CN101889979A - Itraconazole injection for dogs and preparation method thereof - Google Patents
Itraconazole injection for dogs and preparation method thereof Download PDFInfo
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- CN101889979A CN101889979A CN 201010216836 CN201010216836A CN101889979A CN 101889979 A CN101889979 A CN 101889979A CN 201010216836 CN201010216836 CN 201010216836 CN 201010216836 A CN201010216836 A CN 201010216836A CN 101889979 A CN101889979 A CN 101889979A
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Abstract
The invention relates to itraconazole injection for dogs and a preparation method thereof and belongs to an animal medicament. The injection consists of itraconazole, hydroxypropyl-beta-cyclodextrin, propylene glycol, 12 mol.L<-1> of concentrated hydrochloric acid and double distilled water. The preparation method comprises the following steps of: preparing itraconazole inclusion liquid by using hydroxypropyl-beta-cyclodextrin inclusion technology; adding sodium hydroxide solution into the inclusion liquid; adjusting the pH value; filtering the mixture; and circulating vapor for sterilization to obtain the itraconazole injection for the dogs. The injection finished product prepared by the method is yellow and transparent liquid and has the characteristics of high stability, sustained-release property and long-term effectiveness; the inclusion rate of the itraconazole can reach 80 percent; pharmacokinetic characteristic and pharmacodynamics are superior to those of the conventional formulations.
Description
Technical field
The invention belongs to medicine field for animals, what relate generally to is that a kind of dog is used medicine novel form for the treatment of the dog dermatomycosis and preparation method thereof.
Background technology
HP-is the tubular chemical compound that is formed by connecting by α-1.4 glycosidic bond by six glucose molecules, tube inwall cavity is 0.6～1.0nm, because hydroxy group of glucose is distributed in the two ends and externally of tube, sugar glycosidic bond oxygen atom is positioned at the middle part of tube and at tube, the two ends of HP-and outside are hydrophilic, and the outside of tube is a hydrophobicity, by Van der Waals force with some sizes and the suitable drug molecule enclose of shape in circulus, formation ultra micro cryptomere clathrate.It has many advantages, increases the dissolubility of medicine; Increase stability of drug; Local irritant link and improvement; Improve bioavailability; The slow release of medicine and controlled release etc.Along with the development of society, people strengthen gradually to environmental consciousness, and are also more and more high to the requirement of poultry medication.Requirement is efficient a, low-residual etc.People relatively pay attention to developing the medicine novel formulation now, because can not requirement simply study new drug.The precursor beta-schardinger dextrin-of HP-in the application in fields such as chemical industry, medicine, environmental protection more and more widely.At present, following report is arranged, pharmaceutical composition of cyclodextrin-Docetaxel clathrate and preparation method thereof, the supramolecular clathration of vitamin-cyclodextrin characterizes and analytical applications, and beta-schardinger dextrin-and HP-are to the solubilization of dexamethasone etc.And be that the preparation research of carrier is unsatisfactory with the HP-, what succeeded in developing is the quiet drop type of itraconazole of human, in the data of the existing HP-preparation of reporting relevant for animals, it is not very deep that research contents relates to researchs such as preparation technology, inside and outside stability, pharmacodynamic study and clinical observation, pharmacokinetics, remains further to be deepened.
Itraconazole is the synthetic antifungal agent of second filial generation triazole type, and candidiasis and yeast, mycete, dermatophytosis and other pathomycetes are had broad-spectrum antifungal activity.Its capsule and oral liquid come out through drugs approved by FDA respectively at 1992 and 1997.U.S.'s Abbott Laboratories company limited has been developed Itraconazole injection (SPORANOX, itraconazole), and this product went on the market through drugs approved by FDA in 1999, is mainly used in people's systemic fungal infection.2002, Itraconazole injection went on the market in China.Be mainly used in people's systemic fungal infection disease.And on the fungus therapy of dog, what launch research is capsule and tablet.But price is expensive, has limited it and has promoted the use of.
Summary of the invention
The object of the present invention is to provide a kind of Itraconazole injection for dogs and preparation method thereof, this Itraconazole injection for dogs has that curative effect height, drug effect are long, lower-price characteristic, for the treatment of dog cat dermatomycosis provides a kind of even more ideal novel form.
The present invention also aims to provide a kind of controls solvent load and optimizes the preparation Itraconazole injection for dogs method that the enclose condition combines.
The objective of the invention is to be achieved through the following technical solutions:
A kind of Itraconazole injection for dogs, this injection mainly are made up of following each components in certain proportion: itraconazole 1.0g, HP-20.0～30.0g, propylene glycol 5.0mL, 12molL
-1Concentrated hydrochloric acid 370 μ L, distilled water 24-36mL.A kind of aforesaid Itraconazole injection for dogs preparation method, 1. itraconazole that will accurately take by weighing and HP-are put into conical flask A and conical flask B respectively, add propylene glycol in conical flask A, slowly drip 12molL again
-1Concentrated hydrochloric acid; Itraconazole is dissolved fully; Distilled water is injected in the conical flask B, make the HP-dissolving; 2. under the magnetic agitation condition, itraconazole solution among the conical flask A slowly is added dropwise in the conical flask B, mix with HP-solution, the dropping time is every gram itraconazole 15min, B places thermostat water bath with conical flask, enclose under 40 ℃ of conditions, the enclose time is 24-36h, gets inclusion complex in solution.3. with inclusion complex in solution 0.8molL
-1Sodium hydroxide solution carry out pH value and regulate, pH value is 5.5, reuse 0.45 μ m filtering with microporous membrane carries out 100 ℃ of flowing steam sterilizations after the bottling, Itraconazole injection for dogs.
Product of the present invention is used the HP-carrier, by controlling solvent load and improving the inclusion rate that the enclose condition improves itraconazole, thereby prepare the long new medicinal preparation of a kind of curative effect height, drug effect, for the treatment of dog cat dermatomycosis provides a kind of even more ideal novel formulation.Itraconazole injection for dogs of the present invention is a yellow transparent liquid, and the itraconazole inclusion rate reaches 80%, has good stability.
The experiment proved that Itraconazole injection for dogs of the present invention has following characteristics:
1. product of the present invention is by a kind of new medicinal preparation of HP-as preparing carriers, has curative effect height, long, the lower-price characteristic of drug effect.
2. product inclusion rate height of the present invention, drug level is higher, reaches the treatment requirement, and good stability.
3. characteristics of pharmacokinetics is good in the animal body, and medicine has certain slow dispose procedure.
4. product of the present invention absorbs more regular, and can bring into play better therapeutic effect to the mycosis of dog and cat.
The specific embodiment
Further describe the present invention below in conjunction with specific embodiment.
Embodiment 1
Smart 1g itraconazole and the 25g HP-of claiming put into conical flask A and B respectively.In the A bottle, add the 5mL propylene glycol then, slowly drip 12molL again
-1Concentrated hydrochloric acid 370 μ L dissolve fully to itraconazole; HP-among the B is dissolved with the 30mL distilled water.Then, under the magnetic agitation condition, the itraconazole solution among the A slowly is added drop-wise among the B, the dropping time is 15min, after dripping, liquid among the B is moved on in the thermostat water bath, carries out enclose under 40 ℃, and the enclose time is 30h.After enclose finished, enclose liquid concentration was 0.8molL
-1NaOH solution to regulate pH value be 5.5.With 0.45 μ m filtering with microporous membrane, bottle back 100 ℃ of flowing steam sterilizations, i.e. Itraconazole injection for dogs.
In the prepared injection of present embodiment, the itraconazole inclusion rate can reach 80%.Prepared injection clarification, yellow.Place in 3～4 months the color yet constant muddiness that do not change under the room temperature, inclusion rate does not obviously descend,
Embodiment 2
Smart 1g itraconazole and the 20g HP-of claiming put into conical flask A and B respectively.Add the 5mL propylene glycol then in the A bottle, slowly dripping concentration again is 12molL
-1Concentrated hydrochloric acid 370 μ L dissolve fully to itraconazole; HP-among the B is dissolved with the 24mL distilled water.Then, under the magnetic agitation condition, the itraconazole solution among the A slowly is added drop-wise among the B, the dropping time is 15min, after dripping, liquid among the B is moved on in the thermostat water bath, carries out enclose under 40 ℃, and the enclose time is 36h.After enclose finished, enclose liquid concentration was 0.8molL
-1NaOH solution to regulate pH value be 5.5.With 0.45 μ m filtering with microporous membrane, the back 100 ℃ of flowing steam sterilizations of bottling promptly get Itraconazole injection for dogs.
The particle diameter of the liposome that present embodiment is prepared and envelop rate average out to 73%.Prepared injection clarification, yellow.Place under the room temperature and occur muddiness after 2 months, inclusion rate decline.
Embodiment 3
Smart 1g itraconazole and the 30g HP-of claiming put into conical flask A and B respectively.Add the 5mL propylene glycol then in the A bottle, slowly dripping concentration again is 12molL
-1Concentrated hydrochloric acid 370 μ L dissolve fully to itraconazole; HP-among the B is dissolved with the 36mL distilled water.Then, under the magnetic agitation condition, the itraconazole solution among the A slowly is added drop-wise among the B, the dropping time is 15min, after dripping, liquid among the B is moved on in the thermostat water bath, carries out enclose under 40 ℃, and the enclose time is 24h.After enclose finished, enclose liquid concentration was 0.8molL
-1NaOH solution to regulate pH value be 5.5.With 0.45 μ m filtering with microporous membrane, the back 100 ℃ of flowing steam sterilizations of bottling promptly get Itraconazole injection for dogs.
The itraconazole inclusion rate is 86% in the prepared injection of present embodiment.Prepared injection clarification, yellow, viscosity is bigger.Place under the room temperature that color does not become after 5 months, inclusion rate does not have obvious decline.
Each parameters Optimization screening test of test example 1 Itraconazole injection for dogs preparation method of the present invention
Itraconazole is a fat-soluble medicine, for improving its inclusion rate, adopts the HP-inclusion technique, to improve its water solublity.
Prescription design and optimized choice: on the basis that single factor is investigated, further investigating influences all multifactor of enclose quality in the enclose liquid preparation process.Inclusion rate with itraconazole serves as to investigate index, chooses 3 principal elements (dropping time, enclose temperature and enclose time) that influence enclose, adopts L9 (3
4) optimization of orthogonal test preparation technology.
The investigation of dropping time: two kinds of blended times of solution have and must influence concerning HP-and itraconazole combination.This test has investigated 0,5,15,20, five time points of 30min, to determine the best dropping time.
The investigation of enclose temperature: get the small beaker of five 10mL, precision takes by weighing the 0.1g itraconazole and puts into each beaker respectively, adds the 0.5mL propylene glycol then in each beaker, slowly drips 37 μ L concentrated hydrochloric acid (12molL again
-1) itraconazole is dissolved.Get the small beaker of five 10mL again, take by weighing the 2.5g HP-respectively and put into each beaker, add the 3mL distilled water respectively then in each beaker, heating in water bath dissolves HP-fully.Under 30,35,40,45,50 ℃ of water-bath magnetic agitation conditions itraconazole solution is slowly splashed in the HP-aqueous solution respectively, seal each beaker mouth with masking foil, enclose 12h detects inclusion rate.
The selection of enclose time: get the small beaker of five 10mL, precision takes by weighing the 0.1g itraconazole and puts into five beakers respectively, adds 0.5mL then in each beaker, slowly drips 37 μ L concentrated hydrochloric acid (12molL again
-1) itraconazole is dissolved.Get the small beaker of five 10mL again, take by weighing the 2.5g HP-respectively and add in each beaker, add the 3mL distilled water in each beaker respectively, heating in water bath dissolves HP-fully.Under 40 ℃ of water-bath magnetic agitation conditions itraconazole solution is slowly splashed in the HP-aqueous solution, seal each beaker mouth with masking foil, enclose 6,12,18,30,36h detect inclusion rate respectively.
The checking of inclusion rate: adopt optimised process to prepare Itraconazole injection for dogs, make replica test, measure inclusion rate, with the feasibility of verification method.
Result of the test is a yellow transparent liquid for the Itraconazole injection for dogs finished product of this test preparation.By the orthogonal test analysis result as can be known, influence factor's size of inclusion rate is: enclose time＞enclose temperature＞dropping time.Wherein enclose time and enclose temperature two factors have the significance meaning to the influence of inclusion rate.Optimum preparating condition is: the dropping time is 15min, and the enclose temperature is 40 ℃, and the enclose time is 30h.Through evidence, inclusion rate average out to 80.24%, relative standard deviation is 2.33%, shows that this test method is feasible, the injection that makes is comparatively desirable.
The study on the stability of test example 2 Itraconazole injection for dogs products of the present invention
Injection preliminarily stabilised Journal of Sex Research: the result shows that high temperature can reduce the stability of injection, and drug level is reduced, and inclusion rate descends, and occurs muddy; Slight haze appears in the 4 ℃ of injection of placing down inclusion rate declines after 6 months; The injection of placing under room temperature color after 4 months is normal, and inclusion rate does not have to descend substantially.
Test example 3 Itraconazole injection for dogs of the present invention are in the intravital blood plasma pharmacokinetics of dog feature
Water is can't help in 12h fasting before 6 of the dogs, administration, before the administration, in the subcutaneous cephalic vein blood sampling of forelimb 3mL, presses 4mgkg
-1The subcutaneous injection administration of body weight back, subcutaneous cephalic vein of forelimb and the blood sampling of hind leg small saphenous vein place, time point is 0.5,1,2,3,4,5,6,8,12,24,48,72h, each time point blood sampling 3mL, centrifugal, separated plasma adopts the HPLC method to measure blood drug level, 3P97 pharmacokinetics software analysis pharmacokinetic parameters.
The result shows that Ke is 0.0209h
-1, Ka is 1.2928h
-1, T
1/2Be 33.1033h, T
MaxBe 3.2415h, C
MaxBe 239.4724ngmL
-1, AUC is 8614.3587 (ng/mL) h, CL is 0.0019Lkg
-1H
-1, V is 0.0161Lkg
-1Injection blood plasma pharmacokinetics process in the dog body meets one-compartment model.After itraconazole enters in the dog body in the subcutaneous injection mode, because ITZ has higher tissue affinity, so, there is most ITZ to combine with subcutaneous tissue, when ITZ with have only sub-fraction to enter blood circulation after subcutaneous tissue combines through overweight absorption, this has just directly reduced blood drug level.In addition, skin, hair and first are positions fully independently, in case itraconazole enters these organs, just no longer are re-assigned to systemic circulation.So,, can determine that this mode administration can reach fungistatic effect in conjunction with the MIC value of itraconazole to several funguses.
The drug sensitivity test research of test example 4 Itraconazole injection for dogs of the present invention
The preparation of storage liquid: the M38-A scheme according to NCCLS is carried out.It is 1280 μ gmL that Itraconazole injection for dogs and the former powder of ketoconazole are prepared concentration with 100% dimethyl sulfoxide
-1Mother solution, 4 ℃ keep in Dark Place.Carry out doubling dilution with the RPMI-1640 fluid medium during use, make their work final concentration be respectively 0.019～10 μ gmL
-1
The preparation of bacteria suspension: choose Sabouraudites lanosus with inoculating loop and fall, put into the plastic centrifuge tube with cover that normal saline is housed, the vortex vibration, make it be dispersed in the saline fully, leave standstill 3～5min then, get upper strata homogeneous liquid (containing spore and mycelia fragment) to aseptic EP pipe, vibration 30s mixing.At last, with numeration of leukocyte plate microscopy, regulate it to 5 * 106CFUmL
-1(each spore is 1 CFU, and mycelia is designated as 1 CFU with 1 separated place).Be diluted to 5 * 104CFUmL with the RPMI-1640 culture fluid
-1
The preparation of drug sensitive plate: get 96 hole drug sensitive plates, earlier medicine storage liquid is carried out doubling dilution to the twice final concentration, every hole adds RPMI-1640 culture fluid 100 μ L, add the medicinal liquid 100 μ L that dilution finishes in first hole, carry out doubling dilution, make the concentration of medicine diluent be followed successively by 10,5,2.5,1.25,0.625,0.3125,0.1563,0.0781,0.0391,0.0195 μ gmL from high to low
-1Positive control (growth control) is made in the 11st hole, only adds the culture medium of 100 μ L, and blank is made in the 12nd hole.Add the bacteria suspension (double final concentration) that 100 μ L have prepared more successively.
The result shows, detects 8 strains altogether and separates the Sabouraudites lanosus that obtains from the dog body clinically.In result's decision process, simpler for the MIC value judgement of Itraconazole injection for dogs, be 100% inhibition growth.But, be judged to be for the MIC value of ketoconazole and be equivalent to growth control and have 50% or the lowest concentration of drug of more growth when reducing.Be chosen at sun-drenched noon, the interpretation result of the test.Itraconazole injection for dogs is 1.0548 μ gml to the MIC meansigma methods of Sabouraudites lanosus
-1, the former powder of ketoconazole is 2.6094 μ gml to the MIC meansigma methods of Sabouraudites lanosus
-1, show that Sabouraudites lanosus will be higher than the former powder of ketoconazole to the sensitivity of Itraconazole injection for dogs.
The toxicity research of test example 5 Itraconazole injection for dogs of the present invention
Acute toxicity test: 70 white mice are divided into 7 groups at random, 10 every group, male and female half and half, sub-cage rearing.Wherein, the 7th group is matched group (injecting normal saline).Determine respectively to organize the dosage of mice on the basis of trial test, the ratio of dosage is 1.4 between two adjacent groups.Every white mice is pressed 0.02mL g
-1The subcutaneous injection that gives in body weight back, medicinal liquid can dilute with normal saline, various dose group volume injected same concentrations difference.Disposable to the white mice subcutaneous administration, the injection back is observed 7d continuously, and mice dying time and quantity respectively organized in record, observes poisoning manifestations, adopts improved karber's method to calculate LD
50With 95% fiducial limit.The results are shown in Table 1.
Subchronic toxicity test: get 80 of the approaching white mice of body weight, body weight is (16 ± 0.5) g, is divided into 4 groups at random, 20 every group, and male and female half and half.Wherein, 1～3 group is test group, i.e. low dose group, middle dosage group, high dose group.Dosage is respectively 30mgkg
-1D
-1, 60mgkg
-1D
-1And 90mgkg
-1D
-1The 4th group is the blank group.Adopt the back hypodermic medication, medicinal liquid dilutes with normal saline, presses 0.01mLg
-1Body weight successive administration one month, the blank group is injected the normal saline of same volume.In the process of the test, mice ad lib and freely intaking.Weigh every day, adjusts dosage, the results are shown in Table 2.29d after the medication carries out blood parameters and measures, and the results are shown in Table 3.
The result shows: as calculated, Itraconazole injection for dogs is to the median lethal dose(LD 50) (LD of white mice
50) be 129.57mg/kg, LD
50The 95% credible 106.66～157.40mg/kg that is limited to.In the subchronic toxicity test, each is organized in mice preceding 2 days after medication, and the mental status of high dose group part mice is obviously not as other group Mus, and feed intake descends, is reluctant activity.After 2 days, it is normal that feed intake is recovered gradually.Respectively organize searching for food and drinking water no significant difference of mice in all the other times.The GPT of high dose group compares with other 3 groups, significant difference (P＜0.05).The GOT of middle dosage group and high dose group and matched group compare, significant difference (P＜0.05).Other each enzyme value is the indifference opposite sex between each group.
Table 1 is respectively organized dosage and mice dying situation
Annotate: * is in itraconazole content
Table 2 is respectively organized the variation of white mice body weight
Annotate: different persons represent significant difference (P＜0.05) with column data subscript letter
The variation of table 3 Mouse Liver renal function
Annotate: different persons represent significant difference (P＜0.05) with column data subscript letter.
Test example 6 Itraconazole injection for dogs of the present invention are to the therapeutic effect of dog dermatomycosis
(forelimb, affected part, back are become subcircular to come off by hair to have chosen obvious dermatomycosis symptom, there is erythema, skin is covered with a large amount of squamas) 12 dogs, through the scraping blade microscopy, find that The main pathogenic fungi is Sabouraudites lanosus and tinea bacterium, 12 dogs are equally divided into 3 groups at random, treat by 3 kinds of different dosing regimes.First kind of scheme: the 1st group of dog pressed 4mgkg
-1The subcutaneous injection administration, every day 1 time, successive administration is after 1 week, and 2 weeks of drug withdrawal are 1 course of treatment; Second kind of scheme: second group of dog pressed 4mgkg
-1The subcutaneous injection administration, behind 1 successive administration 15d of injection in 1 day, 2 weeks of drug withdrawal are 1 course of treatment; The third scheme: the 3rd group of dog pressed 8mgkg
-1Subcutaneous administration, every 7d administration 1 time, 3 weeks of successive administration are 1 course of treatment.In three kinds of therapeutic schemes, to carry out the scraping blade microscopy every 1 week.After treating 2 courses of treatment disease sites is estimated.
After treating 2 courses of treatment, the erythema of the 1st group of dog disease sites disappears, and has grown new hair gradually, and no gargalesthesia is checked and only found seldom odd spore, illustrates substantially and cures; The 2nd group of dog erythema disappears, and the affected part has grown bright hair, and microscopy is not found spore, and description effect is good; The 3rd group of dog affected part grows virgin wool, but the dog back still has gargalesthesia, rubs wall sometimes, and microscopy finds to have the spore of some to exist, and therapeutic effect is not good.In this case, dosage regimen is being brought into play important effect in therapeutic process.The past therapeutic effect of two groups, Itraconazole injection for dogs has better therapeutic effect to the dermatomycosis of dog.
The clinical efficacy of test example 7 Itraconazole injection for dogs of the present invention is learned test
The dog field of agriculture university's clinic hospital, Harbin and surrounding area has been carried out clinical expansion group therapeutic test and has been applied northeastward, the result shows, Itraconazole injection for dogs of the present invention has notable therapeutic effect to dog cat dermatomycosis, high economic benefit and social benefit have been obtained, be subjected to raiser's favorable comment and welcome, had wide market application prospect.
Claims (2)
1. Itraconazole injection for dogs is characterized in that this injection mainly is made up of following each components in certain proportion: itraconazole 1g, HP-20～30g, propylene glycol 5mL, 12molL
-1Concentrated hydrochloric acid 370 μ L, distilled water 24-36mL.
2. Itraconazole injection for dogs preparation method as claimed in claim 1 is characterized in that:
1. itraconazole that will accurately take by weighing and HP-are put into conical flask A and conical flask B respectively, add propylene glycol in conical flask A, slowly drip 12molL again
-1Concentrated hydrochloric acid; Itraconazole is dissolved fully; Distilled water is injected in the conical flask B, make the HP-dissolving;
2. under the magnetic agitation condition, itraconazole solution among the conical flask A slowly is added dropwise in the conical flask B, mix with HP-solution, the dropping time is every gram itraconazole 15mi n, B places thermostat water bath with conical flask, enclose under 40 ℃ of conditions, the enclose time is 24-36h, gets inclusion complex in solution;
3. with inclusion complex in solution 0.8molL
-1Sodium hydroxide solution carry out pH value and regulate, pH value is 5.5, reuse 0.45 μ m filtering with microporous membrane carries out 100 ℃ of flowing steam sterilizations after the bottling, Itraconazole injection for dogs.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379844A (en) * | 2011-10-31 | 2012-03-21 | 广州维美投资有限公司 | Itraconazole isomer injection |
| CN105687196A (en) * | 2016-01-05 | 2016-06-22 | 黑龙江省兽医科学研究所 | Itraconazole-terbinafine compound injection for dogs and cats and preparation method of compound injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596897A (en) * | 2004-07-26 | 2005-03-23 | 范敏华 | Itraconazole injection and its preparation method |
| CN1615870A (en) * | 2004-09-17 | 2005-05-18 | 北京博尔达生物技术开发有限公司 | Itraconazole freeze-dried powder injection and preparing method |
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2010
- 2010-07-05 CN CN 201010216836 patent/CN101889979A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596897A (en) * | 2004-07-26 | 2005-03-23 | 范敏华 | Itraconazole injection and its preparation method |
| CN1615870A (en) * | 2004-09-17 | 2005-05-18 | 北京博尔达生物技术开发有限公司 | Itraconazole freeze-dried powder injection and preparing method |
Non-Patent Citations (2)
| Title |
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| 《JOURNAL OF PHARMACEUTICAL SCIENCES》 20071130 CHARLES M. BUCHANAN et al Pharmacokinetics of Itraconazole After Intravenous and Oral Dosing of Itraconazole-Cyclodextrin Formulations 第3104页左栏倒数第6行至右栏第18行 1-2 第96卷, 第11期 2 * |
| 《中国生化药物杂志》 20081231 刘恒平 伊曲康唑包合物的制备与研究 第183页至第185页2.2栏至2.3栏 1-2 第29卷, 第3期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379844A (en) * | 2011-10-31 | 2012-03-21 | 广州维美投资有限公司 | Itraconazole isomer injection |
| CN105687196A (en) * | 2016-01-05 | 2016-06-22 | 黑龙江省兽医科学研究所 | Itraconazole-terbinafine compound injection for dogs and cats and preparation method of compound injection |
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