CN1316247A - Clamycin injection and its preparing process - Google Patents
Clamycin injection and its preparing process Download PDFInfo
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- CN1316247A CN1316247A CN 00112690 CN00112690A CN1316247A CN 1316247 A CN1316247 A CN 1316247A CN 00112690 CN00112690 CN 00112690 CN 00112690 A CN00112690 A CN 00112690A CN 1316247 A CN1316247 A CN 1316247A
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- kelamycin
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Abstract
A clamycin injection as a macrolide antibiotic and its preparing process is disclosed. Said injection contains clamycin as active component, cosolvent, chelating agent, blood plasma diffusant, stabilizer, antioxidizing agent, solution osmotic-pressure regulator and pH regulator, and features that the micro-molecular clamycin is wrapped by non-irritation macro-molecular polyvinyl pyrrolidone and poloxamer for lower irritation and higher solubility and stability. Its advantages include simple preparing process, low cost and no generation of phlebitis.
Description
The present invention relates to antibiotic medicine preparation and preparation method, especially relate to macrolide antibiotics injection and preparation method thereof.
Clarithromycin is new 14-membered ring macrolides antibiotic, and clarithromycin is by combining the synthetic antibacterial action that produces of Profilin matter with 50S subunit on the 70S nucleoprotein of antibacterial.Except that the solid preparation dosage form is arranged, also develop multiple dosage forms such as injection both at home and abroad, adopt the number of ways administration more can bring into play the drug action of clarithromycin.
The clarithromycin of at present external injection has lyophilized preparation and two kinds of dosage forms of emulsifying agent: (1) injection clarithromycin lyophilized preparation; At first with clarithromycin and sour salify, through lyophilization, dried frozen aquatic products, before the use again dissolved dilution in 250ml aseptic normal saline or 5% G/W, intravenous drip, this lyophilized preparation complicated process of preparation is used inconvenient; There is 60% above case to produce phlebitis after this lyophilized preparation intravenous drip of external report approximately; Domestic pharmaceutical factory develops the lyophilized preparation of producing, and phlebitis also takes place during intravenous drip, because phlebitis is brought hard to bear misery to patient.(2) clarithromycin vein emulsion; This vein emulsion has overcome the shortcoming of lyophilized preparation, and patient produces phlebitic problem when having solved intravenous drip substantially, but the lecithin materials that this Emulsion adopts costs an arm and a leg making Emulsion cost height.
The objective of the invention is to research and develop out a kind of prescription and preparation method of new preparation Kelamycin injection, patient does not produce phlebitis during this injection intravenous drip, alleviates patient's the painful production cost that can reduce injection simultaneously of medical treatment.
The objective of the invention is to be achieved through the following technical solutions.
We adopt the polyvinylpyrrolidone (plasma substitute) (molecular weight 5000-70000) of nonirritant macromolecule, and poloxamer (molecular weight about 9000) comprises the clathrate that micromolecular clarithromycin (molecular weight 747.96) forms " molecular capsule ".Clarithromycin is a macrolide antibiotics, has ester dissolubility characteristics, is insoluble in water, and its dissolubility is about 1: 1000, and the difficulty for preparing this injection is very big; PH value solution instability on the low side behind the clarithromycin salify, pH value is higher a little in the time of 40 ℃, and clarithromycin just separates out; We are by screening, prescriptions such as a large amount of cosolvents, stabilizing agent, chelating agen, antioxidant, pH regulator agent, osmotic pressure, regulators, finally develop qualified clarithromycin transfusion, through 120 ℃ of sterilizations 30 minutes, the each side index all meets the requirements, pH5.5-7.0 osmotic pressure 284-304 mQsm.
The invention provides the effective way that solves an above difficult problem, through pharmacology aspect Kelamycin injection toxicity test, pharmacodynamics test, hemolytic test, local excitation test, tests such as Kelamycin injection systemic allergy test, pyrogen all meet the requirements.
The in-vitro antibacterial test of Kelamycin injection shows: clarithromycin in-vitro antibacterial spectrum is similar with other macrolide antibiotics such as erythromycin, has strong bacteriostasis to removing from office blue formula positive bacteria.MIC to staphylococcus aureus
50Be 0.06mg/L; To micrococcus scarlatinae, streptococcus pneumoniae, enterococcal MIC
50, MIC
90Be respectively 0.03,0.06mg/L; 0.015,0.5mg/L; 0.06,16mg/L; Stronger 2 times than erythromycin.MIC to bloodthirsty hemophilus influenza
50Be 2mg/L, to the MIC of bacteroides fragilis
50Be 0.5mg/L.In vivo test shows that Kelamycin injection is stronger 6.3 times and 10.2 times than erythromycin to the interior curative effect that mice staphylococcus aureus, micrococcus scarlatinae infect, ED
50Be respectively 10.3mg/kg and 5.4mg/kg.
Kelamycin injection is lower to the acute toxicity of mice, and the Kelamycin injection of intravenous injection Cmax there is no animal dead.LD
50Greater than 127mg/kg.
Haemolysis, the irritation test of Kelamycin injection show that rabbit auricular vein every day is injected the Kelamycin injection 5ml that concentration is 5mg/ml, continuous three times, and no obvious stimulation reaction; The Kelamycin injection 2ml of quadriceps femoris injection 5mg/ml does not also have the obvious stimulation reaction, shows that the local excitation test of this medicine is up to specification.Every Kelamycin injection 0.5ml that intramuscular injection concentration is 5mg/ml next day of Cavia porcellus, totally 3 times.Respectively at attacking in the 14th day and the 21st day after the injection first, symptoms of allergic does not all appear in the result, shows that this medicine hypersensitive test is qualified.
Kelamycin injection has the following advantages:
(1) this injection preparation technology is easy, and cost of material is low;
(2) dosage is little so toxic and side effects is little, nonirritant problem during use;
(3) can directly enter tissue or blood vessel, absorb soon, effect is rapid, human bioavailability 100%;
(4) no anaphylaxis need not to do the human body hypersensitive test, and can race against time in time gives emergency treatment to a patient.
The present invention is described in further detail below in conjunction with embodiment:
The preparation of embodiment Kelamycin injection
1, the prescription of Kelamycin injection
Clarithromycin 0.50g
1,2-propylene glycol 6-12ml
Polyvinylpyrrolidone 4-10.5g
Disodium EDTA 0.02-0.15g
Sodium pyrosulfite 0.01-0.1g
Poloxamer 3-5.5g
Nicotiamide 1.0-3.5g
L-cysteine hydrochloride 0.01-0.06g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Distilled water is to 100ml
2, the preparation process of Kelamycin injection
Recipe quantity clarithromycin, 1,2-propylene glycol, polyvinylpyrrolidone, poloxamer and L-cysteine hydrochloride mixing, add an amount of distilled water, stir extremely dissolving of dripping hydrochloric acid down, add sodium pyrosulfite and nicotiamide, after waiting to dissolve, add sodium chloride and regulate osmotic pressure (being about 284-304mosm) in right amount, adding distil water is to 100ml (regulating pH value with sodium hydroxide is 5.5-7.0), added the proper amount of active carbon agitating heating 15 minutes, filtered while hot, 120 ℃ of autoclavings of subsequent filtrate 30 minutes are promptly.
Test example 1 Kelamycin injection heat stabilization test
40 ℃ of heat stabilization tests of Kelamycin injection (transfusion)
| Lot number | Time (my god) | Color (yellow reference colour level pipe) | Clarity | PH value | Assay | |
| (u/ml) tires | Labelled amount (%) | |||||
| ????990301 | ????0 | ≤ No. 2 | Qualified | ?6.55 | ????5080 | ????100.0 |
| ????1 | No. 2 | Qualified | ?6.50 | ????4917 | ????96.8 | |
| ????3 | No. 2 | Qualified | ?6.42 | ????4828 | ????95.0 | |
| ????5 | No. 2 | Qualified | ?6.39 | ????5047 | ????99.4 | |
| ????10 | No. 2 | Qualified | ?6.36 | ????4895 | ????96.4 | |
60 ℃ of heat stabilization tests of Kelamycin injection (transfusion)
| Lot number | Time (my god) | Color (yellow reference colour level pipe) | Clarity | PH value | Assay | |
| (u/ml) tires | Labelled amount (%) | |||||
| ????990301 | ????0 | ≤ No. 2 | Qualified | 6.55 | ????5080 | ????100.0 |
| ????1 | No. 2 | Qualified | 6.40 | ????5063 | ????99.7 | |
| ????3 | No. 2 | Qualified | 6.24 | ????4928 | ????97.0 | |
| ????5 | No. 2 | Qualified | 6.20 | ????4869 | ????95.8 | |
| ????1?0 | No. 3 | Qualified | 6.01 | ????4765 | ????93.8 | |
80 ℃ of heat stabilization tests of Kelamycin injection (transfusion)
| Lot number | Time (my god) | Color (yellow reference colour level pipe) | Clarity | PH value | Assay | |
| (u/ml) tires | Labelled amount (%) | |||||
| ????990301 | ????0 | ≤ No. 2 | Qualified | 6.55 | ????5080 | ????100.0 |
| ????1 | No. 2 | Qualified | 6.25 | ????4811 | ????94.7 | |
| ????3 | No. 5 | Qualified | 5.85 | ????3981 | ????98.4 | |
| ????5 | No. 7 | Qualified | 5.59 | ????3094 | ????60.9 | |
| ????1?0 | No. 9 | Qualified | 5.26 | ????2209 | ????43.5 | |
The test of test example 2 Kelamycin injection light durabilities
| Lot number | Time (my god) | Color (yellow reference colour level pipe) | Clarity | PH value | Assay | |
| (u/ml) tires | Labelled amount (%) | |||||
| ????990301 | ????0 | ≤ No. 2 | Qualified | 6.55 | ????5080 | ????100.0 |
| ????1 | ≤ No. 2 | Qualified | 6.49 | ????4996 | ????98.3 | |
| ????3 | No. 2 | Qualified | 6.40 | ????4811 | ????94.7 | |
| ????5 | No. 2 | Qualified | 6.38 | ????4919 | ????96.8 | |
| ????10 | No. 2 | Qualified | 6.34 | ????5027 | ????99.0 | |
Test example 3 Kelamycin injection accelerated tests
40 ℃ of 75%RH accelerated tests of Kelamycin injection (transfusion)
| Lot number | Time (moon) | Color (yellow reference colour level pipe) | Clarity | PH value | Assay | |
| (u/ml) tires | Labelled amount (%) | |||||
| ????990301 | ????0 | ≤ No. 2 | Qualified | 6.55 | ????5080 | ????100.0 |
| ????1 | No. 2 | Qualified | 6.32 | ????5056 | ????99.5 | |
| ????2 | 〉=No. 2 | Qualified | 6.17 | ????4942 | ????97.3 | |
| ????3 | No. 3 | Qualified | 6.05 | ????481?3 | ????94.7 | |
| ????990302 | ????0 | ≤ No. 2 | Qualified | 6.95 | ????5038 | ????100.0 |
| ????1 | No. 2 | Qualified | 6.68 | ????5028 | ????99.8 | |
| ????2 | 〉=No. 2 | Qualified | 6.47 | ????4986 | ????99.0 | |
| ????3 | No. 3 | Qualified | 6.34 | ????4830 | ????95.9 | |
| ????990303 | ????0 | ≤ No. 2 | Qualified | 6.20 | ????5101 | ????100.0 |
| ????1 | No. 2 | Qualified | 6.00 | ????5068 | ????99.4 | |
| ????2 | No. 3 | Qualified | 5.86 | ????4986 | ????97.7 | |
| ????3 | No. 4 | Qualified | 5.76 | ????4718 | ????92.5 | |
Test example 4 Kelamycin injection long term tests
25 ℃ of 58%RH long term tests of Kelamycin injection (transfusion)
| Lot number | Time (moon) | Color (yellow reference colour level pipe) | Clarity | PH value | Assay | |
| (u/ml) tires | Labelled amount (%) | |||||
| ????990301 | ????0 | ≤ No. 2 | Qualified | 6.55 | ????5080 | ????100.0 |
| ????3 | ≤ No. 2 | Qualified | 6.42 | ????5085 | ????100.1 | |
| ????6 | No. 2 | Qualified | 6.28 | ????4964 | ????97.7 | |
| ????9 | ≤ No. 2 | Qualified | 6.18 | ????4944 | ????97.3 | |
| ????990302 | ????0 | ≤ No. 2 | Qualified | 6.95 | ????5038 | ????100.0 |
| ????3 | ≤ No. 2 | Qualified | 6.80 | ????4985 | ????98.9 | |
| ????6 | No. 2 | Qualified | 6.64 | ????5000 | ????99.2 | |
| ????9 | No. 2 | Qualified | 6.51 | ????5023 | ????99.7 | |
| ????990303 | ????0 | ≤ No. 2 | Qualified | 6.20 | ????5101 | ????100.0 |
| ????3 | ≤ No. 2 | Qualified | 6.08 | ????5080 | ????99.6 | |
| ????6 | No. 2 | Qualified | 5.95 | ????4985 | ????97.7 | |
| ????9 | No. 2 | Qualified | 5.86 | ????5000 | ????98.0 | |
Test example 5 local excitations test
1, test material
(1) animal: rabbit, the male and female dual-purpose, 2.0-2.5kg purchases white Sichuan laboratory animal administration commission test site.The quality certification number: the real moving pipe 99-14 in river.
(2) experimental animal: test under this with hemolytic.
2, experimental technique
(1) tame rabbit ear edge vascular stimulation test
According to " Chinese medicine development guideline (tentative; in April, 1993) ", get 3 of healthy rabbits, inject the Kelamycin injection 5.0ml that concentration is 5mg/ml in the edge vein of picking up the ears with sterile working's method every day, opposite side is injected the isometric(al) normal saline, continuous three times, rabbit is put to death in 24 hours after having annotated medicinal liquid, dissect animal blood vessels and do the pathology section, observation has or not significant stimulation reactions such as metaplasia or necrosis.
(2) rabbit quadriceps femoris irritant test
Get 3 of healthy rabbits, sentence the Kelamycin injection 2ml that sterile working's method implantation concentration is 5mg/ml in the side quadriceps femoris of every rabbit, the opposite side corresponding site is used with method and is injected the 2ml sterile saline in contrast.In having annotated medicinal liquid sacrificed by exsanguination rabbit after 48 hours, dissect the back and take out quadriceps femoris, vertically cut, observe the irritant reaction of injection site muscle, by general " injection irritant reaction standards of grading " judged result.
3, experimental result:
(1) tame rabbit ear edge vascular stimulation test
Rabbit auricular vein every day is injected the Kelamycin injection 5ml of 5mg/ml, and continuous three times, injection site blood vessel perusal there is no obvious hyperemia or edema phenomenon after 24 hours, also significant stimulation reaction such as inorganization degeneration or necrosis of pathology section examination.
(2) rabbit quadriceps femoris irritant test
Rabbit quadriceps femoris injection concentration is behind the Kelamycin injection 2ml of 5mg/ml 48 hours, does not see the obvious stimulation reaction, and the reaction score value is 0.Show that injection 5mg/ml Kelamycin injection does not have the obvious stimulation effect to rabbit glue musculus quadriceps.
Claims (8)
1, a kind of Kelamycin injection contains active component clarithromycin and cosolvent, chelating agen, blood plasma expansion agent, stabilizing agent and antioxidant, solution osmotic pressure regulator, pH regulator agent.
2, Kelamycin injection as claimed in claim 1, its cosolvent can be Macrogol 200, Liquid Macrogol, PEG400, tween 80,1,2-propylene glycol, glycerol, polyvinylpyrrolidone; Be preferably 1, the 2-propylene glycol.
3, Kelamycin injection as claimed in claim 1, its chelating agen (chelating agent) can be disodium EDTA, polyvinylpyrrolidone; Disodium EDTA has the effect of cosolvent and antioxidant synergist, the effect that polyvinylpyrrolidone has cosolvent, dispersant simultaneously simultaneously.
4, Kelamycin injection as claimed in claim 1, its stabilizing agent and solubilizing agent can be L-cysteine hydrochloride, the husky nurse of pool network, nicotiamide.
5, Kelamycin injection as claimed in claim 1, its antioxidant can be sodium sulfite, sodium sulfite, ascorbic acid, thiourea, sodium pyrosulfite, L-cysteine hydrochloride, is preferably sodium pyrosulfate, L-cysteine hydrochloride.
6, Kelamycin injection as claimed in claim 1, its pH regulator agent can be phosphate buffer, L-cysteine hydrochloride, hydrochloric acid, succinic acid, maleic acid, lactic acid, sodium hydroxide.
7, a kind of preparation method of Kelamycin injection is mixed active component and cosolvent, chelating agent, pH regulator agent, adds suitable quantity of water, after the stirring and dissolving, add stabilizing agent, antioxidant, after waiting to dissolve, add the osmotic pressure of sodium chloride regulator solution, add water to 1000ml, with pH regulator agent adjust pH, add active carbon, filter, 120 ℃ of autoclavings promptly, the Kelamycin injection of making (transfusion) is lurid clear liquid.
8, the preparation method of Kelamycin injection as claimed in claim 5, its pH value is adjusted between the 5.5-7.0.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00112690 CN1316247A (en) | 2000-02-18 | 2000-02-18 | Clamycin injection and its preparing process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00112690 CN1316247A (en) | 2000-02-18 | 2000-02-18 | Clamycin injection and its preparing process |
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| CN1316247A true CN1316247A (en) | 2001-10-10 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101548945B (en) * | 2009-05-27 | 2010-11-10 | 韶山大北农动物药业有限公司 | Long-acting flunixin meglumine injection and method for preparing same |
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2000
- 2000-02-18 CN CN 00112690 patent/CN1316247A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101548945B (en) * | 2009-05-27 | 2010-11-10 | 韶山大北农动物药业有限公司 | Long-acting flunixin meglumine injection and method for preparing same |
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