CN105663126B - The antifungal products of ambroxol hydrochloride joint Fluconazole and its application - Google Patents
The antifungal products of ambroxol hydrochloride joint Fluconazole and its application Download PDFInfo
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- CN105663126B CN105663126B CN201610186067.8A CN201610186067A CN105663126B CN 105663126 B CN105663126 B CN 105663126B CN 201610186067 A CN201610186067 A CN 201610186067A CN 105663126 B CN105663126 B CN 105663126B
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
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Abstract
Antifungal products and its application the invention discloses ambroxol hydrochloride joint Fluconazole, belong to pharmaceutical technology field, and the present invention studies the static state and dynamic syndicated antifungic action of Fluconazole and ambroxol hydrochloride combination to drug resistance Candida albicans in a variety of ways.Effective concentration when ambroxol hydrochloride is applied with fluconazole matches：Fluconazole：Ambroxol hydrochloride=1:64 (μ g/mL), minimum inhibitory concentration is respectively：128 μ g/mL and 2 μ g/mL.When ambroxol hydrochloride combines Fluconazole, antibacterial activity of the Fluconazole to drug resistance Candida albicans can be enhanced, can generate collaboration antifungic action, and can reversing drug resistance Candida albicans to the drug resistance of Fluconazole, exploitation and old medicine for new drug are new with providing research direction.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to ambroxol hydrochloride is combined the antifungal products of Fluconazole and its answered
With.
Background technology
In recent years, with acquired immunodeficiency syndrome (AIDS) patient increase and extensive pedigree antibiotic it is extensive
Using, the development of the medical technology such as organ transplantation technique and microcatheter technology, the incidence of invasive infections with fungi and case fatality rate by
Year rises, particularly aspergillus and candidal infection, and the survival rate of patient is distinguished less than 30% and 70%.Candida albicans
Although the threat infected to clinic is big without the threat caused by aspergillin infection, since this kind of fungi is susceptible to outside drug
Row's enhancing and gene Target alterations (such as ERG11) so that drug resistance is continuously emerged to the candida albicans of triazole antifungal agent object sensitivity
Property, this gives clinical anti-fungal infection to bring great challenge.Statistics indicate that after AIDS patient later infections fungi, more than three points
One of drug resistance, 65% is more up to azole drug resistant rate.Wherein candida albicans especially Candida albicans (Candida
Albicans, CA), be respiratory system, bloodstream infection, digestive system, fungal Infections of Urinary System common separation bacterium.According to U.S.
The data of state nosocomial infection control tissue shows that CA is the 4th pathogenic microorganism for causing bloodstream infection in institute, be the death rate most
High pathogenic bacteria, the death rate may be up to 40%.The high mortality of CA bloodstream infections is also related with the emergence of its drug resistance phenomenon.
It is the approach for solving antifungal agent resistance that new drug research is studied with drug combination.Since drug combination early investment is few, significant effect,
By the extensive concern of domestic and international researcher.It is true with resisting that drug combination research includes two kinds of antifungal joints and non-antifungal
Bacterium medicine is combined, since current useful clinically antifungal drug kind is limited, and mostly it is expensive, toxic side effect is apparent, make
The use in conjunction research for obtaining non-antifungal drug and antifungal drug is concerned.Azole drug in recent years, especially Fluconazole,
Extensive use although achieve good clinical effectiveness, but the appearance of thing followed persister makes clinical treatment become spine
Hand, this causes Candida albicans is overcome to become research hotspot to the resistance problems of Fluconazole.
Ambroxol hydrochloride (Ambroxol hydrochloride, ABH) be it is a kind of treat respiratory disease safely, have
Drug is imitated, is widely used in the resolving sputum, expectoration in common breathing problem.There is clinical application report to find in recent years, salt
Sour ambroxol can play with antibiotic and cooperate with antibacterial actions, can shorten the treatment time of infection in respiratory system, reduce complication
Incidence and case fatality rate are applicable in age broadness, can be widely used for various acute and chronic pulmonary diseases, Respiratory Distress Syndrome(RDS), have
Sputum viscosity, the effect for improving patient's expectoration function and lung function are reduced, curative for effect, patient can usually be resistant to very well.At present,
ABH clinically has and the chance of antifungal drug use in conjunction (Sun Hongshuan, narrow eyes into a slit spring city, Ma Hongfang, Chen Hejun, kind preciousness .1
Pharmaceutical Care [J] .2015 of example Aged Patients With Lung bacteria mixed fungi infected patient, 12 (3)：182-185.), in addition, clinic is controlled
Finding that ambroxol injection is shared with antibacterials in treatment can be such that antibacterials are increased in the distributed density of lung tissue, enhance antibacterial
Drug effect (Wang Yongli, Cao Yongning ambroxol injections treatment 56 cases of mycoplasmal pneumonia in children [J] China medicine company, 2014,
23(19)：97-98.).For the Effect study of the combination anti-candida albicans of ABH and FLC, research there is no to report at present, have
Wide Research Prospects.
Invention content
The purpose of the invention is to overcome the problems, such as current antifungal agent resistance, a kind of ambroxol hydrochloride joint Fluconazole is provided
Antifungal products and its application.
To achieve these goals, the present invention adopts the following technical scheme that：
A kind of application of ambroxol hydrochloride joint Fluconazole in antifungal products are prepared.
It is preferred that：The product is drug.
It is preferred that：The fungi is Candida albicans.
It is preferred that：The effective concentration when ambroxol hydrochloride is applied with fluconazole matches：Fluconazole：Ambroxol hydrochloride
=1:64.
The minimum inhibitory concentration of ambroxol hydrochloride is during the application：128μg/mL.
The minimum inhibitory concentration of Fluconazole is during the application：2μg/mL.
A kind of antifungal products, using ambroxol hydrochloride and Fluconazole as main active.
It is preferred that：The effective concentration of the ambroxol hydrochloride and Fluconazole proportioning is Fluconazole：Ambroxol hydrochloride=1:64.
The minimum concentration of the ambroxol hydrochloride is：128μg/mL.
The minimum concentration of the Fluconazole is：2 μ g/mL the result shows that, ambroxol hydrochloride more than 128 μ g/mL with more than 2
The fluconazole of μ g/mL, which is applied, has collaboration overriding resistance Candida albicans effect.
A kind of antimycotic preparation, is made of ambroxol hydrochloride and Fluconazole and pharmaceutically acceptable auxiliary material.At this
It invents in the preparation provided, pharmaceutically acceptable auxiliary material is the customary adjuvant in pharmaceutical preparation, is recognized for those skilled in the art
For feasible customary adjuvant within protection scope of the present invention, the present invention does not limit herein.
It is a discovery of the invention that ABH can play joint antifungic action with antifungal drug in vitro, it can be seen that, the two association
Being not limited only to ABH with antifungic action makes antibacterials increase this mechanism of action in the distributed density of lung tissue.
The present invention is studied using drug resistance albicans cell, using chessboard broth microdilution antifungal susceptibility test, is evaluated respectively
The joint antifungic action of different drug combination combinations.Particular content is as follows：
A：ABH combines overriding resistance CA effects with FLC：It is minimum when measuring drug combination using chessboard broth microdilution antifungal susceptibility test to have
Concentration is imitated, optimal drug combined concentration is selected with FICI methods and evaluates the effect of combination therapies.In addition, for more intuitively table
The degree that existing drug combination acts on drug resistance CA carries out joint drug sensitive detection data with growth percentage difference model (Δ E)
Further analysis.
B：ABH dosages in Clinical practice are big, safely, effectively, if can play a role at antimycotic aspect, particularly pair
The treatment of drug resistance fungal infection is significant.The study show that ABH use in conjunction FLC can generate the CA effects of collaboration overriding resistance,
Its application range can be expanded, had a good application prospect.
In short, the present invention cooperates with the effect of overriding resistance CA comprising ABH with the generation of FLC use in conjunction.It is above-mentioned to be found to be clinical
Drug combination provides thinking as the scheme for the treatment of drug resistance fungal infection.
In addition to being applied alone other than the activity with anti-candida albicans planktonic cells and biomembrane, inventor is grinding ambroxol hydrochloride
It is also chanced in studying carefully significantly to cooperate with antifungic action with Fluconazole combination generation.ABH and FLC use in conjunction are in vitro
It is and with obvious effects with collaboration overriding resistance CA effects.The ABH of low dosage can make FLC to the MIC value of drug resistance CA from 512 μ g/mL with
On be down to 2 μ g/mL.
Compared with prior art, the present invention haing the following advantages and effect：
1. present invention demonstrates that when ABH is with FLC use in conjunction, antibacterial activities of the FLC to drug resistance CA can be enhanced, can be produced
Raw collaboration antifungic action, and can reversing drug resistance CA to the drug resistance of antifungal drug in triazole class, be the exploitation of new drug and old
Medicine is new with providing research direction.The drug resistant CA to FLC, drug combination can be substantially reduced its minimum inhibitory concentration, 128 μ g/
The FLC of the ABH of mL and 2 μ g/mL share can kill more than 80% fungi, concentration increases again, and effect is stronger.
Clinically application amount is big, safe by 2.ABH, and antimycotic synergistic effect to FLC can expand its application range,
And minimum effective Mlc of FLC is reduced, the dosage of antifungal drug is reduced, so as to reduce the adverse reaction of drug
Occur, overcome the problems, such as clinically antifungal agent resistance.
3. antifungal agent resistance mechanism and its complexity are still still not very clear there are many mechanism, as can ABH resists Fluconazole
Fungi enhanced sensitivity Mechanism Study is thorough, must can be to overcome the problems, such as that antifungal agent resistance provides new thinking.
Description of the drawings
Fig. 1 ambroxol hydrochlorides are combined with Fluconazole to overriding resistance Candida albicans CA10 exercising results；
Fig. 2 ambroxol hydrochlorides are combined with Fluconazole to overriding resistance Candida albicans CA16 exercising results；
Wherein：X-axis represents the concentration of Fluconazole, and Y-axis represents the concentration of ambroxol hydrochloride, and what Z axis represented is each drug
Δ E values under combination, the value higher or lower than plane (Δ E=0) represents to cooperate with respectively or antagonism, the value table around plane
Show unrelated effect, in the color encoding strip for scheming right side, illustrate that synergistic effect is stronger closer to upper end.
Specific embodiment
The invention will be further described with embodiment below in conjunction with the accompanying drawings.
Embodiment ambroxol hydrochloride is measured with fluconazole antifungic action
1. material
1.1 drugs and reagent
Fluconazole (Fluconazole, FLC), Dalian U.S. logical sequence Technology Co., Ltd.；
Ambroxol hydrochloride (Ambroxol hydrochloride, ABH), Dalian U.S. logical sequence Technology Co., Ltd.；
Kerma (unit of kinetic energy) praises Candida chromogenic medium, Zhengzhou Bo Sai bioengineering Co., Ltd；
TTC- sand Borrow's culture mediums, Qingdao high-tech park Hai Bo Bioisystech Co., Ltd；
Yeast extract, the extensive and profound in meaning star biotechnology Co., Ltd in Beijing；
Peptone, the extensive and profound in meaning star biotechnology Co., Ltd in Beijing；
Glucose, Sinopharm Chemical Reagent Co., Ltd.；
Agar powder, Beijing DingGuo ChangSheng Biology Technology Co., Ltd；
PBS phosphate buffer, Beijing DingGuo ChangSheng Biology Technology Co., Ltd；
Sodium hydroxide, state-run Shandong Dan County Organic Chemical Plant, lot number 940420；
Potassium dihydrogen phosphate, the new precious Fine Chemical Works in Shanghai, lot number 200602132.
1640 raw material medicinal powder of RPMI, GIBCO companies of the U.S.；
3- (N- morpholinoes) propane sulfonic acid (MOPS), Beijing DingGuo ChangSheng Biology Technology Co., Ltd；
Menadione (Menadione), Sigma Co., USA；
XTT (dimethoxy azoles is yellow), Nanjing optically-active Science and Technology Ltd.；
Lactated Ringer'S Solution (ringer's solution), Shandong Lukang Cisen Pharmaceutical Co., Ltd；
Acetone, one factory of Shanghai development chemical industry, lot number 200209510；
The preparation of XTT- menadione solution：XTT powder 0.0500g are taken, are dissolved in 100mL autoclaved ringer's solutions
The solution of 0.5mg/mL is made into, is gone out with 0.22 μm of filter membrane filtration；The menadione acetone soln for adding in the 10mmol/L of 10 μ L (takes first
Naphthoquinones 0.0860g is dissolved in 5mL acetone), make its final concentration of 1 μm of ol/L, shake up, 4 DEG C are kept in dark place.
Drug solution：Fluconazole is dissolved with sterile distilled water, is made into the storing solution of 2560 μ g/mL, filtering packing；Hydrochloric acid ammonia
Bromine rope is dissolved with sterile distilled water, is made into the storing solution of 5120 μ g/mL, filtering packing.All liquids are preserved in -20 DEG C of refrigerators,
It is spare.
PBS buffer solution：12gPBS phosphate buffer is weighed to 1L volumetric flasks, adding in distilled water stirring makes it completely molten
Solution, then aquae destillata is added to be dispensed into after reagent bottle the high pressure sterilization 30min at 121 DEG C to graduation mark, 4 DEG C of refrigerators are put after cooling and are protected
It deposits.
Yeast extract-peptone-glucose agar medium：Glucose 10g, peptone 10g, yeast extract 5g, agar
Powder 10g is dissolved in water in 500mL conical flasks, and 121 DEG C of sterilizing 30min after stirring, 4 DEG C of refrigerators preserve after cooling
It is spare.
1640 liquid mediums of RPMI：RPMI 1640 (containing L-Glutamine, without sodium bicarbonate) powder 2.08g is taken,
10% glucose solution 40ml (containing sugared final concentration 2%) and MOPS powder 6.906g is added in, adds distilled water to about 200mL, mixing
At 22 DEG C with the NaOH solution tune pH of 1mol/L it is about 7.0 ± 0.1 after uniformly, is gone out before use with 0.22 μm of composite fibre membrane filtration
Bacterium.
1.2 instrument
1.3 experimental strain
Quality-control strains：Candida albicans ATCC10231, pharmacology teaching and research room of Shandong University give；
Experimental strain：The Candida albicans of Qianfo Mount hospital clinical separation；
Bacterial strain is identified：Experiment is cultivated 48 hours with bacterial strain in the case where Kerma (unit of kinetic energy) praises 35 DEG C of Candida chromogenic medium, and bacterium colony is in green
Color or emerald all bacterial strains are again through Shandong Center for Disease Control ＆ Prevention's microbe research room in standard microbiology method
It is accredited as Candida albicans.
It is prepared by bacterium solution：The Candida albicans preserved at -20 DEG C thaws at room temperature, is inoculated into TTC- sand Borrow's agar mediums
On, 35 DEG C of cultures for 24 hours, take well-developed single bacterium colony to be inoculated with again, and 35 DEG C are cultivated for 24 hours, to ensure that bacterial strain is in growth period.
Choose several single compared with macrocolony, PBS is configured to bacteria suspension, with Chinese bacterial turbidity standard pipe ratio after vortice shaken well
Turbid, adjustment sample cell is consistent with standard pipe turbidity, and the bacteria concentration of Candida albicans is about 1 × 10 at this time6CFU/mL is serially diluted
Work bacterium solution is obtained, and concentration verification is carried out with count plate.
2. content and method
2.1 ambroxol hydrochlorides are measured with the effect of fluconazole overriding resistance Candida albicans
According to the chessboard method of CLSI M27-A3 schemes, 4 times are become with RPMI-1640 fluid nutrient medium dilute liquid medicines
Working concentration, screening ABH and the concentration range of FLC use in conjunction, the i.e. final concentration of ABH final concentration of 256~4 μ g/mL, FLC
For 64~0.125 μ g/mL.50 μ L of FLC liquids are drawn respectively by the sequence of concentration from low to high, are separately added into the of 96 hole plates
2~11 row draw 50 μ L of ABH liquids by concentration sequence from low to high, are separately added into G~A rows of each 96 hole plate, except the
The outer each hole of 12 row adds 100 μ L bacterium solutions respectively again, remaining is supplied less than the hole of 200 μ L with RPMI-1640 culture solutions.Wherein H1 makes a living
Long control, containing only bacterium solution not drug containing, the 12nd is classified as blank control, containing only RPMI-1640 fluid nutrient mediums.According to CLSI
The requirement of M27-A3 schemes puts 96 hole plates of dosing after being cultivated for 24 hours in 35 DEG C of constant incubators, loads 2h with XTT respectively
OD is measured with microplate reader afterwards and records result.All experiments are in triplicate.
2.2 evaluation methods and result judgement
2.2.1Loewe additivity is theoretical
The basic thought of Loewe additivity (LA) theory thinks that drug can not possibly interact with itself,
Therefore drug is applied alone or is combined and generated the concentration (equivalent site) of identical drug effect and be compared.Its analysis method score is antibacterial dense
Index method (fractional inhibitory concentration index, FICI) is spent, is expressed as follows：
Σ FIC=FICA+FICB=CA/MICA+CB/MICB
MICAAnd MICBIt is minimal inhibitory concentration when drug A and B are applied alone respectively, CAWith CBReach phase when being combined for two medicines
Respective concentration during with drug effect.FICI>4 be antagonism, and FICI is addition or unrelated effect between 0.5 and 4, FICI≤
0.5 is defined as acting synergistically.
2.2.2Bliss independence is theoretical
Bliss independence (BI) theory is that (fungi grows the theoretical value of percentage under each concentration of drug with Δ E
And the difference of experiment value) it is Data Analysis Model.Δ E model formulations are as follows：
Δ E=EA×EB-Ecomb
Wherein, EAFor the growth rate of A prescription used time fungies, EBFor the growth rate of B prescription used time fungies, EcombFor A medicines and B
The growth rate of fungi when medicine is combined.During interpretation of result, by Σ SYN and Σ ANT, i.e. all positive value delta E and negative value in 96 orifice plates
The adduction of Δ E judges the interaction of two kinds of drugs for index.When the absolute value of Δ E<When 100%, be expressed as it is weak collaboration or
Weak antagonism；When the absolute value of Δ E is between 100% and 200%, medium collaboration or antagonism are expressed as, as Δ E
Absolute value when being more than 200%, be expressed as to cooperate with by force or antagonism.
3. result
3.1 ambroxol hydrochlorides and fluconazole overriding resistance Candida albicans exercising result
3.1.1 minimum effective Mlc of ambroxol hydrochloride and fluconazole
The computational methods of fungi growth percentage are in each hole：
Fungi grows percentage=(each hole OD values-blank control wells OD values)/growth control hole OD values
By hole fungi growth percentage each in above-mentioned formula calculate flat board, the minimum of fungi growth 80% can be inhibited by taking
With a concentration of interpretation terminal of drug.
When ABH combines antifungic action with FLC, Strong synergy is presented, but to Candida albicans to drug resistance Candida albicans
Without synergistic effect for the sensitive strain of bacterium and non-white candida albicans.The now life persister CA10 and CA16 in 96 orifice plate of dosing
Long percentage experimental result is listed as follows shown in (table 1-3).
Table .1. with chessboard represent ABH and FLC drug combination overriding resistance Candida albicans CA10 growth percentage (with
Drug the best use combination of FICI methods conversion is marked with grey).
Table .2. with chessboard represent ABH and FLC drug combination overriding resistance Candida albicans CA16 growth percentage (with
Drug the best use combination of FICI methods conversion is marked with grey).
3.1.2FICI it acts synergistically associated with model and Δ E model evaluations ABH and FLC
The evaluation index of FICI models is FICI values, and FICI≤0.5 item is defined as acting synergistically.As can be seen from Table 3, respectively
The FICI values of combination are respectively less than 0.5, show as stronger synergistic effect.
The evaluation index of Δ E models is Σ SYN and Σ ANT, as can be seen from Table 3, the summation of each group ∑ SYN and ∑ ANT
It is far longer than 200%, shows as strong synergistic effect, graphics such as Fig. 1 of ABH and FLC combination confrontation CA10 and CA16
And Fig. 2.It can intuitively find out that different pharmaceutical combination is respectively provided with strong synergistic effect from figure.Picture and above-mentioned numerical analysis
It is with uniformity.
Table .3. is with FICI models and Δ E model evaluations ambroxol hydrochloride and fluconazole medication antifungic action
It explains：FLC：Fluconazole；ABH：Ambroxol hydrochloride；MIC：Minimum inhibitory concentration；MICA：Fluconazole when drug is applied alone
Minimum inhibitory concentration；CA：The minimum inhibitory concentration of Fluconazole during drug combination；MICB：Ambroxol hydrochloride is most when drug is applied alone
Low Mlc；CB：The minimum inhibitory concentration of ambroxol hydrochloride during drug combination；FICI：Score Mlc index；ΣSYN：
The sum of all positive value delta E in 96 orifice plates；ΣANT：The sum of all negative value Δ E in 96 orifice plates.
Above-mentioned, although the foregoing specific embodiments of the present invention is described with reference to the accompanying drawings, not protects model to the present invention
The limitation enclosed, those skilled in the art should understand that, based on the technical solutions of the present invention, those skilled in the art are not
Need to make the creative labor the various modifications or changes that can be made still within protection scope of the present invention.
Claims (5)
1. a kind of application of ambroxol hydrochloride joint Fluconazole in anti-candida albicans product is prepared.
2. application as described in claim 1, it is characterized in that：The product is using ambroxol hydrochloride and Fluconazole as chief active
The drug of ingredient.
3. application as claimed in claim 2, it is characterized in that：The product ambroxol hydrochloride with it is effective dense during fluconazole
Degree proportioning：Fluconazole：Ambroxol hydrochloride=1:64.
4. application as claimed in claim 2, it is characterized in that：The minimum inhibitory concentration of the product ambroxol hydrochloride is：128μ
g/mL。
5. application as claimed in claim 2, it is characterized in that：The minimum inhibitory concentration of the product Fluconazole is：2μg/mL.
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| CN106420872B (en) * | 2016-09-30 | 2019-07-09 | 上海市同济医院 | A kind of composition and its application of the ginsenoside and Fluconazole of antifungal antibody-resistant bacterium |
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Non-Patent Citations (3)
| Title |
|---|
| 1例老年肺部细菌合并真菌感染患者的药学监护;孙红爽 等;《中国药物警戒》;20150331;第12卷(第3期);第182-183、185页 * |
| 慢阻肺病患者继发肺部真菌感染用药分析及药学监护;陈颖 等;《中国民族民间医药》;20110915;第83页 * |
| 氟康唑西替利嗪导致氨茶碱浓度升高的病例分析;苗婉清 等;《基层医学论坛》;20150930;第19卷(第27期);第3820-3821页 * |
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