CN1131039C - Kelamycin injection and its preparing process - Google Patents
Kelamycin injection and its preparing process Download PDFInfo
- Publication number
- CN1131039C CN1131039C CN 00131855 CN00131855A CN1131039C CN 1131039 C CN1131039 C CN 1131039C CN 00131855 CN00131855 CN 00131855 CN 00131855 A CN00131855 A CN 00131855A CN 1131039 C CN1131039 C CN 1131039C
- Authority
- CN
- China
- Prior art keywords
- injection
- qualified
- clarithromycin
- kelamycin
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a macrolide antibiotic clamycin injection and a preparing method thereof. The injection contains clarithromycin as an active component, a cosolvent, a chelant, a plasm extender, a stabilizing agent, an antioxidant, a solution osmotic pressure regulating agent and a pH regulating agent. The present invention adopts nonirritant polyvinylpyrrolidone with large molecular weight and no stimulation and poloxamer to coat micromolecular clarithromycin to form an inclusion compound of a molecular capsule. The present invention solves insufferable stimulation of vein dripping injection to patients and solves the problems of dissolvability and stability of clarithromycin simultaneously. The injection has the advantages of simple preparing process and low cost, patients are not affected with phlebitis when vein dripping injection is carried out, so the curative pains for patients can be relieved.
Description
The present invention relates to the preparation method of antibiotic medicine preparation, especially relate to the preparation method of macrolide antibiotics injection.
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, and 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 7000-10000) comprises the clathrate that micromolecular clarithromycin (molecular weight 747.96) forms " molecular capsule ".Clarithromycin is a macrolide antibiotics, has fat-soluble characteristics, is insoluble in water, and its dissolubility is about 1: 1000, and the difficulty for preparing this injection is very big; As pH value injection instability on the low side, 40 ℃ the time, clarithromycin just separates out as the higher then injection of pH value behind the clarithromycin salify; 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 is at 280-310mosm normal range.
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, and gram-positive bacterium is had strong bacteriostasis.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 0.1-1.0g
1,2-propylene glycol 3-50ml
Polyvinylpyrrolidone 1-15g
Calcium disodium chelate salt 0.02-0.5g
Sodium pyrosulfite 0.01-0.2g
Poloxamer 3-5.5g
Nicotiamide 1.0-15g
L-cysteine hydrochloride 0.01-0.5g
Hydrochloric acid is an amount of
Sodium chloride is an amount of
Sodium hydroxide 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 280-310mosm) 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 | |
| 10 | 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 | 78.4 | |
| 5 | No. 7 | Qualified | 5.59 | 3094 | 60.9 | |
| 10 | 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 | 4813 | 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/m1) 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 is available from 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 injected 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 the rabbit quadriceps femoris.
Claims (2)
1, a kind of preparation method of Kelamycin injection, with active component clarithromycin 0.1-1.0 gram and 1,2-propylene glycol 3-50ml, polyvinylpyrrolidone 1-15g, calcium disodium chelate salt 0.02-0.5g, poloxamer 3-3.5g, L-cysteine hydrochloride 0.01-0.5g stirs extremely dissolving of dripping hydrochloric acid down, add sodium pyrosulfite 0.01-0.2g, after nicotiamide 1.0-15g waits to dissolve, add sodium chloride and regulate osmotic pressure (being about 280-310mosm) in right amount, adding distil water is to 100ml, regulate pH value in right amount with sodium hydroxide, added the proper amount of active carbon agitating heating 15 minutes, filtered while hot, promptly the Kelamycin injection of making (transfusion) was yellowish clear liquid to 120 ℃ of autoclavings of subsequent filtrate in 30 minutes.
2, the preparation method of Kelamycin injection as claimed in claim 1, its pH value is adjusted between the 5.5-7.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00131855 CN1131039C (en) | 2000-11-07 | 2000-11-07 | Kelamycin injection and its preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00131855 CN1131039C (en) | 2000-11-07 | 2000-11-07 | Kelamycin injection and its preparing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1317314A CN1317314A (en) | 2001-10-17 |
| CN1131039C true CN1131039C (en) | 2003-12-17 |
Family
ID=4594837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00131855 Expired - Fee Related CN1131039C (en) | 2000-11-07 | 2000-11-07 | Kelamycin injection and its preparing process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1131039C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446049B (en) * | 2013-09-16 | 2015-06-03 | 南通丝乡丝绸有限公司 | Clarithromycin injection and preparation method thereof |
| CN117338729B (en) * | 2023-12-06 | 2024-02-13 | 山东国邦药业有限公司 | Erythromycin thiocyanate soluble particles and preparation method thereof |
-
2000
- 2000-11-07 CN CN 00131855 patent/CN1131039C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1317314A (en) | 2001-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7404964B2 (en) | Injectable compositions for the controlled delivery of pharmacologically active compound | |
| CN112386572B (en) | Gamithromycin injection and preparation method thereof | |
| AU2002327307B2 (en) | Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparations and the use there of | |
| CN106692120A (en) | Medicine composition of lidocaine and application of medicine composition | |
| EP2620153B1 (en) | 5 alpha-androstane (alkyl)-3 beta,5,6 beta-triol injection and preparation method therefor | |
| KR20090095668A (en) | A forsythoside injection and preparation thereof | |
| BRPI0713080A2 (en) | injectable antibiotic formulation and solution for intravenous administration | |
| CN105078909A (en) | Cisatracurium besilate freeze dried composition for injection and preparation method thereof | |
| KR100835002B1 (en) | Pharmaceutical composition based on macrolides for topical application in ophthalmology | |
| CN1131039C (en) | Kelamycin injection and its preparing process | |
| AU2004271909A1 (en) | Methods for the controlled delivery of pharmacologically active compounds | |
| CN102008436B (en) | Nocathiacin antibiotic medicament composition containing emulsifying agent | |
| CN103315947A (en) | Tigecycline composition for injection | |
| CN1316247A (en) | Clamycin injection and its preparing process | |
| CN102697757B (en) | Application of p-hydroxy benzylidene acetone in preparation of drugs for preventing and/or treating encephalopathy | |
| CN102106811A (en) | Ivermectin mixed micelle injection and preparation method thereof | |
| CN100496506C (en) | Puerarin injection | |
| US20060094669A1 (en) | Method for treating bacterial infections in horses or pigs with tilmicosin | |
| CN100396289C (en) | Scutellarin injection preparation and its preparing method | |
| CN1256092C (en) | Methyleritrocina injection | |
| WO2022025831A1 (en) | Pharmaceutical compositions for injection comprising tulathromycin | |
| CN1706391A (en) | Terramycin suspension emulsion | |
| CN105769756A (en) | Sitafloxacin fumarate injection and preparation method thereof | |
| CN1338258A (en) | Antibacterial clindamycin phosphate powder injection and its preparing process | |
| CN1270723C (en) | Azithromycin injection and its preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |