CN107898801A - Composition and its application containing rifamycin and lipiarmycin - Google Patents
Composition and its application containing rifamycin and lipiarmycin Download PDFInfo
- Publication number
- CN107898801A CN107898801A CN201711439495.8A CN201711439495A CN107898801A CN 107898801 A CN107898801 A CN 107898801A CN 201711439495 A CN201711439495 A CN 201711439495A CN 107898801 A CN107898801 A CN 107898801A
- Authority
- CN
- China
- Prior art keywords
- rifamycin
- lipiarmycin
- composition
- rifampin
- bacterium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention discloses one kind to contain rifamycin（rifamycin）With the composition of lipiarmycin (lipiarmycin).Solve to be used to treat bacterium infection in human body, the problem of one of above two antibiotic produces drug resistance there are hepatotoxicity wind agitation and easily is used alone.The weight ratio of rifamycin and lipiarmycin is 10: 1 to 1: 10.Method of the present invention includes following features：(1) two kind of component produces Synergistic biocidal effect, and, toxicity is lower under lower dosage effectively；2）Lower antibiotic nature Resistant frequency.The composition of the present invention can be used in this kind of disease for needing long-term treatment of mycobacterium tuberculosis infection, it is not easy to produces drug resistance, mitigates toxic side effect.
Description
Technical field
The present invention relates to a kind of composition containing rifamycin and lipiarmycin and its application.In particular to one
Composition of the kind containing rifamycin and lipiarmycin, produces cooperative effect, lower for treating bacterium infection in human body
Dosage under effectively, toxicity is lower；Frequency is induced with lower natural drug resistance.The composition of the present invention can be used in tying
This kind of disease for needing long-term treatment of core bacillus infection, it is not easy to produce drug resistance, mitigate toxic side effect.
Background technology
A kind of antibiotic that rifamycinoid antibiotics is produced by Mediterranean Streptothrix.RNA polymerase is acted on, can be suppressed
DNA of bacteria transcription synthesis RNA, available for treatment tuberculosis, enterococcal infection etc., there is very gram-positive cocci, tubercle bacillus
Strong antibacterial action, the effect to drug resistant staphylococcus aureus is also strong, but the effect to gram-negative bacteria is then weaker.With it
His class antibiotic or anti-tubercular drug do not find cross resistance.The structural formula of Ryfamycin derivative rifampin is as follows：
Lipiarmycin is the secondary metabolite produced by multiple-microorganism fermentation, its molecular formula is C51H72Cl2O18, as turn
Record switch, the RNA polymerase inhibited bacteria is combined with DNA, so as to inhibit bacteria breeding, better than the existing medicine such as vancomycin,
With lower recurrence rate.The structural formula of New Year Amycin A4 is as follows：
Rifamycin and lipiarmycin act on RNA polymerase, but the two zone of action is not overlapping, and two kinds of antibiotic are made at the same time
For the different step in the same path in bacterium, cooperative effect is generated.Therefore crossing drug resistant is not present in the two.
Fiest-tire medication of the rifamycin as anti-mycobacterium tuberculosis, the blood concentration, it is necessary to higher, meeting are effectively sterilized to realize
Higher hepatotoxicity wind agitation is produced, limits its use；Meanwhile during the use of rifamycin, there are quite high nature
Resistant rate（6×10-8）, long-time service can gradually lose sterilizing ability.There is same, its nature in the use of lipiarmycin
Resistant rate is 4 × 10-8。
For treating bacterium infection in human body, one of above two antibiotic is used alone and is produced there are hepatotoxicity wind agitation and easily
The problem of raw drug resistance.
The content of the invention
The object of the present invention is to provide a kind of natural resistant rate is low, treatment cycle length, can mitigate toxic side effect containing favourable
The composition and its application of good fortune mycin and lipiarmycin.
What the present invention was realized in：
Composition containing rifamycin and lipiarmycin, the rifamycin are rifamycin As, rifamycin B, and sharp good fortune is mould
Plain C, rifamycin D, rifamycin E, rifamycin-S, Rifamycin Sodium, rifampin, Rifapentine, Mycobutin, sharp good fortune former times
One kind in bright and rifalazil, lipiarmycin is the weight of New Year Amycin A4 and its derivative, rifamycin and lipiarmycin
Than for 10: 1 to 1: 10.
Composition can be presented with pharmaceutically acceptable dosage form.The form of preparation includes tablet, capsule, injection
The form of agent, spray or other absorptions that can be absorbed by the body, two components can separately fabricated be similar and different system
Dosage form formula, can also be fabricated to compound.
Composition containing rifamycin and lipiarmycin is in the medicine for treating bacterium infection in human body is prepared
Application.
The bacterium is Gram-negative bacteria or gram-positive bacteria.
The bacterium is staphylococcus aureus (Staphylococcus aureus) or tubercle bacillus
(Mycobecterium Tuberculosis) or enterobacteria（Escherichia coli）.
Composition of the present invention includes following features：(1) two kind of component produces cooperative effect, and agent is used in lower
Effective under amount, toxicity is lower；2）There is composition lower natural drug resistance to induce frequency, be advantageously used for the disease of long-term treatment
Disease.The composition of the present invention can be used in this kind of disease for needing long-term treatment of mycobacterium tuberculosis infection, it is not easy to produces drug resistance, subtracts
Light toxic side effect.
The present invention has invented a kind of composition containing rifamycin and lipiarmycin, and two kinds of components are made respectively in this method
For RNA polymerase different loci, synergistic effect is produced by different and independent suppression mechanisms immediately.
（1）Cooperative effect is produced between component so that two kinds of antibiotic are more effective under the dosage of lower inferior toxicity；
（2）Lower natural drug resistance induces frequency：In theory 4 × 10-15, it is thousand a ten thousandths that two kinds of antibiotic are used alone,
Be conducive to long-term treatment.In particular for this kind of disease for needing long-term treatment of mycobacterium tuberculosis infection, it is not easy to produce drug resistance, subtract
Light toxic side effect.
These effects are using staphylococcus aureus (Staphylococcus aureus), tubercle bacillus
(Mycobecterium Tuberculosis) and Escherichia coli（Escherichia coli）External evaluation is carried out, the result is shown in
Experimental example：
In vitro, rifampin and when New Year Amycin A4 composition, have Synergistic fungicidal active.Rifampin and New Year Amycin A4 are most
Small Mlc is significantly lower than exclusive use one of which antibiotic.Reduce the minimum effective dose of at least one antibiotic,
Dosage is differed from ten halfs to 60% in the case of difference.
Rifampin and New Year Amycin A4 composition and the natural resistant rate being used alone are respectively： 1）
Staphylococcus aureus ：〈1×10-12 vs. 6×10-8With 4 × 10-8；2）Escherichia coli：〈1×
10-12 vs. 1×10-9With 3 × 10-10；3）Mycobecterium Tuberculosis：〈1×10-12 vs. 1×10-9With
3×10-10 。
Composition is used in human body with pharmaceutically acceptable dosage form.The form of preparation includes tablet, capsule, note
Penetrate agent, spray or other forms that can be absorbed by the body.Two class compounds can separately fabricated be similar and different system
The purpose of dosage form formula, can also be fabricated to compound, all formulations form is can be absorbed by human body, reaches treatment bacterium infection institute
The concentration needed.
Composition of the present invention includes following advantage：
（1）Two kinds of components produce cooperative effect, and, toxicity is lower under lower dosage effectively；2）Composition has lower
Natural drug resistance induce frequency, be advantageously used for the disease of long-term treatment.The composition of the present invention can be used in tubercle bacillus sense
Contaminate this kind of disease for needing long-term treatment, it is not easy to produce drug resistance, mitigate toxic side effect.
Brief description of the drawings
Fig. 1 is one of equivalent line analysis chart of the present invention.
Fig. 2 is the two of the equivalent line analysis chart of the present invention.
Embodiment
With reference to embodiment, the embodiment of the present invention is described in further detail.Following embodiments are used for
Illustrate the present invention, but be not limited to the scope of the present invention.Present invention encompasses all possible in Claims scope
Alternative, improvement project and equivalents.The particular technique or condition being not specified in following embodiments, be routine techniques or
Condition, or carried out according to the described technology of document in the art or condition, or according to product description.
Embodiment 1：
Rifampin and New Year Amycin A4 composition.The weight ratio of rifampin and New Year Amycin A4 is 10:1 to 1:10, preparation is note
Penetrate agent.
Experimental example 1：
Rifampin and the equivalent line analysis of New Year Amycin A4.
Reference literature J.infect.Dis.140,629-633 (1979) and Pain 98,163-168 (2002), utilize leather
Lan Shi positive bacterium S. aureus (Staphylococcus aureus) CMCC (B) 26 003（5×105）In M-H
When 37 DEG C of cultures 14 of broth bouillon are small, the cooperative effect of the rifampin in embodiment 1 and New Year Amycin A4 composition is carried out
Research, analyzes using isobologram the cooperative effect of two kinds of antibiotic.
Equivalent line analysis chart such as Fig. 1.Rifampin and New Year Amycin A4 equivalent point all when being combined below diagonal,
Two kinds of antibiotic of display possess the synergistic effect of complementation.Compared with exclusive use, combination is so that the concentration of rifampin is reduced to it
Minimal inhibitory concentration（MIC）Ten halfs, the concentration of lipiarmycin is reduced to the half of MIC (second left point), profit
The flat concentration of good fortune is reduced to a quarter of its MIC, and the concentration of lipiarmycin is reduced to 2/5ths (third lefts of MIC
Point) concentration of rifampin is reduced to 1/3rd of its MIC, and the concentration of lipiarmycin is reduced to 1/3rd (left sides of MIC
4th point).Index of correlation γ is 0.57, and both displays possess complementary synergistic effect.
Experimental example 2：
Rifampin reduces nature resistant rate to undetectable level with New Year Amycin A4 composition.
Using colony counting method measure staphylococcus aureus (Staphylococcus aureus) CMCC (B) 26
003（1×108-1×1012Cfu/ tablets）Natural Resistant frequency, when 37 DEG C of M-H broth agar culture mediums culture 14 is small after
Count, different tablets add rifampin, New Year Amycin A4 or embodiment 1 respectively.Experiment be divided into (1) individually add 1 ×, 2 ×, 4
The MIC concentration of × rifampin；（2）Independent addition 1 ×, 2 ×, the MIC concentration of 4 × New Year Amycin A4；（3）Addition 1 ×, 2 ×, 4
The MIC concentration of × rifampin and addition 1 ×, 2 ×, the MIC concentration of 4 × New Year Amycin A4.All experiments are using the thin of 4 kinds of concentration
Bacterium is repeated 4 times.
Shown from table 1, rifampin, New Year Amycin A4 and natural medicament-resistant mutation frequency associated with the two are respectively 6 × 10-8, 3 × 10-8With undetectable level (＜ 1 × 10-12).
1 rifampin of table, New Year Amycin A4 or natural resistant rate associated with the two（S.aureus ）
Using colony counting method measure Escherichia coli (Escherichia coli) CMCC (B) 44 103（1×108-1×
1012Cfu/ tablets）Natural Resistant frequency, when 37 DEG C of nutrient agar culture 24 is small after count, different tablets difference
Addition rifampin, New Year Amycin A4 or both add together.Experiment is divided into the MIC concentration that (1) individually adds 2 × rifampin；（2）
Independent addition 2 ×, the MIC concentration of New Year Amycin A4；（3）Add the MIC concentration of 2 × rifampin and the MIC of 2 × New Year Amycin A4
Concentration.All experiments are repeated 5 times using the bacterium of 5 kinds of concentration.The analysis and evaluation resistant rate of 95% confidential interval.
Shown from table 2, rifampin, New Year Amycin A4 and natural medicament-resistant mutation frequency associated with the two are respectively 4 × 10-9, 6 × 10-10With undetectable level (＜ 1 × 10-12).
Shown from table 3, rifampin, New Year Amycin A4 and resistant rate associated with the two are respectively 1 × 10-9, 3 × 10-10And nothing
Level (the ＜ 1 × 10 of method detection-12).
2 rifampin of table, New Year Amycin A4 or natural resistant rate associated with the two（Escherichia coli ）
3 rifampin of table, New Year Amycin A4 or resistant rate associated with the two（Escherichia coli ）
Experimental example 3：
The cooperative effect of rifampin and New Year Amycin A4 composition.
Reference literature J.infect.Dis.140,629-633 (1979) and Pain 98,163-168 (2002), utilize leather
Lan Shi positive bacterias mycobacterium tuberculosis (Mycobecterium Tuberculosis)（10×1010）In 7H10 agar cultures
37 DEG C of base is cultivated 4-6 weeks, and cooperative effect associated with the rifampin and New Year Amycin A4 to embodiment 1 is studied, using etc.
Imitate the line chart solution analysis cooperative effect of two kinds of antibiotic.
Equivalent line analysis chart such as Fig. 2.Rifampin and New Year Amycin A4 equivalent point all when being combined below diagonal,
Two kinds of antibiotic of display possess the synergistic effect of complementation.Compared with exclusive use, combination is so that the concentration of rifampin is reduced to it
Minimal inhibitory concentration（MIC）1/11st, the concentration of lipiarmycin is reduced to 60% (the second left point) of MIC, Li Fu
Flat concentration is reduced to the 25% of its MIC, and the concentration of lipiarmycin is reduced to 40% (third left point) rifampin of MIC
Concentration is reduced to the 35% of its MIC, and the concentration of lipiarmycin is reduced to 28% (the fourth left point) of MIC.Index of correlation γ is
0.68, both displays possess complementary synergistic effect.
Claims (5)
1. the composition containing rifamycin and lipiarmycin, it is characterised in that：The rifamycin is rifamycin A, profit
Good fortune mycin B, rifamycin C, rifamycin D, rifamycin E, rifamycin-S, Rifamycin Sodium, rifampin, Rifapentine, profit
Good fortune pudding, one kind in rifaximin and rifalazil, lipiarmycin is the weight of New Year Amycin A4, rifamycin and lipiarmycin
Amount is than being 10:1 to 1:10.
2. according to claim 1 contain rifamycin and lipiarmycin composition, it is characterised in that：Composition can be with
Presented with pharmaceutically acceptable dosage form, the form of preparation includes tablet, capsule, injection, spray or it is other can
The form for the absorption being absorbed by the body, two components can it is separately fabricated be similar and different dosage form, can also be fabricated to
Compound.
3. the composition according to claim 1 or 2 containing rifamycin and lipiarmycin is being prepared in human body
Treat the application in the medicine of bacterium infection.
4. according to claim 3 preparing the application in being used to treat the medicine of bacterium infection in human body, its feature
It is：The bacterium is Gram-negative bacteria or gram-positive bacteria.
5. according to claim 4 preparing the application in being used to treat the medicine of bacterium infection in human body, its feature
It is：The bacterium is staphylococcus aureus or tubercle bacillus or enterobacteria.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711439495.8A CN107898801A (en) | 2017-12-27 | 2017-12-27 | Composition and its application containing rifamycin and lipiarmycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711439495.8A CN107898801A (en) | 2017-12-27 | 2017-12-27 | Composition and its application containing rifamycin and lipiarmycin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107898801A true CN107898801A (en) | 2018-04-13 |
Family
ID=61871439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711439495.8A Pending CN107898801A (en) | 2017-12-27 | 2017-12-27 | Composition and its application containing rifamycin and lipiarmycin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107898801A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110179967A (en) * | 2019-05-28 | 2019-08-30 | 中国医药集团总公司四川抗菌素工业研究所 | The composition and its application of polymyxins parent nucleus and a kind of antibiotic |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150031640A1 (en) * | 2012-02-06 | 2015-01-29 | Richard H. Ebright | Antibacterial agents: combination of a rifamycin and a switch region inhibitor |
-
2017
- 2017-12-27 CN CN201711439495.8A patent/CN107898801A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150031640A1 (en) * | 2012-02-06 | 2015-01-29 | Richard H. Ebright | Antibacterial agents: combination of a rifamycin and a switch region inhibitor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110179967A (en) * | 2019-05-28 | 2019-08-30 | 中国医药集团总公司四川抗菌素工业研究所 | The composition and its application of polymyxins parent nucleus and a kind of antibiotic |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Fischer et al. | Antibacterial activity of sphingoid bases and fatty acids against Gram-positive and Gram-negative bacteria | |
| Choi et al. | Antibacterial activity of Ecklonia cava against methicillin-resistant Staphylococcus aureus and Salmonella spp. | |
| Patel et al. | Antimicrobial activity of ginger and honey on isolates of extracted carious teeth during orthodontic treatment | |
| Smith et al. | Targeting iron uptake to control Pseudomonas aeruginosa infections in cystic fibrosis | |
| Jørgensen et al. | Rifampicin-containing combinations are superior to combinations of vancomycin, linezolid and daptomycin against Staphylococcus aureus biofilm infection in vivo and in vitro | |
| Guay et al. | Tomatidine and analog FC04–100 possess bactericidal activities against Listeria, Bacillus and Staphylococcus spp | |
| US20230094112A1 (en) | Methods to control infection using new generation small molecule growth inhibitors | |
| Kumar et al. | In vitro antibacterial screening of six proline-based cyclic dipeptides in combination with β-lactam antibiotics against medically important bacteria | |
| Choi et al. | Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm | |
| Hossain et al. | In vitro synergistic potentials of novel antibacterial combination therapies against Salmonella enterica serovar Typhimurium | |
| Obiang-Obounou et al. | In vitro potentiation of ampicillin, oxacillin, norfloxacin, ciprofloxacin, and vancomycin by sanguinarine against methicillin-resistant Staphylococcus aureus | |
| Sukumar et al. | Pomegranate extract specifically inhibits Clostridium difficile growth and toxin production without disturbing the beneficial bacteria in vitro | |
| CN107898801A (en) | Composition and its application containing rifamycin and lipiarmycin | |
| CN107073124A (en) | The antimicrobial of synergy | |
| Das et al. | Antibacterial properties of endophytic bacteria isolated from a fern species Equisetum arvense L. against foodborne pathogenic bacteria Staphylococcus aureus and Escherichia coli O157: H7 | |
| US20060073156A1 (en) | Fosfomycin and n-acetylcysteine for the treatment of biofilms caused by escheric ia coli and other pathogens of the urinary tract | |
| Olusola et al. | The potential of different extraction methods of soursop (Annona muricata Linn) leaves as antimicrobial agents for aquatic animals | |
| PAREI et al. | Antibacterial activity of curcumin against Lebanese clinical isolates of Staphylococcus aureus | |
| Božić et al. | Inhibition of multidrug‐resistant Staphylococci by sodium chlorate and select nitro‐and medium chain fatty acid compounds | |
| Perumal et al. | Combination of epicatechin 3-gallate from Euphorbia hirta and cefepime promotes potential synergistic eradication action against resistant clinical isolate of Pseudomonas aeruginosa | |
| Chen et al. | Effects of glycyrrhetinic acid β on growth and virulence of Aeromonas hydrophila | |
| Yin et al. | Tyramine, one quorum sensing inhibitor, reduces pathogenicity and restores tetracycline susceptibility in Burkholderia cenocepacia | |
| Hossain et al. | Thymoquinone as a novel antibiotic and chemotherapeutic agent: a natural therapeutic approach on Staphylococcus aureus, Bacillus anthracis, and four NCI-60 cancer cell lines | |
| CN107320727A (en) | Antibacterial peptide and antibiotic combinations antibacterials and its application method | |
| CN109432107A (en) | The composition and its application in the drug for preparing bacterial infection disease of melbine and Doxycycline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180413 |
|
| WD01 | Invention patent application deemed withdrawn after publication |