SG11201809708PA - Physiologically balanced injectable formulations of fosnetupitant - Google Patents
Physiologically balanced injectable formulations of fosnetupitantInfo
- Publication number
- SG11201809708PA SG11201809708PA SG11201809708PA SG11201809708PA SG11201809708PA SG 11201809708P A SG11201809708P A SG 11201809708PA SG 11201809708P A SG11201809708P A SG 11201809708PA SG 11201809708P A SG11201809708P A SG 11201809708PA SG 11201809708P A SG11201809708P A SG 11201809708PA
- Authority
- SG
- Singapore
- Prior art keywords
- international
- fosnetupitant
- pct
- physiologically balanced
- zardi
- Prior art date
Links
- HZIYEEMJNBKMJH-UHFFFAOYSA-N [4-[5-[[2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl]-methylamino]-4-(2-methylphenyl)pyridin-2-yl]-1-methylpiperazin-1-ium-1-yl]methyl hydrogen phosphate Chemical compound C=1N=C(N2CC[N+](C)(COP(O)([O-])=O)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HZIYEEMJNBKMJH-UHFFFAOYSA-N 0.000 title abstract 3
- 229950010727 fosnetupitant Drugs 0.000 title abstract 3
- 239000007972 injectable composition Substances 0.000 title abstract 2
- 238000009472 formulation Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 230000008520 organization Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Otolaryngology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 14 December 2017 (14.12.2017) WIP0 I PCT ill~~~~~~~~ 011101010VIIIVIIIun Hol omolio11 °nom oimIE (10) International Publication Number WO 2017/211663 Al (51) International Patent Classification: A61K 9/08 (2006.01) A61K 47/26 (2006.01) A61K 9/19 (2006.01) A61K 31/675 (2006.01) (21) International Application Number: PCT/EP2017/063268 (22) International Filing Date: 01 June 2017 (01.06.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/345,942 06 June 2016 (06.06.2016) US (71) Applicant: HELSINN HEALTHCARE SA [CH/CH]; Via Pian Scairolo 9, 6912 Lugano / Pazzallo (CH). (72) Inventors: VENTURINI, Alessio; Via Majano 1, 21100 Varese (IT). CANNELLA, Roberta; Via Al Colle 42, 21100 Varese (IT). (74) Agent: ZARDI, Marco; c/o M. ZARDI & Co SA, Via Pi- oda, 6, 6900 Lugano (CH). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) N 1-1 (54) Title: PHYSIOLOGICALLY BALANCED INJECTABLE FORMULATIONS OF FOSNETUPITANT \" (57) : Injectable dosages and formulations of fosnetupitant and pharmaceutically acceptable salts thereof are provided that are 0 efficacious, chemically stable and physiologically balanced for safety and efficacy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662345942P | 2016-06-06 | 2016-06-06 | |
| PCT/EP2017/063268 WO2017211663A1 (en) | 2016-06-06 | 2017-06-01 | Physiologically balanced injectable formulations of fosnetupitant |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SG11201809708PA true SG11201809708PA (en) | 2018-11-29 |
Family
ID=59055193
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SG11201809708PA SG11201809708PA (en) | 2016-06-06 | 2017-06-01 | Physiologically balanced injectable formulations of fosnetupitant |
Country Status (37)
| Country | Link |
|---|---|
| US (5) | US10624911B2 (en) |
| EP (2) | EP3435980B1 (en) |
| JP (2) | JP6936817B2 (en) |
| KR (1) | KR102459416B1 (en) |
| CN (1) | CN109310627B (en) |
| AR (1) | AR108676A1 (en) |
| AU (1) | AU2017276588B2 (en) |
| BR (1) | BR112018074655B1 (en) |
| CA (1) | CA3025837C (en) |
| CL (1) | CL2018003338A1 (en) |
| CO (1) | CO2018011686A2 (en) |
| CY (1) | CY1122755T1 (en) |
| DK (1) | DK3435980T3 (en) |
| EA (1) | EA036605B1 (en) |
| EC (1) | ECSP19000169A (en) |
| ES (1) | ES2771226T3 (en) |
| GE (1) | GEP20207189B (en) |
| HR (1) | HRP20200196T1 (en) |
| IL (1) | IL263126B (en) |
| JO (1) | JOP20170137B1 (en) |
| LT (1) | LT3435980T (en) |
| MA (1) | MA44513B1 (en) |
| MD (1) | MD3435980T2 (en) |
| MX (1) | MX376118B (en) |
| MY (1) | MY194081A (en) |
| PE (1) | PE20190347A1 (en) |
| PH (1) | PH12018502524B1 (en) |
| PL (1) | PL3435980T3 (en) |
| PT (1) | PT3435980T (en) |
| RS (1) | RS59852B1 (en) |
| SG (1) | SG11201809708PA (en) |
| SI (1) | SI3435980T1 (en) |
| TW (1) | TWI725191B (en) |
| UA (1) | UA122285C2 (en) |
| UY (1) | UY37273A (en) |
| WO (1) | WO2017211663A1 (en) |
| ZA (1) | ZA201807932B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11654154B2 (en) | 2019-01-29 | 2023-05-23 | Navinta Iii Inc | Process for preparing injectable Fosaprepitant Dimeglumine compositions having improved storage stability |
| US12097197B2 (en) | 2021-12-21 | 2024-09-24 | Slayback Pharma Llc | Stable liquid compositions of netupitant and palonosetron |
| WO2023182388A1 (en) * | 2022-03-23 | 2023-09-28 | 大鵬薬品工業株式会社 | Stabilized formulation for fosnetupitant or pharmaceutically acceptable salt thereof, and a method for producing same |
| WO2025036703A1 (en) * | 2023-08-13 | 2025-02-20 | Helsinn Healthcare Sa | Fosnetupitant for administration via intravenous bolus |
| WO2025056094A1 (en) * | 2023-09-15 | 2025-03-20 | 广州帝奇医药技术有限公司 | Freeze-dried preparation, injection, and preparation method therefor |
| WO2026002808A1 (en) | 2024-06-24 | 2026-01-02 | Helsinn Healthcare Sa | Prevention of nausea and vomiting from antibody-drug conjugates and other long-acting emetogenics |
| CN119185243A (en) * | 2024-11-28 | 2024-12-27 | 山东齐都药业有限公司 | Fonetupitant palonosetron oral taste masking granule and preparation method and application thereof |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL166267B1 (en) * | 1989-11-28 | 1995-04-28 | Syntex Inc | Method of producing new tricyclic compounds PL PL PL PL |
| IL111960A (en) | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
| IL112134A (en) | 1993-12-29 | 1999-12-22 | Merck Sharp & Dohme | Substituted morpholine derivatives their preparation and pharmaceutical compositions containing them |
| IL112778A0 (en) | 1994-03-04 | 1995-05-26 | Merck & Co Inc | Substituted heterocycles, their preparation and pharmaceutical compositions containing them |
| JO2735B1 (en) * | 2003-01-30 | 2013-09-15 | هيلسين هيلث كير أس ايه. | Liquid pharmaceutical formations of balloonosterone |
| US20060167072A1 (en) * | 2004-01-30 | 2006-07-27 | Helsinn Healthcare Sa | Liquid pharmaceutical formulations of palonosetron |
| US20100048607A1 (en) * | 2008-08-25 | 2010-02-25 | Chandrashekhar Kocherlakota | Formulations comprising palonosetron |
| CN105412110B (en) * | 2011-10-18 | 2018-05-25 | 赫尔森保健股份公司 | The Therapeutic combinations of Netupitant and palonosetron |
| US8426450B1 (en) * | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| PL2866797T3 (en) * | 2012-07-06 | 2020-11-02 | Pharmathen S.A. | Stable injectable pharmaceutical composition of neurokinin 1 receptor antagonist and process for preparation thereof |
-
2017
- 2017-06-01 CA CA3025837A patent/CA3025837C/en active Active
- 2017-06-01 DK DK17729822.1T patent/DK3435980T3/en active
- 2017-06-01 PL PL17729822T patent/PL3435980T3/en unknown
- 2017-06-01 EP EP17729822.1A patent/EP3435980B1/en active Active
- 2017-06-01 EA EA201892837A patent/EA036605B1/en unknown
- 2017-06-01 PE PE2018003074A patent/PE20190347A1/en unknown
- 2017-06-01 RS RS20200100A patent/RS59852B1/en unknown
- 2017-06-01 UA UAA201812842A patent/UA122285C2/en unknown
- 2017-06-01 MD MDE20190164T patent/MD3435980T2/en unknown
- 2017-06-01 EP EP19200383.8A patent/EP3626231A1/en not_active Withdrawn
- 2017-06-01 MX MX2018015036A patent/MX376118B/en active IP Right Grant
- 2017-06-01 HR HRP20200196TT patent/HRP20200196T1/en unknown
- 2017-06-01 JP JP2018563684A patent/JP6936817B2/en active Active
- 2017-06-01 PT PT177298221T patent/PT3435980T/en unknown
- 2017-06-01 SI SI201730178T patent/SI3435980T1/en unknown
- 2017-06-01 AU AU2017276588A patent/AU2017276588B2/en active Active
- 2017-06-01 PH PH1/2018/502524A patent/PH12018502524B1/en unknown
- 2017-06-01 GE GEAP202014974A patent/GEP20207189B/en unknown
- 2017-06-01 LT LTEP17729822.1T patent/LT3435980T/en unknown
- 2017-06-01 MA MA44513A patent/MA44513B1/en unknown
- 2017-06-01 SG SG11201809708PA patent/SG11201809708PA/en unknown
- 2017-06-01 WO PCT/EP2017/063268 patent/WO2017211663A1/en not_active Ceased
- 2017-06-01 ES ES17729822T patent/ES2771226T3/en active Active
- 2017-06-01 KR KR1020187034943A patent/KR102459416B1/en active Active
- 2017-06-01 MY MYPI2018001970A patent/MY194081A/en unknown
- 2017-06-01 CN CN201780034681.5A patent/CN109310627B/en active Active
- 2017-06-01 BR BR112018074655-0A patent/BR112018074655B1/en active IP Right Grant
- 2017-06-02 UY UY0001037273A patent/UY37273A/en active IP Right Grant
- 2017-06-02 US US15/611,785 patent/US10624911B2/en active Active
- 2017-06-02 AR ARP170101521A patent/AR108676A1/en unknown
- 2017-06-06 TW TW106118613A patent/TWI725191B/en active
- 2017-06-06 JO JOP/2017/0137A patent/JOP20170137B1/en active
-
2018
- 2018-11-09 CO CONC2018/0011686A patent/CO2018011686A2/en unknown
- 2018-11-19 IL IL263126A patent/IL263126B/en active IP Right Grant
- 2018-11-22 CL CL2018003338A patent/CL2018003338A1/en unknown
- 2018-11-23 ZA ZA2018/07932A patent/ZA201807932B/en unknown
-
2019
- 2019-01-02 EC ECSENADI2019169A patent/ECSP19000169A/en unknown
-
2020
- 2020-02-10 CY CY20201100123T patent/CY1122755T1/en unknown
- 2020-03-13 US US16/817,683 patent/US11529362B2/en active Active
-
2021
- 2021-08-27 JP JP2021138576A patent/JP7223084B2/en active Active
-
2022
- 2022-11-15 US US17/986,934 patent/US12208109B2/en active Active
-
2024
- 2024-12-23 US US18/999,533 patent/US20250235473A1/en active Pending
-
2025
- 2025-10-01 US US19/347,686 patent/US20260027138A1/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SG11201809708PA (en) | Physiologically balanced injectable formulations of fosnetupitant | |
| SG11201809912UA (en) | Hybrid carriers for nucleic acid cargo | |
| SG11201809344QA (en) | Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde | |
| SG11201810628XA (en) | Nasal pharmaceutical compositions with a porous excipient | |
| SG11201900480YA (en) | Anti-tim-3 antibodies | |
| SG11201808990QA (en) | Compositions for topical application of compounds | |
| SG11201811431VA (en) | Multispecific antibodies against cd40 and cd137 | |
| SG11201808237UA (en) | Substituted indole compound derivatives as dengue viral replication inhibitors | |
| SG11201808108XA (en) | Synthesis of indazoles | |
| SG11201811470PA (en) | Pyrazolopyrimidine derivatives as kinase inhibitor | |
| SG11201807051VA (en) | Replication competent attenuated vaccinia viruses with deletion of thymidine kinase with and without the expression of human flt3l or gm-csf for cancer immunotherapy | |
| SG11201908786VA (en) | Substituted indoline derivatives as dengue viral replication inhibitors | |
| SG11201908465QA (en) | Substituted indoline derivatives as dengue viral replication inhibitors | |
| SG11201808222RA (en) | Methods of treatment of cholestatic diseases | |
| SG11201900633XA (en) | Piperidine cxcr7 receptor modulators | |
| SG11201808270PA (en) | Substituted indoline derivatives as dengue viral replication inhibitors | |
| SG11201811442UA (en) | Formulation of a peptide vaccine | |
| SG11201808138YA (en) | Substituted indole derivatives as dengue viral replication inhibitors | |
| SG11201809499UA (en) | Processes for preparing phosphorodiamidate morpholino oligomers | |
| SG11201900558RA (en) | Spiro-lactam nmda receptor modulators and uses thereof | |
| SG11201901986SA (en) | Process for the manufacture of a solid pharmaceutical adminstration form | |
| SG11201900554YA (en) | Spiro-lactam nmda modulators and methods of using same | |
| SG11201810965YA (en) | 1h-pyrazolo[4,3-b]pyridines as pde1 inhibitors | |
| SG11201900551WA (en) | Spiro-lactam nmda receptor modulators and uses thereof | |
| SG11201900546UA (en) | Spiro-lactam and bis-spiro-lactam nmda receptor modulators and uses thereof |