CN104606187A - Levo ornidazole once-daily medicine dosage form - Google Patents

Levo ornidazole once-daily medicine dosage form Download PDF

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Publication number
CN104606187A
CN104606187A CN201310538735.5A CN201310538735A CN104606187A CN 104606187 A CN104606187 A CN 104606187A CN 201310538735 A CN201310538735 A CN 201310538735A CN 104606187 A CN104606187 A CN 104606187A
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Prior art keywords
ornidazole
laevo
pharmaceutical composition
daily
administration
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CN201310538735.5A
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Chinese (zh)
Inventor
王勇
张仓
孙熠
张小兰
王志强
李玉秀
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Nanjing Sanhome Pharmaceutical Co Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a levo ornidazole once-daily medicine dosage composition comprising a therapeutically effective amount of levo ornidazole or a pharmaceutically acceptable salt thereof, and at least a pharmaceutically acceptable carrier. The invention also relates to a medicine product containing the levo ornidazole and application of the medicine composition in preparation of drugs used for the prevention and / or treatment of bacterial, parasitic and fungal infections. The curative effect of the levo ornidazole once-daily medicine dosage composition and the curative effect of a twice-daily dosage control preparation are same, the daily dosage is reduced, he medicine accumulation is reduced, and the side effect is reduced.

Description

Laevo-ornidazole is dosage form once a day
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to drug-delivery preparation once a day and the application thereof of laevo-ornidazole.
Background technology
The levo form that laevo-ornidazole (1-(3-chloro-2-S-(-) hydroxypropyl)-2-5-nitro imidazole, has another name called l-ornidazole, Levornidazole) is ornidazole (Ornidazole, CAS16773-42-5).Ornidazole is nitro imidazole derivatives, being the medicine of a kind of powerful anaerobe resistant, protozoacide and anti-fungal infection, is also the third generation nitro imidazole derivatives that curative effect is higher, the course for the treatment of is shorter, toleration is better, distribution in vivo is wider be newly developed into after metronidazole.Removing the anti-microbial effect of ornidazole is in oxygen-free environment, be reduced into amino by the nitro in its molecule, or is interacted by the formation of free radical and cell component, thus causes the death of microorganism.Research shows, the maincenter toxicity of laevo-ornidazole is starkly lower than ornidazole and right ornidazole, laevo-ornidazole has good anaerobe resistant effect simultaneously, its anti-anaerobic activity and ornidazole basic simlarity, all have good antibacterial activity to anaerobe such as bacteroides fragilis, bacteroides thetaiotaomicron, dyspepsiacoccus and peptostreptococcus, Fusobacterium, gingiva bacteroids.
Laevo-ornidazole and ornidazole preparation commercially all have sale at present, and laevo-ornidazole kind is excellent promise peace such as, the such as excellent human relations of ornidazole kind, Sheng Nuo, Sheng Nuoan, appropriate Soviet Union, interior moral taste etc.The laevo-ornidazole of current listing and ornidazole preparation are the dosage form of 0.5g, 0.25g or 0.1g content, are designed to each administration 0.5g dosage, the daily dosage regimen of twice.For laevo-ornidazole preparation commercially available at present as excellent promise pacifies daily twice, the therapeutic scheme of each 0.5g can be patient tolerance well, if but can daily once, and daily dose can reduce to some extent, therapeutic effect is constant simultaneously, then while the compliance of patient is greatly enhanced, can reduce medical expense again.In addition, although laevo-ornidazole is compared with ornidazole, can obviously reduce cental system toxicity, but, it likely causes other side effect similar with ornidazole.Such as, it is reported that ornidazole has the toxicity to liver, reduce the untoward reaction such as leukocyte, its sickness rate is relevant with dosage.
Therefore, wish the dosage form once a day developing laevo-ornidazole, thus while maintenance therapeutic effect is constant, can daily dose be reduced, reduce side effect, improve the compliance of patient.
Summary of the invention
An object of the present invention is to provide the laevo-ornidazole or its officinal salt that comprise treatment effective dose, and the pharmaceutical composition of the pharmaceutically acceptable carrier of at least one, described compositions delivers medicine to individuality once a day, the therapeutic effect obtained.
Another object of the present invention is to provide pharmaceutical composition of the present invention for the preparation of the application prevented and/or treated in the medicine of antibacterial, parasite, fungal infection.
Foregoing invention object, is achieved by the following technical programs.
The invention provides a kind of pharmaceutical composition, it comprises laevo-ornidazole or its officinal salt for the treatment of effective dose, carrier pharmaceutically acceptable with at least one, in wherein said compositions the amount of laevo-ornidazole be when by described compositions daily one time time the bioavailability that demonstrates and/or drug effect and daily dose be its 4/3rds (4/3) laevo-ornidazole control formulation doubly according to the bioavailability of daily secondary and/or drug effect suitable.
The present invention also provides one to prevent and/or treat antibacterial in individuality, parasite, the method of fungal infection, the method comprises and gives described individuality pharmaceutical composition of the present invention once a day, said composition comprises laevo-ornidazole or its officinal salt for the treatment of effective dose, carrier pharmaceutically acceptable with at least one, in wherein said compositions the amount of laevo-ornidazole be when by described compositions daily one time time the bioavailability that demonstrates and/or drug effect and daily dose be its 4/3rds (4/3) laevo-ornidazole control formulation doubly according to the bioavailability of daily secondary and/or drug effect suitable.
In this article, " the treatment effective dose " of laevo-ornidazole refers to when it is as therapeutic scheme a part of, in treatment antibacterial, parasite, fungal infection, administration once a day provides treatment effective every daily dose, suitable dose in people is the gauge with laevo-ornidazole, in the scope being greater than 0.5g to about 2g, preferably within the scope of about 0.6g to about 1.5g, such as 0.75g or 1.0g.
In this article, described " bioavailability is suitable " refers to compared with the bioavailability that the bioavailability of pharmaceutical composition thing of the present invention administration once a day and daily dose are the every twice-daily administration of its control formulation of 4/3rds times, P value does not have statistical significance, P>0.05.In this article, described " drug effect is suitable " refers to and reaches AUC according to daily secondary to bacteroides fragilis when be once daily its laevo-ornidazole control formulation of 4/3rds times with daily dose by described pharmaceutical composition 0-24hthe CFR of/MIC=70 target value all>=99.9%.
According to the present invention, the form of described compositions can be discrete dosage unit.In one embodiment, the amount of the laevo-ornidazole in pharmaceutical composition of the present invention, exists according to the mode of single administration one to several dosage unit, is enough to provide daily dose.Preferably, whole daily dose comprises in the composition with single dosage unit.In one embodiment, with the gauge of laevo-ornidazole, described compositions is contained in laevo-ornidazole or its officinal salt of the about 0.5g in single dosage unit to about 2.0g.Preferably, described compositions is contained in laevo-ornidazole or its officinal salt of the about 0.6g in single dosage unit to about 1.5g.More preferably, described compositions is contained in laevo-ornidazole or its officinal salt of the about 0.75g in single dosage unit to about 1.0g.In a specific embodiment, described compositions is contained in laevo-ornidazole or its officinal salt of the 0.75g in single dosage unit.In another specific embodiment, described pharmaceutical composition is contained in laevo-ornidazole or its officinal salt of the 0.75g in two to several discrete dosage unit, such as described compositions is made up of 3 dosage units containing 0.25g laevo-ornidazole or its officinal salt, or is made up of 1 dosage unit containing 0.25g laevo-ornidazole or its officinal salt and 1 dosage unit containing 0.5g laevo-ornidazole or its officinal salt.In another specific embodiment, described compositions is contained in laevo-ornidazole or its officinal salt of the 1.0g in single dosage unit.In another specific embodiment, described pharmaceutical composition is contained in laevo-ornidazole or its officinal salt of the 1.0g in two to several discrete dosage unit, such as described pharmaceutical composition is made up of the dosage unit that 4 contain 0.25g laevo-ornidazole or its officinal salt, or be made up of 2 dosage units containing 0.25g laevo-ornidazole or its officinal salt and 1 dosage unit containing 0.5g laevo-ornidazole or its officinal salt, or be made up of 2 dosage units containing 0.5g laevo-ornidazole or its officinal salt.
As long as depending on that its administration once a day reaches as defined herein for the selection of the amount of laevo-ornidazole in described compositions is its 4/3rds (4/3) laevo-ornidazole control formulation doubly with daily dose according to the bioavailability of daily secondary and/or drug effect quite.
According to the present invention, pharmaceutical composition of the present invention is formulated as pharmaceutical preparation, described preparation comprises oral formulations or parenteral formulations.In some embodiments, described oral formulations comprises tablet, lozenge, capsule, granule, drop pill, Emulsion, solution, fat micro sphere preparation.Such as, described tablet comprises oral conventional tablet, dispersible tablet, Film coated tablets, enteric coatel tablets etc., and described capsule comprises soft capsule and hard capsule.Pharmaceutical composition of the present invention can also make mouthful cheek sheet or oral cavity pasting tablet, is used for the treatment of oral cavity infection.Described parenteral formulations comprises injection such as large capacity transfusion preparation and low capacity infusion preparation, injectable powder, external preparation for skin gel, vagina administration preparation as vaginal effervescent tablet, vaginal suppository or vagina gel.Pharmaceutical composition of the present invention can also be prepared into slow releasing agent or time delay releasing agent etc.
Appropriate carrier for oral formulations can comprise disintegrating agent, binding agent, lubricant, filler etc., can be one or more mixture wherein.Wherein filler is preferably one or more mixing in pregelatinized Starch, starch, dextrin, sucrose, lactose, glucose, mannitol, microcrystalline Cellulose, calcium sulfate, calcium carbonate, light magnesium oxide; Lubricant is preferably one or more mixing in stearic acid, calcium stearate, magnesium stearate, Pulvis Talci, hydrogenated vegetable oil, Polyethylene Glycol, sodium lauryl sulphate, Stepanol MG; Disintegrating agent is preferably one or more mixing in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sodium lauryl sulphate; Binding agent is preferably hydroxypropyl cellulose, polyvidone, starch slurry, dextrin, sucrose, syrup, the gelatin solution of 10-20%, the gumwater of 10%-25%, one or more mixing of cellulose and its derivates.Be preferably 11 to 30mg/kg/ day according to the dosage of oral formulations of the present invention, be more preferably 12 to 20mg/kg/ day.
Appropriate carrier for intravenous administration formulation can comprise osmotic pressure regulator, organic solvent etc.Preferred osmotic pressure regulator is any proportioning combination of one or more of sodium chloride, glucose, potassium gluconate, gluconic acid sodium salt, calcium gluconate, Ferrous gluconate, magnesium gluconate, carboxyethyl starch, low molecular dextran, glycerol, sodium bicarbonate, potassium hydrogen phosphate, magnesium sulfate, calcium chloride, potassium chloride, sodium lactate, xylitol, sorbic acid, maltose, fructose, is more preferably any proportioning combination of one or more of sodium chloride, glucose.Preferred organic solvent is propylene glycol, ethanol or Polyethylene Glycol, is more preferably propylene glycol.According to the dosage of intravenous formulations of the present invention, with artificial example, be preferably 11 to 30mg/kg/ day, be more preferably 12 to 20mg/kg/ day, most preferably be 12 to 17mg/kg/ day.In preferred embodiments, intravenous formulations of the present invention is sodium chloride injection, glucose injection, sodium chloride-glucose injection, propylene glycol injection or formula mannitol injection liquid.
The present invention also provides described pharmaceutical composition for the preparation of preventing and/or treating antibacterial, parasite, application in the medicine of fungal infection, wherein said compositions comprises laevo-ornidazole or its officinal salt for the treatment of effective dose, carrier pharmaceutically acceptable with at least one, in wherein said compositions the amount of laevo-ornidazole be when by described compositions daily one time time the bioavailability that demonstrates and/or drug effect and daily dose be its 4/3rds (4/3) laevo-ornidazole control formulation doubly according to the bioavailability of daily secondary and/or drug effect suitable.
The present invention also provides laevo-ornidazole or its officinal salt for the preparation of the application prevented and/or treated in the medicine of antibacterial, parasite, fungal infection, wherein said medicine is to be greater than 0.6g to being less than 2.0g, be preferably greater than 0.6g to being less than 1.5g, more preferably 0.75g to 1.0g, delivering medicine to individuality once a day, is preferably people.According to the application of laevo-ornidazole of the present invention, wherein said medicine is oral or forms for parenteral administration.In one embodiment, described medicine is the forms for parenteral administration by mucosa absorption or percutaneous absorbtion.Preferably, described medicine is intravenous administration dosage form.In a preferred embodiment, according to the application of laevo-ornidazole of the present invention, the dosage of wherein said medicine is 0.75g.
The present invention also provides a kind of kit product, it comprises medicine containing laevo-ornidazole or its officinal salt and administration description, wherein with the gauge of laevo-ornidazole, the dosage of described medicine is for being greater than 0.6g to being less than 2.0g, described administration description indicates described medicine to be greater than 0.6g to being less than 2.0g with daily dose, once a day, successive administration 1-14 time, the administration 1-7 cycle.Preferably, according to kit product of the present invention, wherein with the gauge of laevo-ornidazole, the dosage of described medicine is for being greater than 0.6g to being less than 1.5g, more preferably 0.75g to 1.0g.Preferably, according to kit product of the present invention, wherein said administration description indicates described medicine to be greater than 0.6g to being less than 1.5g with daily dose, once a day, and successive administration 1-10 time, an administration 1-5 cycle.In a specific embodiment, kit product according to the present invention comprises medicine containing laevo-ornidazole or its officinal salt and administration description, wherein with the gauge of laevo-ornidazole, the dosage of described medicine is 0.75g, and described administration description indicates described medicine with 0.75g, once a day, successive administration 1-7 time, such as 3 times, 4 times, 5 times, 6 times, 7 times, an administration 1-3 cycle, such as 1,2 or 3 cycles, each period distances 2-5 day.
Pharmaceutical composition of the present invention may be used for treating antibacterial, especially anaerobic infection, treatment men and women urogenital tract trichomonacide, Albendazole, as trichomonal vaginitis infects, treatment digestive system ameba parasitosis, as amebic dysentery, amebic liver abscess infect, be used for the treatment of fungal infection etc.
According to the present invention, preferably, the officinal salt of described laevo-ornidazole refers to the salt of higher solubility in water.Exemplary salt comprises the standby salt of use processed with acid below: hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, P-hydroxybenzoic acid, benzoic acid, acetic acid, tartaric acid, maleic acid, malic acid, citric acid, lactic acid, succinic acid, ascorbic acid, glycolic, gluconic acid, oxaloacetic acid, fumaric acid, aspartic acid, glutamic acid, salicylic acid etc.In one embodiment, the officinal salt of described laevo-ornidazole is pharmaceutical salts such as the (s)-ornidazole disodium phosphate salt or its hydrate of levo-ornidazole phosphate, such as (s)-ornidazole disodium phosphate pentahydrate, hexahydrate.In another embodiment, the officinal salt of described laevo-ornidazole is the amino acid salts of levo-ornidazole phosphate.In another embodiment, the officinal salt of described laevo-ornidazole is laevo-ornidazole succinate salt, such as laevo-ornidazole succinate sodium.
The present inventor surprisingly finds, what demonstrate when pharmaceutical composition of the present invention administration once a day uses AUC usually 0-∞the bioavailability represented and daily dose are its laevo-ornidazole control formulation of 4/3rds times such as excellent promise suitable according to the bioavailability of every twice-daily administration.Meanwhile, find that working as pharmaceutical composition of the present invention is once daily its laevo-ornidazole control formulation of 4/3rds times such as excellent promise with daily dose according to daily secondary, AUC is reached to bacteroides fragilis 0-24hthe CFR of/MIC=70 target value all>=99.9%.
Daily pharmaceutical composition once of the present invention demonstrates many wonderful benefits:
A., compared with the laevo-ornidazole control formulation of every twice-daily, when obtaining identical treatment effect, daily dose obviously reduces (such as, reducing 1/4th);
B., compared with the laevo-ornidazole control formulation of every twice-daily, there is not serious adverse events;
C., compared with the laevo-ornidazole control formulation of every twice-daily, laevo-ornidazole accumulation in vivo can obviously be reduced;
D. compared with the laevo-ornidazole control formulation of every twice-daily, safety is higher, and the case load that abnormal liver function occurs is less.
Herein, the abbreviation full name of use:
Except as otherwise noted, all technology used herein and scientific terminology have the identical implication usually understood with those skilled in the art.
Herein, described laevo-ornidazole or the amount of its officinal salt all represent with the amount of laevo-ornidazole.
Should be appreciated that described laevo-ornidazole or its officinal salt comprise their crystal formation, hydrate and solvate herein.
In this article, the animal that described " individuality " is any kind, preferred mammal, optimum is chosen.Unless otherwise indicated by context, " treatment " herein comprises prophylactic treatment.
Form of administration once a day of the present invention, when therapeutic effect is suitable, daily dose obviously reduces, thus side effect reduces, and medical expense reduces, and the compliance of patient is improved.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further elaborated, but the invention is not restricted to these embodiments.
Embodiment 1:
This embodiment is the laevo-ornidazole preparation (0.75g laevo-ornidazole) of tablet form.
1. prescription composition
2. preparation process
To make 1000 tablets of laevo-ornidazole tablets, concrete preparation method is as follows: first supplementary material is crossed 100 mesh sieves, take laevo-ornidazole and the pregelatinized Starch mix homogeneously of recipe quantity, add 8% starch slurry soft material, granulate, dry, granulate, recipe quantity carboxymethyl starch sodium and magnesium stearate is added, tabletting, the Opadry 95% alcoholic solution coating with 8% in granule.
Embodiment 2:
This embodiment is the laevo-ornidazole preparation (0.75g laevo-ornidazole) of Capsule form.
1. prescription composition
(a) laevo-ornidazole 750mg/ grain
(b) starch 135mg/ grain
(c) magnesium stearate 6mg/ grain
2. preparation process
To make 1000 laevo-ornidazole capsules, concrete preparation method is as follows: first supplementary material is crossed 100 mesh sieves, take laevo-ornidazole and the starch mix homogeneously of recipe quantity, add 6% starch slurry soft material, granulate, dry, granulate, recipe quantity magnesium stearate mix homogeneously is added, filled capsules in granule.
Embodiment 3:
This embodiment is the laevo-ornidazole preparation (1.00g laevo-ornidazole) of granular form.
1. prescription composition:
2. preparation process
To prepare 1000 bags of laevo-ornidazole granules.Concrete preparation method is as follows: first supplementary material is crossed 100 mesh sieves, takes the laevo-ornidazole of recipe quantity, mannitol, Icing Sugar and carboxymethyl starch sodium mix homogeneously, adds 8% starch slurry soft material, granulates, and dries, granulate, packaging.
Embodiment 4:
This embodiment is the laevo-ornidazole preparation (0.75g laevo-ornidazole) of injection form.
1. prescription consists of:
(a) laevo-ornidazole 5mg/ml
(b) sodium chloride 8.3mg/ml
C () water for injection adds to 150ml
2. preparation process
To make 100 bottles of L-ornidazole sodium chloride injection preparations, concrete preparation method is as follows: the laevo-ornidazole and the sodium chloride that first take recipe quantity, adds 40 DEG C of water for injection 12L, stirs, and dissolves; PH to 4.0 is adjusted with 0.1mol/L hydrochloric acid; Add 40 DEG C of waters for injection to full dose; In above-mentioned solution, add 0.1% active carbon, stir, place 15min, the de-charcoals of 5 μm of titaniums rod, then through the microporous filter membrane fine straining of filter cartridge 0.45 μm and 0.22 μm; Embedding is in soft bag, plastic bottle or glass infusion bottle, and loading amount is 150ml, in 115 DEG C of pressure sterilizing 30min, to obtain final product.
Embodiment 5:
This embodiment is the laevo-ornidazole preparation (0.75g laevo-ornidazole) of injection form
1. prescription composition:
(a) laevo-ornidazole 75mg/ml
(b) sodium chloride 8.0mg/ml
C () water for injection adds to 100ml
2. preparation process
To prepare 100 bottles of L-ornidazole sodium chloride injections.Concrete preparation method is as follows: the laevo-ornidazole and the sodium chloride that first take recipe quantity, adds 40 DEG C of water for injection 8L, stirs, and dissolves; PH to 4.0 is adjusted with 0.1mol/L hydrochloric acid; Add 40 DEG C of waters for injection to full dose; In above-mentioned solution, add 0.1% active carbon, stir, place 15min, the de-charcoals of 5 μm of titaniums rod, then through the microporous filter membrane fine straining of filter cartridge 0.45 μm and 0.22 μm; Embedding, in the soft bag of 100ml, plastic bottle or glass infusion bottle, in 115 DEG C of pressure sterilizing 30min, to obtain final product.
Embodiment 6:
This embodiment is the laevo-ornidazole preparation (0.75g laevo-ornidazole) of injection form
1. prescription composition:
(a) laevo-ornidazole 5mg/ml
(b) glucose 50mg/ml
C () water for injection adds to 150ml
2. preparation process
To prepare 100 bottles of laevo-ornidazole glucose injections.Concrete preparation method is as follows: the laevo-ornidazole and the glucose that take recipe quantity are dissolved in the water for injection of 12L45 DEG C, with the hydrochloric acid of 0.1mol/L, regulates pH to 3.5.Add 45 DEG C of waters for injection to full dose.Add 0.15% active carbon, stir, place 15min, the de-charcoals of 5 μm of titaniums rod, then through the microporous filter membrane fine straining of filter cartridge 0.45 μm and 0.22 μm, embedding is in soft bag, plastic bottle or glass infusion bottle, and loading amount is 150ml, in 100 DEG C of flowing steam sterilizing 45min, to obtain final product.
Embodiment 7:
This embodiment is the laevo-ornidazole preparation (1.0g laevo-ornidazole) of injection form.
1. prescription consists of:
(a) laevo-ornidazole 5mg/ml
(b) sodium chloride 8.30mg/ml
C () water for injection adds to 200ml
2. preparation process
To make 100 bottles of L-ornidazole sodium chloride injection preparations, concrete preparation method is as follows: the laevo-ornidazole and the sodium chloride that first take recipe quantity, adds 40 DEG C of water for injection 16L, stirs, and dissolves; PH to 4.0 is adjusted with 0.1mol/L hydrochloric acid; Add 40 DEG C of waters for injection to full dose; In above-mentioned solution, add 0.1% active carbon, stir, place 15min, the de-charcoals of 5 μm of titaniums rod, then through the microporous filter membrane fine straining of filter cartridge 0.45 μm and 0.22 μm; Embedding is in soft bag, plastic bottle or glass infusion bottle, and loading amount is 200ml, in 115 DEG C of pressure sterilizing 30min.
Embodiment 8:
This embodiment is the laevo-ornidazole preparation (0.75g laevo-ornidazole) of injection form.
1. prescription composition:
(a) laevo-ornidazole 750g
(b) mannitol 240g
2. preparation process
To make 1000 bottles of injection laevo-ornidazole preparations, concrete preparation method is as follows: the laevo-ornidazole taking recipe quantity, mannitol, add in 40 DEG C of water for injection 21000ml, be stirred to dissolve, pH to 4.0 is adjusted with 1mol/LHCl solution, inject water to 24000ml, add the needle-use activated carbon of 0.1%, stir, after placing 15min, charcoal is taken off with sand stick sucking filtration, measure intermediates content and pH qualified after, again after the microporous filter membrane fine straining of sintered glass filter and 0.22um, fill is in cillin bottle, every bottle of 24ml, lyophilization, gland, packaging, obtain this product.
Experimental example:
Experimental example of the present invention tests pharmacokinetics (PK) situation of product (containing the laevo-ornidazole 0.75g) administrations once a day of 4 preparations according to the abovementioned embodiments of the present invention, and in conjunction with it to anaerobe Pharmacodynamics in vitro (PD) result, carrying out PK/PD research, providing foundation for formulating clinical dosing regimen.
The laevo-ornidazole control formulation used in this experiment is the excellent promise in commercially available prod injection (lot number: 2009S02895, Nanjing Shenghe Pharmaceutical Co., Ltd, China), its specification is every bottle of 100ml: laevo-ornidazole 0.5g, sodium chloride 0.83g.
1. research design
This research is single centre, open, parallel, single, multiple dose administration EXPERIMENTAL DESIGN, enter the routine healthy volunteer of group 24 altogether, all experimenters are randomized into 2 researchs group (500mg group and 750mg group), often organize 12 examples, men and women half and half, accept single dose and multi-agent intravenous drip L-ornidazole sodium chloride injection 500mg respectively, q12h or 750mg, q24h, leave and take experimenter and accept blood before and after medicine, urine sample, carry out pharmacokinetic analysis and safety analysis, carry out the safety such as clinical observation and lab testing before administration and after administration in 7 days to detect simultaneously.
2. experimenter selects
2.1 inclusion criteria
1) age was at 19 ~ 45 years old, and must not differ more than 10 years old with the age in group, men and women half and half;
2) body weight is in body-mass index range 19 ~ 24, Body Mass Index (BMI)=body weight (kg)/height (m) 2;
3) researcher is according to medical history, physical examination, 12-lead electrocardiogram and lab testing, is judged as healthy experimenter.The Index for examinations such as the heart, liver, kidney, blood are all in normal range;
4) female subjects need meet following condition, and female patient must meet:
1. menolipsis at least 1 year, or
2. row operation sterillization, or
3. Female in child bearing period experimenter must meet following all conditions:
● enter to organize baseline inspection urine gestation reaction for negative;
● during being intended to whole research, use a kind of approved contraceptive device (as: oral contraceptive, spermicide and condom, or intrauterine device).And the contraceptive device that during being intended to whole research together, (making a house call 1 ~ 4) adopts is constant;
● must not suckling.
5) child-bearing period male subject adopts reliable contraceptives (as condom or companion adopt above-mentioned measure) with being intended to duration of test;
6) do not take in three months known to the prejudicial medicine of certain internal organs;
7) other drug clinical trial was not participated in two months;
8) any medicine (comprising Chinese medicine and nonprescription drugs) was not taken in two weeks;
9) Informed Consent Form can be signed voluntarily.
2.2 exclusion standard
1) the system Medical histories such as liver, kidney, cardiovascular, central nervous system are had, and the person that once accepted systematic treating;
2) drug allergy history person is had;
3) person of being positive is had in HIVAb, HBsAg and HCVAb;
4) lab testing abnormal (exceeding normal value ± 10%), and the person person that has been judged as clinical meaning after deliberation;
5) blood pressure, pulse frequency do not meet sign (clinostatism) inclusion criteria (inclusion criteria: systolic pressure is >=90mmHg ,≤140mmHg; Diastolic pressure is >=40mmHg ,≤90mmHg; Pulse frequency >=40 beat/min ,≤99 beats/min);
6) QTc interval, does not meet inclusion criteria (inclusion criteria: QTc≤450msec);
7) alcohol prohibition, ban on opium-smoking and the opium trade person can not be kept in interval experimental period;
8) Drug abuse history person is had;
9) this research administration was once donated blood more than 400ml person in first 90 days;
10) person that cannot accept intravenously administrable;
11) other researcheres judge to be not suitable for the situation of participating in this test.
3. drugs
3.1 dosage regimen
24 routine healthy volunteers, all experimenters are randomized into 2 research groups, and often organize 12 examples, men and women half and half.Concrete dosage regimen is in table 1.
Table 1 laevo-ornidazole two kinds of dosage regimens
Medication: 500mg group and 750mg group experimenter prohibit diet from the 21:00 of administration the previous day, has breakfast before the intravenous drip in morning of next day.
Single dose pharmacokinetic studies:
500mg group and 750mg group experimenter all in 7:00 ± 1:00 constant rate in-travenous infusion laevo-ornidazole morning on the 1st, 500mg group instillation 500mg (1 bottle) 1 time, the instillation time is 60min ± 10min; 750mg group instillation 750mg(every bottle of 0.5g/100mL) 1 time, the instillation time is 90min ± 10min.
Multi-agent pharmacokinetic studies:
500mg group experimenter is in 7:00 ± 1:00 and late 7:00 ± 1:00 constant rate in-travenous infusion laevo-ornidazole 500mg(every bottle of 0.5g/100mL morning every day on the 4th ~ 10th), every day 12h1 time, continuous 7 days; 7:00 ± 1:00 constant rate in-travenous infusion laevo-ornidazole 500mg morning on the 11st (1 bottle) 1 time, the instillation time is 60min ± 10min.
750mg group experimenter is in 7:00 ± 1:00 constant rate in-travenous infusion laevo-ornidazole 750mg(morning every day on the 4th ~ 11st every bottle of 0.5g/100mL) 1 time, the instillation time is 90min ± 10min.Every 24h1 time, totally 8 days.
4. pharmacokinetics sample collection
Laevo-ornidazole 500mg group is with to gather experimenter's hematuria sample time after the administration of 750mg group identical.The concrete time is in table 2.
Table 2. gathers experimenter's hematuria sample concrete time
Gather experimenter's blood sample 3ml in the scheme prescribes time, be positioned in anticoagulant heparin pipe, through centrifugal (3000rpm in 60 minutes, 4 DEG C, 10 minutes) point get blood plasma, plasma sample is added in plastic centrifuge tube 2, place-20 DEG C and following Refrigerator store to be measured.
Collect each interval urine volume of experimenter in the scheme prescribes time, fully mix, measure urine volume; Get 2ml respectively and put into plastic centrifuge tube 2, place-20 DEG C and following Refrigerator store to be measured.Experimenter started to stay urine after bladder empties before staying urine, and at the end of the urine of each interval, even if not think urine, also short its is urinated.
5. the mensuration of pharmacokinetics sample and calculating
The foundation of 5.1 laevo-ornidazole blood, urine sample assay method and checking
Laevo-ornidazole blood, urine sample all adopt Ultra Performance Liquid Chromatography-tandem mass spectrum method (UPLC-MS/MS) to measure laevo-ornidazole and metabolite M1 (the chloro-3-of 1-(2-methylol-5-nitro-1-imidazole radicals)-2-propanol), M2 (2-base-5-nitroimidazole) and M4 (3-(2-methyl-5-nitro-1-imidazole radicals)-1,2-PD) concentration in blood plasma and urine sample.Ultra Performance Liquid Chromatography instrument and mass spectrograph model are respectively WatersUPLC and API4000QTRAP; Immobile phase ACQUITY CSH C 18post (2.1mm × 50mm; 1.7 μm); Mobile phase is 0.1% formic acid solution: acetonihile gradient elution; Flow velocity: 0.6mL/min.Mass Spectrometry Conditions: 1. ionization source: APCI source; 2. detecting pattern: cation multiple-reaction monitoring (MRM); 3. CurtARn gas:20.0psi, Ion Source Gas1:40.0psi; 4. Collision:Median; 5. Nebuilzer Current:4.0; 6. Temperature:500 DEG C.
Blood plasma and urine specimen processing method: get 200 μ L plasma sample solution in Eppendorf pipe, add 600 μ L acetonitriles and 20 μ L1.00 μ g/mL metronidazoles, whirlpool mixes, 12000rpm × 15min is centrifugal, 600 μ L supernatant are transferred in Eppendorf pipe, add 600 μ L ethyl acetate, after rotation mixes and shakes 10min, 12000rpm × 10min is centrifugal, 800 μ L supernatant are transferred in round bottom Eppendorf pipe, volatilize under 40 DEG C of nitrogen current, with 200 μ L acetonitrile-0.1% formic acid solution (5:95, v/v) rebuild, the centrifugal 5min of 12000rpm/min after abundant mixing, supernatant 3 μ L sample introduction is analyzed.
AB Analyst3.13 data handling system (AB SCIEX company) is adopted to carry out automatic integration to SONZ, M1, M2, the M4 in biological sample and interior mark chromatographic peak area, and with standard curve sample SONZ, M1, M2, M4 and interior target peak area ratio to concentration the regression straight line and linear equation.The drug level in blood plasma, urine unknown sample is tried to achieve respectively with plasma solutions, urine solution standard curve.
Laevo-ornidazole is 0.0100 μ g/mL, 0.0250 μ g/mL, 0.0500 μ g/mL, 0.250 μ g/mL, 0.500 μ g/mL, 2.50 μ g/mL and 5.00 μ g/mL at blood plasma and urine solution standard curve concentration, Quality Control concentration of specimens is 0.0100 μ g/mL, 0.0300 μ g/mL, 0.200 μ g/mL and 4.00 μ g/mL, and minimum quantitative concentrations (LLOQ) is 0.0100 μ g/mL; M1 standard curve concentration is: 0.00500 μ g/mL, 0.0125 μ g/mL, 0.0250 μ g/mL, 0.125 μ g/mL, 0.250 μ g/mL, 1.25 μ g/mL and 2.50 μ g/mL, it is 0.00500 μ g/mL that Quality Control concentration of specimens is 0.00500 μ g/mL, 0.0150 μ g/mL, 0.100 μ g/mL and 2.00 μ g/mL, LLOQ; M2 standard curve concentration is: 0.0200 μ g/mL, 0.0500 μ g/mL, 0.100 μ g/mL, 0.500 μ g/mL, 1.00 μ g/mL, 5.00 μ g/mL and 10.0 μ g/mL, it is 0.0200 μ g/mL that Quality Control concentration of specimens is 0.0200 μ g/mL, 0.0600 μ g/mL, 0.400 μ g/mL and 8.00 μ g/mL, LLOQ; M4 standard curve concentration is: 0.00250 μ g/mL, 0.00625 μ g/mL, 0.0125 μ g/mL, 0.0625 μ g/mL, 0.125 μ g/mL, 0.625 μ g/mL and 1.25 μ g/mL; It is 0.00250 μ g/mL that Quality Control concentration of specimens is 0.00250 μ g/mL, 0.00750 μ g/mL, 0.0500 μ g/mL and 1.00 μ g/mL, LLOQ.
High, medium and low and LLQC plasma solutions and urine solution Quality Control sample, after standard methods process, measure wherein left-handed morning nitre azoles and metabolite M1, M2 and M4 concentration, carry out assay method specificity, degree of accuracy and accuracy; Blood plasma and urine specimen ambient temperatare before pretreatment and after pretreatment puts different time ,-40 DEG C of freeze thawing 3 times and-40 DEG C of Stability Determinations placed for a long time, and has investigated the stability of stock solution and blood plasma, the dilution factor stability of urine specimen and blood, urine sample matrix effect.
Method validation result shows: 1. laevo-ornidazole, M1, M2 and M4 are separated well with interior mark (metronidazole) chromatographic peak, mixes peak to base peak all without obviously interference in blank plasma and blank urine solution.2. blank plasma and the matrix effect factor of urine to laevo-ornidazole, M1, M2 and M4 are respectively 96.3 ± 8.9% and 106.1 ± 2.2%, 114.1 ± 2.1% and 98.1 ± 2.0%, 92.7 ± 3.0% and 101.9 ± 3.0%, 98.8 ± 5.2% and 102.1 ± 1.9%.3., in plasma solutions and urine solution, the extraction recovery of laevo-ornidazole, M1, M2 and M4 is respectively 104.5 ± 3.5% and 108.3 ± 8.2%, 97.7 ± 4.4% and 104.7 ± 4.5%, 105.4 ± 3.9% and 112.0 ± 6.9%, 91.3 ± 3.5% and 87.7 ± 5.9%; 4. the in a few days repeatability RSD of laevo-ornidazole blood plasma and urine be respectively≤5.1% and≤10.8%, the response rate is respectively (91.1 ~ 105.1) % and (98.1 ~ 100.9) %; In the daytime measurement result RSD be respectively≤9.3% and≤6.4%, the response rate is respectively (96.2 ~ 101.2) % and (92.8 ~ 105.6) %.The in a few days repeatability RSD of M1 is respectively≤and 8.7% and≤8.2%, the response rate is respectively (95.8 ~ 103.8) % and (96.9 ~ 107.9) %; In the daytime measurement result RSD be respectively≤8.6% and≤7.1%, the response rate is respectively (104.2 ~ 105.7) % and (99.1 ~ 109.2) %.The in a few days repeatability RSD of M2 is respectively≤and 12.2% and≤5.8%, the response rate is respectively (87.8 ~ 96.8) % and (95.1 ~ 102.7) %; In the daytime measurement result RSD be respectively≤9.7% and≤9.4%, the response rate is respectively (91.5 ~ 103.2) % and (95.9 ~ 104.0) %.The in a few days repeatability RSD of M4 is respectively≤and 8.9% and≤8.1%, the response rate is respectively (96.8 ~ 100.6) % and (103.7 ~ 105.9) %; In the daytime measurement result RSD be respectively≤7.2% and≤7.0%, the response rate is respectively (96.5 ~ 103.2) % and (97.9 ~ 105.5) %.5. laevo-ornidazole and metabolite M1, M2, M4 storing solution and interior mark storing solution-40 ± 5 DEG C are placed and are stablized for 5 months.Laevo-ornidazole and metabolite M1, M2, M4 blood plasma and urine solution is high, medium and low and LLOQ concentration Quality Control sample room temperature is placed 24h and stablized, place 48h and stablize after pretreatment, before and after-40 ± 5 DEG C of refrigerator freeze thawing 3 times, concentration are substantially identical; Above-mentioned-40 ± 5 DEG C, blood plasma Quality Control sample is placed to 3 months for a long time and stablizes, and urine specimen-40 ± 5 DEG C is placed to 4 months for a long time and stablizes.6. after laevo-ornidazole plasma sample 10 times dilution, the response rate is 110.5 ± 4.1%, and urine specimen 10 and 100 times of rear response rate of dilution are respectively 103.5 ± 1.8% and 98.2 ± 3.6%; The response rate of M1 plasma sample is 103.7 ± 6.8%, and the response rate of urine specimen is respectively 118.9 ± 5.1% and 101.2 ± 3.2%.The response rate of M2 plasma sample is 104.9 ± 4.1%, and the response rate after urine specimen 10 times dilution is 93.9 ± 3.4%.The response rate of M4 plasma sample is 106.8 ± 1.3%, and the response rate of urine specimen is respectively 111.0 ± 2.1% and 97.6 ± 1.8%.
The mensuration of 5.2 laevo-ornidazole blood, urine sample
Blood, urine sample adopt above-mentioned UPLC-MS/MS to measure the concentration of laevo-ornidazole and metabolite M1, M2 and M4.
5.3 laevo-ornidazoles and metabolite M1, M2 and M4 pharmacokinetics calculate
Laevo-ornidazole and metabolite M1, M2 and M4 blood concentration-time data illustrated with Concentration-time and log concentration-time, comprised and drew individual and meansigma methods blood concentration-time curve.Adopt Phoenix WinNonlin6.0(Pharsight Corp.CA USA) the former medicine of laevo-ornidazole and metabolin M 1 thereof, M2, M4 plasma drug concentration data are done to non-compartment model analysis and tried to achieve pharmacokinetic parameter.Calculate peak concentration (C max), area under the drug-time curve (AUC 0-tand AUC 0-∞), multiterminal eliminate phase half-life (t 1/2), mean residence time (MRT), clearance rate (CL), apparent volume of distribution (V dand V ss), Mean steady state concentration of blood drug (C av), accumulate than the pharmacokinetic parameter such as (AR) and coefficient of variation (DF), calculate the metabolism ratio (MR) of metabolite to characterize the biological conversion ratio of laevo-ornidazole, formula is: MR=AUC simultaneously 0-∞, metabolite/ AUC 0-∞, former medicine× 100%.
In addition, compartment model analysis is done to the plasma drug concentration data of the former medicine of laevo-ornidazole, judge the dynamic characteristic of this medicine in subject.List is first fitted together to as compartment model average data, and the model structure of testing comprises a chamber instillation model and two chamber instillation models.Investigate different weight modes to the impact of fitting result, comprise 1,1/C and 1/C 2.By compartment model structure and the weight mode of the selected the bests such as fitting result chart, weighted residual value (Re) and red pond information criterion (ARC), batch processing mode is then adopted to calculate individual pharmacokinetic parameters.
Laevo-ornidazole and metabolite M1, M2, M4 urine drug level-time data, to accumulate urine discharge rate-time mapping, calculate the excretion situation of the urine sample mesarcs medicine of each time period, calculate UA by the accumulation urinary volume after administration between 0 to 72h 0-72h, and urine medicine accumulation discharge rate (X u), Rate maxget the maximum of urine medicine rate of discharge of each time period, renal clearance (CL r) according to Xu 0-twith AUC 0-tratio obtain.
6. date processing and statistical analysis
The date processing of 6.1 pharmacokinetic parameters and statistical analysis
The former medicine of laevo-ornidazole and metabolin M 1, M2, M4 blood drug level, urine drug level and output and discharge rate all make descriptive statistical analysis, comprise mean, standard deviation, median, maximum, minima.Descriptive statistical analysis is made, the former medicine PK parameter that compartment model method only calculates to the PK parameter of the former medicine adopting non-compartment model method to calculate and metabolite, also makes descriptive statistical analysis.
The difference of pharmacokinetic parameters between the health volunteer adopting independent samples t-test to compare 500mg and 750mg dosage group, pharmacokinetic parameters comprises the non-Atrium parameter of the non-Atrium parameter of former medicine and compartment model parameter and metabolin M 1, M2, M4, check successively the concentration of blood plasma fractions and urinary drug excretion part or parameter, P<0.05 represents that difference has remarkable statistical significance.
6.2 demographic data and baseline characteristic
Two groups of Subject Demographics learn being described property of data statistical analysis, the mean of two groups of quantitative datas, standard deviation, median, maximum, minima, compare between group and adopt t inspection, qualitative data and ranked data list frequency (constituent ratio), percentage ratio, compare qualitative data between group and adopt Fisher ' s precise probabilistic method, ranked data Wilcoxon rank test.
6.3 safety evaluatio
Vital sign: calculate vital sign blood pressure, heart rate, breathing, the mean of body temperature, standard deviation, median, maximum, minima before and after two groups of administrations, situation of change, uses paired t-test with comparing in the group of time point each after administration before administration.According to the comparing of normal reference value, list the change of vital sign index before and after two groups of administrations, and list administration and retrodeviate from inventory normal range.
Physical examination: the abnormal conditions listing physique Index for examination before and after two groups of administrations, and list abnormal case inventory.
Lab testing: calculate laboratory checking index routine blood test, the mean of blood biochemistry, standard deviation, median, maximum, minima before and after two groups of administrations, situation of change, compares employing paired t-test with in the group of time point each after administration before administration.According to the comparing of normal reference value, list the change of laboratory checking index routine blood test, routine urinalysis, blood biochemistry before and after two groups of administrations, and list administration and retrodeviate from inventory normal range.
12-lead electrocardiogram checks: list the abnormal conditions that before and after two groups of administrations, 12 lead electrocardiogram check, and list abnormal case inventory.
Adverse events: calculate two groups of adverse events and adverse reaction rate, wherein untoward reaction be defined as and close with drugs and be " certainly about, probably about, may be about " adverse events.
All testing of hypothesis adopt two-sided test (two-side test).Get α=0.05.P≤0.05 thinks that difference has statistical significance.The credibility of all credibility intervals all gets 95%.
7. result of study
7.1 experimenters enter group situation
500mg and 750mg group is totally 24 routine subject enrollments, and except there being 1 routine experimenter to exit except research in 750mg group, all the other experimenters all complete research.
7.2 experimenter's physical data
500mg group and 750mg group are 6 male 6 female, and except in 750mg group, 2 routine experimenters are that except other nationalitys, all the other are Han nationality, the equal no difference of science of statistics of basic condition such as the age between two groups, height, body weight, Body Mass Index and sex.
The comparison of table 3.500mg and 750mg group experimenter physical data
Note: Mean ± SD(mean ± standard deviation), Min is minima, and Max is maximum.
Vital sign inspection before 12 routine health volunteer's screenings and administration, physical examination and 12 lead electrocardiogram inspections and lab testing are all normal or abnormal without clinical meaning.
7.3 mean blood plasma concentration and statistic analysis result
After 500mg and 750mg group experimenter single intravenous instillation L-ornidazole sodium chloride injection, the mean blood plasma concentration result of the former medicine of laevo-ornidazole and metabolite M1, M2, M4 is respectively in table 4 and table 5, and the mean blood plasma concentration after more divided doses on the 8th ~ 11st the results are shown in Table 6, table 7 and table 8.
The C of the former medicine of laevo-ornidazole, metabolite M1 and M4 after the administration of 500mg group single dose 25hbe respectively 2.52 ± 0.673 μ g/mL, 0.0823 ± 0.0342 μ g/mL and 0.0931 ± 0.0834 μ g/mL, the C of the former medicine of laevo-ornidazole, metabolite M1 and M4 after the administration of 750mg group single dose 25.5hbe respectively 3.62 ± 0.781 μ g/mL, 0.0929 ± 0.0373 μ g/mL and 0.125 ± 0.021 μ g/mL; The concentration of metabolite M2 is all lower than detectability.The C of the former medicine of laevo-ornidazole, metabolite M1, M2 and M4 after 500mg group more divided doses 25hbe respectively 5.24 ± 1.81 μ g/mL, 0.218 ± 0.119 μ g/mL, 0.0247 ± 0.0044 μ g/mL and 0.208 ± 0.050 μ g/mL, the C of the former medicine of laevo-ornidazole, metabolite M1, M2 and M4 after the administration of 750mg group single dose 25.5hbe respectively 5.68 ± 1.10 μ g/mL, 0.171 ± 0.086 μ g/mL, 0.0209 ± 0.0012 μ g/mL and 0.214 ± 0.041 μ g/mL.
The 8th, 9,10 of the former medicine of 750mg group laevo-ornidazole, metabolite M1 and M4 and the Grain volume of 11 days are starkly lower than 500mg group.
7.4 mean urinary concentrations and urine discharge rate
After 500mg group and 750mg group experimenter's single dose and more divided doses intravenous drip L-ornidazole sodium chloride injection on the 11st, the former medicine of laevo-ornidazole and metabolin M 1, M2, M4 mean urinary concentration of each time period, urinary volume and urine discharge rate are respectively in table 9 and table 10.
After the administration of 500mg dosage group single dose, in 0-24h urine, the average accumulated discharge rate of the former medicine of laevo-ornidazole is 7.62 ± 1.92% of dosage, and the more divided doses average accumulated of the 11st day urine discharge rate is 19.7 ± 4.6%; The segmentation urine discharge rate of single dose and multi-agent all reaches the highest in the 0-4h time period, and the urinary volume of the former medicine of this time period laevo-ornidazole is respectively 12.3mg/L and 40.6mg/L.After single dose and more divided doses in 0-24h urine the average accumulated urine discharge rate of M1 be respectively 0.70% and the average accumulated urine discharge rate of 2.81%, M2 be respectively 0.12% and the average accumulated urine discharge rate of 0.36%, M4 be respectively 1.72% and 5.17%.
After the administration of 750mg dosage group single dose, in 0-24h urine, the average accumulated discharge rate of laevo-ornidazole is 7.54 ± 3.08% of dosage, and the average accumulated urine discharge rate of multi-agent is 14.3 ± 20.4%; The segmentation urine discharge rate of single dose and multi-agent all reaches the highest in the 0-4h time period, and the urinary volume of the former medicine of this time period laevo-ornidazole is respectively 19.2mg/L and 51.3mg/L.The excretion rate of laevo-ornidazole metabolite is all lower compared with former medicine, after single dose and more divided doses, in 0-24h urine, the average accumulated urine discharge rate of M1 is respectively 0.72% and 2.22%, M2 average accumulated urine discharge rate be respectively 0.08% and 0.15%, M4 average accumulated urine discharge rate be respectively 1.32% and 3.49%.
7.5 blood drug level parameter and statistic analysis result
7.5.1 non-compartment model method
The former medicine of laevo-ornidazole and metabolin M 1 after 500mg and 750mg group experimenter's single dose and multi-agent intravenous drip L-ornidazole sodium chloride injection, M2, M4 calculate mean serum pharmacokinetic parameter (PK) in table 11, table 12 with non-compartment model method.
After single intravenous instillation laevo-ornidazole, the average C of the former medicine of 500mg dosage group laevo-ornidazole maxand AUC 0 ?∞be respectively 12.5 ± 3.4 μ g/mL and 176 ± 41 μ gh/mL, t 1/2be the C of 11.6 ± 0.8h, metabolin M 1 maxand t 1/2be respectively 0.118 ± 0.043 μ g/mL and 11.8 ± 1.5h, metabolism ratio MR is 2.06 ± 0.55%; The C of metabolite M4 maxand t 1/2be respectively 0.131 ± 0.027 μ g/mL and 12.1 ± 1.2h, metabolism ratio MR is 2.58 ± 0.13%.The average C of the former medicine of 750mg dosage group laevo-ornidazole maxand AUC 0 ?∞be respectively 17.3 ± 2.2 μ g/mL and 265 ± 42 μ gh/mL, t 1/2be 11.9 ± 1.3h; The C of metabolin M 1 maxand t 1/2be respectively 0.150 ± 0.060 μ g/mL and 12.5 ± 2.4h, metabolism ratio MR is 1.63 ± 0.45%; The C of metabolite M4 maxand t 1/2be respectively 0.184 ± 0.030 μ g/mL and 14.2 ± 3.1h, metabolism ratio MR is 2.47 ± 0.39%.
Result shows, the C of the former medicine of 750mg group laevo-ornidazole after single intravenous instillation laevo-ornidazole maxand AUC 0 ?∞all higher than 500mg group (P<0.05); t 1/2, MRT, CL tand V dat the equal not statistically significant of two group differences.The pharmacokinetic parameters of 750mg group metabolite M1 and 500mg group no significant difference, the C of M4 maxand AUC 0 ?∞all be greater than 500mg group (P<0.05), t 1/2extend, and MR and 500mg group quite.
After 500mg group multi-agent intravenous drip laevo-ornidazole, (the 6th administration is tested the 6th) laevo-ornidazole concentration in vivo on the 3rd reaches stable state, the C of the former medicine of multi-agent laevo-ornidazole max_ss, C min_ss, AUC 0 ?∞and t 1/2being respectively 22.2 ± 5.3 μ g/mL, 10.2 ± 3.1 μ g/mL, 384 ± 121 μ gh/mL and 12.2 ± 1.0h, CLss is 2.70 ± 0.63L/h, and accumulating than AR is 2.19 ± 0.30%.The average C of metabolin M 1 max_ss, C min_ssand AUC 0 ?∞be respectively 0.477 ± 0.255 μ g/mL, 0.359 ± 0.201 μ g/mL and 12.6 ± 6.9 μ gh/mL, MR are 3.15 ± 1.09%; The average C of metabolite M4 max_ss, C min_ssand AUC 0 ?∞be respectively 0.432 ± 0.099 μ g/mL, 0.313 ± 0.074 μ g/mL and 12.0 ± 3.0 μ gh/mL, MR are 3.18 ± 0.34%.
After 750mg group multi-agent intravenous drip laevo-ornidazole, (the 3rd administration is tested the 6th) laevo-ornidazole concentration in vivo on the 3rd reaches stable state, the C of the former medicine of multi-agent laevo-ornidazole max_ss, C min_ss, AUC 0 ?∞and t 1/2being respectively 22.1 ± 3.2 μ g/mL, 5.66 ± 1.11 μ g/mL, 395 ± 69 μ gh/mL and 12.4 ± 1.2h, CLss is 2.60 ± 0.43L/h, and accumulating than AR is 1.45 ± 0.16%.The average C of metabolin M 1 max_ss, C min_ssand AUC 0 ?∞be respectively 0.296 ± 0.140 μ g/mL, 0.170 ± 0.087 μ g/mL and 8.95 ± 4.37 μ gh/mL, MR are 2.18 ± 0.77%; The average C of metabolite M4 max_ss, C min_ssand AUC 0 ?∞be respectively 0.348 ± 0.055 μ g/mL, 0.212 ± 0.041 μ g/mL and 11.6 ± 2.2 μ gh/mL, MR are 2.94 ± 0.37%.
The C of the former medicine of 750mg group multi-agent laevo-ornidazole max_ssand AUC 0 ?∞with the no significant difference (C of 500mg group max_ss: 22.1 ± 3.2 μ g/mL vs22.2 ± 5.3 μ g/mL, P=0.936; AUC 0 ?∞: 395 ± 69 μ gh/mL vs384 ± 121 μ gh/mL, P=0.790), C min_ss44.5% is reduced than 500mg group, and V ssadd 45.0% than 500mg group, accumulating than AR is 66.2% of 500mg group, and difference all has statistical significance (P<0.05).Result display and 500mg, q12h dosage regimen are compared, and 750mg, qd administration can reduce laevo-ornidazole accumulation in vivo.The average C of 750mg group metabolin M 1 and M4 max_ss, C min_ssall be less than 500mg group with MR, its difference has statistical significance (P<0.05).
After laevo-ornidazole 750mg and the administration of 500mg single dose, the concentration of metabolite M2 is all lower than detectability.After more divided doses, the blood drug level interindividual variation of the M2 detected is comparatively large, and some experimenter fails corresponding concentration to be detected, the C of 750mg and 500mg dosage group max_ssand AUC 0 ?∞be respectively 0.0257 ± 0.0043 μ g/mL (n=6) and 3.44 ± 0.07 μ gh/mL (n=2), 0.0419 ± 0.0177 μ g/mL (n=8) and 2.11 ± 0.70 μ gh/mL; Metabolism ratio MR is respectively 0.0632 ± 0.0621% (n=8) and 0.104 ± 0.078% (n=4).
7.5.2 compartment model method
After 500mg and 750mg group experimenter's single dose and multi-agent intravenous drip L-ornidazole sodium chloride injection, the former medicine of laevo-ornidazole calculates mean serum pharmacokinetic parameter (PK) respectively in table 13 and table 14 with compartment model method.
After the administration of laevo-ornidazole single dose, the distribution rate constant α in 500mg group health volunteer body and elimination rate constant β is respectively 6.06 ± 5.45h -1with 0.0571 ± 0.0051h -1, k 10, k 12and k 21be respectively 0.0853 ± 0.0266h -1, 1.61 ± 2.54h -1with 4.42 ± 4.07h -1, V 137.7 ± 9.6L and 3.04 ± 0.59L/h is respectively with CL; Distribution rate constant α in 750mg group health volunteer body and elimination rate constant β is respectively 11.1 ± 1.32h -1with 0.0595 ± 0.00825h -1, k 10, k 12and k 21be respectively 0.114 ± 0.069h -1, 3.76 ± 3.37h -1with 7.29 ± 2.88h -1, V 132.4 ± 12.6L and 2.97 ± 0.54L/h is respectively with CL.Result shows, and the distribution rate constant α of laevo-ornidazole in 750mg dosage group health volunteer body is apparently higher than 500mg group (P<0.05), and other pharmacokinetic parameters and 500mg group no difference of science of statistics.
After laevo-ornidazole more divided doses, the distribution rate constant α in 500mg group health volunteer body and elimination rate constant β is respectively 11.4 ± 3.36h -1with 0.0575 ± 0.0054h -1, k 10, k 12and k 21be respectively 0.137 ± 0.057h -1, 5.70 ± 3.18h -1with 5.63 ± 2.82h -1, V 125.1 ± 11.5L and 2.92 ± 0.65L/h is respectively with CL; Distribution rate constant α in 750mg group health volunteer body and elimination rate constant β is respectively 11.5 ± 3.2h -1with 0.0549 ± 0.0052h -1, k 10, k 12and k 21be respectively 0.166 ± 0.052h -1, 7.23 ± 1.92h -1with 4.13 ± 1.84h -1, V 117.3 ± 4.1L and 2.73 ± 0.46L/h is respectively with CL.Result shows, the central compartment distribution volume V of laevo-ornidazole in 750mg dosage group health volunteer body 1be starkly lower than 500mg group (P<0.05), and other pharmacokinetic parameters and 500mg group no difference of science of statistics.
7.6 urine discharge parameter and statistic analysis result
After 500mg and 750mg group experimenter intravenous drip L-ornidazole sodium chloride injection, the mean urinary of the former medicine of laevo-ornidazole and metabolite M1, M2 and M4 discharges parameter in table 15.
After the administration of laevo-ornidazole single dose, the urine accumulation output (U of the former medicine of 500mg group laevo-ornidazole a, 0-24h) and urine medicine discharge flank speed (Rate max) be respectively 38.1 ± 9.5mg and 3.29 ± 1.40mg/h, Ae 0-24hand CL rbe respectively 7.62 ± 1.91% and 0.283 ± 0.075L/h, the Ae of metabolin M 1, M2, M4 0-72hand Rate maxbe respectively 1.05 ± 0.28% and 0.213 ± 0.059mg/h, 0.421 ± 0.863% and 0.124 ± 0.036mg/h, 2.62 ± 0.27% and 0.471 ± 0.027mg/h; The U of the former medicine of 750mg group laevo-ornidazole a, 0-24hand Rate maxbe respectively 56.5 ± 23.1mg and 5.11 ± 2.31mg/h, Ae 0-24hand CL rbe respectively 7.54 ± 3.08% and 0.269 ± 0.097L/h, the Ae of metabolin M 1, M2, M4 0-72hand Rate maxbe respectively 1.03 ± 0.50% and 0.342 ± 0.148mg/h, 0.124 ± 0.036% and 0.0387 ± 0.0098mg/h, 1.97 ± 0.99% and 0.571 ± 0.305mg/h.The Rate of the former medicine of 750mg dosage group laevo-ornidazole and M1 maxhigher than 500mg group (P=0.014), and the Ae of M4 0-72hbe less than 500mg group, all parameters of M2 all do not have significant difference.
After laevo-ornidazole more divided doses, the Ae of the former medicine of 500mg group laevo-ornidazole 0-24h, Rate maxand CL rbe respectively 19.7 ± 4.6mg, 10.5 ± 3.0mg/h and 0.335 ± 0.083L/h, the Ae of metabolin M 1, M2 and M4 0-24hbe respectively 2.81 ± 1.08%, 0.357 ± 0.190% and 5.17 ± 0.57%; The Ae of the former medicine of 750mg group laevo-ornidazole 0-24h, Rate maxand CL rbe respectively 14.3 ± 20.4mg, 13.3 ± 23.3mg/h and 0.306 ± 0.313L/h, the Ae of metabolin M 1, M2 and M4 0-24hbe respectively 2.22 ± 3.76%, 0.152 ± 0.045% and 3.49 ± 5.28%.In two dosage groups, the urine of the former medicine of laevo-ornidazole, M1 and M4 discharges parameter does not all have significant difference, and the Ae of M2 in 750mg dosage group 0-24h, Rate maxand Ae 0-72hall be less than 500mg group (P<0.05).
The mean urinary discharge parameter of the former medicine of laevo-ornidazole and metabolin M 1, M2, M4 and statistic analysis result (n=12) after table 15.500mg and 750mg group experimenter's single dose and multi-agent intravenous drip L-ornidazole sodium chloride injection
Note: CL rrenal clearance, A e0 ?24h(%) 0 ?the 24h time period urinate medicine cumulative excretion percentage rate, A e0 ?72h(%) 0 ?the 72h time period urinate medicine cumulative excretion percentage rate, Rate maxthe maximum discharge rate of urine medicine.
8. safety evaluatio
In 500mg and 750mg2 dosage group there are 9 example 13 example time adverse events in 24 routine experimenters altogether, and adverse events gathers in table 16, and the AE relevant to medicine the results are shown in Table 17.Occur because AE causes testing termination person 1 example in advance, in 750mg group there is gingiva periapical abscess in the 2nd day after intravenous drip in No. 10 experimenters, and blood routine examination neutrophilic granulocyte raises, and takes Drug therapy, this experimenter's termination test, judges may have nothing to do with trial drug.All there is not serious adverse events.
There is AE example 5 example 7 example time in 500mg group, wherein relevant to drugs adverse events is 2 example 3 examples time, is the laboratory abnormalities relevant to drugs altogether.There is AE example 4 example 6 example time in 750mg group, wherein relevant to drugs adverse events is 3 example 5 examples time, is the laboratory abnormalities relevant to drugs altogether.There is AE and ADR incidence rate two group difference not statistically significant (P>0.05) in 500mg group and 750mg group experimenter, the results are shown in Table 18.
After table 16.500mg and 750mg group experimenter intravenous drip L-ornidazole sodium chloride injection, adverse events gathers
Note: " trial drug is relevant " refers to certainly relevant, probably relevant, possible about maybe evaluating with trial drug.
The AE that table 17. is relevant to medicine analyzes
The comparison of table 18. liang group adverse events and adverse reaction rate
9. pharmacokinetics/pharmacodynamic study
Owing to there is no the report that laevo-ornidazole PK/PD studies at present both at home and abroad, the PK/PD result of this research reference similar drugs metronidazole, for bacteroides fragilis, as the AUC of metronidazole 24hgood clinical and microbiology curative effect can be obtained during/MIC>=70.Therefore, AUC is chosen in this research 24h/ MIC>=70 are as the PK/PD target value of laevo-ornidazole to bacteroides fragilis.
This part research is by the pharmacokinetic studies result of more divided doses in laevo-ornidazole health volunteer body, the outer pharmacodynamic information of coalition, application Risk software (5.7 editions, Palisade Decision Tools, U.S. Palisade) carry out Monte Carlo simulation, laevo-ornidazole 2 dosage regimen (500mg are calculated according to PK/PD principle, q12h and 750mg, q24h) under steady plasma-drug concentration to the pharmacodynamics probability up to standard (PTA) under the accumulation percent reaction (CFR) of anaerobe the main pathogenic fungi and different MIC level, thus dosage regimen is evaluated, for in IV clinical trial phase scheme about the formulation of indication and dosage regimen provides reference.
9.1 materials and methods
9.1.1 pharmacokinetic parameters
The PK data of laevo-ornidazole 500mg and 750mg dosage regimen from the clinical pharmacokinetic study portion of this research, AUC 0-24hbe respectively 391.6 ± 103.8 and 294.9 ± 45.3hmg/L, be more divided doses and reach steady-state value, wherein 500mg group is according to 2 × AUC 0-12hobtain.In Risk, apply Latin Hypercube Sampling technology produce AUC 0-24lognormal probability distribution.
9.1.2 drug sensitive test data
Adopt API20A Identification of Anaerobic Bacteria lath (Ref.20300, Biomerieux SA) to carry out the qualification of anaerobe, 365 strain anaerobe all come from the antibacterial storehouse of this institute.Drug sensitive test adopts agar dilution, and antimicrobial drug is metronidazole, ornidazole, laevo-ornidazole and right ornidazole, with reference to 2012 American National Clinical Laboratory Standard committee standard (CLSI) calculate the bacteriostasis rate of medicine.According to MIC distribution frequency, adopt Risk software to set up the discrete type MIC distributed model of often kind of pathogen, wherein shared by the horizontal pathogen of MIC at different levels, percentage rate is considered as frequency.
9.1.3 pharmacodynamics model
With the PK parameter AUC of health volunteer 0-24hpharmacodynamics model is set up: AUC with each pathogenic bacterium PD data (i.e. MIC result) 0-24h/ MIC value.
9.1.4Monte Carlo simulation
This research adopts Risk software to carry out 10000 person-times of Monte Carlo and simulates, and calculates the AUC that laevo-ornidazole 2 kinds of dosage regimens (500mg, q12h and 750mg, q24h) treat the antibacterial scheme-pathogen combination of anaerobic infection 0-24h/ MIC value estimated value.Repeat each time all according to respective probability distribution with different AUC 0-24h/ MIC value calculates, and calculates the different AUC of generation 5000 for often kind of dosage regimen-pathogen combination respectively 0-24h/ MIC value estimated value, AUC 0-24h/ MIC value estimated value is depicted as frequency curve to analyze further.With AUC 0-24h/ MIC value>=70, the target value being satisfied with clinical efficacy can be obtained as expection, calculating 2 kinds of dosage regimen-pathogen is combined in the pharmacodynamics probability up to standard under the accumulation percent reaction of bacteroides fragilis and different MIC level under steady plasma-drug concentration, and formulating for IV clinical trial phase dosage regimen provides pharmacodynamics foundation.
9.2 result
9.2.1 the external susceptibility of laevo-ornidazole
365 strain anaerobe classification results are anaerobism negative bacillus 180 strain (comprise bacteroides fragilis 45 strain, bacteroides thetaiotaomicron 28 strain, bacteroides ovatus 27 strain, other bacteroid 57 strains and Prey and irrigate Pseudomonas 22 strain), anaerobism positive bacillus 131 strain (comprising clostridium difficile 71 strain, bacillus perfringens 45 strain, other clostruidium 7 strains and non-clostruidium 8 strain), anaerobic cocci 54 strain (comprising peptostreptococcus magnus 36 strain, other peptostreptococcus 8 strains and Veillonella 10 strain).
The MIC of laevo-ornidazole to 365 strain anaerobe the results are shown in Table 19, MIC distribution frequency in table 20.The MIC scope of laevo-ornidazole to bacteroides fragilis, other bacteroids, clostridium difficile, bacillus perfringens, peptostreptococcus magnus is respectively 0.25-2mg/L, 0.125-2mg/L, 0.06-1mg/L, 0.5-2mg/L and 0.125-2mg/L, MIC 90be respectively 1mg/L, 2mg/L, 0.25mg/L, 2mg/L and 2mg/L.
Table 19. laevo-ornidazole is to the external susceptibility (unit: mg/L) of all kinds of anaerobe
Table 20. laevo-ornidazole is to the MIC distribution frequency table (%) of each anaerobe
9.2.2 the PK/PD of laevo-ornidazole analyzes
The mean P K/PD parameter of healthy Chinese subjects multi-agent intravenous drip L-ornidazole sodium chloride injection 2 dosage regimens is in table 21.Laevo-ornidazole two kinds of dosage regimens are to the AUC of bacteroides fragilis 0 ?24h/ MIC 50and AUC 0 ?24h/ MIC 90all exceed its pharmacodynamics target value (AUC 0 ?24h/ MIC=70).
750mg, q24h administration and 500mg, q12h two kinds of dosage regimens reach AUC to bacteroides fragilis 0 ?24hthe CFR of/MIC=70 target value all>=99.9%.In addition, to PTA result of calculation display under different MIC level, as the MIC≤2 μ g/mL of pathogen, the probability that 2 kinds of dosage regimens reach pharmacodynamics target value all can reach 100%, can obtain good clinical and microbiology curative effect (table 22).
Table 21. laevo-ornidazole is to the PK/PD parameter (Single-point Calculating Method) of bacteroides fragilis
Note: AUC 0 ?24take from multi-agent steady result, wherein 500mg group AUC 0 ?24according to 2 × AUC 0 ?12obtain.
Table 22. laevo-ornidazole AUC 0 ?24the up to standard probability (PTA) of/MIC under different MIC level
Note: the AUC of 500mg group 0 ?24according to 2 × AUC 0 ?12calculate.
In sum, laevo-ornidazole 750mg, q24h administration and 500mg, q12h two kinds of dosage regimens reach AUC to bacteroides fragilis 0-24hthe CFR of/MIC=70 target value all>=99.9%; As the MIC≤2 μ g/mL of pathogen, the probability that 2 kinds of dosage regimens reach pharmacodynamics target value all can reach 100%, all can obtain good clinical and microbiology curative effect.Therefore, two kinds of dosage regimens all can obtain good microbiology curative effect to anaerobe encountered pathogenic bacteria.
10. Analysis and evaluation
The foundation of 10.1LC/MS/MS detection method
Although the LC-MS/MS method that this research is set up is only for the concentration of laevo-ornidazole in Simultaneously test blood plasma and urine and metabolin M 1 thereof, M2 and M4, undesirable to the Detection results of metabolite M3, but find in testing process that the concentration of M3 in blood plasma and urine is all very low, the testing result of M3 is only for referencial use.
The evaluation of 10.2 laevo-ornidazoles, two kinds of dosage regimens
Pharmacokinetic parameters result shows: the C of 750mg group max_ssand AUC 0-∞with the no significant difference of 500mg group, C min_ss44.5% is reduced than 500mg group, and V ssadd 45.0% than 500mg group, accumulating than AR is 66.2% of 500mg group, and difference all has statistical significance (P<0.05).Result display and 500mg, q12h dosage regimen are compared, and 750mg, qd administration can reduce laevo-ornidazole accumulation in vivo.
Two kinds of dosage regimen expections all can reach microbiology curative effect, and discovery is compared in its safety, and the exception that liver function occurs 750mg group is less than 500mg group.
11. brief summaries and conclusion
The pharmacokinetics of the former medicine of 11.1 laevo-ornidazole and metabolite
The pharmacokinetic trial of single-dose: experimenter's single dose intravenous instillation 500mg laevo-ornidazole, the C of laevo-ornidazole maxbe 12.5 ± 3.4 μ g/mL, AUC 0-∞be 176 ± 41 μ gh/mL, t 1/2be the C of 11.6 ± 0.8h, metabolin M 1 and M4 maxbe respectively 0.118 ± 0.043 μ g/mL and 0.131 ± 0.027 μ g/mL, metabolism ratio MR is 2.06 ± 0.55% and 2.58 ± 0.13%; The accumulative urine discharge rate Ae of laevo-ornidazole, M1, M2 and M4 0-24hbe respectively 7.62 ± 1.91%, 0.702 ± 0.172%, 0.117 ± 0.072% and 1.72 ± 0.18%.Experimenter's single dose intravenous instillation 750mg L-ornidazole sodium chloride injection, the C of laevo-ornidazole maxand AUC 0-∞be respectively 17.3 ± 2.2 μ g/mL and 265 ± 42 μ gh/mL, t 1/2be 11.9 ± 1.3h; The C of metabolin M 1 and M4 maxbe respectively 0.150 ± 0.060 μ g/mL and 0.184 ± 0.030 μ g/mL, metabolism ratio MR is 1.63 ± 0.45% and 2.47 ± 0.39%; The accumulative urine discharge rate Ae of laevo-ornidazole, M1, M2 and M4 0-24hbe respectively 7.54 ± 3.08%, 0.717 ± 0.352%, 0.080 ± 0.030% and 1.32 ± 0.75%.The concentration of two dosage group metabolite M2 in blood plasma is all lower than detectability (0.020 μ g/mL).
The pharmacokinetic trial of multiple dosing: each 500mg, after twice continuous several times intravenous drip administration every day, the blood drug level of (the 6th administration is tested the 6th) laevo-ornidazole on the 3rd reaches stable state, the C of multi-agent laevo-ornidazole max_ss, C min_ss, AUC 0-∞and t 1/2be respectively 22.2 ± 5.3 μ g/mL, 10.2 ± 3.1 μ g/mL, 384 ± 121 μ gh/mL and 12.2 ± 1.0h; The urine accumulation discharge rate Ae of laevo-ornidazole, M1, M2 and M4 0-24hbe respectively 19.7 ± 4.6%, 2.81 ± 1.08%, 0.357 ± 0.190% and 5.17 ± 0.57%.Each 750mg, after the laevo-ornidazole of continuous several times intravenous drip once a day, the blood drug level of (the 3rd administration is tested the 6th) laevo-ornidazole on the 3rd reaches stable state, the C of multi-agent laevo-ornidazole max_ss, C min_ss, AUC 0-∞and t 1/2be respectively 22.1 ± 3.2 μ g/mL, 5.66 ± 1.11 μ g/mL, 395 ± 69 μ gh/mL and 12.4 ± 1.2h; The Ae of laevo-ornidazole, M1, M2 and M4 0-24hbe respectively 14.3 ± 20.4%, 2.22 ± 3.76%, 0.152 ± 0.045% and 3.49 ± 5.28%.The C of 750mg group max_ssand AUC 0-∞with the no significant difference of 500mg group, C min_ss44.5% is reduced than 500mg group, and V ssadd 45.0% than 500mg group, accumulating than AR is 66.2% of 500mg group, and difference all has statistical significance (P<0.05).Result display and 500mg, q12h dosage regimen are compared, and 750mg, qd administration can reduce laevo-ornidazole accumulation in vivo.
The safety of 11.2 two kinds of dosage regimens
Serious adverse events is all there is not after two groups of experimenters give laevo-ornidazole.There is AE4 example 6 example time in 500mg group, wherein stomach discomfort 1 example 1 example time altogether, AE totally 3 example 5 examples time of lab testing exception.This group is without clinical ADR, laboratory abnormalities ADR3 example 5 example time.There is AE5 example 7 example time in 750mg group, clinical AE is AE3 example 4 example time of 3 example 4 examples time, lab testing exception, and wherein 1 example accompanies clinical and lab A E simultaneously altogether.There is gingiva periapical abscess in the 2nd day after intravenous drip in these No. 10 experimenters, blood routine examination neutrophilic granulocyte raises, and takes Drug therapy, and this experimenter stops, and judges may have nothing to do with trial drug.This group is without clinical ADR, lab A DR totally 2 example 3 times.Before and after two groups of snibject, the vital sign such as blood pressure and heart rate, the inspection of 12-lead electrocardiogram are all without significant difference.
The PK/PD research of 11.3 laevo-ornidazoles
Laevo-ornidazole 750mg, q24h administration and 500mg, q12h two kinds of dosage regimens reach AUC to bacteroides fragilis 0-24hthe CFR of/MIC=70 target value all>=99.9%; As the MIC≤2 μ g/mL of pathogen, the probability that 2 kinds of dosage regimens reach pharmacodynamics target value all can reach 100%, all can obtain good clinical and microbiology curative effect.Therefore, two kinds of dosage regimens all can obtain good microbiology curative effect to anaerobe encountered pathogenic bacteria.
In sum, laevo-ornidazole 500mg is similar with characteristics of pharmacokinetics after the administration of 750mg single dose; More divided doses display and 500mg, q12h compare, and 750mg, qd obviously can reduce laevo-ornidazole accumulation in vivo; 500mg, q12h and 750mg, the safety of qd dosage regimen is good, and expection all can obtain good microbiology curative effect.
From above experimental result, can find out, laevo-ornidazole of the present invention once a day form of administration and daily dose is that its control formulation of 4/3rds times is suitable according to the therapeutic effect of every twice-daily administration, and daily dose obviously reduces, and side effect reduces.
Although be below described in detail the present invention, it will be appreciated by those skilled in the art that and can carry out various amendment and change to the present invention under prerequisite without departing from the spirit and scope of the present invention.Interest field of the present invention is not limited to done detailed description above, and should belong to claims.

Claims (12)

1. a pharmaceutical composition, it comprises laevo-ornidazole or its officinal salt for the treatment of effective dose, carrier pharmaceutically acceptable with at least one, in wherein said compositions the amount of laevo-ornidazole be when by described compositions daily one time time the bioavailability that demonstrates and/or drug effect and daily dose be its laevo-ornidazole control formulation of 4/3rds times according to the bioavailability of daily secondary and/or drug effect suitable.
2. pharmaceutical composition according to claim 1, wherein said bioavailability quite refers to compared with the bioavailability that the bioavailability of described pharmaceutical composition thing administration once a day and daily dose are the every twice-daily administration of its control formulation of 4/3rds times, P value >0.05, described drug effect quite refers to and reaches AUC according to daily secondary to bacteroides fragilis when be once daily its laevo-ornidazole control formulation of 4/3rds times with daily dose by described pharmaceutical composition 0-24hthe CFR of/MIC=70 target value all>=99.9%.
3., according to the pharmaceutical composition of claim 1 or 2, wherein said compositions is included in the whole daily doses in single dosage unit.
4., according to the pharmaceutical composition of claim 1 or 2, the form of wherein said compositions is discrete dosage unit.
5. pharmaceutical composition according to claim 4, wherein in each dosage unit, the amount of laevo-ornidazole is enough to provide daily dose according to the mode of administration once a day to several dosage unit.
6. according to the pharmaceutical composition of any one of claim 1-5, with the gauge of laevo-ornidazole, it comprises and is greater than 0.5g to the laevo-ornidazole or its officinal salt that are less than 2.0g, be preferably greater than 0.6g to the laevo-ornidazole or its officinal salt that are less than 1.5g, more preferably the laevo-ornidazole of 0.75g to 1.0g or its officinal salt.
7., according to the pharmaceutical composition of any one of claim 1-6, wherein said compositions is formulated as oral formulations or parenteral formulations.
8. pharmaceutical composition according to claim 7, wherein said oral formulations is tablet, lozenge, capsule, granule, drop pill, Emulsion.
9. pharmaceutical composition according to claim 7, wherein said parenteral formulations is injection, injectable powder, external-use gel, vaginal effervescent tablet, vaginal suppository or vagina gel.
10. pharmaceutical composition according to claim 9, wherein said injection is sodium chloride injection, glucose injection, sodium chloride-glucose injection, propylene glycol injection or formula mannitol injection liquid.
11. according to the pharmaceutical composition of any one of claim 1-10 for the preparation of the application prevented and/or treated in the medicine of antibacterial, parasite, fungal infection.
12. 1 kinds of kit product, it comprises medicine containing laevo-ornidazole or its officinal salt and administration description, wherein with the gauge of laevo-ornidazole, the dosage of described medicine is for being greater than 0.6g to being less than 2.0g, be preferably greater than 0.6g to being less than 1.5g, more preferably 0.75g to 1.0g, described administration description indicates described medicine to be greater than 0.6g to being less than 2.0g with daily dose, be preferably greater than 0.6g to being less than 1.5g, more preferably the amount of 0.75g to 1.0g, once a day, successive administration 1-10 time, the administration 1-5 cycle.
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Citations (3)

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CN1686117A (en) * 2005-04-28 2005-10-26 南京圣和药业有限公司 Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine
CN1923196A (en) * 2005-11-28 2007-03-07 长沙市华美医药研究所 Medicinal composition containing l-ornidazole and its application
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CN1686117A (en) * 2005-04-28 2005-10-26 南京圣和药业有限公司 Application of levoornidazole in preparation of anti anaerobic bacteria infection medicine
CN1923196A (en) * 2005-11-28 2007-03-07 长沙市华美医药研究所 Medicinal composition containing l-ornidazole and its application
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