CN1965850B - Roxithromycin injection and preparation process thereof - Google Patents
Roxithromycin injection and preparation process thereof Download PDFInfo
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- CN1965850B CN1965850B CN2006100800869A CN200610080086A CN1965850B CN 1965850 B CN1965850 B CN 1965850B CN 2006100800869 A CN2006100800869 A CN 2006100800869A CN 200610080086 A CN200610080086 A CN 200610080086A CN 1965850 B CN1965850 B CN 1965850B
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- roxithromycin
- injection
- aspartic acid
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Abstract
The invention relates to an eritrocina injection, wherein the invention has high solubility, used in vein injection. The eritrocina and aspartic acid will react in water and room temperature to generate soluble salt, while they react in equal mol number; the injection contains 50-500mg eritrocina, and the solution can be made into injection or powder via added supporter. The invention has quick drug release, high stability and quick treatment.
Description
Technical field
The present invention relates to a kind of roxithromycin injection, more particularly, relate to the freeze-dried powder and the solution type injection agent of Aspartic Acid Roxithromycin, the present invention also provides the preparation method of Aspartic Acid Roxithromycin freeze-dried powder and solution type injection agent.
Background technology
Roxithromycin (roxithromycin, RXM) be the early 1990s to drop into clinical novel macrolide antibiotic, chemistry (9E) by name-[the O-[(2-methoxy ethoxy) methyl] oximido] erythromycin, be to introduce an oxime ether side chain, thereby improved its acid-resistant stability in the 9-position of erythromycin.Its antimicrobial spectrum is similar to erythromycin, and gram positive bacteria is had the strong antibiotic effect, and meningococcus, gonococcus, hemophilus influenza, bordetella pertussis, Brucella etc. in the gram negative bacteria are also had antibacterial action preferably; In addition, some spirillum, mycoplasma pneumoniae, rickettsia etc. also there is inhibitory action.Roxithromycin is mainly used in pneumonia, skin and soft tissue infection, urogenital infections and the otorhinolaryngology infection etc. that lower respiratory infection, chlamydia and mycoplasma infection cause clinically.Roxithromycin is except that having antibacterial action, and clinical proof also has the immunity of raising and antiphlogistic effect.Also share the microbial gastric ulcer of treatment helicobacter pylorus in addition with proton pump inhibitor such as omeprazole (omeprazole), lansoprazole (lansoprazole) etc.
Behind health volunteer's single oral dose Roxithromycin 150mg, maximum plasma concentration is 6.6-7.9mg/L, and the C of oral 500mg erythromycin
MaxOnly be 1.78mg/L; Peak time is 1.5-1.9h; The elimination half-life is about 12h.Roxithromycin non-specificlyly and albumin bound, adhesion a little less than, combination rate is about 15.6-26.7%, but specifically with α
1Strong combination takes place in-sour glycoprotein, and saturated phenomenon is arranged; With the lipoprotein combination rate be 7-11%; Seldom combine with erythrocyte and globulin.Early stage pharmacokinetic studies discovery, health volunteer's single oral dose [
14C]-Roxithromycin after, be recovered to 74.2% of dosage altogether, wherein urine accounts for 7.4%, accounts for 53.4% in the feces, respiratory excretion accounts for 13.4%.In urine, find 4 kinds of metabolite.Experimental result shows that the preceding feed of taking medicine can reduce Roxithromycin bioavailability and blood peak concentration of drug in healthy volunteer's body.
Roxithromycin exists first mistake of tangible gastrointestinal tract to eliminate, and under 37 ℃, can take off red mould sugar and geometrical isomerism and transform two degradation pathway in the simulated gastric fluid of pH 1-3, and degradation speed and geometrical isomerism transforming degree all show as the pH dependency.Under the condition of pH 5.0,7.4,10,37 ℃ of hatchings are not degraded.According to the literature, during the Roxithromycin oral administration, the medicine that absorbs through gastrointestinal only accounts for 50% of dosage, remainder all is excreted, cause very big waste, and peroral dosage form can not oral administration administration or the abnormal patient of gastrointestinal absorption function for some, and the comparatively serious patient of some state of an illness and being not suitable for.Therefore being made into injection is very necessary clinically.
2003, CN1452975A disclosed a kind of roxithromycin injection, and its water soluble salt is hydrochloric acid Roxithromycin, tartaric acid Roxithromycin and lactobionic acid Roxithromycin.But discover that originally the aspartate of Roxithromycin has better dissolubility, be more suitable for making injectable dosage forms.
Summary of the invention
The invention provides that some preparation methoies are more convenient, economical, the Roxithromycin water soluble salt injection type that is easy to suitability for industrialized production and preparation method thereof.
The present invention is achieved in that Roxithromycin and Aspartic Acid are 1: 1 reaction salify in molar ratio, can form clear and bright aqueous solution, thereby be applicable to and make injection type.
Injection of the present invention, active ingredient is the Aspartic Acid Roxithromycin, the dissolubility in water can reach 75mg/mL in Roxithromycin, the aqueous solution pH of its formation simultaneously is moderate, in the 5.0-6.5 scope, so both be suitable for intravenously administrable, can guarantee that again Roxithromycin is not damaged; In addition, formed salt is easy to discharge Roxithromycin in aqueous solution, can guarantee that it can fully play drug effect rapidly.
Injection of the present invention can be freeze-dried powder or solution type injection agent.Wherein solution type injection agent can be aqueous injection or transfusion, and wherein aqueous injection is to be formed through sterilization by Aspartic Acid Roxithromycin aqueous solution; Wherein transfusion is to add an amount of osmotic pressure regulator by Aspartic Acid Roxithromycin aqueous solution to form through pressure sterilizing; Wherein freeze-dried powder is to add an amount of proppant by Aspartic Acid Roxithromycin aqueous solution to form through lyophilization.
Injection of the present invention can contain the lyophilizing proppant, osmotic pressure regulator.Wherein the lyophilizing proppant can be mannitol, dextran-20, dextran-40; It can be sodium chloride, glucose that osmotic pressure is adjusted.
Injection of the present invention contains the Aspartic Acid Roxithromycin of effective dose, is equivalent to Roxithromycin 50-500mg.
The preparation method of roxithromycin injection of the present invention, it is characterized in that: place beaker to add water for injection by 1: 1 mol ratio Roxithromycin and Aspartic Acid, stirring and dissolving under room temperature, add needle-use activated carbon, stir 20min down, filter at 40 ℃, the charcoal cake is washed at twice with remaining water for injection, washing liquid stock solution merges through 0.22-0.45 μ m filtering with microporous membrane, is sub-packed in the ampoule bottle by predetermined close, and 100 ℃ of circulation steam sterilization 30min promptly get Aspartic Acid Roxithromycin injection; In water for injection, add the mannitol of 1/3 Roxithromycin dosage, promptly get freeze dried injection behind the packing postlyophilization; Add the sodium chloride of 6 times of amount Roxithromycins, the water for injection of 10000ml can be sub-packed in 100 infusion bottles, promptly gets the transfusion of Aspartic Acid Roxithromycin through 115 ℃ of pressure sterilizing 30min.
Compared with the prior art, the invention has the advantages that: more convenient, economical, be easy to suitability for industrialized production; The Aspartic Acid Roxithromycin is dissolved in water, but rapid release goes out Roxithromycin after making the injection intravenously administrable, reaches effective Mlc, brings into play therapeutical effect rapidly, and pH value is suitable, and intravenously administrable phlebitis and other incidence rate of adverse reaction are low; Injection of the present invention is investigated through stability test, and the result has good stability.In view of the advantage that the present invention had, it has good application prospects and meaning clinically.
By following examples so that the present invention to be described better.But the present invention is not subjected to the restriction of following embodiment.
The specific embodiment
Embodiment 1: the preparation of aspartate for injection Roxithromycin:
Prescription consists of: (by 100 calculating)
Roxithromycin 15.0g
Aspartic Acid 2.4g
Mannitol 5.0g
Water for injection 200mL
Take by weighing the mannitol of recipe quantity, adding water for injection is made into concentration and is about 15% solution, and is standby.Take by weighing the Roxithromycin and the Aspartic Acid of recipe quantity, place the 250mL beaker, add about 120mL water for injection and above-mentioned mannitol solution, under room temperature, be stirred to moltenly entirely, add needle-use activated carbon 0.16g, 40 ℃ were stirred 20 minutes down, filter, the charcoal cake is washed at twice with remaining water for injection, and washing liquid stock solution merges through 0.22 μ m microporous filter membrane aseptic filtration, it is aseptic subpackaged to press predetermined close, and lyophilization promptly.
Embodiment 2: the preparation of Aspartic Acid Roxithromycin injection:
Prescription consists of: (by 100 calculating)
Roxithromycin 15.0g
Aspartic Acid 2.4g
Water for injection 200mL
Take by weighing the Roxithromycin and the Aspartic Acid of recipe quantity, place the 250mL beaker, add about 160mL water for injection, under room temperature, be stirred to moltenly entirely, add needle-use activated carbon 0.16g, 40 ℃ were stirred 20 minutes down, filter, the charcoal cake is washed at twice with remaining water for injection, and washing liquid stock solution merges through 0.45 μ m filtering with microporous membrane, be sub-packed in the ampoule bottle by predetermined close, 100 ℃ of circulation steam sterilization 30min promptly.
Embodiment 3: the preparation of Aspartic Acid Roxithromycin transfusion:
Prescription consists of: (by 100 calculating)
Roxithromycin 15.0g
Aspartic Acid 2.4g
Sodium chloride 90.0g
Water for injection 10000mL
Take by weighing Roxithromycin, Aspartic Acid and the sodium chloride of recipe quantity, place the 10000mL beaker, add about 8000mL water for injection, under room temperature, be stirred to moltenly entirely, add needle-use activated carbon 80.0g, 40 ℃ were stirred 20 minutes down, filter, the charcoal cake is washed at twice with remaining water for injection, and washing liquid stock solution merges through 0.45 μ m filtering with microporous membrane, be sub-packed in the infusion bottle by predetermined close, 115 ℃ of pressure sterilizing 30min promptly.
Following test data can illustrate benefit of the present invention:
Test example 1: Roxithromycin, Aspartic Acid Roxithromycin dissolubility are relatively
Table 1 Roxithromycin, Aspartic Acid Roxithromycin solubility results (20 ℃)
Test example 2: Aspartic Acid Roxithromycin stability test result
Table 2 influence factor experimental result
Annotate: this test is not carried out in "-" expression in the table 2.
Table 3 accelerated tests result
Table 4 experimental result that keeps sample for a long time
Conclusion (of pressure testing): the Aspartic Acid roxithromycin injection has good stability.
The 3 specific safety tests of test example
In order to check Aspartic Acid roxithromycin injection intravenously administrable non-stimulated, irritated, hemolytic reaction are arranged, to determine whether this medicine can be used for intravenously administrable.
3.1 blood vessel irritation experiment
(1) trial drug: the Aspartic Acid roxithromycin injection that the present invention relates to.
(2) experimental animal: rabbit, 1.8～2.5kg, male and female dual-purpose.
(3) test method: get 6 of 1.8～2.5kg rabbit, be divided into 2 groups at random, 3 every group.3 tame rabbit ear vein instillation Aspartic Acid Roxithromycin 15mg/kg (in Roxithromycin), administration volume are 5mL/kg.3 tame rabbit ear veins isometric normal saline that instils, once a day, continuous three times, perusal injection place and away from the vascular reaction of injection place after the administration does not see after the administration that as a result blood vessel has abnormal response, does not relatively have significant difference with the matched group blood vessel.According to table 4 standard blood vessel irritation being marked, is 0 minute.After the last administration 24 hours, rabbit is put to death, respectively get one section blood vessel in injection place with away from the about 5cm of injection place place, be fixed in 10% the formalin, paraffin embedding, the HE Albert'stain Albert, light microscopy checking (40 * 3.2) is observed its histopathology change.The result of histopathologic examination shows Aspartic Acid roxithromycin injection successive administration 3 days, rabbit injection place blood vessel and show no obvious abnormalities change away from injection place vascular tissue, relatively do not have significant difference with normal saline matched group rabbit blood vessel, conclusion is no blood vessel zest.
Table 4 blood vessel irritation perusal standards of grading
Criterion as a result :≤0.5 nonirritant ,≤2.5 minimal irritation ,≤4.5 moderate stimulations ,≤6.0 heavy zests
3.2 allergic experiment
Get male guinea pig, body weight 250～350g is divided into 3 groups at random, 6/group.Experimental group lumbar injection Aspartic Acid Roxithromycin injection 11.6mg/kg (in Roxithromycin), 0.5mL/ only, the next day once, totally 3 times, positive controls is with capacity 1% fresh albumens such as method injections, the blank group is with capacity normal saline such as method injections.After the first administration 14 days, get 3 for every group, intravenous injection Aspartic Acid injection 1.0mL/ only, blank group and positive controls difference intravenous injection normal saline and 1% Ovum Gallus domesticus album 1.0mL/ are only, observe immediately after the administration that animal has or not sneeze, scratches nose, retch or anaphylaxiss such as cough, perpendicular hair, tic, dyspnea, gatism, shock and death, observed 1 hour, and the results are shown in Table 5.Aspartic Acid roxithromycin injection and normal saline group, none allergic symptom, Ovum Gallus domesticus album positive controls 100% shock.Handle with method after 21 days for remaining 3, observe identical index, the result is the same.
The hypersensitive test of table 5 Aspartic Acid roxithromycin injection
Annotate: (-) do not have irritated reaction; (+) has anaphylaxis
3.3 external hemolytic test
Family's rabbit ear central artery blood sampling, according to literature method, bead stirs and defibrinates, with the normal saline washing centrifugal (1000rpm in back, 15min), for several times until the supernatant redfree, be made into 2.0% erythrocyte suspension with normal saline by volume then and be for experiment repeatedly.
Get 7 in test tube for every group, add Aspartic Acid roxithromycin injection different volumes medicinal liquid and erythrocyte suspension respectively by each pipe shown in the table 4,5,6, pipe 6 not dosings add normal saline and make blank, manage 7 adding distil waters and do complete haemolysis contrast.After shaking up gently, each pipe is put in 37 ℃ of water-baths and was placed 3 hours, respectively at 15min, 30min.45min, 1.0h, 2.0h, 3.0h respectively write down once totally 6 times.Have or not haemolysis according to the documentation standards perusal.After last is observed,, observe to have or not and precipitate and agglutination phenomenon, the results are shown in Table 6～9 each test tube shake well.The external hemolytic test of Aspartic Acid roxithromycin injection is not seen haemolysis and hemagglutination phenomenon, compares no significant difference with normal saline.The then complete hemolysis of distilled water group produces red clear solution.Conventional method is made the erythrocyte microscopy, not show cell rupture and paramophia.
The external hemolytic test of table 6 Aspartic Acid roxithromycin injection (5mg/mL) (in Roxithromycin)
Judge: the no haemolysis of (-) expression, no coagulation, no precipitation; (+) expression complete hemolysis.
The external hemolytic test of table 7 Aspartic Acid roxithromycin injection (1.5mg/mL) (in Roxithromycin)
Judge: the no haemolysis of (-) expression, no coagulation, no precipitation; (+) expression complete hemolysis.
The external hemolytic test of table 8 Aspartic Acid Roxithromycin (injection 0.6mg/mL) (in Roxithromycin)
Judge: the no haemolysis of (-) expression, no coagulation, no precipitation; (+) expression complete hemolysis.
Table 9 erythrocyte hemolysis, coagulation criterion
Experiment conclusion:
This medicine does not have haemolysis, no blood vessel zest, does not have irritated reaction.
Claims (11)
1. roxithromycin injection is characterized in that: it comprises the Roxithromycin aspartate that the reaction in 1: 1 in molar ratio of Roxithromycin and Aspartic Acid generates, and contains in the injection and is equivalent to the 50-500mg Roxithromycin, and its pH is 5.0-6.5.
2. roxithromycin injection according to claim 1 is characterized in that: the Aspartic Acid Roxithromycin that contains the Roxithromycin that is equivalent to 150mg in the injection.
3. roxithromycin injection according to claim 1 is characterized in that: described injection is the freeze-dried powder or the solution-type injection of Aspartic Acid Roxithromycin.
4. roxithromycin injection according to claim 1 is characterized in that: freeze-dried powder is to be added an amount of proppant, formed through lyophilization by Aspartic Acid Roxithromycin aqueous solution.
5. roxithromycin injection according to claim 4 is characterized in that: proppant wherein is selected from mannitol, dextran-20 or dextran-40.
6. roxithromycin injection according to claim 3 is characterized in that: described solution type injection agent is aqueous injection or transfusion.
7. roxithromycin injection according to claim 6; It is characterized in that: described roxithromycin injection aqueous injection is that Aspartic Acid Roxithromycin aqueous solution forms through sterilization.
8. roxithromycin injection according to claim 6 is characterized in that: described transfusion is to add an amount of osmotic pressure regulator by Aspartic Acid Roxithromycin aqueous solution to form through sterilization.
9. roxithromycin injection according to claim 8 is characterized in that: described osmotic pressure regulator is sodium chloride or glucose.
10. the preparation method of a roxithromycin injection as claimed in claim 1 is characterized in that: Roxithromycin and Aspartic Acid are made by 1: 1 molar ratio reaction.
11. the preparation method of roxithromycin injection according to claim 10, wherein place beaker to add water for injection Roxithromycin and Aspartic Acid, stirring and dissolving under room temperature, add needle-use activated carbon, stirred 20 minutes down, filter at 40 ℃, the charcoal cake is washed at twice with remaining water for injection, washing liquid stock solution merges through 0.22-0.45 μ m filtering with microporous membrane, is sub-packed in the ampoule bottle by predetermined close, and 100 ℃ of circulation steam sterilizations promptly got Aspartic Acid Roxithromycin injection in 30 minutes; In water for injection, add the mannitol of 1/3 Roxithromycin dosage, promptly get freeze dried injection behind the packing postlyophilization; Add the sodium chloride of 6 times of amount Roxithromycins, the water for injection of 10000ml can be sub-packed in 100 infusion bottles, promptly gets the transfusion of Aspartic Acid Roxithromycin through 115 ℃ of pressure sterilizing 30min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100800869A CN1965850B (en) | 2006-05-11 | 2006-05-11 | Roxithromycin injection and preparation process thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100800869A CN1965850B (en) | 2006-05-11 | 2006-05-11 | Roxithromycin injection and preparation process thereof |
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| CN1965850A CN1965850A (en) | 2007-05-23 |
| CN1965850B true CN1965850B (en) | 2011-09-14 |
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| CN2006100800869A Expired - Fee Related CN1965850B (en) | 2006-05-11 | 2006-05-11 | Roxithromycin injection and preparation process thereof |
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| CN103493811B (en) * | 2013-10-21 | 2015-05-06 | 四川农业大学 | Method for prevention and treatment of Bursaphelenchus mucronatus disease |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3764595A (en) * | 1969-01-15 | 1973-10-09 | Pierrel Spa | Erythromycin aspartate salt |
| CN1452975A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Roxithromycin injection |
| CN1580065A (en) * | 2004-05-18 | 2005-02-16 | 湖北工学院 | Clarithromycin amino acid salt, and its preparing method and use |
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2006
- 2006-05-11 CN CN2006100800869A patent/CN1965850B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3764595A (en) * | 1969-01-15 | 1973-10-09 | Pierrel Spa | Erythromycin aspartate salt |
| CN1452975A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Roxithromycin injection |
| CN1580065A (en) * | 2004-05-18 | 2005-02-16 | 湖北工学院 | Clarithromycin amino acid salt, and its preparing method and use |
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| CN1965850A (en) | 2007-05-23 |
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