CA2141691A1 - Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof - Google Patents
Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereofInfo
- Publication number
- CA2141691A1 CA2141691A1 CA002141691A CA2141691A CA2141691A1 CA 2141691 A1 CA2141691 A1 CA 2141691A1 CA 002141691 A CA002141691 A CA 002141691A CA 2141691 A CA2141691 A CA 2141691A CA 2141691 A1 CA2141691 A1 CA 2141691A1
- Authority
- CA
- Canada
- Prior art keywords
- extended
- production
- release profile
- solid pharmaceutical
- dosage forms
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
-
- 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
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
-
- 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
-
- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The present invention provides solid pharmaceutical compositions in dosage form containing an active ingredient ar princ-iple, preferably memantine, which exhibit an extended two-phase release profile and which are characterized by the presence of both a water-soluble and a water-insoluble salt of casein, preferably sodium and calcium caseinate, in the matrix thereof, in broad proportions and in a total amount between 5 and 98% by weight of the composition, and with a process for the production there-of.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4225730A DE4225730C2 (en) | 1992-08-04 | 1992-08-04 | Process for the preparation of solid dosage forms with protracted 2-stage release |
DEP4225730.1 | 1992-08-04 | ||
PCT/EP1993/002074 WO1994003158A1 (en) | 1992-08-04 | 1993-08-04 | Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2141691A1 true CA2141691A1 (en) | 1994-02-17 |
CA2141691C CA2141691C (en) | 2002-04-09 |
Family
ID=6464804
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002141691A Expired - Lifetime CA2141691C (en) | 1992-08-04 | 1993-08-04 | Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof |
Country Status (17)
Country | Link |
---|---|
US (1) | US5382601A (en) |
EP (1) | EP0582186B1 (en) |
JP (1) | JP3560244B2 (en) |
CN (1) | CN1086708A (en) |
AT (1) | ATE176866T1 (en) |
AU (1) | AU669731B2 (en) |
CA (1) | CA2141691C (en) |
DE (2) | DE4225730C2 (en) |
DK (1) | DK0582186T3 (en) |
ES (1) | ES2128369T3 (en) |
GR (1) | GR3030227T3 (en) |
IL (1) | IL106580A (en) |
LT (1) | LT3201B (en) |
LV (1) | LV10182B (en) |
MX (1) | MX9304675A (en) |
WO (1) | WO1994003158A1 (en) |
ZA (1) | ZA935614B (en) |
Families Citing this family (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5817336A (en) * | 1993-04-02 | 1998-10-06 | Orion-Yhtyma Oy | Composition containing selegiline |
AUPN605795A0 (en) * | 1995-10-19 | 1995-11-09 | F.H. Faulding & Co. Limited | Analgesic pharmaceutical composition |
US6139872A (en) * | 1996-08-14 | 2000-10-31 | Henkel Corporation | Method of producing a vitamin product |
US5866585A (en) * | 1997-05-22 | 1999-02-02 | Synchroneuron, Llc | Methods of treating tardive dyskinesia using NMDA receptor antagonists |
US6057373A (en) * | 1997-05-22 | 2000-05-02 | Synchroneuron, Llc | Methods of treating tardive dyskinesia and other movement disorders using NMDA receptor antagonists |
WO1999003451A1 (en) * | 1997-07-16 | 1999-01-28 | Antrin Research Limited | Pharmaceutical formulations for oral administration |
US5980941A (en) * | 1997-08-20 | 1999-11-09 | Fuisz Technologies Ltd. | Self-binding shearform compositions |
US5840334A (en) * | 1997-08-20 | 1998-11-24 | Fuisz Technologies Ltd. | Self-binding shearform compositions |
US5952389A (en) * | 1998-01-13 | 1999-09-14 | Synchroneuron | Methods of treating tardive dyskinesia and other movement disorders |
US6294583B1 (en) * | 1998-01-13 | 2001-09-25 | Synchroneuron, Llc | Methods of treating tardive dyskinesia and other movement disorders |
DE19809242A1 (en) * | 1998-03-05 | 1999-09-09 | Basf Ag | Process for the production of solid, spherical shaped articles containing pharmaceutical active substances in a binder matrix |
DE19814257A1 (en) * | 1998-03-31 | 1999-10-07 | Asta Medica Ag | effervescent formulations |
US6444702B1 (en) | 2000-02-22 | 2002-09-03 | Neuromolecular, Inc. | Aminoadamantane derivatives as therapeutic agents |
EP1852113A3 (en) * | 2000-12-07 | 2008-03-12 | Neuromolecular Inc. | Methods for treating neuropsychiatric disorders with NMDA receptors antagonists |
US20040122090A1 (en) * | 2001-12-07 | 2004-06-24 | Lipton Stuart A. | Methods for treating neuropsychiatric disorders with nmda receptor antagonists |
KR20060124731A (en) * | 2004-01-29 | 2006-12-05 | 뉴로몰레큘라 파마슈티칼스, 인코포레이티드 | Combination of a nmda receptor antagonist and a mao-inhibitor or a gadph-inhibitor for the treatment of central nervous system-related conditions |
US20050209218A1 (en) * | 2004-02-13 | 2005-09-22 | Meyerson Laurence R | Methods and compositions for the treatment of psychiatric conditions |
CA2556214A1 (en) * | 2004-02-13 | 2005-09-01 | Neuromolecular, Inc. | Combination of an nmda receptor antagonist and an anti-epileptic drug for the treatment of epilepsy and other cns disorders |
US20060002999A1 (en) * | 2004-06-17 | 2006-01-05 | Forest Laboratories, Inc. | Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane |
WO2006096194A2 (en) | 2004-06-17 | 2006-09-14 | Merz Pharma Gmbh & Co. Kgaa | Drinkable immediate release tablet made with direct compression of memantine or neramexane |
EA011446B1 (en) * | 2004-06-17 | 2009-02-27 | Форест Лэборэтериз, Инк. | Preparatory solid oral dosage form of memantine with modified release |
KR100901927B1 (en) * | 2004-06-17 | 2009-06-10 | 메르츠 파마 게엠베하 운트 코. 카가아 | Drinkable immediate release tablet made with direct compression of memantine or neramexane |
US8058291B2 (en) * | 2005-04-06 | 2011-11-15 | Adamas Pharmaceuticals, Inc. | Methods and compositions for the treatment of CNS-related conditions |
US7619007B2 (en) * | 2004-11-23 | 2009-11-17 | Adamas Pharmaceuticals, Inc. | Method and composition for administering an NMDA receptor antagonist to a subject |
SG157415A1 (en) | 2004-11-23 | 2009-12-29 | Adamas Pharmaceuticals Inc | Composition comprising a sustained release coating or matrix and an nmda receptor antagonist, method for administration such nmda antagonist to a subject |
EP1845968A2 (en) | 2004-11-24 | 2007-10-24 | Neuromolecular Pharmaceuticals, Inc | Composition comprising an nmda receptor antagonist and levodopa and use thereof for treating neurological disease |
US20070129402A1 (en) * | 2004-12-27 | 2007-06-07 | Eisai Research Institute | Sustained release formulations |
US20090208579A1 (en) * | 2004-12-27 | 2009-08-20 | Eisai R & D Management Co., Ltd. | Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same |
US20060280789A1 (en) * | 2004-12-27 | 2006-12-14 | Eisai Research Institute | Sustained release formulations |
US20060160852A1 (en) * | 2004-12-27 | 2006-07-20 | Eisai Co. Ltd. | Composition containing anti-dementia drug |
JP2008525313A (en) * | 2004-12-27 | 2008-07-17 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Anti-dementia drug stabilization method |
KR101213345B1 (en) * | 2005-04-28 | 2012-12-17 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Composition containing anti-dementia drug |
WO2006119295A2 (en) * | 2005-05-02 | 2006-11-09 | Combinatorx, Incorporated | Compositions and methods for the treatment of neurodegenerative diseases |
EA013474B1 (en) * | 2005-06-16 | 2010-04-30 | Форест Лэборэтериз, Инк. | Modified and immediate release memantine bead formulation |
US7968351B2 (en) * | 2005-12-23 | 2011-06-28 | Alk-Abello A/S | Method for dissolution testing of pharmaceutical products |
WO2008005534A2 (en) * | 2006-07-06 | 2008-01-10 | Forest Laboratories, Inc. | Orally dissolving formulations of memantine |
US20080067108A1 (en) * | 2006-09-14 | 2008-03-20 | Halliburton Energy Services, Inc. | Methods and compositions for thermally treating a conduit used for hydrocarbon production or transmission to help remove paraffin wax buildup |
GB0623897D0 (en) * | 2006-11-30 | 2007-01-10 | Pliva Istrazivanje I Razvoj D | Pharmaceutical composition of memantine |
US20080182908A1 (en) * | 2007-01-25 | 2008-07-31 | Vinita Umashankar Vyas | Pharmaceutical compositions comprising memantine |
EP2583669A1 (en) | 2007-10-10 | 2013-04-24 | Rubicon Research Private Limited | Taste-masked orally disintegrating tablets of memantine hydrochloride |
US20090247644A1 (en) * | 2008-03-28 | 2009-10-01 | Forest Laboratories Holdings Limited | Memantine formulations |
CA2994873A1 (en) | 2009-12-02 | 2011-06-09 | Adamas Pharmaceuticals, Inc. | Amantadine compositions and methods of use |
EP2363119A1 (en) * | 2010-03-05 | 2011-09-07 | Centre Hospitalier Universitaire d'Angers | New pharmaceutical composition suitable for treating persons affected by neurodegenerative or neurovascular diseases |
WO2012101653A2 (en) | 2011-01-25 | 2012-08-02 | Cadila Healthcare Limited | Modified release pharmaceutical compositions memantine |
EP2675435A1 (en) | 2011-02-17 | 2013-12-25 | Lupin Limited | Sustained release composition of memantine |
TR201104108A2 (en) | 2011-04-27 | 2011-08-22 | Ali̇ Rai̇f İlaç Sanayi̇ A.Ş. | Prolonged release memantine tablets. |
FR2980973B1 (en) * | 2011-10-11 | 2013-11-15 | Univ Clermont Auvergne | COMPOSITION FOR THE PROPHYLACTIC TREATMENT OF NEUROPATHIC PAIN. |
US20130274342A1 (en) * | 2012-04-12 | 2013-10-17 | Cerecor, Inc. | Compositions and methods for treating cough |
US20140050784A1 (en) | 2012-08-16 | 2014-02-20 | Teva Pharmaceuticals Usa, Inc. | Pharmaceutical compositions of memantine |
WO2014122077A1 (en) * | 2013-02-08 | 2014-08-14 | Basf Se | Production of inorganic/organic composite materials by reactive spray drying |
US10154971B2 (en) | 2013-06-17 | 2018-12-18 | Adamas Pharma, Llc | Methods of administering amantadine |
CN111372578A (en) | 2017-08-24 | 2020-07-03 | 阿达玛斯药物有限责任公司 | Amantadine compositions, methods of making and using the same |
US10213393B1 (en) | 2018-02-15 | 2019-02-26 | Osmotica Kereskedelmi és Szolgáltató Korlátolt Feleõsségû Társaság | Composition and method for treating neurological disease |
US20190247331A1 (en) | 2018-02-15 | 2019-08-15 | Osmotica Kereskedelmi és Szolgáltató Korlátolt Felelõsségû Társaság | Composition and method for treating neurological disease |
US10213394B1 (en) | 2018-02-15 | 2019-02-26 | Osmotica Kereskedelmi és Szolgáltató Korlátolt Felelõsségû Társaság | Composition and method for treating neurological disease |
US11602507B2 (en) | 2019-05-27 | 2023-03-14 | Trikona Pharmaceuticals Pvt. Ltd | Extended release oral composition of memantine or its salt and its process for the preparation |
CU20200087A7 (en) | 2020-11-24 | 2022-07-08 | Centro De Neurociencias De Cuba | PHARMACEUTICAL COMPOSITION OF NAPHTHALENE DERIVATIVES AS MULTITARGET THERAPEUTIC AGENTS FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB715874A (en) * | 1952-10-03 | 1954-09-22 | Horlicks Ltd | A tablet for use in treating peptic ulcers |
GB840091A (en) * | 1955-09-08 | 1960-07-06 | Upjohn Co | Improvements in or relating to therapeutic compositions and the manufacture thereof |
US3594467A (en) * | 1968-10-09 | 1971-07-20 | Richardson Merrell Inc | Long-lasting troche |
CH603545A5 (en) * | 1972-04-20 | 1978-08-31 | Merz & Co | |
US4076846A (en) * | 1974-11-22 | 1978-02-28 | Sumitomo Bakelite Company Limited | Protein-starch binary molding composition and shaped articles obtained therefor |
US4127650A (en) * | 1975-03-31 | 1978-11-28 | William H. Rorer, Inc. | Medicinal simethicone containing composition and its method of production |
US4419369A (en) * | 1980-09-22 | 1983-12-06 | Baylor College Of Medicine | Protein mineral dietary module |
US4346112A (en) * | 1981-06-29 | 1982-08-24 | University Patents Inc. | Composition and method for treating patients having Parkinson's Disease |
JPS59101423A (en) * | 1982-12-02 | 1984-06-12 | Takada Seiyaku Kk | Novel solid pharmaceutical preparation of nifedipine |
US4913906B1 (en) * | 1985-02-28 | 2000-06-06 | Yissum Res Dev Co | Controlled release dosage form of valproic acid |
AU593821B2 (en) * | 1985-08-06 | 1990-02-22 | Excel Technologies International Corporation | Treating agent for liquid media |
US4897380A (en) * | 1985-08-30 | 1990-01-30 | Pollack Robert L | Method and composition for relieving dietary-related disorders |
US4853377A (en) * | 1985-10-15 | 1989-08-01 | Pollack Robert L | Method and composition for increasing production of serotonin |
DK179687D0 (en) * | 1987-04-08 | 1987-04-08 | Farma Food As | PREPARATION |
US4792452A (en) * | 1987-07-28 | 1988-12-20 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US4925677A (en) * | 1988-08-31 | 1990-05-15 | Theratech, Inc. | Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents |
ATE94384T1 (en) * | 1989-04-14 | 1993-10-15 | Merz & Co Gmbh & Co | USE OF ADAMANTAN DERIVATIVES FOR PREVENTION AND TREATMENT OF CEREBRAL ISCHAEMIA. |
JP2571874B2 (en) * | 1989-11-06 | 1997-01-16 | アルカーメス コントロールド セラピューティクス,インコーポレイテッド | Protein microsphere composition |
GB9004950D0 (en) * | 1990-03-06 | 1990-05-02 | Kelco Int Ltd | Controlled release formulation |
WO1991017745A1 (en) * | 1990-05-23 | 1991-11-28 | Southwest Research Institute | Filament system for delivering a medicament and method |
FR2664499B1 (en) * | 1990-07-16 | 1994-11-04 | Jacques Dubois | NOVEL PHARMACEUTICAL FORMS, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS. |
-
1992
- 1992-08-04 DE DE4225730A patent/DE4225730C2/en not_active Expired - Lifetime
-
1993
- 1993-07-23 US US08/096,952 patent/US5382601A/en not_active Expired - Lifetime
- 1993-07-28 ES ES93112018T patent/ES2128369T3/en not_active Expired - Lifetime
- 1993-07-28 DK DK93112018T patent/DK0582186T3/en active
- 1993-07-28 EP EP93112018A patent/EP0582186B1/en not_active Expired - Lifetime
- 1993-07-28 AT AT93112018T patent/ATE176866T1/en active
- 1993-07-28 DE DE59309388T patent/DE59309388D1/en not_active Expired - Lifetime
- 1993-08-03 IL IL106580A patent/IL106580A/en not_active IP Right Cessation
- 1993-08-03 MX MX9304675A patent/MX9304675A/en unknown
- 1993-08-03 ZA ZA935614A patent/ZA935614B/en unknown
- 1993-08-04 WO PCT/EP1993/002074 patent/WO1994003158A1/en active Application Filing
- 1993-08-04 AU AU47069/93A patent/AU669731B2/en not_active Expired
- 1993-08-04 LV LVP-93-1013A patent/LV10182B/en unknown
- 1993-08-04 CA CA002141691A patent/CA2141691C/en not_active Expired - Lifetime
- 1993-08-04 LT LTIP839A patent/LT3201B/en not_active IP Right Cessation
- 1993-08-04 CN CN93116211A patent/CN1086708A/en active Pending
- 1993-08-04 JP JP50501594A patent/JP3560244B2/en not_active Expired - Fee Related
-
1999
- 1999-05-14 GR GR990401314T patent/GR3030227T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
JPH07509479A (en) | 1995-10-19 |
EP0582186B1 (en) | 1999-02-24 |
MX9304675A (en) | 1994-03-31 |
AU4706993A (en) | 1994-03-03 |
ZA935614B (en) | 1995-02-03 |
CA2141691C (en) | 2002-04-09 |
DE4225730C2 (en) | 2003-04-30 |
LTIP839A (en) | 1994-08-25 |
US5382601A (en) | 1995-01-17 |
DE4225730A1 (en) | 1994-02-10 |
WO1994003158A1 (en) | 1994-02-17 |
DK0582186T3 (en) | 1999-09-27 |
LV10182B (en) | 1995-04-20 |
IL106580A0 (en) | 1993-12-08 |
LV10182A (en) | 1994-10-20 |
CN1086708A (en) | 1994-05-18 |
EP0582186A1 (en) | 1994-02-09 |
JP3560244B2 (en) | 2004-09-02 |
DE59309388D1 (en) | 1999-04-01 |
LT3201B (en) | 1995-03-27 |
ES2128369T3 (en) | 1999-05-16 |
IL106580A (en) | 1998-02-08 |
GR3030227T3 (en) | 1999-08-31 |
ATE176866T1 (en) | 1999-03-15 |
AU669731B2 (en) | 1996-06-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2141691A1 (en) | Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof | |
CA2232310A1 (en) | Stable compositions containing n-propargyl-1-aminoindan | |
CA2171303A1 (en) | Active principles and gas containing microparticles | |
CA2346662A1 (en) | Compositions containing diphosphonic acids | |
WO2004050058A3 (en) | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base | |
TW280774B (en) | ||
CA2163706A1 (en) | Amino Acid Derivatives of Paclitaxel | |
CA2444587A1 (en) | Pharmaceutical compositions of low salt polyallylamine hydrochloride | |
CA2164776A1 (en) | Pharmaceutical, orally applicable composition | |
CA2342634A1 (en) | Pharmaceutical composition comprising entacapone or nitecapone as well as a cross-linked cellulose derivative | |
CA2000763A1 (en) | Dispersable formulation | |
CA2163218A1 (en) | New macrophages, process for preparing the same and their use as active substances of pharmaceutical compositions | |
CA2110166A1 (en) | Tableting of colestipol hydrochloride | |
TW372193B (en) | Novel pharmaceutical composition for the preparation of a stable powder containing an association of acetylsalicylic acid and metoclopramide as the active ingredient | |
CA2285985A1 (en) | A method for preparing aqueous liposomal compositions comprising an active ingredient which is highly insoluble in water | |
CA2341976A1 (en) | Fish gelatinous composition for use as an ingredient in tablets | |
TH55263B (en) | The finished product is a solid that breaks down quickly. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |