CN111840233B - Montelukast sodium solid dispersion, preparation method and application thereof - Google Patents
Montelukast sodium solid dispersion, preparation method and application thereof Download PDFInfo
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- CN111840233B CN111840233B CN202010742768.1A CN202010742768A CN111840233B CN 111840233 B CN111840233 B CN 111840233B CN 202010742768 A CN202010742768 A CN 202010742768A CN 111840233 B CN111840233 B CN 111840233B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Abstract
The invention provides a montelukast sodium solid dispersion, a preparation method and an application thereof, wherein the mass ratio of montelukast sodium to a hydrophilic carrier is 1: 1-1: 50; trimethyl chitosan with the hydrophilic carrier mass of 4:1-5:1 is added into the solid dispersion according to the hydrophilic carrier. The solid dispersion is prepared from the montelukast sodium, the hydrophilic carrier material and the trimethyl chitosan by adopting a fluidized bed method, so that the montelukast sodium is uniformly distributed in the carrier material, the dissolution rate and the stability of the preparation are improved, and the degradation rate in the long-term storage process is reduced.
Description
Technical Field
The invention relates to a montelukast sodium solid dispersion, a preparation method thereof and a pharmaceutical composition containing the same, belonging to the field of pharmaceutical preparations.
Background
Asthma is a common respiratory disease affecting approximately 10% of children and 5% of adults worldwide. During asthma attack, leukotrienes mediate a series of airway responses such as bronchoconstriction, mucus secretion, increased vascular permeability and eosinophil aggregation, and are one of the important mediators of bronchial asthma, playing a key role in the occurrence and development of asthma. There are studies showing higher levels in asthmatic patients than in normal patients, both in the attack and stationary phase. Leukotriene receptor antagonists are emerging as new avenues for the treatment of asthma.
Montelukast is a new generation oral leukotriene antagonist developed by Merck & co., inc.u.s.a., a powerful oral preparation capable of remarkably improving inflammatory indicators of asthma, has high selectivity, can competitively antagonize the binding of leukotriene D4(LTD4) and Cys-LTl receptors, and has good therapeutic effects on asthma. The chemical name of montelukast sodium as the sodium salt of montelukast is: sodium [ R- (E) ] -1- [ [ [1- [3- [2- (7-chloro-2-quinoline) ethenyl ] phenyl-3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropaneacetate having the chemical structure:
montelukast sodium has poor photostability, and the photostability cannot be improved by simply mixing the montelukast sodium with other auxiliary materials. Meanwhile, due to the existence of hydroxyl in the montelukast sodium molecule, the montelukast ketone is easily oxidized into montelukast ketone under high temperature conditions, and the generation of degradation product sulfoxide is accompanied. The metabolic pathway of montelukast ketone in vivo is basically the same as that of montelukast sodium, but the montelukast ketone has high hepatorenal toxicity and increases the safety risk in clinical application. Therefore, how to stabilize the montelukast sodium in the preparation becomes a technical problem to be solved urgently.
W02003035036A1 discloses a commercially available montelukast sodium granule formula and a preparation method thereof, wherein mannitol is used as a matrix, hydroxypropyl cellulose is used as an adhesive, a fluidized bed granulation mode is adopted to prepare mannitol granules, montelukast sodium is dissolved in purified water, and the solution is coated on the surface of the mannitol granules by a fluidized bed. In order to reduce impurities, the patent adopts nitrogen as fluidized bed carrier gas, has higher requirement on equipment and high cost.
CN201510747141.4 discloses a montelukast sodium particle composition and a preparation method thereof, dodecyl dimethyl amine oxide and glycyrrhizic acid are used as protective agents, and although dodecyl dimethyl amine oxide has a solubilizing effect on main drugs, the dodecyl dimethyl amine oxide serving as an artificially synthesized surfactant still has potential safety hazards to human bodies, particularly gastrointestinal tracts of children.
CN201710762772.2 discloses a montelukast sodium granule composition and a preparation method thereof, wherein povidone and copovidone are used as binding agents, and granules are prepared by wet granulation. The method adopts wet granulation and drying processes to prepare granules, and has high granule hardness and poor dissolution effect.
Solid Dispersion (SD) refers to a dispersion system in solid form formed by highly dispersing a drug in a solid carrier. Important features of the drug solid dispersion are as follows: 1. the drug is present in the carrier in a highly dispersed state. 2. The hydrophilic carrier can increase the solubility and dissolution rate of the insoluble drug, and is beneficial to improving the bioavailability of the drug; the insoluble carrier can delay or control the drug release; enteric carriers control the release of the drug in the small intestine. 3. The carrier can delay the hydrolysis and oxidation of the medicine by the entrapment effect of the carrier. 4. The carrier can mask the unpleasant odor of the drug and reduce irritation. 5. The liquid medicine is solidified. 6. The dispersion state of the medicine is high, the physical stability is not good, and the aging phenomenon is easy to generate after long-term storage.
At present, there is no report on the montelukast sodium solid dispersion.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects of the prior art, the invention aims to solve the technical problem of providing a montelukast sodium solid dispersion and a preparation method thereof, wherein the particle size of a drug in a carrier is 0.001-0.1 mm, the montelukast sodium solid dispersion is used for accelerating and increasing the dissolution of an insoluble drug and improving the bioavailability of the insoluble drug, and meanwhile, as the drug is wrapped in a water-soluble carrier, the contact of the drug with air and moisture can be effectively reduced, the stability of montelukast granules can be obviously improved, the level of sulfoxide impurities in the granules is far lower than that of the granules sold on the market, and the safety of medication is improved.
The technical scheme is as follows: in order to realize the purpose of the invention, the invention adopts the following technical scheme:
the montelukast sodium solid dispersion comprises montelukast sodium and a pharmaceutically acceptable hydrophilic carrier material, wherein the mass ratio of the montelukast sodium to the hydrophilic carrier is 1: 1-1: 50. The hydrophilic carrier is added after being mixed with trimethyl chitosan, the mass ratio of the hydrophilic carrier to the trimethyl chitosan is 4:1-5:1, and the trimethyl chitosan (TMC) is added to solve the problem that a solid dispersion prepared from the montelukast sodium and the hydrophilic carrier is unstable in a long-term storage process.
The preparation method of trimethyl chitosan refers to the literature, Chinese food journal, 2013, 13, No. 5, P117-123.
Preferably, the mass ratio of the montelukast sodium to the hydrophilic carrier is 1: 1-1: 30, and more preferably, the ratio is 1: 1-1: 10.
The hydrophilic carrier is one or a mixture of two or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamer, povidone, copovidone and polyethylene glycol.
The hydroxypropyl cellulose is classified into EF, LF, JF, GF and MF according to average molecular weight. The povidone is 1-vinyl-2-pyrrolidone homopolymer, and the specification is classified by average molecular weight into PVP k12, PVP k15, PVP k17, PVP k25, PVP k30, PVP k29/32, PVP k60 and PVP k120, preferably PVP k 29/32.
The montelukast sodium solid dispersion also comprises pharmaceutically acceptable excipients for preparation.
The excipient can be one or a mixture of more than one of disintegrant, filler and other pharmaceutical excipients except hydrophilic carriers, which are mixed in any proportion, more specifically, the excipient is one or a mixture of more than two of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, starch, pregelatinized starch, sucrose, dextrin, mannitol, calcium sulfate, calcium phosphate and calcium hydrophosphate, and preferably mannitol. The mass ratio of the montelukast sodium to the excipient is 1: 1-1: 240, preferably 1: 10-1: 120.
The montelukast sodium solid dispersion is prepared by a fluidized bed method, and specifically comprises the following steps:
step 1, completely dissolving a hydrophilic carrier and trimethyl chitosan in water, then adding montelukast sodium, and stirring until the montelukast sodium is completely dissolved for later use;
and 2, putting the excipient into a fluidized bed, adding the solution obtained in the step 1 in a top spraying manner, and performing fluidized bed spray granulation to obtain the montelukast sodium solid dispersion.
A montelukast sodium pharmaceutical composition comprises the montelukast sodium solid dispersion and pharmaceutic adjuvants.
The montelukast sodium composition can be tablets, capsules, granules, powder and pills, and preferably granules. The preparation method comprises dry granulation and wet granulation, or adopts a direct filling method.
The pharmaceutic adjuvant can comprise one or a mixture of more than two of a disintegrant, a binder, a filler, a lubricant and the like.
The disintegrant is selected from one or more of croscarmellose sodium, dry starch, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, etc.; the amount of disintegrant used is based on the amount known in the art to achieve a disintegrating effect, and preferably, the content of disintegrant in the pharmaceutical composition is 0.5% to 5%.
The binder can be optionally added or not added according to the requirement of the preparation formula, and specifically, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, starch slurry, gelatin and the like. When the binder is added, the amount of the binder used is based on the amount known in the art to achieve a binding effect, and preferably, the content of the binder in the pharmaceutical composition is 0.5% to 10%.
The filler can be optionally added or not added according to the requirement of a preparation formula, specifically, the filler is selected from one or a mixture of more of sucrose, mannitol, dextrin, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium phosphate, calcium hydrogen phosphate and the like, the amount of the used filler is based on the amount which is known in the art and can realize the filling effect, and preferably, the mass ratio of the filler in the pharmaceutical composition is 20-70%.
The lubricant is selected from one or more of stearic acid, magnesium stearate, superfine silica gel powder, talcum powder and polyethylene glycol, and the amount of the lubricant used is based on the amount which can realize the lubricating effect and is known in the field.
Advantageous effects
(1) Currently, no report on montelukast sodium solid dispersion exists, and the inventor tries to prepare the solid dispersion by mixing montelukast sodium and a pharmaceutically acceptable hydrophilic carrier material by a conventional method, and as a result, the inventor finds that in a long-term stability test, an unstable phenomenon still exists, and after trimethyl chitosan is added, on one hand, because the trimethyl chitosan is a water-soluble material, the montelukast sodium is further solubilized, and on the other hand, the long-term stability of the solid dispersion is improved.
(2) The montelukast sodium solid dispersion prepared by the method has the characteristics of uniform content, high dissolution rate and high bioavailability.
Drawings
FIG. 1 is a graph showing the dissolution profiles of examples 1-4 in water-0.5% SDS medium.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
The montelukast sodium solid dispersion prepared in examples 1 to 4 contains the components and the contents thereof are shown in table 1, and the solid dispersion and the external auxiliary materials are uniformly mixed to obtain the montelukast sodium pharmaceutical composition (granules).
TABLE 1
The preparation method comprises the following steps:
adding the hydrophilic carrier and trimethyl chitosan into purified water, adding montelukast sodium after complete dissolution, stirring, and stopping stirring after complete dissolution for later use. Adding the excipient into a fluidized bed, spraying the prepared solution into the fluidized bed by a spray gun in a top spraying mode for granulation, and drying to obtain the montelukast sodium solid dispersion.
Example 5 stability test
The stability of each of the pharmaceutical compositions (granules) containing the montelukast sodium solid dispersion of the present invention and each of the commercially available dosage form samples under 0 day and accelerated conditions and high temperature (60 ℃) conditions were examined separately. The data for each sample under accelerated (40 ℃ C.; 75% RH) conditions are shown in Table 2, and the results for the high temperature (60 ℃ C.) conditions are shown in Table 3:
TABLE 2
TABLE 3
As can be seen from the data in tables 2 and 3, the pharmaceutical composition (granules) containing montelukast sodium solid dispersion of the present invention has better stability and higher safety in administration during the investigation under accelerated and high temperature conditions compared with the commercially available samples, and the shelf life of the samples is judged to be 3 years according to the data of the stability test.
EXAMPLE 6 dissolution test
FIG. 1 is a graph of the dissolution profiles of examples 1-4 in water-0.5% SDS medium, showing that the formulations of the present invention have slightly higher dissolution rates than the commercially available granules.
The above embodiments do not limit the technical solutions of the present invention in any way, and all technical solutions obtained by means of equivalent replacement or equivalent transformation fall within the protection scope of the present invention.
Claims (3)
1. A montelukast sodium solid dispersion, comprising: the montelukast sodium-containing hydrophilic carrier comprises montelukast sodium and pharmaceutically acceptable hydrophilic carrier materials and excipients, wherein the mass ratio of the montelukast sodium to the hydrophilic carrier is 1: 1-1: 30;
the hydrophilic carrier material is any one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamer, povidone, copovidone and polyethylene glycol; trimethyl chitosan with the hydrophilic carrier mass of 4:1-5:1 is added into the solid dispersion according to the hydrophilic carrier;
the mass ratio of the montelukast sodium to the excipient is 1: 1-1: 120; the excipient is one or a mixture of more than two of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, starch, pregelatinized starch, sucrose, dextrin, mannitol, calcium sulfate, calcium phosphate and calcium hydrogen phosphate;
the preparation method of the montelukast sodium solid dispersion comprises the following steps:
step 1, completely dissolving a hydrophilic carrier and trimethyl chitosan in water, then adding montelukast sodium, and stirring until the montelukast sodium is completely dissolved for later use;
and 2, putting an excipient into a fluidized bed, adding the solution obtained in the step 1 in a top spraying manner, and performing fluidized bed spray granulation to obtain the montelukast sodium solid dispersion.
2. The montelukast sodium solid dispersion according to claim 1, wherein the mass ratio of montelukast sodium to the hydrophilic carrier is 1:1 to 1: 10.
3. A pharmaceutical composition comprising the montelukast sodium solid dispersion of claim 1 and a pharmaceutically acceptable pharmaceutical excipient.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575163A (en) * | 2001-10-26 | 2005-02-02 | 麦克弗罗斯特(加拿大)公司 | Granule formulation |
| CN105078974A (en) * | 2014-05-23 | 2015-11-25 | 深圳信立泰药业股份有限公司 | Allisartan isoproxil solid dispersion and pharmaceutical composition |
| CN109833302A (en) * | 2017-11-29 | 2019-06-04 | 扬子江药业集团有限公司 | A kind of stable Montelukast sodium chewable tablet and preparation method thereof |
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2020
- 2020-07-29 CN CN202010742768.1A patent/CN111840233B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575163A (en) * | 2001-10-26 | 2005-02-02 | 麦克弗罗斯特(加拿大)公司 | Granule formulation |
| CN105078974A (en) * | 2014-05-23 | 2015-11-25 | 深圳信立泰药业股份有限公司 | Allisartan isoproxil solid dispersion and pharmaceutical composition |
| CN109833302A (en) * | 2017-11-29 | 2019-06-04 | 扬子江药业集团有限公司 | A kind of stable Montelukast sodium chewable tablet and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| "丹参酮固体分散物的稳定性";储茂泉 等;《华东理工大学学报》;20021231;第28卷;第107-109页 * |
| Cyclodextrin based ternary system of modafinil: Effect of trimethylchitosan and polyvinylpyrrolidone as complexing agents;Parth Patel,et al.;《International Journal of Biological Macromolecules》;20151214;第84卷;第182-188页 * |
| 以N-三甲基壳聚糖为载体的环孢素A固体分散体的制备及其体内外评价;周小菊 等;《第七届全国天然有机化学学术研讨会论文集》;20080901;第152-153页 * |
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