CN119818454A - Ozagrel hydrochloride capsule and preparation method thereof - Google Patents
Ozagrel hydrochloride capsule and preparation method thereof Download PDFInfo
- Publication number
- CN119818454A CN119818454A CN202510130553.7A CN202510130553A CN119818454A CN 119818454 A CN119818454 A CN 119818454A CN 202510130553 A CN202510130553 A CN 202510130553A CN 119818454 A CN119818454 A CN 119818454A
- Authority
- CN
- China
- Prior art keywords
- ozagrel hydrochloride
- microcrystalline cellulose
- uniformity
- mixing
- preparation
- 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
- Medicinal Preparation (AREA)
Abstract
本发明提供了一种盐酸奥扎莫德胶囊及其制备方法。本发明涉及的盐酸奥扎莫德胶囊含有：盐酸奥扎莫德、胶态二氧化硅、微晶纤维素(PH‑105)、微晶纤维素(PH‑112)和其它辅料；本发明通过在第一步混合工艺中加入胶态二氧化硅和微晶纤维素(PH‑105)，并控制胶态二氧化硅和微晶纤维素(PH‑105)的添加量，不仅解决了小剂量药物，尤其是药物含量在1％以下的小剂量药物的混合均匀性和含量均匀度问题，改善了质量控制，而且提高了盐酸奥扎莫德胶囊在水和pH6.8介质中的溶出速率和批内溶出均一性，同时改善制剂的生物利用度，减少个体差异，提高用药安全性。The present invention provides an Ozamod hydrochloride capsule and a preparation method thereof. The Ozamod hydrochloride capsules involved in the present invention contain: Ozamod hydrochloride, colloidal silicon dioxide, microcrystalline cellulose (PH-105), microcrystalline cellulose (PH-112) and other excipients; the present invention not only solves the mixing uniformity and content uniformity problems of small-dose drugs, especially small-dose drugs with a drug content of less than 1%, but also improves quality control, and improves the dissolution rate and batch dissolution uniformity of Ozamod hydrochloride capsules in water and pH 6.8 medium, while improving the bioavailability of the preparation, reducing individual differences, and improving drug safety.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, relates to an ozagrel hydrochloride preparation, and in particular relates to an ozagrel hydrochloride capsule and a preparation method thereof.
Background
Ozagrel hydrochloride (ozanimod hydrochloride) is 5- (3- { (1S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-inden-4-yl } -1,2, 4-oxadiazol-5-yl) -2- [ (propan-2-yl) oxy ] benzonitrile hydrochloride, has a chemical name of C 23H24N4O3.HCl, a molecular weight of 440.92, and a chemical structural formula of
Ozagrel hydrochloride is an orally active sphingosine-1-phosphate (S1P) receptor modulator that selectively binds with high affinity to S1P receptor subtype 1 (S1P 1) and subtype 5 (S1P 5). Ozagru hydrochloride capsules, trade name ZEPOSIA, specification 0.23mg, 0.46mg, 0.92mg (as ozagru) were marketed by FDA approved us Bai Zhu Guibao (Bristol-Myers quibb, BMS) at 25 months 2020 for the treatment of relapsing multiple sclerosis. The FDA approved ozagrel hydrochloride capsules again for treatment of adult ulcerative colitis 5 months 2021. The ozagru hydrochloride capsule is marketed in the chinese lot under the trade name of hotperxiya at 1 month of 2023 and 31 days.
Ozagrel hydrochloride belongs to a small-sized, high-activity drug which is widely metabolized in the human body to form a plurality of circulating active metabolites, including two main active metabolites, CC112273 and CC1084037. The activity of these two metabolites and the selectivity for S1P1 and S1P5 are similar to the parent drug. After multiple doses, about 94% of the circulating total active is ozagrel (6%), CC112273 (73%) and CC1084037 (15%). In Relapsing Multiple Sclerosis (RMS) patients, the average effective half-life of metabolite CC112273 on a model basis is about 11 days, with an accumulation ratio of about 16. Whereas RMS patients need long-term drug maintenance treatment, metabolites with high accumulation ratios tend to accumulate in the body, increasing adverse drug reactions and possibly even poisoning. Therefore, the small-size, high-activity and high-metabolite accumulation ratio medicines such as ozagrel hydrochloride have high requirements on content uniformity and dissolution uniformity of products, and the content and dissolution difference of the preparation have great influence on the curative effect and safety of the medicines.
The prior ozagrel hydrochloride capsule has the defects of high process difficulty and poor quality controllability. The ozagrel hydrochloride capsule has small specification, and is extremely easy to have the conditions of uneven material mixing and unqualified preparation content uniformity in the preparation process. In addition, commercial ozagrel hydrochloride capsules (hot Percy a) dissolve slowly in water and ph6.8 medium, and have poor intra-batch uniformity, affecting the bioavailability, efficacy and safety of the formulation.
Therefore, the ozagrel hydrochloride capsule preparation process with simple and controllable process, uniform preparation content, quick dissolution and high dissolution uniformity is needed.
Disclosure of Invention
The invention aims to solve the technical problems of uneven content, slow dissolution in partial medium, poor batch uniformity and the like of an ozagrel hydrochloride preparation in the prior art, and provides an ozagrel hydrochloride capsule which has uniform content, quick dissolution, simple and easily controlled process and is suitable for industrialized and totally-enclosed production and a preparation method thereof. The invention provides an ozagrel hydrochloride capsule which comprises ozagrel hydrochloride, colloidal silicon dioxide, microcrystalline cellulose (PH-105), microcrystalline cellulose (PH-112), a disintegrating agent and a lubricant, wherein 0.25mg of the ozagrel hydrochloride capsule is taken as 1 part by mass, and the content of each component is as follows:
the preparation method of the ozagrel hydrochloride capsule comprises the following steps:
Ozagrel hydrochloride, colloidal silicon dioxide and microcrystalline cellulose (PH-105) are premixed, sieved and mixed (first step of mixing), microcrystalline cellulose (PH-112) and disintegrating agent are added, mixing is carried out again (second step of mixing), and finally lubricant is added, mixed (total mixing) and filled into capsules.
As a preferable technical scheme, the ozagrel hydrochloride has the particle size of D90 which is less than or equal to 90 mu m and D50 which is less than or equal to 20 mu m.
As a preferable technical scheme, the dosage of the colloidal silicon dioxide is 2-3 parts by mass, namely 0.5 mg-0.75 mg.
As a preferred embodiment, the colloidal silica is used in an amount of 2 parts by mass, i.e., 0.5mg.
As a preferable technical scheme, the microcrystalline cellulose (PH-105) is used in an amount of 30-40 parts by mass, namely 7.5 mg-10 mg.
As a preferred embodiment, the microcrystalline cellulose (PH-105) is used in an amount of 40 parts by mass, i.e., 10mg.
As a preferable technical scheme, the pore diameter of the screen is 0.4mm-0.5mm.
As a preferable technical scheme, the disintegrating agent is croscarmellose sodium, and the lubricant is magnesium stearate.
The mixed uniformity RSD value of the total mixed material of the ozagrel hydrochloride capsule prepared by the invention is less than or equal to 3.0 percent.
The content uniformity A+2.2S value of the ozagrimod hydrochloride in the ozagrel hydrochloride capsule prepared by the invention is less than or equal to 6.4, and is better than the content uniformity of the commercially available ozagrel hydrochloride capsule.
The ozagrel hydrochloride capsule prepared by the invention is quickly dissolved in each medium, has good uniformity in batch, and is more excellent than the dissolution of the ozagrel hydrochloride capsule sold in the market especially in water and pH6.8 medium.
The invention also provides a preparation method of any one of the ozagrel hydrochloride capsules, which comprises the following steps:
(1) Premixing ozagrel hydrochloride with 0.5-1 mg of colloidal silicon dioxide and 5-10 mg of microcrystalline cellulose (PH-105), and mixing for 15-20min through a sieve with the aperture of 0.4-0.5 mm;
(2) Adding microcrystalline cellulose (PH-112) and disintegrating agent, and mixing for 15-20min;
(3) Adding lubricant, and mixing for 3-5min;
(4) And (5) filling capsules.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, by controlling the adding steps and the adding amount of colloidal silicon dioxide and microcrystalline cellulose (PH-105), the prepared ozagrel hydrochloride total mixed material has high mixing uniformity and uniform content of active ingredients, and the safety and quality controllability of the medication of patients are improved.
2. The dissolution rate of the ozagrel hydrochloride capsule prepared by adopting the technical scheme of the invention in water and a medium with the pH of 6.8 is greatly improved, the uniformity in dissolution batch is also obviously improved, the bioavailability of the ozagrel hydrochloride capsule can be improved, the individual difference is reduced, and the medication safety is improved.
3. The technical scheme of the invention has simple process and easy control, and is suitable for industrialized and totally-enclosed production.
Detailed Description
The colloidal silica used in the present invention is available from the company "Shanghai", inc., model number AEROSIL 200. The rest raw materials and auxiliary materials are all common commercial products. The particle size of the ozagrel hydrochloride is D 90≤90μm,D50 -20 mu m.
The commercial ozagrel hydrochloride capsules have 3 specifications of 0.23mg, 0.46mg and 0.92mg, and the weight of the capsule content is 100mg. It is apparent that the 0.23mg gauge is most difficult to blend and is also most prone to content uniformity problems relative to the other two gauges. Thus, the present invention selects the 0.23mg specification example to illustrate the advantages of the invention and controls the weight of the capsule contents to 100mg by fine tuning the prescribed amount of microcrystalline cellulose (PH-112).
The specific formulations of examples 1-3 are shown in Table 1.
Table 1 examples 1-3 prescriptions
Examples 1-3 preparation method:
Ozagrel hydrochloride, colloidal silica (AEROSIL 200) and microcrystalline cellulose (PH-105) were placed in a mixing drum, premixed for 2min at 20rpm, and discharged. Sieving with a crushing and granulating machine, and setting rotation speed at 300rpm with a sieve with aperture of 0.4 mm. The sieved material was again placed in the mixing drum and mixed for 15min at 20 rpm. Microcrystalline cellulose (pH-112) and croscarmellose sodium were added and mixed at 20rpm for 15 minutes. Magnesium stearate was added and mixed at 20rpm for 3min. Filling into capsule, and making into hollow capsule of gelatin No. 4.
The specific formulations of examples 4-7 are shown in Table 2.
Table 2 examples 4-7 prescriptions
Examples 4-7 were prepared in the same manner as in example 1.
To better illustrate the advantages of the present invention, reference is made to the ozagrel hydrochloride capsule of example 1 and to the process for its preparation, setting up 10 comparative examples.
Specific formulations of comparative examples 1-7 are shown in Table 3.
Table 3 comparative examples 1-7 prescriptions
Comparative examples 1-7 preparation method:
comparative example 1 the preparation was the same as in example 1.
Comparative example 2 ozagrel hydrochloride and microcrystalline cellulose (pH-105) were placed in a mixing drum and pre-mixed for 2min at 20rpm, and discharged. Sieving with a crushing and granulating machine, and setting rotation speed at 300rpm with a sieve with aperture of 0.4 mm. The sieved material was again placed in the mixing drum and mixed for 15min at 20 rpm. Microcrystalline cellulose (PH-112), colloidal silicon dioxide (AEROSIL 200) and croscarmellose sodium were placed in a mixing drum, premixed at 20rpm for 2min, discharged, sieved with a crushing granulator, and a sieve with a pore diameter of 0.8mm was used, and the rotation speed was set at 300rpm. The sieved material was again placed in the mixing drum and mixed for 15min at 20 rpm. Magnesium stearate was added and mixed at 20rpm for 3min. Filling into capsule, and making into hollow capsule of gelatin No. 4.
Comparative example 3 ozagrel hydrochloride and microcrystalline cellulose (pH-105) were placed in a mixing drum and pre-mixed for 2min at 20rpm, and discharged. Sieving with a crushing and granulating machine, and setting rotation speed at 300rpm with a sieve with aperture of 0.4 mm. The sieved material was again placed in the mixing drum and mixed for 15min at 20 rpm. Microcrystalline cellulose (pH-112) and croscarmellose sodium were added and mixed at 20rpm for 15 minutes. Colloidal silica (AEROSIL 200) was added, premixed at 20rpm for 2min, discharged, sieved with a crushing granulator, and set at 300rpm using a sieve with a pore size of 0.8 mm. The sieved material was again placed in a mixing drum, magnesium stearate was added and mixed for 3min at 20 rpm. Filling into capsule, and making into hollow capsule of gelatin No. 4.
Comparative example 4 the preparation was the same as in example 1.
Comparative example 5 ozagrel hydrochloride, talc and microcrystalline cellulose (PH-105) were placed in a mixing drum, premixed at 20rpm for 2min, and discharged. Sieving with a crushing and granulating machine, and setting rotation speed at 300rpm with a sieve with aperture of 0.4 mm. The sieved material was again placed in the mixing drum and mixed for 15min at 20 rpm. Microcrystalline cellulose (pH-112) and croscarmellose sodium were added and mixed at 20rpm for 15 minutes. Magnesium stearate was added and mixed at 20rpm for 3min. Filling into capsule, and making into hollow capsule of gelatin No. 4.
Comparative example 6 the preparation was the same as in example 1.
Comparative example 7 the preparation was the same as in example 1.
Comparative example 8 is a commercially available ozagrel hydrochloride capsule, manufacturer: celgene International Sarl, trade name: lot number K2044AA, specification 0.23mg.
Comparative example 9 is a commercially available ozagrel hydrochloride capsule, manufacturer: celgene International Sarl, trade name: Lot number K2044AA, specification 0.46mg.
Comparative example 10 is a commercially available ozagrel hydrochloride capsule, manufacturer: celgene International Sarl, trade name: Batch No. J2118BA, specification 0.92mg.
Test example 1 uniformity of mixing and content uniformity
Examples 1-7 and comparative examples 1-7 were sampled at 11 different positions of the mixing drum after the end of the total mixing process, and were ready for investigation of the mixing uniformity. The specific sampling method refers to the technical guidelines of research on the mixing uniformity and the central control dosage unit uniformity of chemical oral solid preparation.
And (3) taking a proper amount of the total mixed materials, detecting according to a method under the content measurement item of the ozagrel hydrochloride capsule import drug registration standard (JX 20230003), and calculating the mixing uniformity RSD value of each total mixed material to limit 5.0% (the research technical guidelines of the mixing uniformity and the central control dosage unit uniformity of the chemical oral solid preparation).
The ozagrel hydrochloride capsules prepared in examples 1-7 and comparative examples 1-7 and the ozagrel hydrochloride capsules sold in comparative examples 8-10 were tested according to the method under the content uniformity item of the ozagrel hydrochloride capsule import drug registration standard (JX 20230003), and the content uniformity A+2.2S value of each capsule was calculated, with the limit of 15.0 (four general rules 0941 of Chinese pharmacopoeia 2020 edition).
The RSD values of the mixing uniformity and the a+2.2s values of the content uniformity of the capsules of the total mixture materials of each example and comparative example are shown in table 4.
TABLE 4 results of uniformity of mixing (RSD value) and content uniformity (A+2.2S value)
| Sample of | RSD(%) | A+2.2S |
| Example 1 | 1.8 | 4.1 |
| Example 2 | 2.4 | 5.4 |
| Example 3 | 2.2 | 5.0 |
| Example 4 | 2.9 | 6.4 |
| Example 5 | 2.6 | 5.8 |
| Example 6 | 1.6 | 3.5 |
| Example 7 | 1.3 | 2.8 |
| Comparative example 1 | 5.5 | 13.5 |
| Comparative example 2 | 6.6 | 15.6 |
| Comparative example 3 | 6.5 | 15.3 |
| Comparative example 4 | 3.9 | 9.6 |
| Comparative example 5 | 4.5 | 11.4 |
| Comparative example 6 | 6.8 | 16.0 |
| Comparative example 7 | 6.4 | 15.1 |
| Comparative example 8 | / | 8.0 |
| Comparative example 9 | / | 7.2 |
| Comparative example 10 | / | 6.8 |
As can be seen from the results of the above tables, the mixing uniformity of the total mixture and the content uniformity of the capsules prepared in examples 1 to 7 were both good to the expected technical effect, and the content uniformity was better than that of the commercially available capsules of comparative examples 8 to 10.
Comparative example 1 has a smaller amount of colloidal silica than example 1, has a poor glidant effect, and is not satisfactory in improving the uniformity of mixing of the total mixture and the uniformity of the content of capsules.
Comparative examples 2 to 3 are identical in the amount of colloidal silica added to example 1, but are added in the second-stage mixing process and the total mixing process, respectively. As the particle sizes of the ozagrel hydrochloride and the microcrystalline cellulose (PH-105) are very fine in the first mixing process, the fluidity of the materials is poor, and the mixing effect is general under the condition of no glidant. Even if colloidal silica is added in the second mixing process or the total mixing process, the mixing uniformity of the total mixed material and the content uniformity of the capsules are affected.
Comparative example 4 the amount of colloidal silica added was greater than in example 1. The results show that the addition factor of colloidal silica is not as good as the others.
Comparative example 5 compared to example 1, talc was chosen as a glidant and was significantly less effective than colloidal silicon dioxide.
Comparative example 6 has a smaller amount of microcrystalline cellulose (PH-105) than example 1, and has a poor dilution effect on ozagrel hydrochloride, affecting the mixing uniformity of the first-step mixing process, and thus affecting the mixing uniformity of the total mixture and the content uniformity of the capsules.
Comparative example 7 has a higher addition amount of microcrystalline cellulose (PH-105) than that of example 1, and ozagrel hydrochloride cannot be uniformly mixed in an excessive amount of microcrystalline cellulose (PH-105), resulting in poor mixing uniformity of total mixing and content uniformity of capsules.
Test example 2 dissolution profile
The ozagrel hydrochloride capsules prepared in examples 1, 6 and 7 and the commercial capsules of comparative examples 8 to 10 were tested according to the method under the dissolution rate item of the ozagrel hydrochloride capsule import drug registration standard (JX 20230003), and 0.01N hydrochloric acid solution, pH4.5 acetic acid-sodium acetate buffer, pH6.8 phosphate buffer and water were used as dissolution media, respectively. The cumulative dissolution percentage and the in-batch dissolution uniformity (RSD/%, n=12) were calculated and the results are shown in tables 5 to 8 below.
TABLE 5 dissolution data in 0.01N hydrochloric acid solution
TABLE 6 dissolution data in pH4.5 acetic acid-sodium acetate buffer
TABLE 7 dissolution data in phosphate buffer at pH6.8
TABLE 8 dissolution data in water
The experimental results show that:
the ozagrel hydrochloride capsules prepared in examples 1, 6 and 7 were rapidly dissolved in four dissolution media, and the dissolution batch uniformity was good. In particular, in the aqueous medium and phosphate buffer at pH6.8, the dissolution rate was significantly faster than that of the commercial capsules of comparative examples 8-10, and the dissolution batch uniformity was significantly better than that of the commercial capsules. The invention can obviously improve the dissolution rate and the dissolution batch uniformity of ozagrel hydrochloride in the two media, and is beneficial to the improvement of bioavailability and the quality control of the preparation.
Claims (9)
1. The ozagrel hydrochloride capsule comprises ozagrel hydrochloride, colloidal silicon dioxide, microcrystalline cellulose PH-105, microcrystalline cellulose PH-112, a disintegrating agent and a lubricant, wherein 0.25mg of the ozagrel hydrochloride capsule is taken as 1 part by mass, and the content of each component is as follows:
the preparation method of the ozagrel hydrochloride capsule comprises the following steps:
The preparation method comprises the steps of premixing and sieving ozagrel hydrochloride, colloidal silicon dioxide and microcrystalline cellulose PH-105, mixing in the first step, adding microcrystalline cellulose PH-112 and a disintegrating agent, mixing in the second step, adding a lubricant, mixing in the total, and encapsulating.
2. The ozagrel hydrochloride capsule of claim 1, wherein the ozagrel hydrochloride has a particle size D 90≤90μm,D50 -20 μm.
3. Ozagrel hydrochloride capsule according to claim 1, wherein the colloidal silica is used in an amount of 2-3 parts by mass.
4. Ozagrel hydrochloride capsule according to claim 3, wherein the colloidal silica is used in an amount of 2 parts by mass.
5. Ozagrel hydrochloride capsule according to claim 1, wherein microcrystalline cellulose PH-105 is used in an amount of 30-40 parts by mass.
6. Ozagrel hydrochloride capsule according to claim 5, wherein microcrystalline cellulose PH-105 is used in an amount of 40 parts by mass.
7. Ozagrel hydrochloride capsule according to claim 1, wherein the sieve mesh size of the sieve is 0.4 mm-0.5 mm.
8. Ozagrel hydrochloride capsule according to claim 1, wherein the disintegrant is croscarmellose sodium.
9. Ozagrel hydrochloride capsule according to claim 1, wherein the lubricant is magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202510130553.7A CN119818454A (en) | 2025-02-05 | 2025-02-05 | Ozagrel hydrochloride capsule and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202510130553.7A CN119818454A (en) | 2025-02-05 | 2025-02-05 | Ozagrel hydrochloride capsule and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN119818454A true CN119818454A (en) | 2025-04-15 |
Family
ID=95302776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202510130553.7A Pending CN119818454A (en) | 2025-02-05 | 2025-02-05 | Ozagrel hydrochloride capsule and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN119818454A (en) |
-
2025
- 2025-02-05 CN CN202510130553.7A patent/CN119818454A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN116157391B (en) | Pharmaceutical composition comprising EGFR inhibitor and preparation method thereof | |
| WO2020249002A1 (en) | Oral capsule and preparation method therefor | |
| CN115581686B (en) | Preparation method of pregabalin capsule and pregabalin capsule | |
| Ashokbhai et al. | Premix technologies for drug delivery: manufacturing, applications, and opportunities in regulatory filing | |
| CN113209036B (en) | Azilsartan tablets and preparation method and application thereof | |
| CN117442577B (en) | Candesartan cilexetil microchip and preparation method and application thereof | |
| EP3539536A1 (en) | A pharmaceutical composition of sunitinib or its salt thereof in its polymorphic form i | |
| CN119818454A (en) | Ozagrel hydrochloride capsule and preparation method thereof | |
| CN113827576B (en) | Pharmaceutical composition with naloxone oxalate as active ingredient and preparation method thereof | |
| CN114246836B (en) | Pregabalin sustained release tablet and preparation method thereof | |
| CN114762683B (en) | A drug composition for treating diabetic neuropathy and a preparation method thereof | |
| CN113262207B (en) | Flunarizine hydrochloride capsule preparation and preparation method thereof | |
| CN111000812B (en) | Preparation method of lacosamide tablets | |
| CN117045610A (en) | High-stability dissolution labetalol hydrochloride composition and preparation method thereof | |
| CN112315914A (en) | A kind of lenalidomide pharmaceutical composition and preparation method thereof | |
| WO2022042646A1 (en) | Lurasidone hydrochloride composition and preparation method therefor | |
| CN114306254A (en) | Molnupiravir oral solid preparation and preparation method thereof | |
| CN117695285A (en) | JAK kinase inhibitor pharmaceutical composition | |
| CN121041234B (en) | Nalfurorphine pharmaceutical composition and preparation method thereof | |
| CN118634201B (en) | A kind of janagliflozin metformin tablets and preparation method thereof | |
| CN105456216A (en) | Pramipexole dihydrochloride sustained-release tablet composition and preparation method thereof | |
| CN114028348B (en) | Sildenafil citrate orally disintegrating tablet and preparation method thereof | |
| WO2020155098A1 (en) | Pharmaceutical composition for treating diabetes, preparation method therefor, and use thereof | |
| CN119868291A (en) | Pharmaceutical composition containing propionofovir fumarate, preparation method and application | |
| CN116898818A (en) | An oseltamivir tablet and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |