CN104739834A - Pharmaceutical composition and applications thereof - Google Patents
Pharmaceutical composition and applications thereof Download PDFInfo
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- CN104739834A CN104739834A CN201310730746.3A CN201310730746A CN104739834A CN 104739834 A CN104739834 A CN 104739834A CN 201310730746 A CN201310730746 A CN 201310730746A CN 104739834 A CN104739834 A CN 104739834A
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Abstract
The invention relates to a pharmaceutical composition, which comprises voriconazole and posaconazole, and is used for treatment and/or prevention of invasive fungal infection.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparing the application treated and/or prevented in deep fungal disease medicament.
Background technology
Recent 20 years carrys out deep fungal infection and increases trend in continuing, 1980-1990, and the acquired deep fungal infection rate of United States Hospital is increased to 3.8 ‰ by 2 ‰, and candidiasis bloodstream infection increases by 500.Be reported in the autopsy of teaching hospital according to European portion, fungal infection is increased to 1988-1992 4.1% by 1.6% of 1978-1982.United States Hospital monitoring of infection data (NNIS) shows: during 1995-2002, candidiasis bacteremia accounts for the 4th in infection from hospital bloodstream infection, but case fatality rate ranks first.The large serial epidemiological study display that Center for Disease Control and Prevention (CDC) carries out in 1992-1993, the annual morbidity of deep fungal infection is 178.3/ hundred ten thousand.Wherein, candidiasis annual morbidity is 72.8/ hundred ten thousand, and cryptococcosis is 65.5/ hundred ten thousand, and aspergillosis is 12.4/ hundred ten thousand, and coccidioidomycosis is 15.3/ hundred ten thousand, and histoplasmosis is 7.1/ hundred ten thousand.
The annual morbidity of another large serial epidemiological study display candidemia that CDC carries out the same period is 8 ~ 10,/10 ten thousand, and case fatality rate 29% ~ 40%, within 1 years old, Infants Below annual morbidity is up to 75,/10 ten thousand, and over-65s old people annual morbidity reaches 45/,100,000.Deep fungal infection is poor in advance, case fatality rate is high, the case fatality rate of such as Invasive candidiasis is 10% ~ 49%, Aspergillosis can up to 62% ~ 85%, agranulocytosis patient aspergillus infection case fatality rate is more than 90%, fusarium infection case fatality rate more can up to 79% ~ 87%, dissemination zygomycosis case fatality rate 96%, and matching many spores Pseudomonas infection case fatality rate is 58%.
The main cause that deep fungal infection increases is that the high-risk group that serious fungal infections occurs increases.The basic illness of research display deep fungal infection is HIV (47.4%), malignant tumor (14.7%), diabetes (9.9%), chrome lung illness (9.3%), abdominal part and operation on heart (7.6%), lymphoma (4.0%), leukemia (3.1%), dialysis (3.1%) and organ transplantation (1.3%) etc.
Deep fungal infection primarily of opportunistic fungus, caused by Candida, aspergillus and Cryptococcus, account for hematopoietic stem cell transplantation, organ transplantation and other immune deficient patients's fungal infection more than 80%.In the Candida of clinical separation in recent years, non-Candida albicans is increased (as Oidium tropicale, Candida glabrata etc.), and its drug-resistant intensity is also higher; The sixties in last century and the seventies, in candidiasis bloodstream infection, caused by Candida albicans, person accounts for 85% ~ 90%; 1998-2000 CDC data shows: caused by Candida albicans, person only accounts for 45%, but not person accounts for 55% caused by Candida albicans, comprise Candida glabrata (24.5%), Candida parapsilosis (13.3%), Oidium tropicale (12.2%), Candida krusei (2.0%), Candida lusitaniae (1.0%), other candidiasises (1.1%) [4].The research display carried out in immune deficient patients, the bloodstream infection caused by the non-Candida albicans of 1990-1994 is increased to 53% by 40%.This kind of change may be relevant with prophylactic use fluconazol.Some rare fungal infection also increase to some extent, as engaged Pseudomonas, matching many spores Pseudomonas, Fusarium etc., are mainly seen in Malignancy and Patients Following Bone Marrowtransplantation.
Existing medicine has amphotericin B, AM Bison (AmBisome), fluconazol, itraconazole, voriconazole, posaconazole and Caspofungin etc., and use based on single medicine, there is the shortcomings such as curative effect is remarkable not, drug resistance is relatively more outstanding, toxic and side effects is large in it.
Summary of the invention
The object of this invention is to provide a kind of pharmaceutical composition, comprise voriconazole and posaconazole, this pharmaceutical composition with the use of time there is synergism, the effect treating and/or preventing deep fungal disease can be improved.
Preferably, the weight ratio of voriconazole and posaconazole is 32: 1 ~ 1: 32, and preferred weight ratio is 8: 1 ~ 1: 8, further, the weight ratio of voriconazole and posaconazole is 2: 1 ~ 1: 2, and further, the weight ratio of voriconazole and posaconazole is 2: 1 or 1: 2 or 1: 1.
Pharmaceutical composition of the present invention is also containing one or more pharmaceutically acceptable carriers.Described carrier comprises the diluent of pharmaceutical field routine, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier and lubricant etc.
Unit preparation form of the present invention is the dosage form wherein comprising voriconazole and posaconazole, and preparation can be the solid preparation of oral administration, as tablet, slow releasing tablet, the capsule comprising granule, liquid or powder, liquid preparation etc.Invention unit dosage form preferably comprises the tablet of voriconazole and posaconazole.
Another object of the present invention be to provide a kind of by aforementioned pharmaceutical compositions for the preparation of the application treated and/or prevented in deep fungal disease medicament.
Described deep fungal infection is selected from following one or more: oropharynx or candidiasis of the esophagus; Refractory oropharyngeal and candidiasis of the esophagus; Aspergillosis, candidiasis, fusaridiosis, matches many pityrosporion ovales sick, the infection caused by diphasic fungi, zygomycosis, and the invasive infection caused by rare Molds and yeasts; To other therapies not should or the studies of invasive fungal infections of not intolerant patient; Because of hematologic malignancies, bone marrow or peripheral stem cell Transplatation conditioning scheme experience dose-dense and/or the patient of radiotherapy, and accept to be used for the treatment of acute or chronic graft versus host disease or prevention solid organ transplant rejection combined immunization and suppress candidiasis in therapy patient, aggressive fungal infection.
In vitro Bactericidal Experiments proves, pharmaceutical composition provided by the present invention, comprises voriconazole and posaconazole, has synergism, significantly can increase therapeutic effect, can lower the effective dose of voriconazole and posaconazole, and toxic and side effects is little.
Detailed description of the invention
Be illustrated below in conjunction with embodiment.The voriconazole mentioned in embodiment refers to (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-FU-4-base)-1-(1H-1,2,4-triazol-1-yl)-2-butanols, and chemical structural formula is as follows:
Molecular formula: C
16h
14f
3n
5o, molecular weight: 349.3.
Posaconazole refers to 4-[4-[4-[4-[[(3R, 5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-yl methyl) oxa-penta ring-3-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2S, 3S)-2-hydroxyl penta-3-base]-1,2,4-triazole-3-ketone, chemical structural formula is as follows:.
Molecular formula: C
37h
42f
2n
8o
4
Test method described in following embodiment, if no special instructions, is conventional method; Described reagent and biomaterial, if no special instructions, all can obtain from commercial channels.
Candida albicans (Candida albicans SC5314/ATCCMYA-2876) used in following embodiment is purchased from the biological product collecting center of Unite States Standard.
The interactive antifungal activity test of embodiment 1 voriconazole and posaconazole
Interactive antifungal (Candida albicansSC5314) activity of application chessboard method to posaconazole and posaconazole is tested.Concrete grammar is:
Candida albicans SC5314 in RPIM1640 culture medium, 35 DEG C, humidity 80%, 5%CO
2condition under hatch.Voriconazole and posaconazole being dissolved in respectively in DMSO, is 1mg/mL to concentration, stored for future use in refrigerator.In order to measure minimal inhibitory concentration (MIC), during sample test, adopt doubling dilution.Concrete with reference to American National Clinical Laboratory Standard committee (NCCLS) M-27A scheme, i.e. " yeast liquid media dilution method antifungal susceptibility test scheme ".2 times of dilution methods are adopted to prepare the medicinal liquid of a series of diluted concentration with fluid medium (RPMI1640), then by Candida albicans SC5314 cell (78 μ l, ~ 1*10
4individual) be inoculated in 96 orifice plates, after add 2 μ l drug solutions.First medicine posaconazole is longitudinally arranged by diluted concentration on 96 orifice plates, and second medicine voriconazole is by diluted concentration laterally arrangement.35 DEG C hatch 18 hours after test OD value.MIC value is determined by comparing with the OD value of blank.MIC value is defined as the lowest concentration of drug of energy 100% Antifungi growth herein.
In order to determine to work in coordination with between two medicine voriconazoles and posaconazole, be added or antagonism, we are judged by inhibition concentration coefficient FICI.FICI=(voriconazole in MIC pharmaceutical composition/MIC voriconazole is independent)+(posaconazole in MIC pharmaceutical composition/MIC posaconazole is independent), if FICI is value <0.50, then show to there is interactive activity, if FICI value is between 0.5-4.0, then show active addition, if FICI is value >4.0, then show to there is antagonism therebetween.
Antifungal activity test result worked in coordination with by table 1.
Result shows, is 0.000125 μ g/ml in the concentration of voriconazole, the concentration 0.004 μ g/ml of posaconazole; The concentration of voriconazole is 0.00025 μ g/ml, the concentration 0.002 μ g/ml of posaconazole; The concentration of voriconazole is 0.0005 μ g/ml, the concentration 0.001 μ g/ml of posaconazole; The concentration of voriconazole is 0.00075 μ g/ml, the concentration 0.00075 μ g/ml of posaconazole; The concentration of voriconazole is 0.001 μ g/ml, the concentration 0.0005 μ g/ml of posaconazole; The concentration of voriconazole is 0.002 μ g/ml, the concentration 0.00025 μ g/ml of posaconazole; The concentration of voriconazole is 0.004 μ g/ml, and the concentration 0.000125 μ g/ml of posaconazole, two compounds all exist collaborative antifungic action.When the concentration of its determination of voriconazole and posaconazole is 0.00075 μ g/ml, collaborative antifungal activity is the strongest.
Claims (10)
1. a pharmaceutical composition, comprises voriconazole and posaconazole.
2. pharmaceutical composition according to claim 1, is characterized in that, the weight ratio of described voriconazole and posaconazole is 32: 1 ~ 1: 32.
3. pharmaceutical composition according to claim 2, is characterized in that, the weight ratio of described voriconazole and posaconazole is 8: 1 ~ 1: 8.
4. pharmaceutical composition according to claim 1, is characterized in that, the weight ratio of described voriconazole and posaconazole is 2: 1 ~ 1: 2, further preferably 2: 1 or 1: 1 or 1: 2.
5., according to the pharmaceutical composition in Claims 1 to 4 described in any one, it is characterized in that described pharmaceutical composition also containing pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 5, is characterized in that described pharmaceutical composition is tablet form.
7. according to the application of the pharmaceutical composition in Claims 1 to 4 described in any one in preparation treatment deep fungal disease medicament.
8. application according to claim 7, is characterized in that, described deep fungal disease is oropharynx or candidiasis of the esophagus; Refractory oropharyngeal and candidiasis of the esophagus; Aspergillosis, candidiasis, fusaridiosis, matches many pityrosporion ovales sick, the infection caused by diphasic fungi, zygomycosis, and the invasive infection caused by rare Molds and yeasts; To other therapies not should or the studies of invasive fungal infections of not intolerant patient; Because of hematologic malignancies, bone marrow or peripheral stem cell Transplatation conditioning scheme experience dose-dense and/or the patient of radiotherapy, and accept to be used for the treatment of acute or chronic graft versus host disease or prevention solid organ transplant rejection combined immunization and suppress candidiasis in therapy patient or aggressive fungal infection.
9. according to the application of the pharmaceutical composition in Claims 1 to 4 described in any one in preparation prevention deep fungal disease medicament.
10. application according to claim 8, is characterized in that, described deep fungal disease is oropharynx or candidiasis of the esophagus; Refractory oropharyngeal and candidiasis of the esophagus; Aspergillosis, candidiasis, fusaridiosis, matches many pityrosporion ovales sick, the infection caused by diphasic fungi, zygomycosis, and the invasive infection caused by rare Molds and yeasts; To other therapies not should or the studies of invasive fungal infections of not intolerant patient; Because of hematologic malignancies, bone marrow or peripheral stem cell Transplatation conditioning scheme experience dose-dense and/or the patient of radiotherapy, and accept to be used for the treatment of acute or chronic graft versus host disease or prevention solid organ transplant rejection combined immunization and suppress candidiasis in therapy patient, aggressive fungal infection.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079819A (en) * | 2020-09-24 | 2020-12-15 | 南京易亨制药有限公司 | Improved voriconazole racemate preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079819A (en) * | 2020-09-24 | 2020-12-15 | 南京易亨制药有限公司 | Improved voriconazole racemate preparation method |
| CN112079819B (en) * | 2020-09-24 | 2022-06-17 | 南京易亨制药有限公司 | Improved voriconazole racemate preparation method |
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