CN104784152B - A kind of Thiamphenicol micro-capsule and preparation method and application - Google Patents
A kind of Thiamphenicol micro-capsule and preparation method and application Download PDFInfo
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- CN104784152B CN104784152B CN201410025210.6A CN201410025210A CN104784152B CN 104784152 B CN104784152 B CN 104784152B CN 201410025210 A CN201410025210 A CN 201410025210A CN 104784152 B CN104784152 B CN 104784152B
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Abstract
The invention discloses a kind of Thiamphenicol micro-capsule and preparation method and application.The Thiamphenicol micro-capsule includes following component：Thiamphenicol, silica and the carrier material being made up of sodium carboxymethylcellulose and gelatin.The present invention, by Thiamphenicol microencapsulation, extends the half-life period and medicine effective acting time of Thiamphenicol, reduces administration number of times, reduce drug cost by using spray drying process.
Description
Technical field
The invention belongs to veterinary drug technical field, and in particular to a kind of Thiamphenicol micro-capsule and preparation method thereof, and the first
Application of the hyrazin micro-capsule in veterinary drug preparation.
Background technology
Thiamphenicol（TAP）For chloromycetin broad-spectrum antibiotic, its chemical constitution is similar to chloramphenicol, is the class of chloramphenicol
Like thing, to light, thermally-stabilised, there is hygroscopicity, be referred to as second generation chloramphenicol.Its mechanism of action is identical with chloramphenicol, but its MSM
Base instead of the nitro of chloramphenicol, and effectively overcoming chloramphenicol causes the defect of alpastic anemia, and antibacterial action is more mould than chlorine
It is plain strong, clinically it is mainly used in treating the bacterial infection of livestock and poultry, particularly Escherichia coli, salmonella and Pasteurella etc. draws
Rise respiratory tract, intestines problem.
Thiamphenicol is for oral administration to absorb complete, and each tissue in vivo is distributed widely in after absorption, is mainly drained with prototype from urine.
But its half-life short, the especially half-life period in chicken body are only 2 hours or so.
Application No. CN201010507404.1 patent discloses a kind of preparation method of thiamphenicol suspension emulsifier, its
Using 10-30% micronizing Thiamphenicol, 5-15% emulsifying agent, 20-30% oil phase, 0.02-5% auxiliary stabilizer and remaining
The water of amount is prepared, it is advantageous that medicine with aqueous phase-oil phase-solid phase composition mixed system, has supensoid agent and emulsion concurrently
Good characteristic, intramuscular injection of drugs consumption is reduced, and the stimulation in vivo to livestock and poultry is small, after medication, is scattered in aqueous phase and oil phase
Slowly release is targetted and sustained release long-acting micronized medicine active component so as to reach in vivo.In addition said preparation drugloading rate
Greatly, property is stable, stand and transport after should not be layered and settle, good fluidity is easy to intramuscular injection, is Thiamphenicol in animal doctor
Clinical application opens new approach.But because containing, oil-phase component is higher to cause preparation cost high to the thiamphenicol suspension emulsifier,
And preparation process is complicated, unstable product quality.
The content of the invention
It is few compared with long, times for spraying it is a primary object of the present invention to provide a kind of effective acting time, drug cost it is low and
The Thiamphenicol micro-capsule that preparation technology is simple, product quality is stable.The Thiamphenicol micro-capsule is composed of the following components：MSM is mould
Element, silica and the carrier material being made up of sodium carboxymethylcellulose and gelatin.
Preferably, the Thiamphenicol micro-capsule is composed of the following components：Thiamphenicol 1-10 parts by weight, silica 0.2-
1.0 parts by weight, carrier material 3-30 parts by weight.
Preferably, the weight ratio of sodium carboxymethylcellulose and gelatin is 1 in the carrier material:5.
It is specific as follows another object of the present invention is to provide a kind of preparation method of Thiamphenicol micro-capsule：
1st, take recipe quantity sodium carboxymethylcellulose, gelatin to be configured to 3g/L, 30g/L aqueous solution respectively, both are mixed
Produce carrier solution；
2nd, recipe quantity Thiamphenicol, silica stirring is taken it is dispersed in carrier solution, spray drying is produced
Thiamphenicol micro-capsule.
It is still another object of the present invention to provide a kind of animal medicinal composition, the animal medicinal composition is peroral dosage form, comprising
The Thiamphenicol micro-capsule and excipient substance prepared using the above method.The excipient substance includes but is not limited to starch, sucrose, Portugal
Grape sugar, lactose or its mixture.Preferably, the excipient substance is starch.
Preferably, in animal medicinal composition of the present invention, the peroral dosage form be granule, tablet, powder, capsule or
Pre-mixing agent.
Another aspect of the invention is provides a kind of preparation method of animal medicinal composition, in the above-mentioned Thiamphenicol prepared
Excipient substance is added in micro-capsule, that is, obtains the animal medicinal composition of peroral dosage form.
Preferably, the above-mentioned Thiamphenicol micro-capsule prepared is loaded in fluid bed spray pot as bed material, takes recipe quantity
Excipient substance crosses 100 mesh sieves, and the binder solution for being configured to 10% that adds water is sprayed to Thiamphenicol micro-capsule surface, i.e., as slurry
Obtain Thiamphenicol micro-capsule granules.
Preferably, the Thiamphenicol micro-capsule is 4.2-41 parts by weight, and the excipient substance is 60-100 parts by weight.
Another aspect of the invention is that the animal medicinal composition containing the Thiamphenicol micro-capsule is preparing treatment chicken colibacillosis
Medicine in application.
The present invention, by Thiamphenicol microencapsulation, extends half-life period and the medicine of Thiamphenicol by using spray drying process
Effective acting time, administration number of times is reduced, reduce drug cost.The Thiamphenicol micro-capsule has preparation technology letter simultaneously
The advantages of single, product quality is stable.
Embodiment
The source-information of Thiamphenicol, sodium carboxymethylcellulose, gelatin and silica used in the embodiment of the present invention
It is as follows：
Thiamphenicol, content 99.0%, Shanxi great Hua great achievements Pharmaceutical Technology Co., Ltd；
Sodium carboxymethylcellulose, Henan Jin Run food additives Co., Ltd；
Gelatin, biological level, Tianjin Kermel Chemical Reagent Co., Ltd.；
Silica, the specialization chemical product Co., Ltd of Henan hundred million, 32 μm of particle diameter.
Embodiment 1：The preparation of Thiamphenicol micro-capsule and Thiamphenicol micro-capsule granules
1st, take sodium carboxymethylcellulose 0.5g, gelatin 2.5g to be configured to 3g/L, 30g/L aqueous solution respectively, both are mixed
It is even to produce carrier solution；
2nd, Thiamphenicol 1g, silica 0.2g stirring is taken it is dispersed in carrier solution, spray drying is produced
Thiamphenicol micro-capsule；
3rd, Thiamphenicol micro-capsule is loaded in fluid bed spray pot as bed material, takes 60g starch to cross 100 mesh sieves, add water preparation
Binder solution into 10% is sprayed to Thiamphenicol micro-capsule surface, produces Thiamphenicol micro-capsule granules as slurry.
Embodiment 2：The preparation of Thiamphenicol micro-capsule and Thiamphenicol micro-capsule granules
1st, take sodium carboxymethylcellulose 5g, gelatin 25g to be configured to 3g/L, 30g/L aqueous solution respectively, be by both mixings
Obtain carrier solution；
2nd, Thiamphenicol 10g, silica 1 g stirring is taken it is dispersed in carrier solution, spray drying produces first
Hyrazin micro-capsule；
3rd, Thiamphenicol micro-capsule is loaded in fluid bed spray pot as bed material, takes 100g starch to cross 100 mesh sieves, add water preparation
Binder solution into 10% is sprayed to Thiamphenicol micro-capsule surface, produces Thiamphenicol micro-capsule granules as slurry.
Embodiment 3：The preparation of Thiamphenicol micro-capsule and Thiamphenicol micro-capsule granules
1st, take sodium carboxymethylcellulose 2.5g, gelatin 12.5g to be configured to 3g/L, 30g/L aqueous solution respectively, both are mixed
It is even to produce carrier solution；
2nd, Thiamphenicol 5g, silica 0.5g stirring is taken it is dispersed in carrier solution, spray drying is produced
Thiamphenicol micro-capsule；
3rd, Thiamphenicol micro-capsule is loaded in fluid bed spray pot as bed material, takes 80g starch to cross 100 mesh sieves, add water preparation
Binder solution into 10% is sprayed to Thiamphenicol micro-capsule surface, produces Thiamphenicol micro-capsule granules as slurry.
The entrapment efficiency determination of the Thiamphenicol micro-capsule of embodiment 4
The measure of Thiamphenicol microencapsulation rate is with reference to " drugloading rate and the envelop rate research of ophiopogonin enteric-coated microsphere "
（《Chinese patent drug》, 2004,26（8）:611-613）Middle envelop rate=（Actual drug content/drugloading rate in micro-capsule）× 100% counts
Calculate.Actual drug content is calculated with the content of micro-capsule after washing in micro-capsule, and water-washing step eliminates the medicine that microsphere surface sticks
Thing and absorption embody the amount for the medicine for being really encapsulated into capsule material in the medicine of superfine silica gel powder；After drugloading rate is to be spray-dried
The cubage of gained, can remove influence of the yield factor to envelop rate in preparation technology.
After measured, the envelop rate difference for the Thiamphenicol micro-capsule that embodiment 1, embodiment 2, the step 2 of embodiment 3 are prepared
For 95.8%, 96.4%, 95.2%, envelop rate is higher.
Pharmacokinetic trial of the Thiamphenicol micro-capsule granules of embodiment 5 in chicken body
Make 5% Thiamphenicol particle by oneself, preparation method is as follows：
Step 1：Thiamphenicol and starch crushed 100 mesh sieves respectively, standby；
Step 2：Weigh 95g starch, add water be made 10% binder solution, then weigh 5g Thiamphenicols add adhesive
Mixed in solution, spray drying produces 5% Thiamphenicol particle of self-control.
For reagent product：Thiamphenicol micro-capsule granules prepared by the embodiment of the present invention 1, embodiment 2, embodiment 3；Self-control 5%
Thiamphenicol particle.
Test method：The healthy cross-broiler of 40 20 ages in days is chosen, male and female half and half are randomly divided into 4 groups, every group 10.Examination
It is pre- before testing to raise 2 weeks, free water and feeding during experiment.Stop to raise 12h before administration, normal water is searched for food after 2h after administration.
By 30mg/kg（In terms of Thiamphenicol）The dosage of body weight disposably gavages administration, mined out white blood sample before administration, administration
Taken a blood sample afterwards respectively at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h wing venous.Each blood sampling volume
About 2ml, is placed in the 10ml centrifuge tubes that heparin infiltrated, and 2000r/min centrifugation 10min, separated plasma, -20 DEG C of refrigerators are preserved
It is standby.
After the plasma sample thaw at RT of preservation, the accurate 0.5ml that draws adds 4ml second in 10ml graduated centrifuge tubes
Acetoacetic ester deproteinized, vortex oscillation 5min, 3000r/min centrifugation 10min, Aspirate supernatant is in 30ml hearts bottle, and repetition is gone
Albumen once, merges supernatant.After 65 DEG C of rotations are evaporated, phased soln is flowed with 1ml, vortex 2min is transferred to 1.5ml dactylethraes,
16000r/min centrifuges 15min, takes the μ l of supernatant 20 to be used for high performance liquid chromatography（HPLC）Analysis.With acetonitrile：Water（15:85）For
Mobile phase, flow velocity 0.8ml/min, Detection wavelength is 230nm.
Then according to plasma drug level-time data, compartment model fitting is carried out using 3P97 pharmacokinetics software, calculated
Go out the pharmacokinetic parameters of correlation.
Result of the test：Experiment each group chicken single dose is gavaged after Thiamphenicol particle, the plasma drug level of different time
It is shown in Table 1.
The plasma drug level of each administration group chicken different time of table 1
Note：ND represents to be not detected by.
The pharmacokinetic parameters result of calculation of each Thiamphenicol particle is shown in Table 2.
The pharmacokinetic parameters of each Thiamphenicol particle of table 2
The data comparison in two tables more than, chicken is with 30mg/kg（In terms of Thiamphenicol）Single oral dose is administered, its
The drug concentration-versus-time data variation rule of Thiamphenicol is presented the Room of first order absorption one and opens kinetic model in blood plasma.This hair
Thiamphenicol micro-capsule granules prepared by bright technical scheme relatively make 5% Thiamphenicol particle by oneself and effectively extend Thiamphenicol in chicken
Internal half-life period and effective acting time（Thiamphenicol effective blood drug concentration is 1mg/L-10mg/L）, make medicine useful effect
Time maintains the 24h to after administration.
Clinical trial of the Thiamphenicol micro-capsule granules of embodiment 6 to artificial challenge's chicken colibacillosis
Test method：Healthy chicken inoculation fowl E.coli（O78 blood groups, it is micro- purchased from China Veterinery Drug Inspection Office animal doctor
Biological deposits center）, it is infected chicken colibacillosis.Through prerun, it is every chicken air bag injection 0.6ml bacterium solution to attack poison amount（Often
Milliliter contains viable bacteria about 3 × 108CFU）.The state of mind, appetite, excrement of the front and rear chicken of inoculation etc. are observed and record, it is vertical to dead chicken
Pathology cut open inspection is carried out, separation of bacterial is cultivated from liver, spleen and heart.
150 healthy chickens are taken from 20 age in days chicken mass selections, 5 groups are randomly divided into, every group 30, specific packet and disposition are shown in
Table 3.
The experiment chicken packet of table 3 and disposition
1-4 groups attack 4h after poison and start administration, are used in conjunction 4 days.Continue to observe to 16 days, record its clinical symptoms, to dead chicken
Only carry out cut open inspection and be separately cultured, judge the cause of the death.Death toll respectively to each group test chicken, healing number, significant figure are counted,
The death rate, cure rate, effective percentage are calculated, and card side is carried out to effective percentage（X2）Examine.
Result of the test：Infection control group in 10d after inoculation（5 groups）30 test chickens have 20 death.Its Major Clinical disease
Shape shows as that spirit is depressed, and appetite, drink are intended to decline or useless exhausted, and feather is fluffy and disorderly, and both wings are sagging, eye closing lethargic sleep, peel off slow-witted vertical, arrange dilute
Just, the sleeping ground of severe patient does not rise.Cut open inspection is characterized in：Liver is congested, enlargement is frangible, and liver pulp film is thickened, and has a large amount of exudates；Spleen swells
Greatly；There are a large amount of fibroid exudates in cavum pericardiale；Separated to a large amount of Escherichia coli from liver, spleen, heart.1-4 groups are in administration
Afterwards, compared with 5 groups, there is symptom mitigation or disappearance.
The death rate, cure rate, the efficient result of calculation of each group experiment chicken are shown in Table 4.
The death rate of each group of table 4 experiment chicken, cure rate, effective percentage
| Group | The death rate（%） | Cure rate（%） | It is efficient（%） |
| 1 | 6.7 | 86.7 | 93.3 |
| 2 | 3.3 | 93.3 | 96.7 |
| 3 | 3.3 | 86.7 | 96.7 |
| 4 | 10.0 | 83.3 | 90.0 |
| 5 | 66.7 | 6.7 | 33.3 |
As seen from Table 4,1-4 groups are significantly higher than 5 groups i.e. infection pair to the efficient pole of artificial challenge chicken colibacillosis chicken
According to group（P ＜ 0.01）；Efficient no difference of science of statistics between 1-4 groups（P ＞ 0.05）.
Because 1-3 of the embodiment of the present invention Thiamphenicol micro-capsule granules prepared and 5% Thiamphenicol particle of self-control are pressed respectively
" per Kg body weight 10mg（In terms of Thiamphenicol）It is for oral administration, 1 times a day, be used in conjunction 4 days " and by " per Kg body weight 10mg（With Thiamphenicol
Meter）It is for oral administration, 2 times a day, be used in conjunction 4 days " administration, it is seen then that both dosages differ one times, but drug treatment effect is quite, says
The bright Thiamphenicol micro-capsule granules prepared according to technical solution of the present invention can extend medicine effective acting time, reduce administration time
Number.
The better embodiment of the present invention is the foregoing is only, is not intended to limit the invention, all spirit in the present invention
Within principle, any modification, equivalent substitution and improvements made etc. should be included in the scope of the protection.
Claims (9)
1. a kind of Thiamphenicol micro-capsule, composed of the following components：Thiamphenicol, silica and by sodium carboxymethylcellulose and bright
The weight ratio of sodium carboxymethylcellulose and gelatin is 1 in the carrier material of glue composition, the carrier material:5.
2. Thiamphenicol micro-capsule according to claim 1, it is characterised in that composed of the following components：Thiamphenicol 1-10
Parts by weight, silica 0.2-1.0 parts by weight, the carrier material 3-30 parts by weight being made up of sodium carboxymethylcellulose and gelatin.
3. the preparation method of Thiamphenicol micro-capsule according to claim 1, comprises the following steps：
(1) take recipe quantity sodium carboxymethylcellulose, gelatin to be configured to 3g/L, 30g/L aqueous solution respectively, both are mixed and produced
The weight ratio of sodium carboxymethylcellulose and gelatin is 1 in carrier solution, the carrier material:5；
(2) recipe quantity Thiamphenicol, silica stirring is taken it is dispersed in carrier solution, spray drying produces MSM
Mycin micro-capsule.
4. a kind of animal medicinal composition, it is characterised in that the animal medicinal composition is peroral dosage form, any comprising claim 1~2
Thiamphenicol micro-capsule and excipient substance described in.
5. animal medicinal composition according to claim 4, it is characterised in that the peroral dosage form is granule, tablet, dissipated
Agent, capsule or pre-mixing agent.
6. the preparation method of the animal medicinal composition according to claim 4 or 5, it is characterised in that in claim 1~2 times
Excipient substance is added in Thiamphenicol micro-capsule described in one, the animal medicinal composition of peroral dosage form is obtained.
7. preparation method according to claim 6, it is characterised in that the MSM described in any one of claim 1~2 is mould
Plain micro-capsule loads in fluid bed spray pot as bed material, takes recipe quantity excipient substance to cross 100 mesh sieves, add water be configured to 10% bonding
Agent solution is sprayed to Thiamphenicol micro-capsule surface, produces Thiamphenicol micro-capsule granules as slurry.
8. preparation method according to claim 7, it is characterised in that the Thiamphenicol micro-capsule is 4.2-41 parts by weight,
The excipient substance is 60-100 parts by weight.
9. application of the animal medicinal composition in the medicine for preparing treatment chicken colibacillosis according to claim 4 or 5.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0244118A1 (en) * | 1986-04-29 | 1987-11-04 | Pharmetrix Corporation | Controlled release drug delivery system for the peridontal pocket |
| CN102106843A (en) * | 2011-02-24 | 2011-06-29 | 河南黑马动物药业有限公司 | Slow-release lung targeted microcapsule preparation of florfenicol and preparation method thereof |
-
2014
- 2014-01-20 CN CN201410025210.6A patent/CN104784152B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0244118A1 (en) * | 1986-04-29 | 1987-11-04 | Pharmetrix Corporation | Controlled release drug delivery system for the peridontal pocket |
| CN102106843A (en) * | 2011-02-24 | 2011-06-29 | 河南黑马动物药业有限公司 | Slow-release lung targeted microcapsule preparation of florfenicol and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Preparation and Evaluation of Gelatin/Sodium Carboxymethyl Cellulose Polyelectrolyte Complex Microparticles for Controlled Delivery of Isoniazid;Nirmala Devi et al;《AAPS PharmSciTech》;20091231;第10卷(第4期);第1412-1419页 * |
| 对氟苯尼考靶向制剂的初步性研究;要瑞丽等;《兽药研发》;20100630;第13-14页 * |
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