MX2011013722A - Formulaciones liofilizadas para inmunofarmaceuticos modulares pequeños. - Google Patents
Formulaciones liofilizadas para inmunofarmaceuticos modulares pequeños.Info
- Publication number
- MX2011013722A MX2011013722A MX2011013722A MX2011013722A MX2011013722A MX 2011013722 A MX2011013722 A MX 2011013722A MX 2011013722 A MX2011013722 A MX 2011013722A MX 2011013722 A MX2011013722 A MX 2011013722A MX 2011013722 A MX2011013722 A MX 2011013722A
- Authority
- MX
- Mexico
- Prior art keywords
- small modular
- provides
- present
- lyophilized formulations
- formulations
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
La presente invención proporciona, entre otras cosas, formulaciones estables para proteínas inmunofarmacéuticas modulares pequeñas (SMIPTM). En ciertas modalidades, la presente invención proporciona una formulación que contiene una mezcla liofilizada de una proteína inmunofarmacéutica modular pequeña, en donde menos de 7% de la proteína inmunofarmacéutica modular pequeña liofilizada existe en forma agregada. Las formulaciones de acuerdo con la invención pueden contener agentes reguladores, estabilizadores, agente espesantes, agentes tensioactivos y/u otros excipientes. La presente invención proporciona también formulaciones para liofilización, reconstitución y métodos de uso.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US21838809P | 2009-06-18 | 2009-06-18 | |
US21838609P | 2009-06-18 | 2009-06-18 | |
PCT/US2010/039227 WO2010148337A1 (en) | 2009-06-18 | 2010-06-18 | Lyophilized formulations for small modular immunopharmaceuticals |
Publications (1)
Publication Number | Publication Date |
---|---|
MX2011013722A true MX2011013722A (es) | 2012-05-08 |
Family
ID=43356778
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX2011013722A MX2011013722A (es) | 2009-06-18 | 2010-06-18 | Formulaciones liofilizadas para inmunofarmaceuticos modulares pequeños. |
Country Status (11)
Country | Link |
---|---|
US (1) | US20120114646A1 (es) |
EP (1) | EP2442798A4 (es) |
JP (1) | JP2012530721A (es) |
KR (1) | KR20120027031A (es) |
CN (1) | CN102695499A (es) |
AU (1) | AU2010263058A1 (es) |
CA (1) | CA2764180A1 (es) |
IL (1) | IL217065A0 (es) |
MX (1) | MX2011013722A (es) |
RU (1) | RU2011151286A (es) |
WO (1) | WO2010148337A1 (es) |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3424529A1 (en) | 2007-07-02 | 2019-01-09 | Oncomed Pharmaceuticals, Inc. | Compositions and methods for treating and diagnosing cancer |
JO3672B1 (ar) | 2008-12-15 | 2020-08-27 | Regeneron Pharma | أجسام مضادة بشرية عالية التفاعل الكيماوي بالنسبة لإنزيم سبتيليسين كنفرتيز بروبروتين / كيكسين نوع 9 (pcsk9). |
CA2976671C (en) | 2010-03-01 | 2021-01-12 | Bayer Healthcare Llc | Optimized monoclonal antibodies against tissue factor pathway inhibitor (tfpi) |
AR084938A1 (es) | 2011-01-28 | 2013-07-10 | Sanofi Sa | Anticuerpos humanos contra la proproteina convertasa subtilisina/kexina tipo 9 (anti pcsk9) para usar en metodos para tratar grupos de pacientes |
KR102050339B1 (ko) | 2011-03-15 | 2019-11-29 | 바이오젠 엠에이 인코포레이티드 | 빠른 적정 단계식 증가 투여 요법을 이용한 인터페론의 근육내 투여와 관련된 독감 유사 증상의 감소 방법 |
US8802097B2 (en) | 2011-07-15 | 2014-08-12 | Oncomed Pharmaceuticals, Inc. | Anti-RSPO1 antibodies |
AR087305A1 (es) | 2011-07-28 | 2014-03-12 | Regeneron Pharma | Formulaciones estabilizadas que contienen anticuerpos anti-pcsk9, metodo de preparacion y kit |
ES2369945B1 (es) * | 2011-07-29 | 2012-10-15 | Eduardo Anitua Aldecoa | Procedimiento de obtención de una composición que contiene factores de crecimiento a partir de un compuesto sanguíneo, y composición obtenible por dicho procedimiento. |
AU2012308797B2 (en) | 2011-09-16 | 2017-06-01 | Regeneron Pharmaceuticals, Inc. | Methods for reducing lipoprotein(a) levels by administering an inhibitor of proprotein convertase subtilisin kexin-9 (PSCK9) |
MX2015000565A (es) | 2012-07-13 | 2015-04-10 | Oncomed Pharm Inc | Agentes de union de proteina de r-espondina humana (rspo3) y usos de los mismos. |
US9592297B2 (en) | 2012-08-31 | 2017-03-14 | Bayer Healthcare Llc | Antibody and protein formulations |
PL2916866T3 (pl) | 2012-11-06 | 2018-10-31 | Bayer Pharma Aktiengesellschaft | Formulacja dwuswoistych przeciwciał mobilizujących limfocyty t (bite) |
US11576863B2 (en) | 2013-03-15 | 2023-02-14 | Takeda Pharmaceutical Company Limited | Formulation of an antibody and use thereof |
UY35463A (es) | 2013-03-15 | 2014-10-31 | Biogen Idec Inc | Formulaciones de polipéptido fc-factor ix. |
US10111953B2 (en) | 2013-05-30 | 2018-10-30 | Regeneron Pharmaceuticals, Inc. | Methods for reducing remnant cholesterol and other lipoprotein fractions by administering an inhibitor of proprotein convertase subtilisin kexin-9 (PCSK9) |
KR20160024906A (ko) | 2013-06-07 | 2016-03-07 | 사노피 바이오테크놀로지 | Pcsk9의 억제제를 투여함에 의한 죽상경화증의 억제 방법 |
EP3882273A1 (en) | 2013-11-12 | 2021-09-22 | Sanofi Biotechnology | Dosing regimens for use with pcsk9 inhibitors |
WO2015076285A1 (ja) * | 2013-11-21 | 2015-05-28 | 協和メデックス株式会社 | 血清又は血漿中の低密度リポ蛋白の凍結乾燥による変性抑制剤及び変性抑制方法 |
KR102385372B1 (ko) | 2014-03-24 | 2022-04-11 | 바이오버라티브 테라퓨틱스 인크. | 동결건조된 ix 인자 제형 |
US9937239B2 (en) | 2014-05-21 | 2018-04-10 | The Johns Hopkins University | Preservation and reconstitution of cell-free protein expression systems |
US20170209582A1 (en) * | 2014-06-26 | 2017-07-27 | Amgen Inc. | Protein formulations |
KR20170029613A (ko) | 2014-07-16 | 2017-03-15 | 사노피 바이오테크놀로지 | 이형접합성 가족성 고콜레스테롤혈증(heFH) 환자의 치료방법 |
AU2015301538A1 (en) * | 2014-08-15 | 2017-03-02 | Oncomed Pharmaceuticals, Inc. | RSPO1 binding agents and uses thereof |
US10064937B2 (en) | 2014-09-16 | 2018-09-04 | Oncomed Pharmaceuticals, Inc. | Treatment of dermal fibrosis |
EP3337828A1 (en) | 2015-08-18 | 2018-06-27 | Regeneron Pharmaceuticals, Inc. | Anti-pcsk9 inhibitory antibodies for treating patients with hyperlipidemia undergoing lipoprotein apheresis |
RU2751235C2 (ru) * | 2016-02-24 | 2021-07-12 | Байомарин Фармасьютикал Инк. | Терапевтические слитые белки направленного действия на основе лизосомных ферментов, соответствующие составы и их применения |
GB201608323D0 (en) * | 2016-05-12 | 2016-06-29 | Ucb Biopharma Sprl | Pharmaceutical compositions |
CA3032596A1 (en) | 2016-08-29 | 2018-03-08 | Tiziana Life Sciences Plc | Anti-cd3 antibody formulations |
MY197672A (en) * | 2016-10-07 | 2023-07-03 | Regeneron Pharma | Room temperature stable lyophilized protein |
CN107088224B (zh) * | 2017-02-10 | 2020-06-26 | 温州医科大学 | 人fgf21冻干制剂 |
SG11201910134SA (en) * | 2017-05-02 | 2019-11-28 | Merck Sharp & Dohme | Stable formulations of anti-ctla4 antibodies alone and in combination with programmed death receptor 1 (pd-1) antibodies and methods of use thereof |
EP4364724A2 (en) | 2018-05-10 | 2024-05-08 | Regeneron Pharmaceuticals, Inc. | High concentration vegf receptor fusion protein containing formulations |
UY38238A (es) * | 2018-05-25 | 2019-12-31 | Genzyme Corp | Composiciones farmacéuticas para el tratamiento de la deficiencia de esfingomielinasa ácida |
KR102646145B1 (ko) | 2018-05-31 | 2024-03-11 | 주식회사 엑소코바이오 | 줄기세포 유래의 엑소좀을 유효성분으로 포함하는 모공 축소용 조성물 |
JP7079984B2 (ja) | 2018-07-28 | 2022-06-03 | エクソコバイオ インコーポレイテッド | エキソソームの凍結乾燥方法 |
KR102163806B1 (ko) | 2018-07-30 | 2020-10-07 | 주식회사 엑소코바이오 | 줄기세포 유래의 엑소좀을 유효성분으로 포함하는 피지분비 감소용 조성물 |
US20210079111A1 (en) * | 2018-08-04 | 2021-03-18 | AbCyte Therapeutics Inc. | Cd19-cd20 bispecific and dual passway car-t and methods for use thereof |
MA55033A (fr) | 2019-02-18 | 2021-12-29 | Lilly Co Eli | Formulation d'anticorps thérapeutique |
IL308881A (en) * | 2021-05-28 | 2024-01-01 | Xyone Therapeutics Inc | Multispecific antibody constructs against THEMUC1-C/extracellular domain (MUC1-C/ECD) |
CN116479088A (zh) * | 2022-11-15 | 2023-07-25 | 江苏默乐生物科技股份有限公司 | 一种生物试剂冻干保存的试剂组合、试剂盒、方法及应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6267958B1 (en) * | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6685940B2 (en) * | 1995-07-27 | 2004-02-03 | Genentech, Inc. | Protein formulation |
ATE220558T1 (de) * | 1997-11-22 | 2002-08-15 | Roche Diagnostics Gmbh | Verbessertes verfahren zur stabilisierung von proteinen |
BRPI0618893A2 (pt) * | 2005-11-22 | 2011-09-13 | Wyeth Corp | formulações de proteìna de fusão de imunoglobulina |
AU2008232902B2 (en) * | 2007-03-30 | 2013-10-03 | Medlmmune, Llc | Antibody formulation |
US20090208492A1 (en) * | 2007-06-14 | 2009-08-20 | Elan Pharmaceuticals, Inc. | Lyophilized Immunoglobulin Formulations and Methods of Preparation |
WO2009158529A2 (en) * | 2008-06-26 | 2009-12-30 | Straher, Michael, P. | Lyophilization cycle robustness strategy |
-
2010
- 2010-06-18 EP EP10790288A patent/EP2442798A4/en not_active Withdrawn
- 2010-06-18 AU AU2010263058A patent/AU2010263058A1/en not_active Abandoned
- 2010-06-18 RU RU2011151286/15A patent/RU2011151286A/ru not_active Application Discontinuation
- 2010-06-18 JP JP2012516348A patent/JP2012530721A/ja not_active Withdrawn
- 2010-06-18 MX MX2011013722A patent/MX2011013722A/es not_active Application Discontinuation
- 2010-06-18 CA CA2764180A patent/CA2764180A1/en not_active Abandoned
- 2010-06-18 CN CN2010800271836A patent/CN102695499A/zh active Pending
- 2010-06-18 WO PCT/US2010/039227 patent/WO2010148337A1/en active Application Filing
- 2010-06-18 KR KR1020117030171A patent/KR20120027031A/ko not_active Application Discontinuation
- 2010-06-18 US US13/378,751 patent/US20120114646A1/en not_active Abandoned
-
2011
- 2011-12-18 IL IL217065A patent/IL217065A0/en unknown
Also Published As
Publication number | Publication date |
---|---|
KR20120027031A (ko) | 2012-03-20 |
US20120114646A1 (en) | 2012-05-10 |
EP2442798A4 (en) | 2013-03-13 |
CN102695499A (zh) | 2012-09-26 |
EP2442798A1 (en) | 2012-04-25 |
JP2012530721A (ja) | 2012-12-06 |
RU2011151286A (ru) | 2013-07-27 |
WO2010148337A1 (en) | 2010-12-23 |
AU2010263058A1 (en) | 2012-01-12 |
CA2764180A1 (en) | 2010-12-23 |
IL217065A0 (en) | 2012-02-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
MX2011013722A (es) | Formulaciones liofilizadas para inmunofarmaceuticos modulares pequeños. | |
SG144075A1 (en) | Protein stabilization formulations | |
MX2012002861A (es) | Formulaciones farmaceuticas muy concentradas. | |
AU2016204371A1 (en) | Lyophilised and aqueous anti-CD40 antibody formulations | |
MX2009010179A (es) | Formulaciones estables de anticuerpo. | |
NZ603813A (en) | Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of histidyl-trna synthetases | |
EA201490804A1 (ru) | Препараты этанерцепта, стабилизированные хлоридом натрия | |
PH12015500773B1 (en) | Methods and compositions for live attenuated viruses | |
WO2010100200A3 (en) | Lyophilised antibody formulation | |
MY159464A (en) | Reconstituted surfactant composition containing analogs of surfactant protein b (sp-b) and surfactant protein c (sp-c) | |
NZ602685A (en) | Concentrated protein formulations and uses thereof | |
GEP20125628B (en) | Pharmaceutical compositions containing antagonist anti-cd40 antibody | |
IN2012DN00801A (es) | ||
MX2010002002A (es) | Peptido foxm1 y agente medicinal que lo contiene. | |
MX2010002001A (es) | Peptido cdca1 y agente farmaceutico que comprende elmismo. | |
NZ605873A (en) | Methods and compositions for cns delivery of arylsulfatase a | |
MX2010002018A (es) | Peptido de cdh3 y agente medicinal que comprende al mismo. | |
JO2963B1 (en) | Reconstructed surfactants with improved properties | |
EA200970981A1 (ru) | Пептидная смесь в качестве стабилизатора вина | |
SG10201407944TA (en) | Imp-3 oligopeptides and vaccines including the same | |
NZ631131A (en) | Reconstituted hdl formulation | |
MX2021012939A (es) | Formulaciones de factor ix liofilizadas. | |
CY1115938T1 (el) | Νεα συνθεση για αυξηση της bio-διαθεσιμοτητας της νεουρτουρινης (neurturin) | |
WO2008063865A3 (en) | Biphosphonate inhalant formulations and methods for using the same | |
EA201490363A1 (ru) | Новые составы на основе (триметоксифениламино)пиримидинилов |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FA | Abandonment or withdrawal |