CN106420613A - Florfenicol micelle preparation and preparation method thereof - Google Patents
Florfenicol micelle preparation and preparation method thereof Download PDFInfo
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- CN106420613A CN106420613A CN201611083457.9A CN201611083457A CN106420613A CN 106420613 A CN106420613 A CN 106420613A CN 201611083457 A CN201611083457 A CN 201611083457A CN 106420613 A CN106420613 A CN 106420613A
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- florfenicol
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
The invention belongs to the technical field of veterinary drugs, and particularly discloses a florfenicol micelle preparation and a preparation method thereof. The florfenicol micelle preparation comprises, by weight, 3-5 parts of florfenicol, 8.0-16 parts of PEO (polyethylene oxide)-b-PCL (polycaprolactone) copolymer, 55-70 parts of PBS (poly butylenes succinate) buffer solution, 0-8 parts of additives and pH (potential of hydrogen) regulators with the pH value of 5-7. The PEO-b-PCL copolymer serves as a micelle carrier, the florfenicol micelle preparation is prepared, a superior drug administration method is provided for the florfenicol, the micelle carrier is high in encapsulation efficiency and drug loading ratio, and bioavailability of the florfenicol is improved.
Description
Technical field
The invention belongs to veterinary medicine technical field is and in particular to a kind of florfenicol micellar preparation and preparation method thereof.
Background technology
Florfenicol（Forfenicol）It is the broad-spectrum antiseptic for animals that Schering Plough company of the U.S. develops the end of the seventies
Medicine, is new chloromycetin antibacterial, is characterized in that has a broad antifungal spectrum, absorption are good, widely distributed in vivo, and no potential cause is again
Raw aplastic anemia effect, also no teratogenesis, carcinogenic and mutagenic action；It is white or off-white color crystalline powder, odorless；?
Easily dissolve in dimethylformamide, dissolve in methyl alcohol, slightly molten in glacial acetic acid, soluble,very slightly in water and chloroform.
Florfenicol is mainly used in the bacterial disease of cattle, pig, chicken and Fish, such as the respiratory tract infection of cattle, mastitis；Pig
Contagious pleuropneumonia, yellow scours, Hakuri；Chicken colibacillosis, cholera etc..Poultry are taken orally and intramuscular injection this product absorbs soon, are distributed in vivo
Extensively, long half time, can maintain the effective blood drug concentration of long period.The bioavailability that broiler, calf are taken orally is respectively
55.3%、88%；Pig is taken orally and almost fully absorbs；The half-life of cattle intravenous and intramuscular injection is respectively 2.6,18.3h；Pig intravenous and intramuscular injection
Half-life be respectively 6.7,17.2h；The half-life of chicken intravenous is 5.36h.Most drug is discharged from urine with original shape.
At present, the existing relevant report to dosage forms such as florfenicol injection, pre-mixing agent, powder both at home and abroad.Florfenicol
Because the factors such as has a broad antifungal spectrum, good anti-bacterial effect, small toxicity are widely used in livestock and poultry cultivation.But florfenicol water soluble is very
Difference, have impact on the use in intensive culture overall situation instantly, lot of domestic and international scholar expert is being devoted to increasing its water
Dissolubility.
Amphipathic nature block polymer refers in a molecule containing hydrophilic and lipophile segment one to birds of the same feather flock together compound simultaneously,
Stable micellization structure can be self-assembly of by insoluble segment in selective solvent, and its size is generally less than
200nm, can be used for the preparation of nano material.The micelle of the amphipathic nature block polymer preparation of degradable is in parcel hydrophobicity medicine
The aspects such as thing, prolongation medicine biological activity, Drug controlled release speed, target administration, prolongation medicine half-life in blood
There is remarkable advantage, have preferable application prospect as degradable medicaments transport vehicle in medical science and pharmaceutically, it has also become Ren Menyan
The focus studied carefully.
Content of the invention
The purpose of the present invention aims to provide a kind of florfenicol micellar preparation and preparation method thereof.
For achieving the above object, the technical scheme that the present invention takes is as follows：
A kind of florfenicol micellar preparation, in parts by weight, consisting of：3 ~ 5 parts of florfenicol, PEO-b-PCL（I.e. polycyclic
Oxidative ethane-b- polycaprolactone）8.0 ~ 16 parts of copolymer, 55 ~ 70 parts of PBS, 0 ~ 8 part of additives and pH adjusting agent, pH adjusts
PH 5 ~ 7 is adjusted in section agent.
Preferably, described additives are glucose.
Preferably, described pH adjusting agent is citric acid.
Preparation method, step is as follows：By PEO-b- PCL copolymer adds dissolving in organic solvent, and decompression in water-bath boils off
Film forming after organic solvent, adds the PBS containing florfenicol and additives, stirs aquation, is adjusted with pH adjusting agent
PH, then membrane filtration obtain final product.
Preferably, described organic solvent is dimethylformamide or methanol.
Preferably, bath temperature is 45 ~ 55 DEG C, and hydration time is 2 ~ 3h.
Preferably, filter sizes are 0.45 micron.
Beneficial effect：The present invention is with PEO-b- PCL copolymer is micellar carrier, has prepared florfenicol micellar preparation,
There is provided a more excellent administering mode for florfenicol, and this micellar preparation envelop rate and carrying drug ratio height, improve florfenicol
Bioavailability.
Specific embodiment
Below in conjunction with specific embodiment, technical scheme is described in further detail, but the protection model of the present invention
Enclose and be not limited thereto.
Amphipathic linear block copolymers PEO- in following examplesbThe synthetic operation process of-PCL is as follows：
First to 10ml Schlenk reaction bulb eliminating water, after being cooled to room temperature, add 0.5g（2mmol）PEO, then evacuation is simultaneously
Blown around bottle wall with air pressure gun, continue 2-3h.It is filled with nitrogen after the cooling of question response bottle, steamed with the injection 1.5ml decompression of dry injection device
Evaporate the ε-CL of process, 2 catalyst Sn (Oct)2, tube sealing reacts 4h, stopped reaction at 120 DEG C, slowly drips solution while hot
It is added in the cold petroleum ether of 20 times of volumes, staticly settle, natural filtration, vacuum is drained, and obtains PEO-b- PCL copolymer.
Embodiment 1
A kind of florfenicol micellar preparation, consisting of：Florfenicol 3g, PEO-b- PCL copolymer 8g, 0.01M PBS delays
Rush liquid（pH7.4）55g, glucose 3.0g and appropriate citric acid；
Preparation method（Preparation process lucifuge operates）：
（1）By PEO-b- PCL copolymer is placed in eggplant-shape bottle, adds the dimethylformamide dissolving of meltage, in 45 DEG C of water-baths
Middle decompression boils off film forming after organic solvent；
（2）Florfenicol and glucose PBS are dissolved；
（3）Will（2）Add（1）In, stir aquation 2h, with Fructus Citri Limoniae acid for adjusting pH to 5, then use 0.45um membrane filtration, obtain final product.
Measure the envelop rate of florfenicol and drug loading is respectively 83.6% and 14%.
Embodiment 2
A kind of florfenicol micellar preparation, consisting of：Florfenicol 3.5g, PEO-b- PCL copolymer 1 2.5g, 0.01M
PBS（pH7.4）58g, glucose 4g and appropriate citric acid.
Preparation method（Preparation process lucifuge operates）：
（1）By PEO-b- PCL copolymer is placed in eggplant-shape bottle, adds the dimethylformamide dissolving of meltage, in 50 DEG C of water-baths
Middle decompression boils off film forming after organic solvent；
（2）Florfenicol and glucose PBS are dissolved；
（3）Will（2）Add（1）In, stir aquation 2.5h, with Fructus Citri Limoniae acid for adjusting pH to 6, then with 0.45 um membrane filtration, that is,
?.
Measure the envelop rate of florfenicol and drug loading is respectively 85.6% and 15%.
Embodiment 3
A kind of florfenicol micellar preparation, consisting of：Florfenicol 5.0g, PEO-b- PCL copolymer 1 6g, 0.01M PBS
Buffer（pH7.4）70g, glucose 8.0g, citric acid 1.1g.
Preparation method（Preparation process lucifuge operates）：
（1）By PEO-b- PCL copolymer is placed in eggplant-shape bottle, adds the dimethylformamide dissolving of meltage, in 55 DEG C of water-baths
Middle decompression boils off film forming after organic solvent；
（2）Florfenicol and glucose PBS are dissolved；
（3）Will（2）Add（1）In, stir aquation 3h, with Fructus Citri Limoniae acid for adjusting pH to 7, then use 0.45um membrane filtration, obtain final product.
Measure the envelop rate of florfenicol and drug loading is respectively 82.8% and 14%.
Embodiment 4
A kind of florfenicol micellar preparation, consisting of：Florfenicol 4.0g, PEO-b- PCL copolymer 1 4.5g, 0.01M
PBS（pH7.4）60g, citric acid 1.0g.
Preparation method（Preparation process lucifuge operates）：
（1）By PEO-b- PCL copolymer is placed in eggplant-shape bottle, adds the dimethylformamide dissolving of meltage, in 55 DEG C of water-baths
Middle decompression boils off film forming after organic solvent；
（2）Florfenicol and glucose 0.01M PBS are dissolved；
（3）Will（2）Add（1）In, stir aquation 2.5h, with Fructus Citri Limoniae acid for adjusting pH to 6, then use 0.45um membrane filtration, that is,
?.
Measure the envelop rate of florfenicol and drug loading is respectively 80.2% and 11%.
In the R＆D process of the present invention, the present inventor also using other copolymers as carrier, is simultaneously
Row contrast test, specific as follows：
Reference examples 1
With the difference of embodiment 2, it is：By PEO-b-PCL copolymer be replaced by with its etc. weight PS-b-PEG copolymerization
Thing.Other is all with embodiment 2.PS-b-PEG copolymer synthesizes with reference to prior art.
Reference examples 2
With the difference of embodiment 2, it is：By PEO-b-PCL copolymer be replaced by with its etc. weight PEG-b-PCL copolymerization
Thing.Other is all with embodiment 2.PEG-b-PCL copolymer synthesizes with reference to prior art.
Reference examples 3
With the difference of embodiment 2, it is：By PEO-b-PCL copolymer be replaced by with its etc. weight PEO-b-PAA-b-
PS copolymer.Other is all with embodiment 2.PEO-b-PAA-b-PS copolymer synthesizes with reference to prior art.
The envelop rate of florfenicol micellar preparation of embodiment 1 ~ 4 and reference examples 1 ~ 3 preparation and drug loading test result
It is shown in Table 1.
The florfenicol micellar preparation index contrast of the different block copolymer preparation of table 1
As shown in Table 1：The present invention chooses PEO-b- PCL block copolymer is as carrier, the florfenicol micellar preparation bag of preparation
, all more than 80%, drug loading is more than 10% for envelope rate；In research process, contrast the preparation bag that other copolymers measure as carrier
Envelope rate and drug loading are below the present invention, and the present invention has good market value and prospect.
Claims (7)
1. a kind of florfenicol micellar preparation is it is characterised in that in parts by weight, consisting of：3 ~ 5 parts of florfenicol, PEO-b
8.0 ~ 16 parts of-PCL copolymer, 55 ~ 70 parts of PBS, 0 ~ 8 part of additives and pH adjusting agent, pH adjusting agent adjusts pH 5 ~ 7.
2. florfenicol micellar preparation as claimed in claim 1 it is characterised in that：Described additives are glucose.
3. florfenicol micellar preparation as claimed in claim 1 it is characterised in that：Described pH adjusting agent is citric acid.
4. one kind prepare the florfenicol micellar preparation as described in any one of claim 1 ~ 3 method it is characterised in that
Step is as follows：By PEO-b- PCL copolymer adds dissolving in organic solvent, and decompression in water-bath boils off film forming after organic solvent, then
Add the PBS containing florfenicol and additives, stir aquation, adjust pH with pH adjusting agent, then membrane filtration is
?.
5. florfenicol micellar preparation as claimed in claim 4 preparation method it is characterised in that：Described organic solvent is two
Methylformamide or methanol.
6. florfenicol micellar preparation as claimed in claim 5 preparation method it is characterised in that：Bath temperature is 45 ~ 55
DEG C, hydration time is 2 ~ 3h.
7. florfenicol micellar preparation as claimed in claim 6 preparation method it is characterised in that：Filter sizes are micro- for 0.45
Rice.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611083457.9A CN106420613A (en) | 2016-11-30 | 2016-11-30 | Florfenicol micelle preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611083457.9A CN106420613A (en) | 2016-11-30 | 2016-11-30 | Florfenicol micelle preparation and preparation method thereof |
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| Publication Number | Publication Date |
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| CN106420613A true CN106420613A (en) | 2017-02-22 |
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| CN201611083457.9A Pending CN106420613A (en) | 2016-11-30 | 2016-11-30 | Florfenicol micelle preparation and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6469132B1 (en) * | 1999-05-05 | 2002-10-22 | Mcgill University | Diblock copolymer and use thereof in a micellar drug delivery system |
| WO2005118672A1 (en) * | 2004-06-02 | 2005-12-15 | The Governors Of The University Of Alberta | Polymer based nano-carriers for the solubilization and delivery of hydrophobic drugs |
| CN102397237A (en) * | 2011-11-23 | 2012-04-04 | 河南牧翔动物药业有限公司 | Tilmicosin micelle preparation and preparation method thereof |
-
2016
- 2016-11-30 CN CN201611083457.9A patent/CN106420613A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6469132B1 (en) * | 1999-05-05 | 2002-10-22 | Mcgill University | Diblock copolymer and use thereof in a micellar drug delivery system |
| WO2005118672A1 (en) * | 2004-06-02 | 2005-12-15 | The Governors Of The University Of Alberta | Polymer based nano-carriers for the solubilization and delivery of hydrophobic drugs |
| CN102397237A (en) * | 2011-11-23 | 2012-04-04 | 河南牧翔动物药业有限公司 | Tilmicosin micelle preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 何伟娜: "聚(ε-己内酯)-b-聚氧化乙烯结晶性胶束的形貌调控和控制生长", 《中国博士学位论文全文数据库 工程科技I辑》 * |
| 陈芳等: "聚合物胶束载药制备方法研究进展", 《亚太传统医药》 * |
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Application publication date: 20170222 |