CN105496949A - Preparation method of slow-released levofloxacin injection - Google Patents
Preparation method of slow-released levofloxacin injection Download PDFInfo
- Publication number
- CN105496949A CN105496949A CN201510964056.3A CN201510964056A CN105496949A CN 105496949 A CN105496949 A CN 105496949A CN 201510964056 A CN201510964056 A CN 201510964056A CN 105496949 A CN105496949 A CN 105496949A
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- CN
- China
- Prior art keywords
- levofloxacin
- preparation
- organic solvent
- fatty acid
- injection
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
The invention provides a preparation method of a slow-released levofloxacin injection, and belongs to a slow-released injection for animals. The levofloxacin injection is prepared from, by weight, 5%-20% of levofloxacin, 1%-4% of fatty acid, 5%-35% of stabilizer and the balance organic solvent. The preparation method comprises the steps that levofloxacin and the organic solvent are taken and stirred for dissolution, the fatty acid is added to conduct a complexation reaction with a dissolved product, the stabilizer is added, after sufficient dissolution is achieved, the organic solvent is added for the scale volume, and the slow-released levofloxacin injection is obtained after membrane filtration is conducted. According to the preparation method of the slow-released levofloxacin injection, levofloxacin or a salt hydrate thereof is reacted with the fatty acid to form a new compound, the release time of levofloxacin can be prolonged, the effective blood drug concentration of a drug in an animal body can be maintained for a long time, and therefore the purposes of decreasing the frequency of drug delivery and reducing drug stress are achieved.
Description
Technical field
The present invention relates to a kind of preparation method of Injection for animals, especially relate to a kind of preparation method of slow release levofloxacin.
Background technology
Levofloxacin (Norfloxacin has another name called Noroxin, Fulgram), another name: Eoroxin, norfloxacin, pouring jinx, its chemistry fluoro-Isosorbide-5-Nitrae of 1-ethyl-6--dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid by name.For second filial generation Comprecin, its effect is the effect of the DNA helicase hindering malignant bacteria in digestive tract, hinders bacterium DNA replication, has inhibitory action to antibacterial, is the common medicine for the treatment of enteritis and dysentery and urinary system infection.
Recent years, China's livestock and poultry breeding industry is frequently subject to the puzzlement of extensive respiratory tract and infectious disease of the digestive tract, and respiratory tract and digestive tract disease have usually, and sickness rate is high, the feature of course of disease length, needs long-time multiple dosing over the course for the treatment of.Levofloxacin is common medicine and the specific drug of the large-scale cultivated animals such as chicken, pig, but the common levofloxacin half-life is short, for meeting the Treatment need of ill poultry, need repetitively administered, improve the labor cost of modern livestock and poultry breeding industry and increase the stress of cultivated animals.Therefore the task of top priority that long-acting slow-release levofloxacin becomes modern poultry industry is developed.
Summary of the invention
The present invention is intended to the defect for prior art, a kind of preparation method that can extend the levofloxacin half-life is provided, need repeated multiple times medication to solve in prior art in long course of disease Animal diseases therapeutic process, increase animal and meet an urgent need and increase the problem of aquaculture cost.
For realizing above technical purpose, the present invention by the following technical solutions:
A preparation method for slow release levofloxacin, described levofloxacin comprises following composition by weight percentage;
Levofloxacin 5-20%
Fatty acid 1-4%
Stabilizing agent 5-35%
Surplus is organic solvent
The preparation steps of described preparation method is as follows:
5) levofloxacin and organic solvent stirring and dissolving is got;
6) lysate adding fatty acid and step 1 carries out complex reaction;
7) stabilizing agent is added;
8) slow release levofloxacin is namely obtained with membrane filtration after organic solvent standardize solution.
The present invention prepares the method for levofloxacin, and described levofloxacin is salt or its hydrate of the form such as hydrochlorate, lactate, methanesulfonic acid, malic acid of the former medicine of levofloxacin or levofloxacin.
The present invention prepares the method for levofloxacin, described organic solvent is that dissolve each other with water, pharmaceutically acceptable organic solvent, and preferred organic solvent is on this basis: tetrahydrofurfuryl alcohol, propylene glycol, N-Methyl pyrrolidone, glycerol triacetate arbitrary.
The present invention prepares the method for levofloxacin, and described fatty acid is C
9-C
18between containing the fatty acid of even number of carbon atoms, preferred fatty acid is further on this basis: capric acid, lauric acid, Palmic acid, oleic acid arbitrary.
The present invention prepares the method for levofloxacin, described stabilizing agent be poloxamer, fatty acid glyceride, PVP, polyoxyethylene hydrogenated Oleum Ricini arbitrary.
The present invention prepares the method for levofloxacin, and described levofloxacin organic solvent dissolution product and fatty acid complexation time are 1-4h.
Owing to have employed technique scheme, the present invention has following beneficial effect:
Traditional levofloxacin is mainly Levofloxacin Hydrochloride or lactate aqueous solution, its half-life is in animal body 4-10 hour, clinical administration needs 2 times/day and continuous use 3-5d, the levofloxacin disclosed by the invention half-life is in animal body 20-24h, every day, single-dose can meet clinical application requirement, greatly reduced the emergency reaction of medication animal while significantly reducing clinical treatment workload.Meanwhile, levofloxacin provided by the invention, due to levofloxacin and fatty acid complexation, extends levofloxacin release time in animal body, its can in 3-10 days continuous release of active compounds.
Accompanying drawing explanation
Fig. 1 is that slow release levofloxacin compares with the blood drug level of traditional levofloxacin in piglet body.
In figure: 1, the change of traditional levofloxacin blood drug level in piglet body; 2, the change of levofloxacin caprate injection blood drug level in piglet body; 3, the change of levofloxacin laruate injection blood drug level in piglet body; 4, the change of levofloxacin palmitate injection blood drug level in piglet body; 5, the change of levofloxacin oleate injection blood drug level in piglet body.
Detailed description of the invention
Below will be described in detail the specific embodiment of the present invention.In order to avoid too much unnecessary details, in the examples below to belonging to known structure or function will not be described in detail.
Embodiment 1
The preparation of 5% levofloxacin caprate injection
Get 5g levofloxacin (pure) and 40g tetrahydrofurfuryl alcohol, stirring and dissolving, to clarification, adds after 1g capric acid slowly stirs complexation 1h, add 5g poloxamer to continue to stir to clarify, tetrahydrofurfuryl alcohol is settled to 100ml, with 0.45 μm of organic membrane filter, obtains 5% levofloxacin.
Embodiment 2
The preparation of 10% levofloxacin laruate injection
Get 10g levofloxacin (pure) and 40g propylene glycol, stirring and dissolving is to clarification, add after 2g lauric acid slowly stirs complexation 2h, add 10g fatty acid glyceride to continue to stir to clarify, propylene glycol is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 10% levofloxacin laruate injection.
Embodiment 3
The preparation of 15% levofloxacin palmitate injection
Get 15g levofloxacin (pure) and 40gN-methyl pyrrolidone, stirring and dissolving is to clarification, add after 3g Palmic acid slowly stirs complexation 3h, add 20g PVP to continue to stir to clarify, N-Methyl pyrrolidone is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 15% levofloxacin palmitate injection.
Embodiment 4
The preparation of 20% levofloxacin oleate injection
Get 20g levofloxacin (pure) and 40g glycerol triacetate, stirring and dissolving is to clarification, add after 4g oleic acid slowly stirs complexation 4h, add 35g polyoxyethylene hydrogenated Oleum Ricini to continue to stir to clarify, glycerol triacetate is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 20% levofloxacin oleate injection.
Embodiment 5
Slow release levofloxacin of the present invention compares with the blood drug level of traditional levofloxacin in piglet body
1, laboratory animal
Select sodium selenite 15 in 6 week age, male and female has concurrently, average weight (14.0 ± 1.5) kg, carries out routine and raises, free choice feeding and drinking-water in dedicated experiments district, and feedstuff is not containing any antibacterials.
2, injection formula
1) traditional levofloxacin: levofloxacin hydrochloride water for injection is mixed with 5% injection (in levofloxacin, lower same);
2) levofloxacin caprate injection: prepare by embodiment 1;
3) levofloxacin laruate injection: prepare by embodiment 2;
4) levofloxacin palmitate injection; Prepare by embodiment 3;
5) levofloxacin oleate injection: prepare by embodiment 4.
3, laboratory animal grouping and administration
15 healthy test pig are divided into 5 groups at random, often group 3 is parallel, numbers, weighs, by body weight intramuscular injection levofloxacin 10mg/kg ((in levofloxacin), take free choice feeding and drinking-water, feedstuff is complete feed (not containing antibiotics).
4, the collection of sample
Test pig is lain on the back Baoding by Baoding personnel, gathers blank blood sample before administration from vena cava anterior.After levofloxacin intramuscular delivery 0.1,0.5,1,2,4,6,8,10,12,18,24,48,72,96,120,144,168,192h blood sampling.Each blood sampling 3ml, adds corresponding heparin sodium, through the centrifugal 10min of low-temperature and high-speed centrifuge 10000r/min, gets upper plasma in-20 DEG C of preservations.
5, the mensuration of blood drug level
Get blood plasma 0.5mL, add ofloxacin (interior mark) the 10 μ L of 50mg/L, high speed centrifugation after methanol Deproteinization, on supernatant, machine fluorescence detector detects.Chromatographic condition: Nova-PakC18 post (4 μm, 4.6mm × 200mm); Mobile phase is water-acetonitrile (92: 8), includes 0.015mol/L tetrabutyl ammonium bromide, and phosphoric acid adjusts pH to be 3.0; Flow velocity 1.0mL/min; Excitation wavelength 278nm, emission wavelength 465nm.Result as shown in Figure 1, tradition levofloxacin holding time of effective blood drug concentration in experimental animals is significantly less than injection of the present invention, the time that tradition levofloxacin reaches peak plasma concentrations is in vivo about 2h, after this decay rapidly, and the injection of levofloxacin of the present invention reaches the time of peak plasma concentrations in vivo between 8-12 hour, holding time of effective blood drug concentration reaches more than 18h.
Claims (6)
1. a preparation method for slow release levofloxacin, is characterized in that: described levofloxacin component and mass percent are:
Levofloxacin 5-20%
Fatty acid 1-4%
Stabilizing agent 5-35%
Surplus is organic solvent;
The preparation steps of described preparation method is as follows:
1) levofloxacin and organic solvent stirring and dissolving is got;
2) lysate adding fatty acid and step 1 carries out complex reaction;
3) stabilizing agent is added;
4) slow release levofloxacin is namely obtained with membrane filtration after organic solvent standardize solution.
2. the preparation method of a kind of slow release levofloxacin according to claim 1, is characterized in that: described levofloxacin is salt or its hydrate of the form such as hydrochlorate, lactate, methanesulfonic acid, malic acid of the former medicine of levofloxacin or levofloxacin.
3. the preparation method of a kind of slow release levofloxacin according to claim 1, is characterized in that: described organic solvent be tetrahydrofurfuryl alcohol, propylene glycol, N-Methyl pyrrolidone, glycerol triacetate any one.
4. the preparation method of a kind of slow release levofloxacin according to claim 1, is characterized in that: described fatty acid be capric acid, lauric acid, Palmic acid, oleic acid any one.
5. the preparation method of a kind of slow release levofloxacin according to claim 1, is characterized in that: described stabilizing agent be poloxamer, fatty acid glyceride, PVP, polyoxyethylene hydrogenated Oleum Ricini any one.
6. the preparation method of a kind of slow release levofloxacin according to claim 1, is characterized in that: described levofloxacin organic solvent dissolution product and fatty acid complexation time are 1-4h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510964056.3A CN105496949A (en) | 2015-12-18 | 2015-12-18 | Preparation method of slow-released levofloxacin injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510964056.3A CN105496949A (en) | 2015-12-18 | 2015-12-18 | Preparation method of slow-released levofloxacin injection |
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| Publication Number | Publication Date |
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| CN105496949A true CN105496949A (en) | 2016-04-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510964056.3A Pending CN105496949A (en) | 2015-12-18 | 2015-12-18 | Preparation method of slow-released levofloxacin injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108567761A (en) * | 2018-07-25 | 2018-09-25 | 江苏黄河药业股份有限公司 | A kind of Levofloxacin Hydrochloride Capsules and preparation method thereof |
-
2015
- 2015-12-18 CN CN201510964056.3A patent/CN105496949A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108567761A (en) * | 2018-07-25 | 2018-09-25 | 江苏黄河药业股份有限公司 | A kind of Levofloxacin Hydrochloride Capsules and preparation method thereof |
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Application publication date: 20160420 |