CN101703465A - Azithromycin injection and preparation method thereof - Google Patents
Azithromycin injection and preparation method thereof Download PDFInfo
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- CN101703465A CN101703465A CN200910172751A CN200910172751A CN101703465A CN 101703465 A CN101703465 A CN 101703465A CN 200910172751 A CN200910172751 A CN 200910172751A CN 200910172751 A CN200910172751 A CN 200910172751A CN 101703465 A CN101703465 A CN 101703465A
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Abstract
The invention discloses an azithromycin injection, which comprises the following components by weight in 3000 ml injection: 250.0 g or 500.0 g of azithromycin, 1.0 g of citric acid, 120.0 g of mannitol, 18.0 g of medicinal carbon and the balance of water for injection. The preparation method comprises the following steps of: (1) adding the mannitol into the water for injection, heating for dissolving, adding the medicinal carbon, boiling for 30 minutes, decarburizing and filtrating; (2) preparing a suspension by adding the azithromycin to the water for injection; (3) after dissolving the citric acid, adding the dissolved citric acid into the azithromycin suspension for fully dissolving the azithromycin with the pH value controlled to be 5.7-5.9, adding the medicinal carbon, stirring, standing, decarburizing and filtrating; (4) adding the mannitole filtrate into the azithromycin solution with the pH value controlled to be 5.7-5.9, adding the water for injection till a prepared full dose, filtrating through microfiltration membranes with 0.45 micrometers and 0.22 micrometers; (5) measuring the content of a semi-finished product by adopting an optical rotation test method; (6) if the semi-finished product is tested to be qualified, transmitting the medicinal solution to a bottling department, wherein the bottled injection holding volume is 3 ml; (7) freeze-drying, totally pressing pistons, pressing covers, and light-inspecting, and if the semi-finished product is qualified after the quality test, label-sticking, packaging and obtaining the product.
Description
Technical field:
The present invention relates to a kind of injection and production method thereof, particularly relate to prescription of a kind of Azithromycin injection and preparation method thereof, belong to the biologic pharmacological science field.
Background technology:
Azithromycin is first 15 yuan of macrolide antibiotics, owing to inserted nitrogen-atoms in ring, also is referred to as lipid antibiotic in the azo-cycle.This distinctive molecular structure is given many important chemistry of azithromycin and pharmacological property just.Azithromycin has broad spectrum antibiotic activity.Azithromycin is except keeping the effect of erythromycin to gram positive bacteria, and to the part gram negative bacteria, anaerobe and intracellular pathogen also have good antibacterial activity, and this helps the treatment of mixed infection especially.Strong more than 4 times as azithromycin to hemophilus influenza and gonococcal specific activity erythromycin, active strong 2 times to legionella, to also effective by isolated helicobacter pylori in the duodenal ulcer patients intestinal mucosa, to other pathogenic microorganisms, better curative effect is also arranged as mycoplasma pneumoniae, trachoma clothing original paper etc.The azithromycin oral bioavailability is 37% only, makes injection and can improve bioavailability, and it is wide to distribute in the tissue concentration height, body, and more is applicable to critical patient's treatment.Azithromycin is eliminated in serum slowly, and the half-life reaches 46 hours, and only need be administered once every day, makes things convenient for doctor and patient's medication.Its metabolism mainly is that the original shape medicine is got rid of from the biliary tract secretion.In addition, azithromycin also has characteristics such as short treating period, absolute acid stability be good.
Because azithromycin is water insoluble, so numerous enterprises and research unit are arranged in the research of carrying out the azithromycin injection, but they become salt, double salt or organic salt to azithromycin, after water-soluble, make injection, process operation is loaded down with trivial details like this, time-consuming length, and the medicinal liquid for preparing has the embedding sterilization time limit, so stability is just relatively poor, is easy to generate side effect.
All the time, the production technology personnel of applicant company are actively seeking redress, and through secular arduous exploration, rely on pharmaceutical developments company of group company and part colleges and universities inside the province, have solved the technical barrier of this product, have obtained important breakthrough.
Summary of the invention:
Technical problem to be solved by this invention is: overcome the deficiencies in the prior art, a kind of preparation method of stable Azithromycin injection is provided, satisfy needs clinically.
The technical scheme that the present invention is taked for the technical solution problem is:
A kind of Azithromycin injection, in the injection of 3000ml, contain following each composition: the azithromycin of 250.0g, the citric acid of 1.0g, the mannitol of 120.0g, the medicinal charcoal of 18.0g, surplus is a fresh water for injection.
The Azithromycin injection of another specification, in the injection of 3000ml, contain following each composition: the azithromycin of 500.0g, the citric acid of 1.0g, the mannitol of 120.0g, the medicinal charcoal of 18.0g, surplus is a fresh water for injection.
The content of azithromycin recited above calculates according to anhydride.
The preparation method of two kinds of Azithromycin injections recited above, its concrete steps are as follows:
1., mannitol is added in the fresh water for injection of dose volume 10%, heating is dissolved it fully, adds half medicinal charcoal of formula ratio, boils decarbonization filtering 30 minutes;
2., the azithromycin of formula ratio is added in the water for injection below 20 ℃ of dose volume 60%, make into suspension;
3., citric acid dissolving back is slowly added in the Azithromycin mix suspension liquid, the limit edged stirs, and azithromycin is dissolved fully with an amount of water for injection, strict control liquid PH value is 5.7~5.9, adds second half medicinal charcoal of formula ratio, stirs 10 minutes, left standstill decarbonization filtering 20 minutes;
4., mannitol filtrate is added in the azithromycin solution, the repetition measurement liquid PH value should add the injection water to preparing full dose 5.7~5.9, stirs, through 0.45 μ m, 0.22 μ m filtering with microporous membrane;
5., check that the visible foreign matters of medicinal liquid is qualified after, the censorship semi-finished product adopt the optical rotation detection method to measure half-finished content;
6., the inspection of semifinished product is qualified, and medicinal liquid is reached bottling department, fill injection loading amount is 3ml;
7., lyophilization, the total head plug, gland, lamp inspection, after quality inspection was qualified, labeling, packing promptly obtained Azithromycin injection.
The main innovate point of the present invention on production technology has with the lower part:
1, this product adopts citric acid and azithromycin salify, makes the freeze-drying prods azithromycin injection in an amount of excipient of adding through lyophilization, and its technology is a domestic initiation.This production technology has solved the characteristic that azithromycin is insoluble in water, and its dissolubility strengthened greatly, meets quality of production requirement.
2, the azithromycin injection semi-finished product adopt polarimetry to measure its semi-finished product content; changed the azithromycin injection method of the microbial detection method control of usefulness in process of production, this method is simple, and is quick; can in time instruct Workshop Production, adapt to needs of scale production.
The composition of raw materials of Azithromycin injection of the present invention such as following table:
1. fill a prescription:
Name of material | 1000 consumptions (0.25g) | 1000 consumptions (0.5g) |
Azithromycin (by anhydride) | ??250g | ??500g |
Citric acid | ??1.0g | ??1.0g |
Mannitol | ??120g | ??120g |
Medicinal charcoal | ??18.0g | ??18.0g |
Fresh water for injection | Add to 3000ml | Add to 3000ml |
2. supplementary material is supplied producer:
Semi-finished product content check innovation is reported as follows:
In order further to determine the half-finished feasibility of optical rotation detection method mensuration azithromycin injection injection, the applicant has carried out a large amount of contrast tests, and test method and apparatus are as follows:
(1), polarimetry is measured:
1, detects requirement according to polarimetry.Required key instrument is: the automatic polariscope of WZZ-2B.
2, reagent: the azithromycin raw material that Beijing Taiyang Pharmaceutical Co., Ltd. produces, lot number 030804,030922,031017.
3, method:
(1), the preparation of standard solution: decide azithromycin, citric acid, mannitol according to the accurate title of the ratio of producing recipe quantity 100%, add in an amount of water for injection, stir and make dissolving fully, make every milliliter of solution that contains azithromycin (pure) 0.25 gram.
(2), with the mensuration pipe of 2dm, the optical rotation of the accurate solution of mark is a;
(3), be a1 according to optical rotation with the method working sample;
4, calculate according to following formula: the content=a1/a*100% that measures liquid
(2), the antibiotic microorganism method is measured:
1, detect requirement according to the antibiotic microorganism method, required main instruments is:
The microorganism measuring instrument of tiring.
2, reagent and material: the azithromycin raw material that Beijing Taiyang Pharmaceutical Co., Ltd. produces, lot number 030804,030922,031017.
A, strain: Bacillus pumilus;
B, culture medium: antibiotic calibrating culture medium (PH7.8~8.0);
C, buffer: Plondrel acid buffer (pH value 7.8);
D, condition of culture: 7 ℃ of temperature, 14~16 hours;
E, antibiotic concentration scope: 5~10KUL-1.
3, method: it is an amount of that precision is measured sample, add aquesterilisa and make the solution that contains azithromycin 1000 units among every 1ml, it is an amount of that other gets the azithromycin standard substance, add ethanol (every 10mg adds ethanol 4ml) dissolving, add water and make the solution that contains azithromycin 1000 units among every 1ml approximately, measure according to the method that the antibiotic microorganism calibrating is sent out under (two appendix XIA of Chinese Pharmacopoeia version in 2000) Zitromax prime implicant.1000 azithromycin units are equivalent to the C of 1mg
38H
72N
2O
12
(3), research process and data:
According to test requirements document, the sample to three lot numbers detects respectively, and the optical rotation of 100% sample is respectively:
??030804 | ??-6.250° |
??030922 | ??-6.380° |
??031017 | ??-6.090° |
The preparation of sample and labelling:
According to azithromycin injection production prescription, carry out the preparation of test specimen respectively, amount of preparation is three samples of each lot number, manufactures experimently with 95%, 100% and 105% of recipe quantity respectively, and lot number is respectively as following table:
Feed intake | ??95% | ??100% | ??105% |
??030804 | ??031101a | ??031101b | ??031101c |
??030922 | ??031102a | ??031102b | ??031102c |
??031017 | ??031103a | ??031103b | ??031103c |
Respectively same sample is measured according to two diverse ways respectively, each sample carries out three times respectively to be measured, and asks its meansigma methods as the last content of measuring, and specifically detects data such as following table:
Show by above-mentioned data and to utilize polarimetry to measure the half-finished content of azithromycin injection and utilize antibiotic microorganism method measurement result not have significant difference, meet statistics normal deviate scope, can correctly determine the half-finished content of azithromycin.
The various performances of the Azithromycin injection of producing with the present invention are as follows:
[nomenclature of drug] adopted name: azithromycin injection.
[composition] this product Main Ingredients and Appearance is an azithromycin.Adjuvant: citric acid, mannitol.
[character] this product is the loose block of white or off-white color.
[indication] this product is applicable to the caused following infection of responsive pathogenic strain: by the microbial community acquired pneumonia that need at first take the intravenous drip treatment of Chlamydia pneumoniae, hemophilus influenza, legionella pneumophilia, mucositis mora bacterium, mycoplasma pneumoniae, staphylococcus aureus or pneumonia streptococcus; The needs that caused by chlamydia trachomatis, Diplococcus gonorrhoeae, mycoplasma hominis are at first taked the pelvic inflammatory disease of intravenous drip treatment.
[specification] 0.25g (250,000 unit) 0.5g (500,000 unit)
[usage and dosage] fully dissolves this product with an amount of sterilized water for injection, is mixed with 0.1g/ml, joins in the sodium chloride injection or 5% glucose injection of 250ml or 500ml again, and final azithromycin concentration is 1.0~2.0mg/ml, intravenous drip then.Concentration is 1.0mg/ml, and the instillation time is 3 hours; Concentration is 2.0mg/ml, and the instillation time is 1 hour.
The treatment community acquired pneumonia: the 0.5g that is grown up a time, 1 time on the one, continuous use is 2 at least, and that continues uses azithromycin oral preparation 0.5g on the one instead, and 7~10 is a course of treatment.Transferring the oral medication time to should be definite according to the clinical treatment reaction by the doctor.
The treatment pelvic inflammatory disease: the 0.5g that is grown up a time, 1 time on the one, medication is used azithromycin oral preparation 0.25g on the one instead after 1 day or 2 days, and 7 is a course of treatment.Transferring the oral medication time to should be definite according to the clinical treatment reaction by the doctor.
[untoward reaction]
1. this product common adverse reactions has:
(1) gastrointestinal reaction: diarrhoea, stomachache, loose stool, feel sick, vomiting etc.
(2) local response: injection site pain, local inflammation etc.
(3) dermoreaction: erythra, pruritus.
(4) other reactions: as sitophobia, vaginitis, stomatitis, dizziness or dyspnea etc.
2. this product also can cause following reaction:
(1) digestive system: strain bacterium disease, gastritis etc. are read in dyspepsia, flatulence, mucositis, oral cavity.
(2) nervous system: headache, drowsiness etc.
(3) anaphylaxis: bronchospasm etc.
(4) other reactions: parageusia etc.
(5) lab testing: serum aminotransferase, creatinine, lactic acid dehydrogenase, bilirubin and alkali phosphatase raise, and leukocyte, neutrophilic granulocyte and platelet count reduce.
[taboo] is to azithromycin, erythromycin or other any Macrocyclolactone lactone kind medicine allergy sufferers forbiddings
[points for attention] slight renal insufficiency patient (creatinine clearance rate>40ml/ minute) need not make dose titration, but azithromycin is to than the non-avaible still of the use among the severe renal functional defect patient, should be prudent when using azithromycin for these patients.
Because liver and gall is the excretory main path of azithromycin, the careful usefulness of hepatic insufficiency person, serious hepatopath should not use.Regular follow-up liver function during the medication.
If anaphylaxis (as vasodilation, dermoreaction, Stevous-Jonson syndrome and the necrosis of toxicity epidermis etc.) takes place during the medication, drug withdrawal immediately, and take appropriate measures.
During the treatment,, should consider that pseudomembranous enterocolitis takes place if symptom of diarrhea appears in the patient.If diagnosis is established, should take the corresponding treatment measure, comprise and keep water, electrolyte balance, additional protein etc.
This product at every turn the time of instiling must not be less than 60 minutes, drip liquid concentration must not be higher than 2.0mg/ml.
If suspect the merging anaerobic infection, should share anti-anaerobic agent during the treatment pelvic inflammatory disease.
[storage] shading, airtight, preserve at the drying place.
[dosage form] lyophilized injectable powder.
[inner packaging material] hangs down borosilicate antibiotic bottle, halogenated butyl rubber plug.
[packing specification] 0.25g * 1/capsule * 300 capsules/case
0.25g * 2/capsule * 300 capsules/case
0.25g * 6/capsule * 120 capsules/case
0.5g * 1/capsule * 300 capsules/case
The specific embodiment:
Embodiment one: a kind of specification is 0.25g (250,000 a unit) Azithromycin injection, in the injection of 3000ml, contains following each composition: the azithromycin of 250.0g (anhydride), 1.0g citric acid, 120.0g mannitol, the medicinal charcoal of 18.0g, surplus is a fresh water for injection.
The preparation method of Azithromycin injection recited above, its concrete steps are as follows:
1., mannitol is added in the fresh water for injection of dose volume 10%, heating is dissolved it fully, adds half medicinal charcoal of formula ratio, boils decarbonization filtering 30 minutes;
2., the azithromycin of formula ratio is added in the water for injection below 20 ℃ of dose volume 60%, make into suspension;
3., citric acid dissolving back is slowly added in the Azithromycin mix suspension liquid, the limit edged stirs, and azithromycin is dissolved fully with an amount of water for injection, strict control liquid PH value is 5.7~5.9, adds second half medicinal charcoal of formula ratio, stirs 10 minutes, left standstill decarbonization filtering 20 minutes;
4., mannitol filtrate is added in the azithromycin solution, the repetition measurement liquid PH value should add the injection water to preparing full dose 5.7~5.9, stirs, through 0.45 μ m, 0.22 μ m filtering with microporous membrane;
5., check that the visible foreign matters of medicinal liquid is qualified after, the censorship semi-finished product adopt the optical rotation detection method to measure half-finished content;
6., the inspection of semifinished product is qualified, and medicinal liquid is reached bottling department, fill injection loading amount is 3ml;
7., lyophilization, the total head plug, gland, lamp inspection, after quality inspection was qualified, labeling, packing promptly obtained Azithromycin injection.
Embodiment two: a kind of specification is 0.5g (500,000 a unit) Azithromycin injection, in the injection of 3000ml, contains following each composition: the azithromycin of 500.0g, 1.0g citric acid, 120.0g mannitol, the medicinal charcoal of 18.0g, surplus is a fresh water for injection.
The preparation method of Azithromycin injection recited above, its concrete steps are as follows:
1., mannitol is added in the fresh water for injection of dose volume 10%, heating is dissolved it fully, adds half medicinal charcoal of formula ratio, boils decarbonization filtering 30 minutes;
2., the azithromycin of formula ratio is added in the water for injection below 20 ℃ of dose volume 60%, make into suspension;
3., citric acid dissolving back is slowly added in the Azithromycin mix suspension liquid, the limit edged stirs, and azithromycin is dissolved fully with an amount of water for injection, strict control liquid PH value is 5.7~5.9, adds second half medicinal charcoal of formula ratio, stirs 10 minutes, left standstill decarbonization filtering 20 minutes;
4., mannitol filtrate is added in the azithromycin solution, the repetition measurement liquid PH value should add the injection water to preparing full dose 5.7~5.9, stirs, through 0.45 μ m, 0.22 μ m filtering with microporous membrane;
5., check that the visible foreign matters of medicinal liquid is qualified after, the censorship semi-finished product adopt the optical rotation detection method to measure half-finished content;
6., the inspection of semifinished product is qualified, and medicinal liquid is reached bottling department, fill injection loading amount is 3ml;
7., lyophilization, the total head plug, gland, lamp inspection, after quality inspection was qualified, labeling, packing promptly obtained Azithromycin injection.
Claims (4)
1. Azithromycin injection is characterized in that: in the injection of 3000ml, contain following each composition: the azithromycin of 250.0g, and the citric acid of 1.0g, the mannitol of 120.0g, the medicinal charcoal of 18.0g, surplus is a fresh water for injection.
2. Azithromycin injection is characterized in that: in the injection of 3000ml, contain following each composition: the azithromycin of 500.0g, and the citric acid of 1.0g, the mannitol of 120.0g, the medicinal charcoal of 18.0g, surplus is a fresh water for injection.
3. Azithromycin injection according to claim 1 and 2 is characterized in that: the content of described azithromycin calculates according to anhydride.
4. the preparation method of an Azithromycin injection as claimed in claim 1 or 2, its concrete steps are as follows:
1., mannitol is added in the fresh water for injection of dose volume 10%, heating is dissolved it fully, adds half medicinal charcoal of formula ratio, boils decarbonization filtering 30 minutes;
2., the azithromycin of formula ratio is added in the water for injection below 20 ℃ of dose volume 60%, make into suspension;
3., citric acid dissolving back is slowly added in the Azithromycin mix suspension liquid, the limit edged stirs, and azithromycin is dissolved fully with an amount of water for injection, strict control liquid PH value is 5.7~5.9, adds second half medicinal charcoal of formula ratio, stirs 10 minutes, left standstill decarbonization filtering 20 minutes;
4., mannitol filtrate is added in the azithromycin solution, the repetition measurement liquid PH value should add the injection water to preparing full dose 5.7~5.9, stirs, through 0.45 μ m, 0.22 μ m filtering with microporous membrane;
5., check that the visible foreign matters of medicinal liquid is qualified after, the censorship semi-finished product adopt the optical rotation detection method to measure half-finished content;
6., the inspection of semifinished product is qualified, and medicinal liquid is reached bottling department, fill injection loading amount is 3ml;
7., lyophilization, the total head plug, gland, lamp inspection, after quality inspection was qualified, labeling, packing promptly obtained Azithromycin injection.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102429863A (en) * | 2011-11-29 | 2012-05-02 | 湖南科伦制药有限公司 | Azithromycin injection packed by double-cavity bag and preparation method thereof |
CN112629990A (en) * | 2021-01-24 | 2021-04-09 | 深圳博泰尔生物技术有限公司 | Azithromycin reference substance and preparation method thereof |
US11779595B2 (en) * | 2017-02-02 | 2023-10-10 | Mcmaster University | Bicarbonate as a potentiator for antimicrobial agents |
-
2009
- 2009-11-27 CN CN200910172751A patent/CN101703465A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102429863A (en) * | 2011-11-29 | 2012-05-02 | 湖南科伦制药有限公司 | Azithromycin injection packed by double-cavity bag and preparation method thereof |
US11779595B2 (en) * | 2017-02-02 | 2023-10-10 | Mcmaster University | Bicarbonate as a potentiator for antimicrobial agents |
CN112629990A (en) * | 2021-01-24 | 2021-04-09 | 深圳博泰尔生物技术有限公司 | Azithromycin reference substance and preparation method thereof |
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Open date: 20100512 |