CN105496967A - Ranitidine hydrochloride releasing-controlling dry suspension and preparing method thereof - Google Patents
Ranitidine hydrochloride releasing-controlling dry suspension and preparing method thereof Download PDFInfo
- Publication number
- CN105496967A CN105496967A CN201510969953.3A CN201510969953A CN105496967A CN 105496967 A CN105496967 A CN 105496967A CN 201510969953 A CN201510969953 A CN 201510969953A CN 105496967 A CN105496967 A CN 105496967A
- Authority
- CN
- China
- Prior art keywords
- ranitidine hydrochloride
- dry suspension
- releasing
- preparation
- controlling
- 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.)
- Granted
Links
Classifications
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a ranitidine hydrochloride releasing-controlling dry suspension and a preparing method thereof. The ranitidine hydrochloride releasing-controlling dry suspension comprises ranitidine hydrochloride and polymers which can be accepted in the pharmacy and comprises, by weight, 10%-90% of ranitidine hydrochloride, 10%-90% of auxiliary materials and the balance other auxiliary materials. The auxiliary materials with the releasing controlling effect are one or more of positive ion exchange resin, methylcellulose, ethyl cellulose, acrylic resin and hydroxypropyl methylcellulose. Compared with an immediate-release preparation, the releasing-controlling preparation can keep the effective blood concentration within 24 hours, curative effects are improved, toxic and side effects are small, taking and carrying are convenient, and the taking times are reduced. Compared with a sustained-release preparation, the releasing-controlling preparation can keep the more stable blood concentration within 24 hours, curative effects are improved, and toxic and side effects are small. According to the ranitidine hydrochloride releasing-controlling dry suspension, dosing only needs to be carried out once in one day; the releasing-controlling preparation is used for treating benign gastric ulcer and duodenal ulcer in clinic.
Description
Technical field
The present invention relates to treatment benign gastric ulcer, the ranitidine hydrochloride controlled release dry suspension of duodenal ulcer with and preparation method thereof.
Background technology
Ranitidine hydrochloride is N '-methyl-N-(2-(((5-((dimethylamino) methyl)-2-furyl)-methyl) sulfo-) ethyl)-2-nitro-1,1-ethylene diamine hydrochlorate.This product is off-white color or light yellow crystalline powder; There is foreign odor; Mildly bitter flavor band is puckery; Very easily deliquescence, darkens after the moisture absorption.T
1/2be about 2-3h.Easily molten in water or methanol, slightly molten in ethanol.System is a kind of potent, long-acting H
2-receptor antagonist, act on stronger than cimetidine 5-8 times, its action time, comparatively the latter was long, and dose energy gastric acid secretion inhibiting reaches 12 hours, can effectively suppress basic gastric acid and gastrin to stimulate the gastric acid secretion caused, and reduced the activity of gastric acid and gastric enzyme.Be mainly used in clinically treating duodenal ulcer, gastric ulcer, postoperative ulcer.Also can be used for upper gastrointestinal hemorrhage and the disease such as exedens dyspepsia and chronic colitis of steroid-induced.Be mainly used in the diseases such as treatment taste-blindness rate, ranitidine commercially price is cheap, and number of users is numerous, comes out at the top all the time in similar drug.Untoward reaction occurs less, and occasionally have constipation, diarrhoea, abdominal distention, headache, dizziness etc., long-term taking toleration is good.
General preparation, often needs administration several times on the one, as conventional tablet administration on the one 2 times, each 1 (150mg/ sheet).Because pain, the reason patient such as to dislike trouble consciously or unconsciously can change Dosing Regimens, miss once or twice, blood plasma is large with the levels of drugs composition fluctuations in tissue, even if continuation medication, treatment concentration is not reached in a short time yet, can only could rebuild treatment level by repeated drug taking, not only waste medicine but also delay treatment.
Oral sustained-release preparation means can prolong drug effect in vivo, reduces a class new medicinal preparation of medicining times, has minimizing toxic and side effects, the advantages such as the toleration improving patient and the blood drug level that provides lasting stability.But dosage form and the preparation of the suitable particular patients ' such as child and old man are very limited.Due to this kind of patient and the adult difference in physiological function, except the difference of dosage, also different requirements is had to the requirement of dosage form and the compliance of taking medicine, the problems such as the uncomfortable or dysphagia of the solid preparation Chang Yinwei mouthfeel such as oral controlled-release tablet or capsule and not easily divided dose, and cause the inconvenience of taking of this type of patient, affect the performance with drug effect that completes of normal therapeutic scheme, some film control formula sheets or slow releasing tablet split broken after take, even there is serious side effects.And by contrast, the agent of controlled release dry suspension have absorb fast, can administered in divided doses, be easy to packed and transported, easily by old man and child the feature that accepts.Therefore the great attention that the good and controlled release dry suspension that can extend drug effect of mouthfeel is subject to medicament scholar and clinician is researched and developed.
Although controlled release preparation, particularly controlled release dry suspension have more advantage relative to common slow releasing preparation and obtain the great attention of medicament scholar and clinician, but prior art only has the slow releasing preparation of ranitidine hydrochloride, external sustained release profile in vivo test effect can only be reached, can not reach controlled-release effect makes in vivo release more steady, untoward reaction is less, also there is not ranitidine hydrochloride controlled release preparation, more there is not the controlled release dry suspension of ranitidine hydrochloride.Applicant believes that this is that the controlled release dry suspension therefore preparing ranitidine hydrochloride has larger difficulty to those skilled in the art technically because some physical property of ranitidine hydrochloride is disadvantageous for being prepared as the controlled release dry suspension of routine at least partly.
The present inventor carrys out Drug controlled release by creatively adopting ion exchange and WURST fluidized bed coating film two kinds of technology simultaneously, unexpectedly obtain the ranitidine hydrochloride controlled release dry suspension of realizing controlled-release, thus making blood drug level in ranitidine hydrochloride body more steady, drug effect is more lasting.
Summary of the invention
The present invention is intended to by creatively adopting ion exchange and coating membrane two kinds of technology to carry out Drug controlled release simultaneously, prepare the ranitidine hydrochloride novel controlled release dry suspension be administered once for a kind of a day, patient only need take and once can reach therapeutic effect every day.The present invention is directed to the deficiency of existing preparation, according to the slow releasing preparation one consumption per day determination ranitidine hydrochloride 300mg that goes on the market, to guarantee the effectiveness of novel formulation.Carry out a large amount of preparation researches according to the character of ranitidine hydrochloride again, complete the development work of the controlled release dry suspension that is administered once for 1st.The present invention mainly comprises principal agent, blocker, impregnating agent, plasticizer, and other adjuvant such as suspensoid forms.
Slow-release material selected by the present invention can be selected from cation exchange resin and methylcellulose, ethyl cellulose, acrylic resin, hydroxypropyl methylcellulose wherein one or more.
Impregnating agent can be selected from one or more in methylcellulose, glycerol, PEG4000 etc.
Plasticizer can be selected from one or more in diethyl phthalate, dibutyl sebacate, PEG400 etc.
Suspensoid can be selected from one or more in PVP, HPMC, tragcanth, Carbopol, AvicelRC591 etc.
Correctives can be selected from mannitol, xylitol, stevioside, lactose, fructose, sucrose, protein sugar, maltose alcohol, glycyrrhizin, Sodium Cyclamate, gelatin, aspartame, flavoring banana essence, flavoring pineapple essence, vanillin, fragrant citrus essence, flavoring orange essence, Mint Essence, ginseng essence, strawberry essence, citric acid, citric acid etc.
In order to ensure the stable of principal agent, appropriate antioxidant and antiseptic etc. can also be added.
Ranitidine hydrochloride controlled release dry suspension provided by the invention, said preparation is containing, for example lower composition by weight percentage:
Ranitidine hydrochloride 10-90%;
Play the adjuvant 10-90% of controlled-release function;
Other adjuvant surplus.The percentage ratio sum of each component is 100% above.
Preferably, the adjuvant of above-mentioned controlled-release function is cation exchange resin and methylcellulose, ethyl cellulose, acrylic resin, hydroxypropyl methylcellulose wherein one or more.
Preferably, other adjuvant described is selected from one or more in blocker, impregnating agent, plasticizer and suspending agent.
Preferred further, described preparation is solid dry suspension.
The method for the preparation of above-mentioned ranitidine hydrochloride controlled release dry suspension that the present invention provides simultaneously, comprises the following steps:
1) preparation is loaded with the medicine carrying resin of ranitidine hydrochloride;
2) described medicine carrying resin is flooded;
3) medicine carrying resin microcapsule is prepared;
4) above-mentioned medicine carrying resin microcapsule is utilized to prepare dry suspension.
Accompanying drawing explanation
Fig. 1 is the In-vitro release curves figure of the ranitidine hydrochloride controlled release dry suspension according to embodiment 1 preparation;
Fig. 2 is according to releasing curve diagram in the ranitidine hydrochloride controlled release dry suspension of embodiment 1 preparation and the beagle dog body of commercially available slow releasing tablet.
Detailed description of the invention
Preparation technology:
1. the preparation of medical resin
Cation exchange resin is added appropriate deionized water, under agitation adds medicine mixing, timing sampling, measure the concentration of drug in solution.When drug level no longer time to time change time and balance to be achieved, wash away the non-bound drug of resin surface with deionized water, be drying to obtain medicine carrying resin at 40 DEG C-60 DEG C.
2. the dipping of medical resin
Get medicine carrying resin appropriate, add in the aqueous solution of the PEG4000 of 20%, stir 0.5 hour, the medical resin that drying and screening must be flooded.
3. the preparation of medical resin microcapsule
Adopt bottom spraying type fluid unit, the medical resin 150g of the dipping of 180 ~ 200 μm is put into fluidising chamber, use the spray gun of nozzle diameter 1mm, air quantity is regulated to make particle in fluidising chamber, be in desirable fluidized state, atomization gas pressure is adjusted to 0.2Mpa, at the uniform velocity pumps into coating solution with constant flow pump, makes coating solution atomizing effect good, continuous coating Non-intermittent drying time, to guarantee in coating process between micropartical substantially without adhesion phenomenon.
4. the preparation of medical resin microcapsule dry suspension
Get drug-resin microcapsule a certain amount of, suspending agent (PVP, HPMC, tragcanth, one or more in Carbopol, AvicelRC591 etc.) is appropriate, and namely mix homogeneously obtains drug-resin controlled release dry suspension.In addition, in order to improve the taste of dry suspension, appropriate correctives can also be added, as mannitol, xylitol, stevioside, lactose, fructose, sucrose, protein sugar, maltose alcohol, glycyrrhizin, Sodium Cyclamate, gelatin, aspartame, flavoring banana essence, flavoring pineapple essence, vanillin, fragrant citrus essence, flavoring orange essence, Mint Essence, ginseng essence, strawberry essence, citric acid, citric acid etc.In order to ensure the stable of principal agent, appropriate antioxidant and antiseptic etc. can also be added.
Following examples intention illustrates the present invention and its scope unrestricted further.
Embodiment
According to aforementioned preparation technology, adopt following formula preparation ranitidine hydrochloride controlled release of the present invention dry suspension.
Embodiment 1:
Embodiment 2:
Embodiment 3:
The vitro release experiment of experimental example 1 ranitidine hydrochloride controlled release dry suspension
In vitro tests is the important means of screening prescription determination technique, and the quality control important role to preparation, investigates mainly through dissolution rate.The present invention's employing is release medium through the 900ml0.15mol/lNacl of degassed process: rotating speed 50r/min, temperature 37 DEG C.According to Chinese Pharmacopoeia 2000 editions annex Ⅹ C paddle method operations, respectively at 2,4,6,8,12,18,24h samples 5ml, filter through 0.45 μm of microporous filter membrane, discard just filtrate, get subsequent filtrate for subsequent use, add synthermal in time, the respective media of same volume, subsequent filtrate is measured absorbance in 307nm place, calculates different time sample liquid concentration according to standard curve, investigate the Cumulative release amount of 12 hours and the relation of time.
Experimental result as shown in fig. 1.Result shows, the vitro release of ranitidine hydrochloride controlled release dry suspension prepared in embodiment 1 12 hours is 75%-85%, and sustained release thus can be made to enter in body.
The stability experiment of experimental example 2 ranitidine hydrochloride controlled release dry suspension
The ranitidine hydrochloride controlled release dry suspension made according to the present invention has been carried out high temperature, high humidity, illumination, exposure air experiment, result shows that this product is under the condition of high temperature, high humidity, illumination, exposure air, and stability is better.
The interior medicine dynamics research of experimental example 3 ranitidine hydrochloride controlled release dry suspension
Pharmacokinetics (pharmacokinetics) is principle and the mathematical processing methods of applied dynamics, the dynamic rule that medicine enters absorption in body, distribution, the process such as metabolism and excretion is by all means described quantitatively, namely the Present site of drug disposition, the relation between concentration and time is studied, and the science of the relationship required for these data that provides an explanation.
Adopt high performance liquid chromatography as detection method, carry out the beagle dog Internal pharmacokinetics research of ranitidine hydrochloride controlled release dry suspension.Result as shown in Figure 2.Result shows ranitidine hydrochloride controlled release dry suspension, and release is more steady than slow releasing tablet in vivo, and duration of efficacy is longer.
As mentioned above, the controlled release dry suspension comprising ranitidine hydrochloride of the present invention can realize the controlled-release effect improved, and provide dissolution rate and the stability of improvement, every day is only administered once can provide effective blood drug level.
Although describe the present invention according to above-mentioned specific embodiment, but should admit, those skilled in the art may make various modification and transformation to the present invention, and these are modified and change and belong to equally in scope of the present invention that appended claims defines.
Claims (5)
1. ranitidine hydrochloride controlled release dry suspension, is characterized in that, said preparation is containing, for example lower composition by weight percentage:
Ranitidine hydrochloride 10-90%;
Play the adjuvant 10-90% of controlled-release function;
Other adjuvant surplus.
2. ranitidine hydrochloride controlled release dry suspension according to claim 1, is characterized in that the adjuvant of controlled-release function is cation exchange resin and methylcellulose, ethyl cellulose, acrylic resin, hydroxypropyl methylcellulose wherein one or more.
3. ranitidine hydrochloride controlled release dry suspension according to claim 1, described in it is characterized in that, other adjuvant is selected from one or more in blocker, impregnating agent, plasticizer and suspending agent.
4. the ranitidine hydrochloride controlled release dry suspension according to claim 1 or 2 or 3, is characterized in that described preparation is solid dry suspension.
5. preparation is according to the method for the ranitidine hydrochloride controlled release dry suspension one of claim 1-4 Suo Shu, said method comprising the steps of:
1) preparation is loaded with the medicine carrying resin of ranitidine hydrochloride;
2) described medicine carrying resin is flooded;
3) medicine carrying resin microcapsule is prepared;
4) above-mentioned medicine carrying resin microcapsule is utilized to prepare dry suspension.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510969953.3A CN105496967B (en) | 2015-12-22 | 2015-12-22 | Ranitidine hydrochloride controlled release dry suspensoid agent and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510969953.3A CN105496967B (en) | 2015-12-22 | 2015-12-22 | Ranitidine hydrochloride controlled release dry suspensoid agent and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105496967A true CN105496967A (en) | 2016-04-20 |
| CN105496967B CN105496967B (en) | 2018-07-03 |
Family
ID=55705532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510969953.3A Active CN105496967B (en) | 2015-12-22 | 2015-12-22 | Ranitidine hydrochloride controlled release dry suspensoid agent and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105496967B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176672A (en) * | 2016-08-30 | 2016-12-07 | 江苏苏南药业实业有限公司 | The preparation method of famotidine medical resin microcapsule |
| CN106176670A (en) * | 2016-08-30 | 2016-12-07 | 江苏苏南药业实业有限公司 | A kind of famotidine medical resin microcapsule |
| CN110327295A (en) * | 2019-08-05 | 2019-10-15 | 五邑大学 | A kind of formula and preparation method thereof of ranitidine hydrochloride slow-release suspension |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080248107A1 (en) * | 2005-08-24 | 2008-10-09 | Rubicon Research Pvt. Ltd. | Controlled Release Formulation |
| CN101927002A (en) * | 2010-07-16 | 2010-12-29 | 钟术光 | Medicament and coating composition |
| CN101987081A (en) * | 2010-07-16 | 2011-03-23 | 钟术光 | Controlled release preparation |
-
2015
- 2015-12-22 CN CN201510969953.3A patent/CN105496967B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080248107A1 (en) * | 2005-08-24 | 2008-10-09 | Rubicon Research Pvt. Ltd. | Controlled Release Formulation |
| CN101927002A (en) * | 2010-07-16 | 2010-12-29 | 钟术光 | Medicament and coating composition |
| CN101987081A (en) * | 2010-07-16 | 2011-03-23 | 钟术光 | Controlled release preparation |
Non-Patent Citations (3)
| Title |
|---|
| 徐斌: "离子交换树脂在药物制剂中的研究进展", 《中南药学》 * |
| 杨宏图等: "盐酸雷尼替丁控释微丸的制备和释药机理的研究", 《中国药师》 * |
| 许真玉等: "离子交换树脂控释混悬剂的研究进展", 《沈阳药科大学学报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176672A (en) * | 2016-08-30 | 2016-12-07 | 江苏苏南药业实业有限公司 | The preparation method of famotidine medical resin microcapsule |
| CN106176670A (en) * | 2016-08-30 | 2016-12-07 | 江苏苏南药业实业有限公司 | A kind of famotidine medical resin microcapsule |
| CN106176672B (en) * | 2016-08-30 | 2019-01-04 | 江苏苏南药业实业有限公司 | The preparation method of famotidine medical resin micro-capsule |
| CN106176670B (en) * | 2016-08-30 | 2019-02-01 | 江苏苏南药业实业有限公司 | A kind of famotidine medical resin micro-capsule |
| CN110327295A (en) * | 2019-08-05 | 2019-10-15 | 五邑大学 | A kind of formula and preparation method thereof of ranitidine hydrochloride slow-release suspension |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105496967B (en) | 2018-07-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101094657B (en) | Controlled release complex formulation for oral administration of medicine for diabetes and method for the preparation thereof | |
| JP4260370B2 (en) | Oral sustained release formulation of fasudil hydrochloride | |
| CN101732275B (en) | Double-layer osmotic pump controlled release tablet of isosorbide mononitrate and preparation method thereof | |
| KR20000029530A (en) | Tramadol multiple unit formulations | |
| CN103889455B (en) | Stabilize Eperisone medical component and the sustained release preparation containing above-mentioned constituent | |
| US11504345B2 (en) | Extended release liquid compositions of metformin | |
| JP2021516260A (en) | Programmable pharmaceutical composition for time release of drug | |
| CN105496967A (en) | Ranitidine hydrochloride releasing-controlling dry suspension and preparing method thereof | |
| WO2019130749A1 (en) | Novel fine particle coating (drug-containing hollow particle and method for manufacturing same) | |
| NO171827B (en) | METHOD OF PREPARING A PREPARATION FOR RETARDED SEPARATION OF THEOPHYLLINE | |
| CN106963736A (en) | Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof | |
| KR20080076667A (en) | Thixotropic pharmaceutical compositions | |
| CN105213425A (en) | One treats hypertensive compound recipe reserpine oral cavity disintegration tablet and preparation method thereof | |
| CN101869544A (en) | Ambroxol hydrochloride controlled release suspension and preparation method thereof | |
| CN107987033A (en) | The application of vanillic aldehyde and its isomers in NA inhibitor is prepared | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| CN107530342A (en) | Oral administration medical composition | |
| CN102552208B (en) | Daidzein solid dispersion micro-pill capsule and preparation method thereof | |
| CN105748421B (en) | A kind of sustained release tablets and preparation method thereof of hydrochloric Trazodone | |
| CN100518725C (en) | Venlafaxine hydrochloride liquid slow-release preparation and its preparation method | |
| CN109330995B (en) | Pellet coated with short-acting hypoglycemic agent and preparation method thereof | |
| CN105902564A (en) | Pharmaceutical composition for treating hypertension and preparation method thereof | |
| KR101067224B1 (en) | Controlled releasing syrup containing ibuprofen and its manufacturing method | |
| WO2019230937A1 (en) | Solid oral dosage form having excellent dissolution properties | |
| JP4775879B2 (en) | Vitamin composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |