CN102406643B - Medical application of clofazimine in tuberculosis treatment - Google Patents
Medical application of clofazimine in tuberculosis treatment Download PDFInfo
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- CN102406643B CN102406643B CN 201110379091 CN201110379091A CN102406643B CN 102406643 B CN102406643 B CN 102406643B CN 201110379091 CN201110379091 CN 201110379091 CN 201110379091 A CN201110379091 A CN 201110379091A CN 102406643 B CN102406643 B CN 102406643B
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Abstract
The invention discloses a new medical application of clofazimine in tuberculosis treatment, wherein the chemical name of Clofazimine is 10-(p-chlorophenyl)-2,10-dihydro-3-(p-chlorophenyl amino)-2-isopropyl imino phenazine. According to the invention, clofazimine can be used as raw material of medicines and can be prepared into soft capsule, tablet, capsula, injection and other medical preparations. Lots of experiments show that medicines disclosed in the invention can be used for treating clofazimine and is safe and effective in clinical practices.
Description
Invention field
The present invention relates to a kind of new purposes of medicine, particularly a kind of new medicine use of clofazimine.The application is dividing an application of No. 200910131770.9 patent application.
Technical background
Tuberculosis is the chronic infectious disease that tubercule bacillus causes, approximately has the population that accounts for the world 1/3 to infect tulase at present.China's tuberculosis epidemic situation also is spreading trend, has that prevalence is high, the resistant rate high, is one of the high burden of global tuberculosis country.
Clofazimine is 10-(p-chlorphenyl)-2, and 10-dihydro-3-(p-chlorobenzene is amino)-2-isopropyl imido grpup azophenlyene is pressed dry product and calculated, and contains C
27H
22Cl
2N
4Must not be less than 98.0%, former name is clofazimine, and clofazimine is brownish red or crystallization russet or crystalline powder; Odorless.The agent of chlorine method is bright is antileprotic, leprosy bacillus, mycobacterium buruli is had suppress and killing action, has in addition antiinflammatory action, all effective to treatment and prevention II type lepra reaction nodositas and erythema multiforme etc.Its antibacterial action may be combined with its DNA by the nucleic acid metabolism of interference leprosy bacillus, suppresses to rely on the RNA polymerase of DNA, stops the synthetic of RNA, thereby its antibacterial action is brought into play in synthesizing of anti-bacteria albumen.
Summary of the invention
The object of the invention is to disclose a kind of medicine and be used for the treatment of new purposes lungy.
The present invention seeks to be achieved through the following technical solutions:
Medicine clofazimine of the present invention is 10-(p-chlorphenyl)-2, and 10-dihydro-3-(p-chlorobenzene is amino)-2-isopropyl imido grpup azophenlyene is pressed dry product and calculated, and contains C
27H
22Cl
2N
4Must not be less than 98.0%.
Press practice of pharmacy, medicine clofazimine of the present invention is prepared into the various clinical pharmaceutical dosage form as the treatment tuberculosis, comprises soft gelatin capsule, tablet, capsule, soft capsule, drop pill, honeyed pill, pill, granule, soft extract with bee honey agent, slow releasing preparation, quick releasing formulation, controlled release preparation, oral liquid or ejection preparation.
Medicine of the present invention is a kind of phenazine dyes, suppresses by being combined with the DNA of mycobacterium to suppress to transcribe to produce the effect that mycobacterium grows; Its another one important function is to share with beta-interferon, can recover the effect of cytophagy and bactericidal activity, thereby becomes cytophagous exciting agent, belongs to the part of immunization therapy.
Following experimental example and embodiment are used for further illustrating but being not limited to the present invention.
Experimental example 1 clofazimine treatment pharmacodynamic experiment lungy
1, experiment purpose: observe clofazimine (clofazimine, CLF) against mycobacterium tuberculosis activity in external and body, for clinical practice provides foundation.
2, experiment material
Bacterial strain: mycobacterium tuberculosis H
37R
V(ATCC27294) this research department preserves bacterial strain; 30 strain substance of medicines-resistant branched tubercle bacillus clinical separation strains are national tuberculosis Reference Lab and preserve bacterial strain.
Reagent: culture medium: take 7H9 culture medium (U.S. Difico company) 4.7g, be dissolved in the 900ml distilled water, add 2.0ml glycerol, 121 ℃ of high pressure 10min, the nourishing additive agent albumin dextrose catalase (albumin dextrose catalase, ADC) that adds 0.1 volume fraction before to be used.ALMA blue (Alamar blue); Britain Setotec company product, 4 ℃ keep in Dark Place.Dimethyl sulfoxide (DMSO) analytical pure, Chengdu chemical reagent factory product.
Animal: SPF level 6-8 age in week, female BALB/C mice was 36, and body weight is 18-20g, available from Capital University of Medical Sciences's Experimental Animal Center.
Medicine: isoniazid (INH), rifampicin (RFP) are U.S. Sigma company product; Clofazimine is that the Nanjing pharmaceutical Co. Ltd of setting up one's own business is so kind as to give.
3, experimental technique
(1) MIC measures; 200 μ l aquesterilisa are added in each hole of aseptic 96 orifice plate surroundings, prevent the composition evaporation in the incubation mesopore.Make initial concentration with DMSO or sterile purified water dissolved substance, be diluted to required concentration with 7H9 culture medium (not containing twecn80), add aseptic 96 orifice plate 100 μ 1, measure H
97R
VEach medicine final concentration of MIC is respectively: INH:0.0125,0.025,0.05,0.1,0.2,0.4 μ g/ml; RFP:0.0125,0.025,0.05,0.1,0.2,0.4 μ g/ml; CLF:0.03,0.06,0.12,0.24,0.48,0.96,1.92 μ g/ml.Mensuration is respectively each medicine final concentration of substance of medicines-resistant branched tubercle bacillus clinical separation strain MIC: INH:1,5,10,20,40 μ g/ml; RFP:1,5,10,20,40 μ g/ml; CLF:0.06,0.12,0.24,0.48,0.96,1.92,3.84 μ g/ml.Choose H
37R
VMake bacteria suspension with the culture of the 30 anti-multiple medicines clinical isolates of strain strains, be inoculated in the 7H9 culture medium that contains 0.05%tween80,10%ADC, in 37 ℃ of static cultivation 1-2 weeks, growing to turbidity is that MoFarland 1.0 (is equivalent to 10
7CFU/ml) time, add each hole 100 μ l after dilution in 1: 20, the final concentration of bacterium liquid is 10
6CFU/ml.Every plate is all established 2 growth control holes that do not contain antimicrobial drug, and 96 orifice plates are hatched in 37 ℃.The mixed liquor that adds growth control hole 20 μ l 10 * Alamar blue and 5%t,wee,n80 50 μ l after 7d, hatch 24h for 37 ℃, if color becomes pink colour from blueness, the Alamar blue and the tween80 mixed liquor that add above-mentioned amount in the hole of each Experimental agents, hatch the color that 24h records each hole for 37 ℃, blue Kong Weiwu growth, pink hole is for there being growth.MIC is defined as the lowest drug concentration that stops change color (becoming pink from blueness).
(2) foundation of mice tuberculosis model and treatment: choose mycobacterium tuberculosis H
37R
VIt is (5 * 10 that the culture in 2-3 week is made concentration
5) bacteria suspension of CFU/ml, 36 female BALB/C mice tail vein injection 0.2ml/ only, infection dosage 10
5CFU/ only.Dissected 6 mices so that the basic value that spleen is heavy, lung heavily reaches viable count to be provided on the 2nd day after infecting.All the other mices are divided into 5 groups at random, 6 every group.And beginning administration in the 2nd day after infecting, the blank group: 0.5% Carboxymethyl cellulose sodium (CMC), INH organizes (negative control group): 25mg/kg, and administration is 5 times weekly; CLF-1 group: 20mg/kg, administration is 5 times weekly; CLF-2 group: 10mg/kg, administration is 5 times weekly; CLF-3 group: 20mg/kg, administration is 2 times weekly; Isoniazid and clofazimine are all used 0.5%CMC and are made the suspension oral gavage administration, are administered to infect rear 30d.Next day after last 1 administration, each group mice is put to death, carry out mice spleen, lung count plate.Count plate method: record Mouse Weight, dissect under the sterile working, get spleen, lung homogenate respectively, add normal saline to make and organize suspension, that gets respectively mice spleen, lung organizes 10 times of dilutions of suspension series, get 0.1ml and be inoculated in modified Russell medium, 3 of each concentration inoculations of each sample cultivated for 4 weeks for 37 ℃.Observe the bacterial growth situation, calculate viable count (CFU).
(3) statistical procedures: data with
± S represents, adopts SPSS11.0 software, relatively adopts one factor analysis of variance between group, the LSD method of analysis of variance, and there is statistical significance P＜0.01 for difference.
4, experimental result
(1) minimum inhibitory concentration result
Clofazimine is to mycobacterium tuberculosis H
37R
VMIC be 0.12-0.24 μ g/ml; The MIC of isoniazid and rifampicin is respectively 0.025,0.05 μ g/ml; Clofazimine is 0.12-1.92 μ g/ml to the MIC scope of 30 strain substance of medicines-resistant branched tubercle bacillus clinical separation strains, and concrete data see Table 1.
The MIC (μ g/ml) of table 1 clofazimine to 30 substance of medicines-resistant branched tubercle bacillus clinical separation strains
(2) mice tuberculotherapy experimental result
1. the painted situation of mouse skin mucosa: treatment 7d left and right CLF-1 group mice ears and breast abdominal part fur begin to occur pale red, treatment 30d when finishing experiment the CLF-1 group (accumulated dose: 400mg/kg), the CLF-2 group (accumulated dose: 200mg/kg) and the CLF-3 group (accumulated dose: 160mg/kg) ears and the dyeing of breast abdominal part fur all appear in mice, and CLF-1 is the most obvious.The organ in the visible 3 groups of mice breasts of when dissected, abdominal cavity is painted, and the CLF-1 group is the most obvious.During whole infection and treatment, death does not appear in mice.
2. the heavy and heavy situation of lung of body weight, spleen: the 2nd day of mouse infection, average weight is (20.88 ± 0.17) g, average spleen heavy (0.07 ± 0.01), heavy (0.15 ± 0.05) g of average lung, the heavy index 0.003 ± 0.002 of spleen, the heavy index 0.007 ± 0.002 of lung.After infecting 30d, Mouse Weight, spleen weight, the lung for the treatment of group heavily are not respectively (24.09 ± 1.84) g, (0.46 ± 0.07) g, (0.24 ± 0.02) g.The heavy index of the heavy exponential sum lung of spleen is respectively 0.019 ± 0.002 and 0.010 ± 0.001, all be significantly increased, the Mouse Weight of each treatment group and blank group are without significant difference, but, lung heavy at spleen heavily reaches on the heavy index of spleen, the heavy index of lung all lower than the blank group, (the F value is respectively 46.64,27.57,58.97,34.56 to have statistical significance, p＜0.01, concrete data see Table 2.
Table 2 tuberculosis model mice treatment 30d respectively organizes body weight, spleen is heavy and the heavy situation of lung
Annotate:
#P＜0.01 is compared with the blank group
3. count plate situation: the 2nd day of infection, the full spleen viable count of mice is (5.61 ± 0.14) lgCFU, infects 30d and is increased to (7.14 ± 0.07) lgCFU.INH group spleen viable count is than the low 3.56lgCFU of blank group, and the CLF-1 group is hanged down 2.25lgCFU, and CLF-2 group and CLF-3 organize all low 1.57lgCFU.Each treatment group is compared difference and is had statistical significance (F=130.58, p＜0.01) with the blank group.Concrete data see Table 3.Infect the 2nd day, the full lung viable count of mice was (5.24 ± 0.23) log
10CFU infects 30d and increases to (8.07 ± 0.01) l gCFU.INH group lung viable count is than the low 4.68lgCFU of blank group, and the CLF-1 group is hanged down 2.92lgCFU.The low 1.78lg CFU of CLF-2 group, the low 1.39lgCFU of CLF-3 group.Each treatment group is compared difference and is had statistical significance (F=74.09, p＜0.01) with the blank group.Concrete data see Table 3
The count plate situation (lg CFU) of each group of table 3 tuberculosis model mice treatment 30d
Annotate:
ΔP＜0.01 is compared with the blank group
5, experiment conclusion
The experiment in vitro result shows that clofazimine has stronger vitro antibacterial activity to the substance of medicines-resistant branched tubercle bacillus of mycobacterium tuberculosis type strain and anti-isoniazid and rifampicin.Its mechanism of action is mainly interfere RNA metabolism and energy metabolism, is difficult for producing drug resistance, without crossing drug resistant, there is no inherent interaction with cytochrome P 450 enzymes with existing antituberculotics.
Show in mice tuberculotherapy model, clofazimine can reduce 1.8-2.9lgCFU with the mycobacterium tuberculosis in the mice lungs, reduces 1.5-2.5lgCFU in spleen, shows to have the interior tuberculosis effect of body preferably.
Experimental example 2 clinical experimental datas
Be selected into 25 tuberculosis patients, allow it regularly take the clofazimine soft gelatin capsule, the results are shown in Table 4.
Table 4 Drug therapy of the present invention clinical experimental data lungy
Result shows, medicine clofazimine treatment effective percentage lungy of the present invention and obvious effective rate are nearly 96%, illustrates that clofazimine has the effect lungy for the treatment of.
Following embodiment all can realize the effect of above-mentioned experimental example.
The specific embodiment
Embodiment 1: the clofazimine soft gelatin capsule
Clofazimine adds the refining of edible vegetable oil and grinds to form fine powder and adjust concentration, and suspendible is made.Contain clofazimine (C
27H
22Cl
2N
4) be 90.0%～110.0% of labelled amount.Oral, a 50～100mg, 1-3 time on the one, treatment tuberculosis.
Embodiment 2: the clofazimine sheet
Add conventional adjuvant to make according to a conventional method tablet, oral, a 50～100mg, 1-3 time on the one, treatment tuberculosis.
Embodiment 3: the clofazimine granule
Add the granulation agent according to a conventional method of conventional adjuvant, oral, a 50～100mg, 1-3 time on the one, treatment tuberculosis.
Claims (1)
1. the application of clofazimine soft gelatin capsule in the anti-multiple medicines tuberculosis medicine of preparation treatment is characterized in that clofazimine is unique active constituents of medicine in soft gelatin capsule; Described soft gelatin capsule adds the refining of edible vegetable oil by clofazimine and grinds to form fine powder and adjust concentration, and suspendible is made; The content of clofazimine is 90.0%-110.0% of labelled amount; Oral, a 50～100mg, 1-3 time on the one; Described pathogenic bacterium lungy are the substance of medicines-resistant branched tubercle bacillus of mycobacterium tuberculosis type strain and anti-isoniazid and rifampicin.
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|---|---|---|---|
| CN 201110379091 CN102406643B (en) | 2008-04-01 | 2009-04-01 | Medical application of clofazimine in tuberculosis treatment |
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|---|---|---|---|
| CN200810103174 | 2008-04-01 | ||
| CN200810103174.5 | 2008-04-01 | ||
| CN 201110379091 CN102406643B (en) | 2008-04-01 | 2009-04-01 | Medical application of clofazimine in tuberculosis treatment |
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| RU2553310C2 (en) * | 2013-05-07 | 2015-06-10 | Общество с ограниченной ответственностью "ЭДВАНСД ТРЕЙДИНГ" | Capsular form of clofazimine |
| CN111728973A (en) * | 2020-05-27 | 2020-10-02 | 中国医学科学院病原生物学研究所 | Medicine for resisting novel coronavirus SARS-CoV-2 and its application |
| CN114344273A (en) * | 2021-12-08 | 2022-04-15 | 余述南 | A soft capsule for treating tuberculosis and multi-drug resistant tuberculosis |
| CN114376979A (en) * | 2021-12-08 | 2022-04-22 | 余述南 | Preparation method of soft capsule for treating tuberculosis and multi-drug resistant tuberculosis |
| CN114507189A (en) * | 2021-12-08 | 2022-05-17 | 余述南 | Chemically synthesized bulk drug and application thereof in treating tuberculosis and drug-resistant tuberculosis |
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