD rat PLA 2. The terbutaline/ambrisentan group can remarkably reduce PLA2 and IL-8 of COPD rats, and compared with a model group, the difference is remarkable. The experimental results show that the terbutaline and ambrisentan can obviously improve the lung inflammation characteristics of a rat in a COPD model, and the combined effect is obviously better than that of single-drug application (P <0.05 or P < 0.01). When a golden positive average Q value method is used for analyzing PLA2 and IL-8 of the terbutaline/ambrisentan group rats, Q values are 1.22 and 1.46 respectively, and are both larger than 1.15, which indicates that the terbutaline and ambrisentan generate unexpected synergistic effect after being combined.
The research results show that the pharmaceutical composition provided by the invention has a synergistic effect in the aspect of treating chronic obstructive pulmonary disease, and the invention provides a therapeutic effect which is obviously superior to that of beta for treating chronic obstructive pulmonary disease2Pharmaceutical compositions of receptor agonists.
Example 8: clinical observations of terbutaline in combination with ambrisentan for treatment of COPD
46 patients who met the diagnostic criteria for COPD were enrolled, in half a male and a female, and aged 50-75 years. All patients drawn blood on an empty stomach in the early morning before administration, plasma hs-CRP, ET-1 content was determined, radial artery blood was taken for blood gas analysis, PO was determined2And PCO2And the like. The pulmonary function instrument detects the pulmonary function of a subject and records indexes of VC, FEV/FVC and the like of a patient in detail. The patients were then randomized into study and control groups of 23 patients, the study group being given terbutaline + ambrisentan (1.25mg +2.5mg) treatment and the control group being given terbutaline only (1.25mg), for a treatment period of 4 weeks, once daily, one tablet at a time. The above criteria were measured in the same manner after the treatment.
Table 5: treatment of Hs-CRP, ET-1 Effect on COPD patients with the compositions of the invention
P <0.05, P <0.01 compared to the terbutaline group.
After two groups of treatment, hs-CRP of patients is reduced, but compared with terbutaline singly, the effect of reducing hs-CRP by terbutaline and ambrisentan is more obvious and has significant difference (P <0.01), which proves that the composition can more effectively reduce inflammatory reaction caused by hs-CRP. Plasma ET-1 (endothelin) has the function of contracting blood vessels, capillary vessel endothelium injury is caused by infection, hypoxia and other factors in the attack stage and the remission stage of a dosage form of a COPD patient, and ET-1 can be released to cause further contraction of pulmonary vessels, so that the respiratory function is influenced. After two groups of treatment, ET-1 of a patient is reduced, but compared with terbutaline used alone, the effect of reducing ET-1 by terbutaline and ambrisentan is more obvious and has significant difference (P is less than 0.01), and the composition provided by the invention can be used for more effectively reducing the contraction reaction of a gas collecting tube caused by ET-1 and effectively relaxing an airway.
Table 6: the composition of the invention compares the lung function parameters of the patient with blood gas analysis
As compared to the pre-grouping comparison,#P<0.05,##P<0.01, P compared to terbutaline group<0.05,**P<0.01。
Vital Capacity (VC): the maximum breath is taken after the maximum inspiration, and the maximum expired air volume (VC ═ TV + IRV + ERV) is obtained. Forced expiratory volume in one second (FEV1) and FEV 1% (FEV 1/FVC): during forced rapid expiration after deep inspiration, the expired air volume in the first second is referred to as FEV1, and is clinically evaluated by the ratio of one-second forced expiration volume to forced vital capacity (FEV 1%). PaO2The partial pressure of blood oxygen refers to the tension (or pressure) generated by oxygen molecules in the blood. PaCO 2: arterial blood partial pressure of carbon dioxide
Compared with the single terbutaline, the combined medicine group of the invention has obviously improved vital capacity VC after the combined treatment of terbutaline and ambrisentan (P)<0.01)，FEV/FVC、PO2Is obviously increased (P)<0.01)，PCO2Is obviously reduced (P)<0.01), which shows that the addition of ambrisentan has the effect of synergistically improving the airway obstruction, can obviously improve the lung function in the treatment of COPD, and greatly improves the treatment effect.
Claims (7)
1. A pharmaceutical composition for treating chronic obstructive pulmonary disease comprises the following components:
(1) a therapeutically effective amount of terbutaline;
(2) a therapeutically effective amount of ambrisentan;
(3) a pharmaceutically acceptable carrier.
2. Pharmaceutical composition according to claim 1, characterized in that the terbutaline content is 1.25-5mg, preferably 1.25-2.5 mg.
3. Pharmaceutical composition according to claim 1, characterized in that the ambrisentan is in an amount of 2.5-10mg, preferably 2.5-5 mg.
4. Pharmaceutical composition according to claim 1, characterized in that the composition of the pharmaceutical composition is 1.25mg of terbutaline, 2.5mg of ambrisentan.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as an oral dosage form selected from the group consisting of tablets, capsules, and granules.
6. Use of a pharmaceutical composition according to claims 1-5 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.
7. Use of a pharmaceutical composition according to claims 1-5 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease with pulmonary hypertension.
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| US20040105819A1 (en) * | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Respiratory drug condensation aerosols and methods of making and using them |
| 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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| US20040105819A1 (en) * | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Respiratory drug condensation aerosols and methods of making and using them |
| 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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