CN104784152A - Thiamphenicol microcapsule, and preparation method and application thereof - Google Patents
Thiamphenicol microcapsule, and preparation method and application thereof Download PDFInfo
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- CN104784152A CN104784152A CN201410025210.6A CN201410025210A CN104784152A CN 104784152 A CN104784152 A CN 104784152A CN 201410025210 A CN201410025210 A CN 201410025210A CN 104784152 A CN104784152 A CN 104784152A
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Abstract
The invention discloses a thiamphenicol microcapsule, and a preparation method and an application thereof. The thiamphenicol microcapsule includes thiamphenicol, silica and a carrier material composed of carboxymethylcellulose sodium and gelatin. Thiamphenicol is microencapsulated through adopting a spray-drying process, so the half life and the drug effective action time of thiamphenicol are prolonged, the administration frequency is reduced, and the medication cost is reduced.
Description
Technical field
The invention belongs to veterinary drug technical field, be specifically related to a kind of thiamphenicol microcapsule and preparation method thereof, and the application of this thiamphenicol microcapsule in veterinary drug preparation.
Background technology
Thiamphenicol (TAP) is chloromycetin broad ectrum antibiotic, and its chemical constitution is similar to chloromycetin, is the analog of chloromycetin, to light, thermally-stabilised, has hygroscopicity, is called as second filial generation chloromycetin.Its mechanism of action is identical with chloromycetin, but its methylsulfonyl instead of the nitro of chloromycetin, effectively overcome the defect that chloromycetin causes aplastic anemia, antibacterial action is stronger than chloromycetin, be mainly used in respiratory tract, intestinal tract disease that the bacterial infection, particularly escherichia coli for the treatment of poultry, Salmonella and pasteurellosis bacillus etc. cause clinically.
Thiamphenicol is for oral administration to be absorbed completely, is distributed widely in each tissue in body after absorption, mainly with prototype excretion from urine.But its half-life is short, the half-life especially in chicken body is only 2 hours.
Application number is the preparation method that patent discloses a kind of thiamphenicol suspension emulsifier of CN201010507404.1, it adopts the micronization thiamphenicol of 10-30%, the emulsifying agent of 5-15%, the oil phase of 20-30%, the auxiliary stabilizer of 0.02-5% and the water of surplus are prepared and obtain, it is advantageous that medicine is with aqueous phase-oil phase-solid phase composition mixed system, have the good characteristic of suspensoid and Emulsion concurrently, intramuscular injection of drugs consumption reduces, little to the body internal stimulus of poultry, after medication, be scattered in micronized medicine active component in aqueous phase and oil phase slow releasing thus reach targeting and slow release long-acting in vivo.In addition said preparation drug loading is large, stable in properties, and leave standstill and unsuitable layering and sedimentation after transport, good fluidity, is convenient to intramuscular injection, for thiamphenicol opens new approach in the application of veterinary clinic.But this thiamphenicol suspension emulsifier is because of high containing the higher preparation cost that causes of oil-phase component, and preparation process is complicated, unstable product quality.
Summary of the invention
Main purpose of the present invention be to provide a kind of effective acting time compared with long, times for spraying is few, drug cost is low and preparation technology simple, the thiamphenicol microcapsule of constant product quality.Described thiamphenicol microcapsule is composed of the following components: thiamphenicol, silicon dioxide and the carrier material be made up of sodium carboxymethyl cellulose and gelatin.
Preferably, described thiamphenicol microcapsule is composed of the following components: thiamphenicol 1-10 weight portion, silicon dioxide 0.2-1.0 weight portion, carrier material 3-30 weight portion.
Preferably, in described carrier material, the weight ratio of sodium carboxymethyl cellulose and gelatin is 1:5.
Another object of the present invention is to the preparation method that a kind of thiamphenicol microcapsule is provided, specific as follows:
1, get the aqueous solution that recipe quantity sodium carboxymethyl cellulose, gelatin are mixed with 3g/L, 30g/L respectively, namely both mixings are obtained carrier solution;
2, get recipe quantity thiamphenicol, silicon dioxide stirring makes it be dispersed in carrier solution, namely spraying dry obtains thiamphenicol microcapsule.
Another object of the present invention is to provide a kind of animal medicinal composition, and described animal medicinal composition is peroral dosage form, comprises the thiamphenicol microcapsule and excipient substance that adopt said method to prepare.Described excipient substance includes but not limited to starch, sucrose, glucose, lactose or its mixture.Preferably, described excipient substance is starch.
Preferably, in animal medicinal composition of the present invention, described peroral dosage form is granule, tablet, powder, capsule or pre-mixing agent.
Another aspect of the invention, for providing a kind of preparation method of animal medicinal composition, adds excipient substance, namely obtains the animal medicinal composition of peroral dosage form in the above-mentioned thiamphenicol microcapsule prepared.
Preferably, the above-mentioned thiamphenicol microcapsule for preparing to be loaded in fluid bed spray pot as bed material, gets recipe quantity excipient substance and cross 100 mesh sieves, add water be mixed with 10% binder solution as slurry, be sprayed to thiamphenicol microcapsule surface, obtain thiamphenicol micro-capsule granules.
Preferably, described thiamphenicol microcapsule is 4.2-41 weight portion, and described excipient substance is 60-100 weight portion.
Another aspect of the invention is the application of animal medicinal composition in the medicine of preparation treatment chicken colibacillosis containing described thiamphenicol microcapsule.
The present invention, by adopting spray drying method by thiamphenicol microencapsulation, extends half-life and medicine effective acting time of thiamphenicol, decreases administration number of times, reduce drug cost.This thiamphenicol microcapsule has the advantages such as preparation technology is simple, constant product quality simultaneously.
Detailed description of the invention
The source-information of the thiamphenicol used by the embodiment of the present invention, sodium carboxymethyl cellulose, gelatin and silicon dioxide is as follows:
Thiamphenicol, content 99.0%, Shanxi great Hua great achievement Pharmaceutical Technology Co., Ltd;
Sodium carboxymethyl cellulose, Henan Jin Run food additive company limited;
Gelatin, biological level, Tianjin Kermel Chemical Reagent Co., Ltd.;
Silicon dioxide, Henan hundred million specialization chemical product company limited, particle diameter 32 μm.
Embodiment 1: the preparation of thiamphenicol microcapsule and thiamphenicol micro-capsule granules
1, get sodium carboxymethyl cellulose 0.5g, aqueous solution that gelatin 2.5g is mixed with 3g/L, 30g/L respectively, namely both mixings are obtained carrier solution;
2, getting thiamphenicol 1g, silicon dioxide 0.2g stirring makes it be dispersed in carrier solution, and namely spraying dry obtains thiamphenicol microcapsule;
3, thiamphenicol microcapsule to be loaded in fluid bed spray pot as bed material, gets 60g starch and cross 100 mesh sieves, add water be mixed with 10% binder solution as slurry, be sprayed to thiamphenicol microcapsule surface, obtain thiamphenicol micro-capsule granules.
Embodiment 2: the preparation of thiamphenicol microcapsule and thiamphenicol micro-capsule granules
1, get sodium carboxymethyl cellulose 5g, aqueous solution that gelatin 25g is mixed with 3g/L, 30g/L respectively, namely both mixings are obtained carrier solution;
2, getting thiamphenicol 10g, silica 1 g stirring makes it be dispersed in carrier solution, and namely spraying dry obtains thiamphenicol microcapsule;
3, thiamphenicol microcapsule to be loaded in fluid bed spray pot as bed material, gets 100g starch and cross 100 mesh sieves, add water be mixed with 10% binder solution as slurry, be sprayed to thiamphenicol microcapsule surface, obtain thiamphenicol micro-capsule granules.
Embodiment 3: the preparation of thiamphenicol microcapsule and thiamphenicol micro-capsule granules
1, get sodium carboxymethyl cellulose 2.5g, aqueous solution that gelatin 12.5g is mixed with 3g/L, 30g/L respectively, namely both mixings are obtained carrier solution;
2, getting thiamphenicol 5g, silicon dioxide 0.5g stirring makes it be dispersed in carrier solution, and namely spraying dry obtains thiamphenicol microcapsule;
3, thiamphenicol microcapsule to be loaded in fluid bed spray pot as bed material, gets 80g starch and cross 100 mesh sieves, add water be mixed with 10% binder solution as slurry, be sprayed to thiamphenicol microcapsule surface, obtain thiamphenicol micro-capsule granules.
The entrapment efficiency determination of embodiment 4 thiamphenicol microcapsule
The mensuration of thiamphenicol microencapsulation rate is with reference to " drug loading of ophiopogonin enteric-coated microsphere and envelop rate research " (" Chinese patent medicine ", 2004,26(8): 611-613), envelop rate=(in microcapsule actual drug content/drug loading) × 100% calculates.In microcapsule, actual drug content calculates with the content washing rear microcapsule, and water-washing step eliminates the medicine that microsphere surface sticks and the medicine being adsorbed on micropowder silica gel, embodies the real amount being encapsulated into the medicine of capsule material; Drug loading, with the cubage of gained after spraying dry, can to remove in preparation technology yield factor to the impact of envelop rate.
After measured, the envelop rate of the thiamphenicol microcapsule that embodiment 1, embodiment 2, embodiment 3 step 2 prepare is respectively 95.8%, 96.4%, 95.2%, and envelop rate is higher.
The pharmacokinetic trial of embodiment 5 thiamphenicol micro-capsule granules in chicken body
Make 5% thiamphenicol granule by oneself, preparation method is as follows:
Step 1: thiamphenicol and starch pulverized 100 mesh sieves respectively, for subsequent use;
Step 2: take 95g starch, add water make 10% binder solution, then take 5g thiamphenicol and add in binder solution and mix, namely spraying dry obtains self-control 5% thiamphenicol granule.
For reagent product: the thiamphenicol micro-capsule granules of the embodiment of the present invention 1, embodiment 2, embodiment 3 preparation; Make 5% thiamphenicol granule by oneself.
Test method: choose 40 healthy cross-broilers of 20 ages in days, male and female half and half, are divided into 4 groups at random, often organize 10.Raise 2 weeks in advance before test, duration of test is freely drunk water and is searched for food.Stop before administration to raise 12h, after administration, after 2h, normal water is searched for food.
By 30mg/kg(in thiamphenicol) dosage of body weight is disposable gavages administration, adopts blank blood sample, respectively at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h wing venous blood collection after administration before administration.Each blood sampling volume is about 2ml, is placed in the 10ml centrifuge tube that heparin infiltrated, the centrifugal 10min of 2000r/min, and separated plasma ,-20 DEG C of Refrigerator stores are for subsequent use.
After the plasma sample thaw at RT of preservation, accurately draw 0.5ml in 10ml graduated centrifuge tube, add 4ml ethyl acetate Deproteinization, the centrifugal 10min of vortex oscillation 5min, 3000r/min, Aspirate supernatant is in 30ml Cor Gigeriae Galli bottle, repeat Deproteinization once, merge supernatant.After 65 DEG C of rotation evaporates to dryness, dissolve with 1ml mobile phase, vortex 2min, proceeds to 1.5ml dactylethrae, the centrifugal 15min of 16000r/min, gets supernatant 20 μ l and analyzes for high performance liquid chromatography (HPLC).With acetonitrile: water (15:85) is mobile phase, flow velocity 0.8ml/min, determined wavelength is 230nm.
Then according to plasma drug level-time data, adopt 3P97 pharmacokinetics software to carry out compartment model matching, calculate relevant pharmacokinetic parameters.
Result of the test: test after each group of chicken single dose gavage thiamphenicol granule, the plasma drug level of different time is in table 1.
The plasma drug level of table 1 each administration group chicken different time
Note: ND represents and does not detect.
The pharmacokinetic parameters result of calculation of each thiamphenicol granule is in table 2.
The pharmacokinetic parameters of each thiamphenicol granule of table 2
From Data Comparison in above two tables, chicken in 30mg/kg(with thiamphenicol) single oral dose administration, in its blood plasma, the drug concentration-versus-time data variation rule of thiamphenicol presents the open kinetic model in first order absorption one Room.Thiamphenicol micro-capsule granules prepared by technical solution of the present invention is comparatively made 5% thiamphenicol granule by oneself and is effectively extended the half-life of thiamphenicol in chicken body and effective acting time (thiamphenicol effective blood drug concentration is 1mg/L-10mg/L), makes medicine be maintained to 24h after administration effective acting time.
Embodiment 6 thiamphenicol micro-capsule granules is to the clinical trial of artificial challenge's chicken colibacillosis
Test method: healthy chicken inoculation fowl E.coli (O78 blood group, purchased from China Veterinery Drug Inspection Office's veterinary microorganism preservation center), makes its infected chicken colibacillosis.Through prerun, counteracting toxic substances amount is that (every milliliter containing viable bacteria about 3 × 10 for every chicken air bag injection 0.6ml bacterium liquid
8cFU).Observe and record the mental status, appetite, feces etc. of inoculating front and back chicken, carry out pathology immediately to dead chicken and cut open inspection, from liver, spleen and heart, separation of bacterial is cultivated.
Get 150 healthy chickens from 20 age in days chicken mass selections, be divided into 5 groups at random, often organize 30, concrete grouping and disposition are in table 3.
Table 3 tests chicken grouping and disposition
After 1-4 group counteracting toxic substances, 4h starts administration, is used in conjunction 4 days.Continue to observe to 16 days, record its clinical symptoms, inspection is cutd open and separation and Culture to dead chicken, judge the cause of the death.Respectively to the death toll of each group of test chicken, cure number, significant figure adds up, calculate mortality rate, cure rate, effective percentage, and card side (X carried out to effective percentage
2) inspection.
Result of the test: infecting matched group (5 groups) 30 test chickens after inoculation in 10d has 20 death.It is depressed that its main clinic symptoms shows as spirit, and appetite, drink are for declining or giving up absolutely, and feather is fluffy and disorderly, and both wings are sagging, eye closing lethargy, and peel off slow-witted vertical, passage of loose stools, severe patient does not rise sleepingly.Cuing open inspection feature is: liver is congested, enlargement is frangible, and liver pulp film thickens, and has a large amount of exudate; Splenomegaly; A large amount of fibroid exudate is had in pericardial cavity; All separable to a large amount of escherichia coli from liver, spleen, heart.1-4 group upon administration, compared with 5 groups, occurs that symptom alleviates or disappears.
Each group of test mortality rate of chicken, cure rate, effective percentage result of calculation are in table 4.
Table 4 respectively group tests mortality rate, cure rate, the effective percentage of chicken
| Group | Mortality rate (%) | Cure rate (%) | Effective percentage (%) |
| 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, the effective percentage pole of 1-4 group to artificial challenge's chicken colibacillosis chicken is significantly higher than 5 groups and namely infects matched group (P < 0.01); Effective percentage no difference of science of statistics (P > 0.05) between 1-4 group.
The thiamphenicol micro-capsule granules prepared due to embodiment of the present invention 1-3 and self-control 5% thiamphenicol granule respectively by " every Kg body weight 10mg(is in thiamphenicol) for oral administration; 1 time on the one; be used in conjunction 4 days " and by " every Kg body weight 10mg(is in thiamphenicol) for oral administration; 2 times on the one; be used in conjunction 4 days " administration, visible, both dosages differ one times, but drug treatment effect is suitable, illustrate that the thiamphenicol micro-capsule granules prepared according to technical solution of the present invention can prolong drug effective acting time, reduce administration number of times.
The foregoing is only better embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a thiamphenicol microcapsule, composed of the following components: thiamphenicol, silicon dioxide and the carrier material be made up of sodium carboxymethyl cellulose and gelatin.
2. thiamphenicol microcapsule according to claim 1, is characterized in that, composed of the following components: thiamphenicol 1-10 weight portion, silicon dioxide 0.2-1.0 weight portion, the carrier material 3-30 weight portion be made up of sodium carboxymethyl cellulose and gelatin.
3. thiamphenicol microcapsule according to claim 2, is characterized in that, in described carrier material, the weight ratio of sodium carboxymethyl cellulose and gelatin is 1:5.
4. the preparation method of thiamphenicol microcapsule according to claim 1, comprises the following steps:
(1) get the aqueous solution that recipe quantity sodium carboxymethyl cellulose, gelatin are mixed with 3g/L, 30g/L respectively, namely both mixings are obtained carrier solution;
(2) get recipe quantity thiamphenicol, silicon dioxide stirring makes it be dispersed in carrier solution, namely spraying dry obtains thiamphenicol microcapsule.
5. an animal medicinal composition, is characterized in that, described animal medicinal composition is peroral dosage form, comprises the thiamphenicol microcapsule described in any one of claims 1 to 3 and excipient substance.
6. animal medicinal composition according to claim 5, is characterized in that, described peroral dosage form is granule, tablet, powder, capsule or pre-mixing agent.
7. the preparation method of the animal medicinal composition according to claim 5 or 6, is characterized in that, in the thiamphenicol microcapsule described in any one of claims 1 to 3, add excipient substance, obtains the animal medicinal composition of peroral dosage form.
8. preparation method according to claim 7, it is characterized in that, thiamphenicol microcapsule described in any one of claims 1 to 3 is loaded in fluid bed spray pot as bed material, get recipe quantity excipient substance and cross 100 mesh sieves, add water be mixed with 10% binder solution as slurry, be sprayed to thiamphenicol microcapsule surface, obtain thiamphenicol micro-capsule granules.
9. preparation method according to claim 8, is characterized in that, described thiamphenicol microcapsule is 4.2-41 weight portion, and described excipient substance is 60-100 weight portion.
10. the application of the animal medicinal composition according to claim 5 or 6 in the medicine of preparation treatment chicken colibacillosis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106822034A (en) * | 2016-12-02 | 2017-06-13 | 北京科百大科技有限责任公司 | The capsule core material or micro-capsule of drug containing are prepared as capsule core material with maize cob meal |
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| 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 |
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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 |
|---|
| NIRMALA DEVI ET AL: "Preparation and Evaluation of Gelatin/Sodium Carboxymethyl Cellulose Polyelectrolyte Complex Microparticles for Controlled Delivery of Isoniazid", 《AAPS PHARMSCITECH》 * |
| 要瑞丽等: "对氟苯尼考靶向制剂的初步性研究", 《兽药研发》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106822034A (en) * | 2016-12-02 | 2017-06-13 | 北京科百大科技有限责任公司 | The capsule core material or micro-capsule of drug containing are prepared as capsule core material with maize cob meal |
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