CN1663563A - Compound troxerutin and piracetam formulation and application thereof - Google Patents
Compound troxerutin and piracetam formulation and application thereof Download PDFInfo
- Publication number
- CN1663563A CN1663563A CN 200510005379 CN200510005379A CN1663563A CN 1663563 A CN1663563 A CN 1663563A CN 200510005379 CN200510005379 CN 200510005379 CN 200510005379 A CN200510005379 A CN 200510005379A CN 1663563 A CN1663563 A CN 1663563A
- Authority
- CN
- China
- Prior art keywords
- preparation
- piracetam
- troxerutin
- pharmaceutical preparation
- per unit
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a compound troxerutin and piracetam formulation and application thereof, wherein the preparation comprises pharmaceutical active components of Troxerutin, Piracetam and right amount of acceptable adjuvant. The preparation possesses the function of synergy treatment for cerebrovascular diseases and platelet agglutination.
Description
Technical field:
The present invention relates to a kind of potentiation treatment cardiovascular and cerebrovascular vessel and platelet aggregation compound medicinal formulation, this pharmaceutical preparation comprises active constituents of medicine troxerutin and piracetam and an amount of acceptable auxiliary.
Background technology:
Troxerutin has weak blood capillary contraction, reduce capillary permeability and fragility, prevent the edema that raises and to cause because of vascular permeability, the blood vessel injury that can cause medmain, Kallidin I, bacteriotoxin, oxygen-derived free radicals, increase capillary resistance, reduce capillary permeability.The blood vessel injury that causes, the protection vascular endothelial cell.
Troxerutin can alleviate the caused spasm of blood vessel metabolism; combine with the adenosine carrier protein on the platelet membrane, the content of cyclic adenosine monophosphate (cAMP) in the platelet increasing, thus suppress erythrocyte and platelet aggregation; offset hematoblastic undesired activity, prevent thrombosis.Can increase oxygen content and oxygen saturation in the blood, the activity of enzyme under the protection anaerobic condition, microcirculation improvement promotes neovascularity to generate to promote collateral circulation.Thereby the cerebral blood flow increasing amount is improved the blood supply in half blanking bar zone, and can make the blood circulation of grey matter ischemic region recover normal, alleviates the edema of neighboring area, reduces brain infarction area.
Edema, lymphedema, burn and the traumatic edema that the preceding syndrome of hemiplegia, aphasia, coronary heart disease infarction, central retinitis, thrombophlebitis, the vascular permeability rising that the disease that troxerutin can effectively be treated has obliterated cerebral vascular disease to cause causes, arteriosclerosis etc.
Piracetam can increase the energy of neurocyte, thereby synthesizing of biosynthesis, the especially phospholipid of promotion cell can promote that the conduction function of nervous tissue and brain are proteic synthetic, promotes memory indirectly; When big cerebral anoxia, the effect of piracetam is more obvious, can activate adenyl cyclase in the body, under the situation of deficiency of oxigen or glucose, continues to keep the normal level of ketone salt, prevents Lactated generation and acidosic generation.
Piracetam is the derivant of γ-An Jidingsuan; be a kind of novel short thinking memory medicine, easily can directly act on cerebral cortex, promote brain phospholipid and amino acid whose utilization by blood brain barrier; increase brain to proteinic synthetic, the effect that have protection, activates and repair neurocyte.Can make the ADP in the brain be converted into ATP, improve brain intracellular metabolite energy supply situation.Influence the excited transmission of cholinergic neuron, promote acetylcholine synthetic.Can resist the injury of brain function due to physical factor and the chemical factor, quicken between cerebral hemisphere to improve one's memory, strengthen of the control of brain cortex neuromechanism under the cortex through callosal information transmission.Reduce cerebral vascular resistance, blood flow increasing and improve cerebral circulation improves study, memory and memory ability.
Be applicable to the memory and light, the moderate disordered brain function that cause by aging, cerebrovascular accident, cerebral trauma, CO poisoning etc.
By troxerutin and the bonded compound preparation of piracetam, can increase capillary resistance, reduce capillary permeability.The blood vessel injury that causes, the protection vascular endothelial cell.Suppress platelet aggregation, antithrombotic forms.And the effect that has protection, activates and repair neurocyte.Can make the ADP in the brain be converted into ATP, improve brain intracellular metabolite energy supply situation.Influence cholinergic neuron and discharge acetylcholine, blood flow increasing and improve cerebral circulation improves study, memory and memory ability, and the two has synergism, can increase clinical efficacy each other, brings into play multiple effect, is an excellent drug prescription.
Summary of the invention:
The present invention relates to a kind of compound medicinal formulation, contain the pharmaceutical preparation of troxerutin and metabolic medicine of at least a promotion brain and an amount of pharmaceutically useful adjuvant.The metabolic medicine of described short brain is: piracetam.
Pharmaceutical preparation of the present invention in the preparation of per unit dosage, contains 25～400mg troxerutin and 100～6000mg piracetam.Pharmaceutical preparation of the present invention can be oral formulations, is selected from: tablet, capsule, enteric coatel tablets, enteric coated capsule, soft capsule, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, powder, oral cavity disintegration tablet or drop pill.Above oral formulations in the preparation of per unit dosage, contains troxerutin 50～300mg and piracetam 100～1200mg.Preferably contain troxerutin 100～200mg and piracetam 200～400mg.
Pharmaceutical preparation of the present invention can be ejection preparation, is selected from: injection, lyophilized powder, aseptic powder, glucose sugar injection, sodium chloride injection.Above injection in the preparation of per unit dosage, contains troxerutin 50～300mg and piracetam 1000～4000mg.Preferably contain troxerutin 100～200mg and piracetam 2000～3000mg.
The present invention also comprise pharmaceutical preparation of the present invention syndrome, central retinitis, thrombophlebitis, vascular permeability before preparation is used for the treatment of hemiplegia that obliterated cerebral vascular disease causes, aphasia, coronary heart disease infarction raise the edema that causes and because aging, cerebrovascular accident, cerebral trauma, CO are poisoned etc. the memory that causes and gently, the application in the medicine of moderate disordered brain function disease.
Pharmaceutical preparation of the present invention, preferred tablet.
Pharmaceutical preparation of the present invention, the preparation of wherein said per unit dosage refers to the dosage form of each minimum individual, as every of tablet, capsular every, every bottle of injection etc.
The invention is characterized in: be administered three times every day be used for the treatment of syndrome before hemiplegia that obliterated cerebral vascular disease causes, aphasia, the coronary heart disease infarction, central retinitis, thrombophlebitis, vascular permeability raise the edema that causes and because aging, cerebrovascular accident, cerebral trauma, CO are poisoned etc. the memory that causes and gently, moderate disordered brain function etc.
Brain metabolic drug preparation provided by the invention comprises the medicine acceptable auxiliary.These adjuvants comprise: filler, binding agent, disintegrating agent, lubricant.
Filler can be selected in the pharmaceutical preparation: starch, calcium phosphate, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, mannitol etc.Preferably: starch, microcrystalline Cellulose, lactose.
Binding agent can be selected in the preparation: PVP-K30, hydroxypropyl cellulose, starch slurry, ethyl cellulose, hypromellose, gelling starch etc.Preferably: PVP-K30, starch slurry.
Disintegrating agent can be selected in the preparation: polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.Preferably: polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.
Lubricant can be selected in the preparation: magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
The invention is characterized in that pharmaceutical preparation can be made into injection.This injection comprises active constituents of medicine troxerutin, piracetam and acceptable auxiliary.These adjuvants comprise: pH value regulator, osmotic pressure regulator etc.
The present invention also provides the preparation method of pharmaceutical preparation of the present invention: can adopt direct powder compression can adopt wet granulation again.Preparation method of the present invention can be operated according to galenic pharmacy routine techniques method.Preparation method is simple, does not need special installation, is fit to large-scale production.
Following data declaration beneficial effect of the present invention by experiment:
Drug synergism
In order to prove that troxerutin and piracetam drug combination have the increase curative effect, synergism, we have collected Patients with Cerebral Infarction 120 examples between year December of in January, 2003～2004, be and fall ill 72 hours with interior internal carotid artery system Patients with Cerebral Infarction, meet the diagnostic criteria of the whole nation the 4th boundary cerebrovascular academic conference, and make a definite diagnosis through cranium brain CT or MRI inspection.120 examples are divided into two groups at random, and 60 examples are organized in the treatment of compound troxerutin piracetam, simple troxerutin matched group 60 examples.Two groups of ages, sex, courses of disease, fall ill, comparability is arranged to administration time, history of past illness, complication there was no significant difference.Two groups of patients all take the circumstances into consideration to use dehydrant and other symptomatic treatments, but all without medicines such as other blood vessel dilating, anticoagulants.Treatment suite gram rutin 200mg, piracetam 3g add among the normal saline 500ml quiet jointly, and every day 1 time, 14 days was 1 course of treatment.Matched group adds among the normal saline 500ml quiet for troxerutin 400mg, and every day 1 time, 14 days was 1 course of treatment.Observe the variation of two groups of patient function of nervous system, hemorheology index before and after the treatment.Efficacy assessment standard for be almost recovered, 5 grades of marked improvements, progress, no change, deterioration.
The result shows: curative effect relatively has significant difference (P＜0.01) between treatment group and the matched group, sees Table 1.The neurologic impairment integration is relatively treated and is compared no significant difference (P＞0.05) between preceding two groups before and after the treatment, and treatment back treatment group neurologic impairment obviously alleviates (P＜0.01) than matched group, sees Table 2.Whole blood viscosity and plasma viscosity are all than obviously reducing (P＜0.01) before the treatment before and after two groups of treatments.And during treating, do not find apparent side effect.
The two groups of clinical efficacies in table 1 compound troxerutin piracetam treatment back relatively
| Group | ??n | Be almost recovered | Marked improvement | Progressive | No change | Worsen | Total effective rate | ||||||
| ??n | ??％ | ??n | ??％ | ??n | ??％ | n | ％ | ???n | ????％ | ????n | ????％ | ||
| Treatment group matched group | 60 60 | ??13 ??6 | ??21.7 ??10.0 | ??28 ??22 | ??46.7 ??36.7 | ??15 ??19 | ??25.0 ??31.7 | ??3 ??9 | ?5.0 ?15.0 | ??1 ??3 | ??1.7 ??5.0 | ??56 ??47 | ??93.3 ??68.4 |
Compare P＜0.01 with matched group
Neurologic impairment integration comparison before and after the table 2 liang group treatment (x ± s)
| Group | Before the treatment | After the treatment |
| Treatment group matched group | ????20.11±5.29 *????20.24±5.15 | ????5.60±2.31 Δ????8.10±2.82 |
Compare with matched group
*P＞0.05 Δ P＜0.01
Treat 60 routine acute cerebral infarction patients by finding compound preparation in this test, total effective rate is 93.3%, obvious effective rate is 70%, with matched group significant difference is arranged relatively, and treatment back neurologic impairment integration obviously reduces, the sticking viscosity of whole blood, plasma viscosity obviously improve in the hemorheology, curative effect obviously is better than simple troxerutin matched group, show that troxerutin and piracetam can improve cerebral blood flow and blood viscosity, obviously alleviate the neurologic impairment of cerebral infarction, and do not have obvious adverse reaction, the two has synergism.This compound preparation is the active drug of treatment cerebral infarction.
In addition, our randomized, double-blind paired observation the compound troxerutin pyrrole draw the curative effect of agent and simple piracetam treatment Alzheimer ' s disease (AD), carried out the follow-up investigation in 1 year.Curative effect is followed up a case by regular visits to and is finished 30 routine patients, male 12 examples, and women 18 examples in year at age 57～81 (average 66.4 ± 8.2), are clarified a diagnosis.Be divided into 14 routine treatment groups and 16 routine matched groups at random, treatment is organized everyone day clothes troxerutin pyrrole and is drawn 100/400mg tid, matched group everyone day clothes piracetam 400mg tid, and no significant differences such as two groups of mean aves, level of intelligence have comparability.
The result shows that the treatment group is quite a lot of than matched group, and ANOVA showed significant is named memory, memory, memory at a specified future date all help to delay PD in the recent period, and its correlation coefficient is respectively 0.32,0.22,0.158.Show that the two has synergism, can effectively delay PD, aspect name memory, recent memory, the memory at a specified future date bigger effect is being arranged.After the follow-up observation in 1 year, the attention aspect is also variant, can hypermnesis and attention, and long-term treatment can delay AD patient and worsen advance degree aspect cognitive.
Pharmaceutical preparation of the present invention can be used for treating syndrome before hemiplegia that obliterated cerebral vascular disease causes, aphasia, the coronary heart disease infarction, central retinitis, thrombophlebitis, vascular permeability raise the edema that causes and because aging, cerebrovascular accident, cerebral trauma, CO are poisoned etc. the memory that causes and gently, moderate disordered brain function etc.
Dosage and administration: adult's usual amounts is oral: starting dose is I, II side, reaches therapeutic effect as 2 Zhou Houwei, rises to III and IV.Every day three times, early, middle and late taking.Dosage can be adjusted as required.
Prescription is formed:
Oral agents
(injection)
(chloride injection agent)
Specific embodiment is as follows:
Embodiment 1: preparation troxerutin+piracetam Film coated tablets
Prescription: 1000
Troxerutin 100g
Piracetam 400g
Starch 50g
Microcrystalline Cellulose 75g
8% polyvidone aqueous solution 20g
Cross-linking sodium carboxymethyl cellulose 25g
Magnesium stearate 3g
Micropowder silica gel 6g
Preparation method: take by weighing recipe quantity troxerutin, piracetam, starch, cross-linking sodium carboxymethyl cellulose (2/3) and cross 80 mesh sieves respectively, with 8% polyvidone aqueous solution system soft material, cross 20 mesh sieves, 60 ℃ of dryings, 18 mesh sieve granulate add microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate, micropowder silica gel direct powder compression.The ordinary tablet that makes is done the sheet heart, and film coating promptly.
Embodiment 2: preparation troxerutin+piracetam granule
Prescription: 100 bags
Troxerutin (crossing 80 mesh sieves) 10g
Piracetam (crossing 80 mesh sieves) 80g
Icing Sugar (crossing 80 mesh sieves) 405g
Sodium carboxymethyl cellulose 5g
60% alcoholic solution is an amount of
Preparation method: with troxerutin, piracetam fine powder, Icing Sugar, sodium carboxymethyl cellulose mix homogeneously, with 60% ethanol system soft material, 18 mesh sieves are granulated, 40 ℃ of dryings, and 16 mesh sieve granulate, pack is promptly.
Embodiment 3: preparation troxerutin+piracetam oral solutin
Prescription: 1000ml
Troxerutin 20g
Piracetam 80g
Citric acid 0.1g
Malic acid 0.5g
Sodium benzoate 1.5g
2% ethyl hydroxybenzoate alcoholic solution 15ml
60% simple syrup 250ml
Distilled water adds to 1000ml
Preparation method: troxerutin, piracetam are stirred in an amount of distilled water of adding, under stirring, add citric acid, malic acid, sodium benzoate, 2% ethyl hydroxybenzoate alcoholic solution, 60% simple syrup, stir, measure pH value (pH value is controlled between 5.0～6.5), filter, distilled water diluting is to capacity, every bottle of 10ml of fill sterilized 30 minutes for 100 ℃.
Embodiment 4: preparation troxerutin+piracetam injection
Prescription: 1000ml
Troxerutin 20g
Piracetam 200g
0.1mol/L hydrochloric acid solution is an amount of
Water for injection adds to 1000ml
Preparation method: take by weighing in recipe quantity troxerutin, the piracetam stirring adding 800ml water for injection and dissolve, regulate pH value between 5.5～7.0 with the 0.1mol/L hydrochloric acid solution, the needle-use activated carbon with 0.1% is in 30 ℃ of 60 ℃ of insulations, and charcoal is taken off in filtration while hot.Add water for injection to total amount,, be sub-packed in the 10ml ampoule bottle (every bottle of about 10m1) in 115 ℃ of sterilizations 30 minutes with the filter membrane fine straining of 0.22 μ m.
Prescription 5: preparation troxerutin+piracetam sodium chloride injection
Prescription: 1000ml
Troxerutin 0.4g
Piracetam 20g
Sodium chloride 9g
0.1mol/L hydrochloric acid solution is an amount of
Water for injection adds to 1000ml
Preparation method: take by weighing in recipe quantity troxerutin, the piracetam stirring adding 800ml water for injection and dissolve, regulate pH value between 5.5～7.0 with the 0.1mol/L hydrochloric acid solution, the needle-use activated carbon with 0.1% is in 30 ℃ of 60 ℃ of insulations, and charcoal is taken off in filtration while hot.Add water for injection to total amount,, under aseptic condition, be sub-packed in (every bottle of 250ml) in the 250ml cillin bottle with the filter membrane fine straining of 0.22 μ m.
Claims (10)
1 one kinds of pharmaceutical preparatioies contain the troxerutin and the metabolic medicine of at least a promotion brain of effective dose.
The pharmaceutical preparation of 2 claim 1, the metabolic medicine of described short brain is: piracetam.
The pharmaceutical preparation of 3 claim 1 in the preparation of per unit dosage, contains 25～400mg troxerutin and 100～6000mg piracetam.
The pharmaceutical preparation of 4 claim 3 is oral formulations, is selected from: tablet, capsule, enteric coatel tablets, enteric coated capsule, soft capsule, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, powder, oral cavity disintegration tablet or drop pill.
The pharmaceutical preparation of 5 claim 4 in the preparation of per unit dosage, contains troxerutin 50～300mg and piracetam 100～1200mg.
The pharmaceutical preparation of 6 claim 7 in the preparation of per unit dosage, contains troxerutin 100～200mg and piracetam 200～400mg.
The pharmaceutical preparation of 7 claim 3 is ejection preparation, is selected from: injection, lyophilized powder, aseptic powder, glucose sugar injection, sodium chloride injection.
The pharmaceutical preparation of 8 claim 7 in the preparation of per unit dosage, contains troxerutin 50～300mg and piracetam 1000～4000mg.
The pharmaceutical preparation of 9 claim 7 in the preparation of per unit dosage, contains troxerutin 100～200mg and piracetam 2000～3000mg.
The pharmaceutical preparation of 10 claim 1 syndrome, central retinitis, thrombophlebitis, vascular permeability before preparation is used for the treatment of hemiplegia that obliterated cerebral vascular disease causes, aphasia, coronary heart disease infarction raise the edema that causes and because aging, cerebrovascular accident, cerebral trauma, CO are poisoned etc. the memory that causes and gently, the application in the medicine of moderate disordered brain function disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510005379 CN1663563A (en) | 2005-02-04 | 2005-02-04 | Compound troxerutin and piracetam formulation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510005379 CN1663563A (en) | 2005-02-04 | 2005-02-04 | Compound troxerutin and piracetam formulation and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1663563A true CN1663563A (en) | 2005-09-07 |
Family
ID=35034991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510005379 Pending CN1663563A (en) | 2005-02-04 | 2005-02-04 | Compound troxerutin and piracetam formulation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1663563A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7935367B2 (en) * | 2006-03-08 | 2011-05-03 | Hhc Formulations Ltd. | Compositions and methods for increasing adipose metabolism, lipolysis or lipolytic metabolism via thermogenesis |
| CN102125524B (en) * | 2010-01-16 | 2012-06-27 | 青岛科技大学 | Piracetam orally disintegrating tablets |
| US10639294B2 (en) | 2018-10-02 | 2020-05-05 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite |
| US11304968B2 (en) | 2018-11-16 | 2022-04-19 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
-
2005
- 2005-02-04 CN CN 200510005379 patent/CN1663563A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7935367B2 (en) * | 2006-03-08 | 2011-05-03 | Hhc Formulations Ltd. | Compositions and methods for increasing adipose metabolism, lipolysis or lipolytic metabolism via thermogenesis |
| CN102125524B (en) * | 2010-01-16 | 2012-06-27 | 青岛科技大学 | Piracetam orally disintegrating tablets |
| US10639294B2 (en) | 2018-10-02 | 2020-05-05 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide metabolite |
| US11304968B2 (en) | 2018-11-16 | 2022-04-19 | Janssen Pharmaceutica Nv | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101053572A (en) | Citicoline enteric coated preparation and its preparation method | |
| CN1663563A (en) | Compound troxerutin and piracetam formulation and application thereof | |
| CN1092986C (en) | CoA oral preparation for reducing blood fat and its preparation method | |
| CN1303989C (en) | Zinc gluconate oral disintegrating tablet and its preparation process | |
| CN1091441C (en) | Amlo dipine mesylate and its preparation and application | |
| CN1718566A (en) | Ferulaic acid and its sodium salt used for preventing and treating senile dementia medicine | |
| CN1175811C (en) | Slow-releasing Anixitan tablet | |
| CN1636581A (en) | Safflower medicine composition and its prepn process and use | |
| CN1123344C (en) | Slowly releasing piperazine ferulate | |
| CN1414847A (en) | Sustained-releasing antihelmintic compositions comprising praziquantel | |
| CN1729988A (en) | Composite medicine of creatine phosphate sodium and magnesium salt | |
| CN1504191A (en) | Cucurbitacin lipsome preparation method and formulation | |
| CN1262270C (en) | Application of levocarnitine and its derivative in preventing and treating high altitude diseases | |
| CN1663600B (en) | Compound preparation composed of ginkgo leaf extracts and medicines promoting cerebral metabolism and its application | |
| CN1608623A (en) | Enteric coated donepezil hydrochloride tablet and its perpn process | |
| CN1267094C (en) | Orally disintegrating tablet of safflor yellow and its preparation process | |
| CN1224390C (en) | Pharmaceutical composition comprising pyrroloquinoline quinone for curing and preventing fatty liver | |
| CN1679611A (en) | Compound preparation of piracetam and its use | |
| CN1771992A (en) | Brain extract and its prepn and use | |
| CN1768760A (en) | Medicinal composition containing safflower total flavone and its preparation process and usage | |
| CN1715277A (en) | Compound for treating cardiocerebral vascular disease and its preparing method and its use in pharmaceutical field | |
| CN1679608A (en) | Compound preparation of inosine, triphosphoadenosine and vitamin C and use thereof | |
| CN1040063C (en) | Application of zinc gluconate in preparing medicine for relieving asthma and cough | |
| CN116687885A (en) | Painless gel sustained-release canker sore patch containing PDRN microspheres and preparation method thereof | |
| CN106074398A (en) | A kind of freeze dried lentinan holoside powder injecta and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |