CN106309360B - A kind of preparation method of long-acting ceftiofur hydrochloride injection - Google Patents
A kind of preparation method of long-acting ceftiofur hydrochloride injection Download PDFInfo
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- CN106309360B CN106309360B CN201610822133.6A CN201610822133A CN106309360B CN 106309360 B CN106309360 B CN 106309360B CN 201610822133 A CN201610822133 A CN 201610822133A CN 106309360 B CN106309360 B CN 106309360B
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- ceftiofur
- grinding
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- soybean oil
- ceftiofur hydrochloride
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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
- A61K9/08—Solutions
-
- 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
Abstract
Soybean oil is first heated to 140~150 DEG C and keeps the temperature 60 minutes sterilizing postcoolings to room temperature by a kind of preparation method of long-acting ceftiofur hydrochloride injection disclosed by the invention it is characterized in that using soybean oil as solvent；The Span 80 of the lecithin and 0.5~1.5wt% that take 0.5~2.0wt% of recipe quantity is dissolved or dispersed in 70%~80% sterile vehicle, colloid mill is then introduced into be ground, 10.2%~10.8wt% Ceftiofur Hydrochlorides of recipe quantity are added after grinding, then circular grinding and the acyclic alternate mode of grinding is used to be ground, check that grain fineness reaches 2.5 5.0 μm, stop grinding after meeting the requirements, sterile vehicle to formula ratio is added both to obtain intermediate products；After taking intermediate products to examine Ceftiofur content, product characteristics and consistence test qualification, filling, outsourcing, ware-house-in inspection content, sterile, granularity, after related substance qualification to obtain the final product.The results show that when Span 80 and the dosage of lecithin are 1%, the production technology and product quality of Ceftiofur Hydrochloride injecta are relatively stablized.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular, to a kind of preparation side of long-acting ceftiofur hydrochloride injection
Method.
Background technology
Ceftiofur (Ceftiofur) also known as ceftiofur, be earliest by Bernard Labeeuw et al. in 1984 first
Synthesis, is the dedicated Third generation Cephalosporins antibiotic of first livestock and poultry；Thereafter Pharmacia-Pu Qiang companies
(Pharmacia＆Upjohn) made sodium salt freeze-dried powder and hydrochloride suspension (trade name Naxcel,
Excenel) it is used for the treatment of Animal diseases.
Ceftiofur absorbs rapid, bioavilability height；It is high with vivo protein Percentage bound, inventory's sterilizing power is formed, partly
Phase of declining is long, lasting medicine；Compared with other antibiotic, which is unique in that content of the drug in infected tissue than non-
It is 2~4 times high in infected tissue, in the integrated distribution for having target, play bactericidal effect.
Ceftiofur mainly kills bacterium by acting on transpeptidase and blocking the synthesis of bacteria cell wall；To various leather orchid
Family name's positive bacteria (such as staphylococcus), Gram-negative bacteria (such as Escherichia coli, salmonella, Pseudomonas aeruginosa) and some anaerobic bacterias are all
There is very strong antibacterial activity.Ceftiofur remains low within the organization, and safety is good, molecular structure stabilized and will not be by beta-lactam
Enzyme destroys, and is not likely to produce drug resistance and cross resistance, is the strongest antibiotic of sterilizing power for animals on the market now, has current
The incomparable multiple superiority of other antibiotic of veterinary drug market popularity.
The preparation of China's approval at present has Ceftiofur soluble powder and suspension injection, these products are treatment animal
Disease has played due effect.However since the effective blood drug concentration of above-mentioned preparation was held time mostly in 24-32 hours
Between, daily injection is needed when clinical treatment, is made troubles to the treatment work of animal doctor, while also resulting in the discomfort for the treatment of animal
Ying Xing.
Applicant has invented a kind of long-acting ceftiofur hydrochloride injection and preparation method thereof (Chinese patent applications thus
Number 200910050126.9), it is formulated by the raw material of following weight percent：10.2%~10.8% hydrochloric acid cephalo thiophene
Furan, 2.0~6.5% pharmaceutic adjuvants, surplus are injection soybean oil.Additives include lecithin, Span-80 and propylene glycol.Ovum
Content of phospholipid is 0.5~2.0%, preferably 1.0%.Span-80 content is 0.5~1.5%, preferably 1.0%.Propylene glycol contains
Amount is 1.0~3.0%, preferably 2.0%.The long-acting ceftiofur hydrochloride injection, preparation method are the injections with heating
Additives are dissolved with soybean oil, are sterilized after stirring and evenly mixing, Ceftiofur Hydrochloride is added after cooling, are mixed using homogenizer equal
It is even, it is aseptic subpackaged to obtain injection finished product.
The long-acting ceftiofur hydrochloride injection can be held time with slow release drug effect, Blood drug concentration 72 hours with
On, it is much higher than existing Ceftiofur Hydrochloride injecta, injection one in 3 days is once reduced to by the daily injection of regular dosage form
It is secondary, and stability is good.The preparation method of the long-acting ceftiofur hydrochloride injection is simple, is carried out using high-shear homogenizing machine even
Slurry operation, obtains 10-15 μm of Nanoparticle liquid, reduces irritation of the liquid to injection site.
But the long-acting ceftiofur hydrochloride injection tablets in vitro tests T50%Only 3.8h, after 6 months accelerated tests
Ceftiofur content is only the 92.5~93.3% of former content.
Invention content
Technical problem to be solved by the present invention lies in for disclosed in Chinese Patent Application No. 200910050126.9
A kind of the problems of long-acting ceftiofur hydrochloride injection and preparation method thereof and a kind of long-acting ceftiofur hydrochloride is provided
The preparation method of injection.Long-acting ceftiofur hydrochloride injection prepared by the preparation method is ensureing that suspension sedimentation is slow,
While being easy to the characteristic of redisperse, tablets in vitro T50%And the stable content after 6 months accelerated tests is significantly increased.
The technical problems to be solved by the invention can be achieved through the following technical solutions：
A kind of preparation method of long-acting ceftiofur hydrochloride long-acting injection：Using soybean oil as solvent, first soybean oil is added
Heat is to 140~150 DEG C and keeps the temperature 60 minutes sterilizing postcoolings to room temperature；Take the lecithin and 0.5 of 0.5~2.0wt% of recipe quantity
The Span-80 of~1.5wt% is dissolved or dispersed in 70%~80% sterile vehicle, is then introduced into colloid mill and is ground,
10.2%~10.8wt% Ceftiofur Hydrochlorides of recipe quantity are added after grinding, then use circular grinding and acyclic grind
It grinds alternate mode to be ground, checks that grain fineness reaches 2.5-5.0 μm, stop grinding after meeting the requirements, add sterile vehicle
Intermediate products are both obtained to formula ratio；After taking intermediate products to examine Ceftiofur content, product characteristics and consistence test qualification, fill
Dress, outsourcing, ware-house-in inspection content, sterile, granularity, after related substance qualification to obtain the final product.
In a preferred embodiment of the invention, the lecithin content is 1%, and Span-80 content is 1%.
As a result of technical solution as above, the long-acting ceftiofur hydrochloride injection body prepared using the method for the present invention
Outer Drug Releasing Test T50%Reach 5.2h, Ceftiofur content is the 98.8% of former content after 6 months accelerated tests.
Specific implementation mode
1. instrument and reagent
Colloid mill (Shanghai Dong Hua high pressure homogenizers factory)；1100 high performance liquid chromatographs of A gillent；AG285 type electronics
Assay balance (Mei Teletuo benefits Instrument Ltd. of Switzerland)；Ceftiofur reference substance (China Veterinery Drug Inspection Office, batch
Number：K0330702)；Span-80 (Shanghai Shen Yu medication chemistries Co., Ltd)；Lecithin (the limited public affairs of Shanghai Ai Kang fine chemistry industries
Department)；Injection soybean oil (Tian Yu camellia oils development corporation, Ltd.).
2. method and result
2.1 prescriptions and technique
2.1.1 composition
Ceftiofur Hydrochloride 5kg, Span-80 (wetting agent) 0.5L, lecithin (suspending agent) 0.5L, injection soybean oil
(solvent) adds to 50L.
2.1.2 technical process
All open surfaces contacted with liquid such as preparation, filtering, pipeline, are handled by the following method in production process：Match
1%NaOH solution → washing processed or bubble 5min → water for injection are cleaned to neutrality, then are dried up with nitrogen.
Using soybean oil as solvent, soybean oil is first heated to 140~150 DEG C and keeps the temperature 60 minutes sterilizing postcoolings to room
Temperature.The suspending agent and wetting agent for taking recipe quantity are dissolved or dispersed in 70%~80% sterile vehicle, are then introduced into colloid mill
It is ground, the Ceftiofur Hydrochloride of recipe quantity is added after grinding, circular grinding and acyclic grinding is then used to replace
Mode be ground, check grain fineness reach 2.5-5.0 μm, after meeting the requirements stop grinding, add sterile vehicle to be formulated
Amount both obtains intermediate products；After taking intermediate products to examine Ceftiofur content, product characteristics and consistence test qualification, filling, outsourcing,
Ware-house-in inspection content, sterile, granularity, after related substance qualification to obtain the final product.
2.2 technical study
It by the difference that Span-80 (v/v) and lecithin (v/v) is added, is operated with method, the body of product is detected using dialysis
Outer drug release situation and stability.
2.2.1 tablets in vitro is tested
Precision measures the sample formulation of different formulations, puts into bag filter, both ends tighten, with the Ammoniom-Acetate of 0.05mol/L:
Acetonitrile (80: 20v/v) is dissolution medium, is stirred, is dialysed in the case of 37.5 DEG C of heated at constant temperature, not with the speed of 100rpm
With absorption 0.4ml release liquids at time point, while supplementing the dissolution medium of same amount.Cephalo in dissolution medium is detected using HPLC
Thiophene furan concentration, investigates the vitro release of sample.
2.2.2 accelerated stability test
It is respectively placed under 40 ± 2 DEG C of water bath conditions, makees after the durative action preparation sample of different formulations was measured content in the same day
It is sampled with after 6 months.Using HPLC detection levels, while observing the color change of preparation.
2.2.3 result
By the different amounts of Span-80 and lecithin, adopts and sample is made with the aforedescribed process.The release in vitro situation of sample
And stability result is shown in Table 1.As it can be seen that when the dosage of wetting agent Span-80 is 1%, the dosage of suspending agent lecithin is 1%,
The sample has preferable slow releasing function and more stable.
The formula of 1 Span-80 of table and lecithin investigates result
By the different amounts of Span -8 and lecithin, according to one disclosed in Chinese Patent Application No. 200910050126.9
Contrast sample is made in the preparation method of kind long-acting ceftiofur hydrochloride injection.The release in vitro situation and stability of contrast sample
It the results are shown in Table 2.As it can be seen that when the dosage of wetting agent Span-80 is 1%, the dosage of suspending agent lecithin is 1%, the comparative sample
The slow releasing function of product is worse than the present invention, and stability is also worse than the present invention.
The formula of 2 Span-80 of table and lecithin investigates result
3. discussing
Ceftiofur Hydrochloride is crystalline powder, readily soluble in water, insoluble in oil phase.Ceftiofur Hydrochloride is in oil phase
Dispersion be suspended, suspending agent need to be used to increase suspension dynamic stability.Suspending agent is a kind of sticking hydrophilic gel of tool
Body substance, using suspending agent can increase dispersion matchmaker viscosity, slow down the sinking speed of particle, and can be adsorbed on microparticle surfaces at
For the barrier for preventing particles agglomerate from luming.It also needs to keep material evenly dispersed in the oil using wetting agent simultaneously, wetting agent can be with
Make that dispersed phase dispersion degree is big, stability is good, is not easy to be influenced by extraneous factor.Not phase inversion when disperse phase concentration increases, not by micro- life
The decomposition and destruction of object, while keeping that there is enough electrostatic repulsions between different undissolved substance, it is therefore prevented that between each other
Polymerization is generated after collision, to make suspension generate ideal dispersion effect.
The size that main ingredient discriminating, content etc. are had an impact according to auxiliary material in experimentation, in combination with the heavy of suspension
The parameter requests such as drop volume ratio, redispersibility screen auxiliary material, and prescription is determined further according to stability test data.By examining
Single-factor influence of the different suspending agents to long-acting ceftiofur hydrochloride injection is examined, is determined using lecithin as suspending agent.
On the basis of this, then influence situation of the different wetting agent to suspension is investigated, according to pertinent literature report and trial test as a result, selection
Determine Span-80 as wetting agent.Investigated different amounts Span-80 and lecithin to product release and stability
It influences, the results show that when the dosage of Span-80 and lecithin is 1%, the production technology of Ceftiofur Hydrochloride injecta and production
Quality is relatively stablized.
Claims (1)
1. a kind of preparation method of long-acting ceftiofur hydrochloride injection will first be noted it is characterized in that inject soybean oil as solvent
Penetrate soybean oil be heated to 140~150 DEG C and keep the temperature 60 minutes sterilizing postcooling to room temperature obtain sterile vehicle；Take the ovum of recipe quantity
Phosphatide and Span-80 are dissolved or dispersed in 70%~80% sterile vehicle, are then introduced into colloid mill and are ground, have ground
The Ceftiofur Hydrochloride of recipe quantity is added after finishing, circular grinding and the acyclic alternate mode of grinding is then used to be ground,
It checks that grain fineness reaches 2.5-5.0 μm, stops grinding after meeting the requirements, sterile vehicle to recipe quantity is added both to obtain intermediate products；
After taking intermediate products to examine Ceftiofur content, product characteristics and consistence test qualification, filling, outsourcing, ware-house-in inspection content, nothing
Bacterium, granularity, after related substance qualification to obtain the final product；The prescription be Ceftiofur Hydrochloride 5kg, Span-80 0.5L, lecithin 0.5L,
Injection soybean oil adds to 50L.
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| CN201610822133.6A CN106309360B (en) | 2016-09-13 | 2016-09-13 | A kind of preparation method of long-acting ceftiofur hydrochloride injection |
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| CN201610822133.6A CN106309360B (en) | 2016-09-13 | 2016-09-13 | A kind of preparation method of long-acting ceftiofur hydrochloride injection |
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| CN106309360B true CN106309360B (en) | 2018-08-10 |
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| CN112924633B (en) * | 2021-05-10 | 2021-08-10 | 天津瑞普生物技术股份有限公司 | Sterility detection method for ceftiofur oil suspension injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101406447A (en) * | 2007-10-12 | 2009-04-15 | 河南农业大学 | Technique for preparing compound ceftiofur oil suspension injection |
| CN101874773A (en) * | 2009-04-28 | 2010-11-03 | 上海市动物疫病预防控制中心 | Long-acting ceftiofur hydrochloride injection and preparation method thereof |
| CN102018669A (en) * | 2010-11-19 | 2011-04-20 | 武汉回盛生物科技有限公司 | Long-acting ceftiofur hydrochloride injection and preparation method thereof |
-
2016
- 2016-09-13 CN CN201610822133.6A patent/CN106309360B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101406447A (en) * | 2007-10-12 | 2009-04-15 | 河南农业大学 | Technique for preparing compound ceftiofur oil suspension injection |
| CN101874773A (en) * | 2009-04-28 | 2010-11-03 | 上海市动物疫病预防控制中心 | Long-acting ceftiofur hydrochloride injection and preparation method thereof |
| CN102018669A (en) * | 2010-11-19 | 2011-04-20 | 武汉回盛生物科技有限公司 | Long-acting ceftiofur hydrochloride injection and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| 兽用抗菌药缓释注射剂研究;贾艳华等;《兽医导刊》;20071231(第4期);35-37 * |
| 头孢噻呋混悬注射液的研制及疗效试验;司红彬等;《河南农业大学学报》;20080229;第42卷(第1期);71-76 * |
| 长效盐酸头孢噻呋注射液的生产工艺研究;张文刚等;《上海畜牧兽医通讯》;20150430(第2期);50-51 * |
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