CN110251677B - Pharmaceutical composition for treating pulmonary fibrosis and application thereof - Google Patents

Pharmaceutical composition for treating pulmonary fibrosis and application thereof Download PDF

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CN110251677B
CN110251677B CN201910698156.4A CN201910698156A CN110251677B CN 110251677 B CN110251677 B CN 110251677B CN 201910698156 A CN201910698156 A CN 201910698156A CN 110251677 B CN110251677 B CN 110251677B
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pharmaceutical composition
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pulmonary fibrosis
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刘海英
徐颖
于得泓
曲治权
战伟
周鑫
王书惠
赵志轩
刘伦翠
白吉祥
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Mudanjiang Medical University
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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
    • A61K31/13—Amines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

The invention relates to a pharmaceutical composition for treating pulmonary fibrosis, and belongs to the field of medicines. The pharmaceutical composition comprises an NMDA receptor antagonist and an angiotensin converting enzyme inhibitor. The weight ratio of the NMDA receptor antagonist to the angiotensin converting enzyme inhibitor is 1: 1-100. The invention also provides a related preparation containing the pharmaceutical composition and application thereof.

Description

Pharmaceutical composition for treating pulmonary fibrosis and application thereof
Technical Field
The invention relates to a pharmaceutical composition for treating pulmonary fibrosis, and belongs to the field of medicines.
Background
Pulmonary Fibrosis (PF) is a severe pulmonary disease and is the ultimate outcome of the progression of Interstitial Lung Disease (ILD) caused by various etiologies. Many patients with ILD of unknown origin have finally been diagnosed as being associated with Connective Tissue Disease (CTD), known as connective tissue disease-associated interstitial lung disease, with the highest incidence of systemic sclerosis, which can be as high as 60-70%. Once a patient develops pulmonary fibrosis, the prognosis is very poor and can die in the short term from severe infection and/or respiratory failure.
The exact pathogenesis of pulmonary fibrosis is not clear at present; it is generally thought to be associated with inflammatory responses, cytokines, oxidative stress, alveolar epithelial cell injury, and fibroblast proliferation.
Lung transplantation is the most effective means for treating pulmonary fibrosis at present, and single lung transplantation can improve symptoms, delay life and improve life quality. However, many patients are unable to perform organ transplantation due to shortage of donated organ resources, rejection, infection, complications and high cost, limiting its application.
For patients who can not be treated by lung transplantation, the current clinical drug treatment of lung fibers mainly comprises the following steps: glucocorticoids, immunosuppressants (cyclophosphamide), colchicine, cytokines and inhibitors thereof, angiotensin converting enzyme inhibitors (captopril), antioxidants, and the like. Clinical findings with pulmonary fibrosis therapy have shown poor efficacy in treating interstitial lung disease, whether with corticosteroids or immunosuppressants and other therapies; the above drug treatments are not effective in improving the prognosis and survival of patients with pulmonary fibrosis.
Due to the complex mechanism of pulmonary fibrosis and a plurality of participation factors, the current treatment still has no breakthrough progress. With the application of modern molecular biology technology and the continuous and deep research on the occurrence mechanism and the pathophysiological change of the disease, the multi-target point cooperative treatment of different pathways becomes a new trend for treating pulmonary fibrosis.
Disclosure of Invention
A first aspect of the invention provides a pharmaceutical composition for the treatment of pulmonary fibrosis; it includes NMDA receptor antagonists and angiotensin converting enzyme inhibitors.
In one embodiment, the NMDA receptor antagonist is selected from the group consisting of: MK-801, ketamine, memantine and/or ifenprodil. Preferably, the NMDA receptor antagonist is memantine.
In another embodiment, the angiotensin converting enzyme inhibitor is selected from the group consisting of: captopril, enalapril, benazepril and/or ramipril. Preferably, the angiotensin converting enzyme inhibitor is ramipril.
In a further embodiment, the NMDA receptor antagonist and angiotensin converting enzyme inhibitor are present in a weight ratio of 1: 1-100. Preferably, the weight ratio of the NMDA receptor antagonist to the angiotensin converting enzyme inhibitor is 1: 5-20. More preferably, the weight ratio of the NMDA receptor antagonist to the angiotensin converting enzyme inhibitor is 1: 10.
in a preferred embodiment, the pharmaceutical composition; it comprises NMDA receptor antagonist, angiotensin converting enzyme inhibitor and glycyrrhizic acid. The weight ratio of the NMDA receptor antagonist to the angiotensin converting enzyme inhibitor to the glycyrrhizic acid is 1: 5-20: 0.1-10. Preferably, the weight ratio of the NMDA receptor antagonist, the angiotensin converting enzyme inhibitor and the glycyrrhizic acid is 1:10: 0.5-2.
A second aspect of the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition, which comprises the pharmaceutical composition and a pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical formulation is an oral formulation, an injectable formulation or a spray.
The third aspect of the invention provides the application of the pharmaceutical composition in preparing a medicament for treating pulmonary fibrosis.
The invention discovers that the NMDA receptor antagonist and the angiotensin converting enzyme inhibitor generate obvious synergistic effect on the aspects of inhibiting the proliferation of lung fibroblasts and the damage and transformation of alveolar epithelial cells, and the synergistic effect is further enhanced after glycyrrhizic acid is added. The pharmaceutical composition has a great market development value, and can be deeply researched and developed as a medicine for treating pulmonary fibrosis.
Detailed Description
The invention may be further understood by reference to the following examples, which illustrate some methods of making or using. However, it is to be understood that these examples do not limit the present invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the invention as described herein and claimed below.
In the present invention, the synergistic effect generally refers to the biological effect of the components in combination, and the activity of the composition is significantly higher than the additive effect of the individual components based on the content required to produce a given biological effect when the individual components are used alone. Colloquially, the composition produces a biological effect of 1+1> 2.
Based on the theory of synergy described above, it can be established whether there is synergy, addition or antagonism between specific compound components according to the criteria set forth in non-patent documents Chou T C. theoretical basis, experimental design, and formulated basis of synergy and anti-inflammatory in drug combination study [ J ]. Pharmacological Reviews,2006,58(3): 621) 681, the multicomponent synergy being calculated using the following formula:
CI＝A/Ae+B/Be+C/Ce
A. b and C refer to the doses of the three compound components of the pharmaceutical composition, Ae、BeAnd CeRefers to the dosage of the individual components required to achieve an inhibitory effect of the pharmaceutical composition alone, where a CI (combination index) value of less than 1 indicates a synergistic effect between the components, and a smaller CI value indicates a greater synergy between the components, and a CI value of 1 or greater indicates an equivalent or antagonistic effect. For specific test data processing, the calculation of the relevant synergistic effect can be carried out by Calcusyn V2.0(BIOSOFT, MO, USA)
EXAMPLE 1 Effect of pharmaceutical compositions on proliferation of rat Lung fibroblasts
Primary culture of rat lung fibroblasts: taking out Wistar suckling mouse 1-4 days after the mouse is taken out, soaking the suckling mouse in alcohol, taking out the suckling mouse, transferring the suckling mouse to a glass culture dish on a super clean bench, and taking out the lung tissue of the suckling mouse through an operation after disinfection. The cells were placed in a glass dish containing PBS (containing 200U/ml penicillin streptomycin) and washed to remove blood. The lung was divided into several lobes with ophthalmic scissors, peripheral blood clots and fibrous tissue were removed with forceps, bronchi and blood vessels were cut off at the hilum of the lung with ophthalmic scissors, and then washed 1 time with PBS containing diabody. Cutting lung tissue into pieces of 1mm3And (3) adding PBS containing double antibody, blowing open the lung tissue block, standing for 15min, and replacing with new PBS. Suction deviceInoculating the tissue blocks into culture bottles, wherein each bottle has about 20-25 blocks, and the distance between every two small blocks is about 0.5 cm. After the tissue blocks are placed, the culture bottle is turned slightly, the bottom of the culture bottle is upward, about 2ml of culture solution (DMEM low-sugar medium containing 10% FBS, Hyclone, USA) is added into the culture bottle, the bottle cap is covered, the culture bottle is obliquely placed in an incubator, after the culture bottle is attached to the wall for 3 hours, the culture bottle is slowly turned and horizontally placed, and standing culture is continued. After the sticking block adheres to the wall for 72h, a large amount of fibroblasts can climb out under the microscope, the tissue block is removed, the culture is continued for 2-3 days, and the passage can be carried out after the cells grow full. The lung fibroblasts are in a long fusiform shape and usually grow in a vortex shape; cells in logarithmic growth phase after 5 passages were used for subsequent experiments.
The test method comprises the following steps: the obtained rat primary lung fibroblasts were cultured at 5X 104One/ml was inoculated in 96 well cell culture plates at 200ul per well; directly adding DMEM culture medium to blank group, adding drug-containing culture medium to administration group (memantine and/or ramipril are added to each group), and adding 5% CO at 37 deg.C to 5 wells of each group2Culturing in an incubator for 24h, then measuring the cell activity by adopting an MTT method, and calculating the inhibition rate of each group.
Inhibition rate (blank OD value-administration OD value)/blank OD value × 100%
The specific results are as follows:
memantine Ramipril Inhibition ratio (%) CI
Blank group - - 0 -
Administration group 1 0.25ug/ml - 1.3±0.6 -
Administration group 2 0.5ug/ml - 4.1±0.3 -
Administration group 3 1ug/ml - 7.4±0.4 -
Administration group 4 - 1ug/ml 10.9±0.8 -
Administration group 5 - 5ug/ml 33.2±1.7 -
Administration group 6 - 10ug/ml 48.9±1.3 -
Administration group 7 1ug/ml 5ug/ml 53.6±1.9 0.499
Administration group 8 0.5ug/ml 5ug/ml 55.8±1.6 0.424
Administration group 9 0.25ug/ml 5ug/ml 50.3±1.1 0.535
In the case of pulmonary fibrosis, the primary clinical manifestations are alveolar damage, fibroblast hyperproliferation in lung tissue, and lung parenchymal cell depletion, although the pathogenic mechanisms are not yet well understood. Therefore, how to inhibit the excessive proliferation of lung fibroblasts is an important target point for treating pulmonary fibrosis.
The ACEI is a clinically common medicament for treating pulmonary fibrosis, and based on the fact that a plurality of pathway inhibitors which possibly have therapeutic effects on pulmonary fibers are screened by combining literature research, certain synergistic effects of the NMDA receptor antagonist and the ACEI are found in preliminary experiments, so that the combined effect of the NMDA receptor antagonist and the ACEI is further examined in detail. From the above results, it can be seen that the combination of NMDA receptor antagonist and ACEI produces a clear synergistic effect on the inhibition of proliferation of rat primary lung fibroblasts, and is most effective at a weight ratio of 1: 10.
Based on the above results, we further examined the combined effects of NMDA receptor antagonist, ACEI and glycyrrhizic acid, as above, with the following specific results:
memantine Ramipril Glycyrrhizic acid Inhibition rate CI
Blank group - - 0 -
Administration group 1 - - 0.05ug/ml 0.3±0.1％ -
Administration group 2 - - 0.25ug/ml 1.2±0.3％ -
Administration group 3 - - 1ug/ml 2.3±0.6％ -
Administration group 7 0.5ug/ml 5ug/ml 0.05ug/ml 57.4±2.1％ 0.396
Administration group 8 0.5ug/ml 5ug/ml 0.25ug/ml 64.9±1.8％ 0.283
Administration group 9 0.5ug/ml 5ug/ml 1ug/ml 65.2±1.4％ 0.280
The results show that the synergistic effect is further enhanced after the glycyrrhizic acid is added into the pharmaceutical composition, wherein the synergistic effect is best when the weight ratio of the memantine to the ramipril to the glycyrrhizic acid is 1:10: 0.5-2.
EXAMPLE 2 Effect of pharmaceutical compositions on model of TGF-. beta.1 induced fibrosis of human alveolar epithelial cells
In the case of pulmonary fibrosis, the fibroblast proliferation is derived in part from its self-proliferation and in part from the conversion of alveolar epithelial cells to fibroblasts under the conditions of injury, induced by cytokines. Therefore, based on the test results of example 1, we further examined the effect of the pharmaceutical composition on the model of TGF- β 1-induced fibrosis of human alveolar epithelial cells.
The test method comprises the following steps: a human alveolar epithelial cell line (A549) in logarithmic growth phase was collected at 5X 103One/ml was inoculated in 96 well cell culture plates at 200ul per well; culturing in DMEM medium containing 10% FBS for 24 hr; and then adding TGF-beta 1 (model group) with the final concentration of 10ng/ml, adding an equivalent culture medium without TGF-beta 1 into the blank group, digesting and extracting partial cell tissues after 5 days of incubator culture, then grinding and crushing the cell tissues and extracting protein, further measuring the contents of type I collagen and fibronectin in each group of protein by adopting an ELISA kit to verify whether the model is successful, and carrying out the next test after the result is confirmed.
Wells to which TGF- β 1 was added were grouped, the administration group was added with the pharmaceutical composition at different concentrations, and the model group and blank group were added with the same amount of medium, followed by incubation for 72 h.
1) The MTT method is adopted to determine the influence of the drug on the cell proliferation inhibition rate.
Inhibition rate (model group OD value-administration group OD value)/model group OD value × 100%
2) The expression level of type I collagen (ColI) and Fibronectin (FN) in the supernatant of each cell group was determined by ELISA kit
The experimental results are as follows:
1. change in expression levels of collagen type I (ColI) and Fibronectin (FN) after TGF-beta 1 induction
ColI FN
Blank group 0.5±0.2ng/ml 1.4±0.1ng/ml
Model set 3.2±0.7ng/ml 5.9±0.4ng/ml
Collagen type I (ColI) and Fibronectin (FN) are important markers for the transformation of alveolar epithelial cells to fibroblasts, so that the expression levels of ColI and FN are greatly increased after the induction of 10ng/ml TGF-beta 1, which indicates that the modeling is successful, and the next pharmacodynamic evaluation test can be carried out.
2. Effect of pharmaceutical composition on TGF-beta 1 induced fibrosis of alveolar epithelial cells
Memantine Ramipril Glycyrrhizic acid Inhibition rate CI
Model set - - - 0 -
Administration group 1 0.5ug/ml - - 8.3±0.6％ -
Administration group 2 - 5ug/ml - 40.8±1.1％ -
Administration group 3 - - 0.25ug/ml 5.2±0.4％ -
Administration group 4 0.5ug/ml 5ug/ml - 62.9±1.9％ 0.409
Administration group 5 0.5ug/ml 5ug/ml 0.25ug/ml 75.3±1.6％ 0.233
3. Effect of pharmaceutical composition on the amount of ColI and FN expression induced by TGF-beta 1 in alveolar epithelial cells
ColI FN
Model set 3.6±0.4ng/ml 6.3±0.9ng/ml
Administration group 1 3.3±0.3ng/ml 5.8±0.4ng/ml
Administration group 2 1.9±0.6ng/ml* 2.7±0.5ng/ml**
Administration group 3 3.5±0.5ng/ml 6.1±0.4ng/ml
Administration group 4 1.2±0.3ng/ml** 2.1±0.6ng/ml**
Administration group 5 0.8±0.1ng/ml** 1.6±0.3ng/ml**
By Oneway-ANOVA test, P <0.05 and P <0.01 are represented by
ColI and FN are not only markers of fibroblast transformation, but are also important components of the extracellular matrix ECM of lung tissue, which is also an important pathogenic cause of pulmonary fibrosis. As can be seen from the above results, the pharmaceutical composition can inhibit not only proliferation of fibroblasts transformed with alveolar epithelial cells but also secretion of ColI and FN into fibroblasts.
Example 3 Effect of pharmaceutical compositions on bleomycin-induced pulmonary fibrosis model in rats
The test method comprises the following steps: selecting about 200g Wistar rats, and randomly grouping into a control group, a model group and an administration group; after the rats are fasted for one night, the rats are anesthetized by injecting 10% chloral hydrate into the abdominal cavity, after anesthesia, the rats are fixed on a rat plate in a supine position, the skin of the neck is cut open, the muscles of the neck are separated in a blunt mode, the trachea is fully exposed, 5mg/kg of bleomycin is injected into the trachea by the model group and the administration group at one time, the medicine liquid is uniformly distributed in the lung, a popular pulmonary fibrosis model is established, and the control group is injected with the same amount of normal saline. After the rats are awake, intraperitoneal injection administration is started, the administration is carried out once a day, the model group and the control group are injected with the same amount of physiological saline for 3 weeks continuously, and the rats are killed to take lung tissues for relevant detection.
The following doses were administered to each group:
memantine Ramipril Glycyrrhizic acid
Administration group 1 10mg/kg
Administration group 2 10mg/kg
Administration group 3 10mg/kg
Administration group 4 0.91mg/kg 9.09mg/kg
Administration group 5 0.87mg/kg 8.7mg/kg 0.43mg/kg
Detection indexes are as follows:
1) before killing the rat, lavaging the left lung of the rat with sterile saline, washing three times, collecting bronchoalveolar lavage fluid, centrifuging a part of a specimen after filtering with gauze to obtain a cell mass, smearing, taking a Reishi-Giemsa staining solution, dripping the Reishi-Giemsa staining solution on a slide coated with cells, placing at room temperature, and performing microscopic examination to obtain the percentages of lymphocytes and neutrophils. Another lavage sample was assayed for protein content using BCA.
2) After taking lung tissue, weighing and calculating lung coefficient.
3) After calculating the lung coefficient, taking part of lung tissue, grinding and crushing, collecting protein, and measuring the content of hydroxyproline by adopting an ELISA kit.
The results are as follows:
1. effect of pharmaceutical composition on bronchoalveolar lavage fluid of rat pulmonary fibrosis model
Lymphocyte (%) Neutrophil (%)
Control group 2.7±1.5 5.3±2.3
Model set 17.2±4.1## 14.3±3.6##
Administration group 1 15.7±2.9 12.8±2.5
Administration group 2 11.2±3.2* 10.7±3.4
Administration group 3 16.7±2.6 13.6±4.2
Administration group 4 8.4±3.7** 8.9±2.2**
Administration group 5 6.3±3.4** 7.1±0.4**
By Oneway-ANOVA test, P <0.05 and P <0.01 are represented by
2. Effect of pharmaceutical composition on bronchoalveolar lavage fluid of rat pulmonary fibrosis model
Total protein (g/L)
Control group 0.17±0.06
Model set 1.34±0.19##
Administration group 1 1.22±0.14
Administration group 2 0.85±0.17*
Administration group 3 1.28±0.21
Administration group 4 0.53±0.09**
Administration group 5 0.38±0.11**
Coefficient of lung
Control group 7.21±0.74
Model set 16.37±1.82##
Administration group 1 15.14±1.58
Administration group 2 12.61±2.03*
Administration group 3 15.82±1.94
Administration group 4 10.53±1.16**
Administration group 5 8.81±1.49**
By Oneway-ANOVA test, P <0.05 and P <0.01 are represented by
3. Effect of pharmaceutical compositions on pulmonary factor
By Oneway-ANOVA test, P <0.05 and P <0.01 are represented by
4. Effect of pharmaceutical compositions on hydroxyproline expression
Hydroxyproline (g/mg)
Control group 1.17±0.32
Model set 5.61±0.86##
Administration group 1 5.03±0.91
Administration group 2 4.52±0.53*
Administration group 3 5.23±0.61
Administration group 4 3.17±0.44**
Administration group 5 2.04±0.39**
By Oneway-ANOVA test, P <0.05 and P <0.01 are represented by
Hydroxyproline is most abundant in collagen, which is a main component constituting collagen fibers in connective tissues. The hydroxyproline content may therefore indicate the collagen distribution in lung tissue. The results show that the medicinal composition group has obvious inhibition effect on inhibiting the expression of hydroxyproline and is obviously superior to a single medicinal group.
This summary merely illustrates some embodiments which are claimed, wherein one or more of the features recited in the claims can be combined with any one or more of the embodiments, and such combined embodiments are also within the scope of the present disclosure as if they were specifically recited in the disclosure.

Claims (5)

1. A pharmaceutical composition for the treatment of pulmonary fibrosis; which include NMDA receptor antagonists and angiotensin converting enzyme inhibitors; the NMDA receptor antagonist is memantine, and the angiotensin converting enzyme inhibitor is ramipril; the weight ratio of the NMDA receptor antagonist to the angiotensin converting enzyme inhibitor is 1: 5-20.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition; the drug comprises an NMDA receptor antagonist, an angiotensin converting enzyme inhibitor and glycyrrhizic acid, wherein the weight ratio of the NMDA receptor antagonist to the angiotensin converting enzyme inhibitor to the glycyrrhizic acid is 1:10: 0.5-2.
3. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-2, comprising the pharmaceutical composition and a pharmaceutically acceptable carrier.
4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is an oral formulation, an injectable formulation or a spray.
5. Use of a pharmaceutical composition according to any one of claims 1-2 for the manufacture of a medicament for the treatment of pulmonary fibrosis.
CN201910698156.4A 2019-07-29 2019-07-29 Pharmaceutical composition for treating pulmonary fibrosis and application thereof Active CN110251677B (en)

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