CN106309420A - Novel application of carbocisteine - Google Patents

Abstract

The invention relates to a novel application of a medicament, and specifically relates to an application of carbocisteine and pharmaceutically acceptable salts thereof to preparation of the medicament for preventing or treating bronchiectasis. Carbocisteine and pharmaceutically acceptable salts thereof are used for substantially inhibiting oxidative stress and inflammatory injury of bronchiectasis model animals, so that carbocisteine and pharmaceutically acceptable salts thereof can be applied to preparation of the medicament for preventing or treating bronchiectasis.

Description

S-( Carboxymethyl )-L- The new application of cysteine

Technical field

The present invention relates to drug world, specifically, the present invention relates to the new medicine use of S-(carboxymethyl)-Cys and pharmaceutically acceptable salt thereof.

Background technology

Bronchiectasis (bronchiectasis is called for short " expand ") refers to, due to bronchus and the chronic inflammatory disease of surrounding tissue thereof and airway obstruction, cause bronchial tissue's structure by more serious pathological destruction, cause the disease of lumen distention, deformation.Typical clinical symptoms has chronic cough, coughs a large amount of purulent sputum and spitting of blood etc. repeatedly.Propping up expansion main pathogenic is bronchial infection, obstruction and tractive, and part has congenital heredity factor.Patient has the medical histories such as measles, pertussis or bronchopneumonia more.Infection is the most common reason (Gao causing bronchus to expand Y, Guan W, Xu G, et al. The role of viral infection in pulmonary exacerbations of bronchiectasis in adults: A prospective study. Chest. 2015;147 (6): 1635-43.).Pulmonary tuberculosis, pertussis, adenovirus pneumonia can secondary bronchiectasis, aspergillosis and mycoplasma and cause the bronchopneumonic pathogen of chronic necrosis also can secondary bronchiectasis (Guan WJ, Gao YH, Xu G, et al. Aetiology of bronchiectasis in Guangzhou, southern China. Respirology. 2015;20 (5): 739-48.).It is generally acknowledged, propping up the pathogenesis expanded is that Different types of etiopathogenises causes bronchus and surrounding tissue generation chronic inflammatory disease thereof, neutrophilic granulocyte produces oxygen-derived free radicals, inflammatory factor and elastoser, destroy tube wall elastic fibers, smooth muscle and cartilage, tube wall deformation and expansion, and inflammation causes bronchial mucosa swelling, mucilage secretion increases, and increases the weight of bronchial obstruction；In addition the ciliary dyskinesia on bronchial mucosa expanded, makes the mucus of secretion not excrete, increases the weight of local infection, bacteria breed, makes infection more serious, forms vicious cycle.

The target propping up expansion treatment is to reduce acute exacerbation number of times and improve the quality of living.In addition to active treatment underlying diseases, according to pathogenesis, common method for the treatment of includes infection, antiinflammatory, removing airway secretions, surgical operation etc., but therapeutic effect is limited, thus, it is found that other effective expansion medicine clinical meaning is great.

S-(carboxymethyl)-Cys (carbocisteine, carboxymethylcysteine), also known as carbocisteine, first developed in 1961 by Joullie company of France and be applied to clinic, for mucolytic drugs, the secretion of bronchus body of gland can be affected, make the secretion of low viscous sialomucin increase, the mucinous generation of full-bodied rock algae is reduced, and can be done directly on mucinous disulfide bond, make mucin molecular cleavage reduce sputum viscosity, it is easy to bring up；MCC can be improved；Reduce airway hyperreactivity.Easily sloughing carboxymethyl after CMC entrance is internal and form cysteine, its contained sulfydryl can interact with the electrophilic group of active oxygen (reactive oxygen species, ROS) etc., play direct antioxidation；Additionally, cysteine is also the precursor of glutathion (GSH), can have bioactive GSH by resynthesis, increase the concentration of internal GSH, play indirect antioxidant effect.CMC is mainly used in treating thick sputum, the dys-expectoration etc. that the disease such as chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), bronchial asthma causes clinically.Recently, have been reported that CMC can suppress external rhinovirus, IL-1 β, hydrogen peroxide etc. stimulate caused by the inflammatory factors such as IL-6, IL-8 release (Yasuda H, Yamaya M, Sasaki T, et al. Carbocisteine inhibits rhinovirus infection in human tracheal epithelial cells. Eur Respir J. 2006;28(1):51-8. Nogawa H, Ishibashi Y, Ogawa A, et al. Carbocisteine can scavenge reactive oxygen species in vitro. Respirology. 2009;14(1):53-9. Wang W, Zheng JP, Zhu SX, et al. Carbocisteine attenuates hydrogen peroxide-induced inflammatory injury in A549 cells via NF-κB and ERK1/2 MAPK pathways. Int Immunopharmacol. 2015;, and suppression Model of Emphysema rat oxidative stress caused by smoke from cigarette and release (Hanaoka M, the Droma of matrix metalloproteinase (MMP-2, MMP-9) 24 (2): 306-13) Y, Chen Y, et al. Carbocisteine protects against emphysema induced by cigarette smoke extract in rats. Chest. 2011;139 (5): 1101-8.).Carbocisteine has certain antioxidation, antiinflammatory action, but has no for a report expanded.

Summary of the invention

It is directed to this, it is an object of the invention to, a kind of S-(carboxymethyl)-Cys of offer and the pharmaceutically acceptable salt new application in preparation prevention and treatment bronchiectasis medicine, can alleviate such patient's oxidative stress and inflammatory damage effectively.For realize S-(carboxymethyl)-Cys and pharmaceutically acceptable salt in preparation for preventing and treating the application in bronchiectasic medicine, can by S-(carboxymethyl)-Cys and pharmaceutically acceptable salt make capsule, tablet, pill, oral liquid, soft capsule or drop pill.

The present invention solves the technical scheme that technical problem uses: by S-(carboxymethyl)-Cys and the one during pharmaceutically acceptable salt makes tablet, capsule, oral liquid, granule, dry suspension, pill or drop pill thereof, for realizing the preparation of these preparations, pharmaceutically acceptable adjuvant need to be added, such as filler, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives, preservative, substrate etc. when preparing these dosage forms.Filler includes: starch, pregelatinized Starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.；Disintegrating agent includes: starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.；Lubricant includes: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.；Suspending agent includes: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar-agar, hydroxypropyl methyl cellulose etc.；Binding agent includes: starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.；Sweeting agent includes: saccharin sodium, Aspartane, sucrose, cyclamate, enoxolone etc.；Correctives includes: sweeting agent and various essence；Preservative includes: parabens, benzoic acid, sodium benzoate, sorbic acid and its esters, benzalkonium bromide, fixed, the eucalyptus oil of acetic acid chloroethene etc..

In the present invention, term " pharmaceutically acceptable salt " includes the carboxylate formed with inorganic base, such as the salt of the inorganic bases such as sodium, potassium, calcium, magnesium, ammonium；The carboxylate formed with organic base, such as meglumine, glucosamine, Trimethylamine, triethylamine, dicyclohexylamine, N, the salt of N-dibenzyl-1，2-diaminoethane, arginine, lysine etc., or avirulent salt.

S-(carboxymethyl)-Cys that the present invention provides and pharmaceutically acceptable salt can applied in preparation prevention or treatment bronchiectasis medicine, and the bronchiectasis that can treat includes cystic fibrosis bronchiectasis and non-bladder fibrosis bronchiectasis.And its bronchiectasis that can treat can be caused by bronchial infection, obstruction and tractive；Or can be caused by immunodeficiency；Or can be caused by congenital heredity factor.Yet further, it can treat merging chronic bronchitis, chronic obstructive pulmonary disease or the bronchiectasis of bronchial asthma.

In order to be more fully understood that the essence of the present invention, below by S-(carboxymethyl)-Cys result of the test in animal body, its new application at pharmaceutical field is described.

Effect of drugs is tested

1. Experimental technique

1.1 Prop up the preparation expanding Mus

90 rats are randomly divided into 6 groups, respectively normal group, model group, positive group, S-(carboxymethyl)-Cys senior middle school low dose group, often group 15.In addition to normal group, after remaining 5 groups of rat pentobarbital sodium anesthesia, dorsal position is fixed, routine disinfection, separates trachea, carries out tracheal intubation, and tracheal intubation is to right lung bottom leaf, and (concentration is 10 to be rapidly injected 20 μ L bacillus pyocyaneus bacterium solution⁵And 1mL air CFU/L).Extract rapidly and intubate and hold up fixed plate, keep the perpendicular position of rat, to alleviate respiratory disorder.Incision of trachea, cervical region muscle group and skin is sewed up after rats breathing is steady.Lumbar injection penicillin prevents wound infection.

Pharmaceutical intervention

Starting after modeling 14 days to be administered, normal group, model group all give normal saline gavage；Positive group perfusion levofloxacin (0.0645 G/kg), S-(carboxymethyl)-Cys high, medium and low dosage group perfusion various dose (0.30,0.15,0.075 mg/kg) trial drug；Every day 1 time, continuous 4 weeks.

Index determining

Terminate latter second day eye socket in experiment and take blood, separate serum and leave and take lung tissue, take right lung bottom leaf and carry out pathologic detection, remaining lung carries out lung homogenate, measure oxidative stress index lipid peroxide (LPO), malonaldehyde (MDA), reduced glutathion (GSH) content and superoxide dismutase (SOD) activity, inflammatory mediator TNF-α and the concentration of IL-8.

Experimental result

2.1 Pathological change

Control rats peribronchial alveolar structure is clear, bubble intracavity is transparent, NIP cellular infiltration.Bronchial mucosa basement membrane of epithelium is complete, and cilium marshalling, peribronchiolar has no obvious inflammatory cell infiltration (see accompanying drawing 1).Model group rats leaf bronchus tube wall has destruction, lumen distention in various degree, bronchial mucosa basement membrane of epithelium destroys substantially, Submucosa, smooth muscle layer structure disturbance atrophy, a large amount of cell infiltration Submucosas, smooth muscle layer, peribronchial lung tissue (see accompanying drawing 2).Positive group rat leaf bronchus tube chamber is slightly expanded, and bronchial mucosa basement membrane of epithelium is substantially complete, has inflammatory cell infiltration (see accompanying drawing 3) at Submucosa, smooth muscle layer, peribronchial lung tissue and alveolar.The rats in test groups leaf light moderate distension of bronchus tube chamber, bronchial mucosa basement membrane of epithelium is the most complete；Submucosa, smooth muscle layer are substantially complete, without atrophy；Alveolar structure light damage, a small amount of inflammatory cell infiltration Submucosa, smooth muscle layer, peribronchial lung tissue etc. (see accompanying drawing 4).

The mensuration of oxidative stress index

Compare with normal group, in model group rats lung and serum oxidation index LPO, MDA content significantly increase (P< 0.05), Antioxidant Indexes GSH and SOD content all significantly reduce cost (P< 0.05), show animal model success.Compared with model group, after giving trial drug treatment, in lung and serum, LPO, MDA content all significantly reduces, GSH and SOD content significantly raises, and (refers to table 1, table 2) in a certain amount of effect relationship.

The table 1 impact (± SD) on oxidation index

Note: compare with model group, *P<0.05

The table 2 impact (± SD) on Antioxidant Indexes

Note: compare with model group, *P<0.05

2.3 The mensuration of inflammation index

Compare with normal group, in model group rats lung and serum TNF-α, IL-8 content significantly increase (P< 0.05), show animal model success.Compared with model group, giving trial drug treatment, TNF-α, IL-8 content reduce simultaneously, and in a certain amount of effect relationship.Result of the test is shown in Table 3.

The table 3 impact (± SD) on inflammation index

Note: compare with model group, *P<0.05

3. Experiment conclusion

The body inflammatory reaction to infecting, oxidation/antioxidation is unbalance etc. is all a key character expanded.Preliminary pharmacodynamic results shows, an expansion rat model gives, after modeling success, the generation that trial drug can substantially reduce oxide, increases the level of antioxidant, the oxidation-antioxidation that regulation is disorderly；The generation of inflammatory mediator simultaneously reduces, and the damage tackling lung tissue mutually substantially alleviates, this with pathology section examination to result match.

Beneficial effect

S-(carboxymethyl)-Cys medical compounds selected by the present invention, particularly S-(carboxymethyl)-Cys, expansion rat model oxidative stress, an inflammatory damage can be significantly improved, may be used for the prevention expanded and a treatment.

Accompanying drawing explanation

Accompanying drawing 1 show the section of normal rats pathologic, and HE dyes (× 400).

Accompanying drawing 2 show the section of model group rats pathologic, and HE dyes (× 400).

Accompanying drawing 3 show positive group lung tissue of rats pathological section, and HE dyes (× 400).

Accompanying drawing 4 show the section of rats in test groups pathologic, and HE dyes (× 400).

Specific embodiment

Being below the detailed description of the invention of the present invention, described embodiment is to further describe the present invention, but is not limiting as the present invention.

Embodiment 1 The preparation of Tablets

S-(carboxymethyl)-Cys 500 g

Pregelatinized Starch 500g

Magnesium stearate 10g

Fully being mixed by above-mentioned S-(carboxymethyl)-Cys 500g and pregelatinized Starch 500g, add water soft material processed, pelletizes, material all in one piece after drying, add magnesium stearate, be pressed into totally 1000, tablet, containing S-(carboxymethyl)-Cys 500mg in every part.

Embodiment 2 The preparation of granule of the present invention

S-(carboxymethyl)-Cys 500 g

Pregelatinized Starch 500g

Magnesium stearate 10g

Fully being mixed by above-mentioned S-(carboxymethyl)-Cys 500g and pregelatinized Starch 500g, soft material processed, pelletize, dry, pack, totally 1000 bags after granulate, every bag contains S-(carboxymethyl)-Cys 500mg.

Embodiment 3 The preparation of oral administration solution of the present invention

S-(carboxymethyl)-Cys 500 g

Sucrose 500g

Essence In right amount

Add water Extremely 1000mL

Above-mentioned S-(carboxymethyl)-Cys 500g, sucrose 500g and appropriate amount of essence fully being mixed dissolving, adds water to 1000mL, be packed as 10mL/ bottle, totally 1000 bottles, every contains S-(carboxymethyl)-Cys 500mg.

Claims (9)

1.S-(carboxymethyl)-Cys and pharmaceutically acceptable salt are used for preventing or treating the purposes in bronchiectasic medicine in preparation.

The purposes of S-the most according to claim 1 (carboxymethyl)-Cys and pharmaceutically acceptable salt, it is characterised in that: described medicine be with S-(carboxymethyl)-Cys and pharmaceutically acceptable salt as effective ingredient and the pharmaceutical composition of pharmaceutical carrier.

The purposes of S-the most according to claim 1 (carboxymethyl)-Cys and pharmaceutically acceptable salt, it is characterised in that: described medicine is S-(carboxymethyl)-Cys.

The purposes of S-the most according to claim 1 (carboxymethyl)-Cys and pharmaceutically acceptable salt, it is characterized in that: described pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, meglumine salt, glucosamine salt, trismethylamine salt, triethyl amine salt, dicyclohexyl amine salt, N, N-dibenzyl-1，2-diaminoethane salt, arginine salt, lysinate.

5. according to S-(the carboxymethyl)-Cys described in claim 1-4 and the purposes of pharmaceutically acceptable salt thereof, it is characterised in that: described bronchiectasis includes cystic fibrosis bronchiectasis and non-bladder fibrosis bronchiectasis.

6. according to S-(the carboxymethyl)-Cys described in claim 1-4 and the purposes of pharmaceutically acceptable salt thereof, it is characterised in that: described bronchiectasis is caused by bronchial infection, obstruction and tractive.

7. according to S-(the carboxymethyl)-Cys described in claim 1-4 and the purposes of pharmaceutically acceptable salt thereof, it is characterised in that: described bronchiectasis can be caused by immunodeficiency.

8. according to S-(the carboxymethyl)-Cys described in claim 1-4 and the purposes of pharmaceutically acceptable salt thereof, it is characterised in that: described bronchiectasis can be caused by congenital heredity factor.

9. according to S-(the carboxymethyl)-Cys described in claim 1-4 and the purposes of pharmaceutically acceptable salt thereof, it is characterised in that: described bronchiectasis can merge chronic bronchitis, chronic obstructive pulmonary disease or bronchial asthma.