JP7110196B2 - カルバメート化合物を含む非経口用液剤 - Google Patents

カルバメート化合物を含む非経口用液剤 Download PDF

Info

Publication number
JP7110196B2
JP7110196B2 JP2019531627A JP2019531627A JP7110196B2 JP 7110196 B2 JP7110196 B2 JP 7110196B2 JP 2019531627 A JP2019531627 A JP 2019531627A JP 2019531627 A JP2019531627 A JP 2019531627A JP 7110196 B2 JP7110196 B2 JP 7110196B2
Authority
JP
Japan
Prior art keywords
cyclodextrin
formula
parenteral
parenteral solution
carbamate compound
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.)
Active
Application number
JP2019531627A
Other languages
English (en)
Japanese (ja)
Other versions
JP2020502108A (ja
Inventor
ペク・ミョンギ
イ・ジヘ
チェ・ソヨン
Original Assignee
エスケー バイオファーマスティカルズ カンパニー リミテッド
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by エスケー バイオファーマスティカルズ カンパニー リミテッド filed Critical エスケー バイオファーマスティカルズ カンパニー リミテッド
Publication of JP2020502108A publication Critical patent/JP2020502108A/ja
Application granted granted Critical
Publication of JP7110196B2 publication Critical patent/JP7110196B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Psychology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
JP2019531627A 2016-12-14 2017-12-14 カルバメート化合物を含む非経口用液剤 Active JP7110196B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR20160170389 2016-12-14
KR10-2016-0170389 2016-12-14
PCT/KR2017/014727 WO2018111000A1 (ko) 2016-12-14 2017-12-14 카바메이트 화합물을 포함하는 비경구용 액상 제제

Publications (2)

Publication Number Publication Date
JP2020502108A JP2020502108A (ja) 2020-01-23
JP7110196B2 true JP7110196B2 (ja) 2022-08-01

Family

ID=62559693

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2019531627A Active JP7110196B2 (ja) 2016-12-14 2017-12-14 カルバメート化合物を含む非経口用液剤

Country Status (17)

Country Link
US (2) US12070447B2 (enExample)
EP (1) EP3556349B1 (enExample)
JP (1) JP7110196B2 (enExample)
KR (1) KR102605030B1 (enExample)
CN (2) CN118766839A (enExample)
AU (1) AU2017374450B2 (enExample)
CL (1) CL2019001617A1 (enExample)
DK (1) DK3556349T3 (enExample)
ES (1) ES2901427T3 (enExample)
IL (1) IL267192B2 (enExample)
MX (1) MX390841B (enExample)
MY (1) MY200159A (enExample)
PL (1) PL3556349T3 (enExample)
PT (1) PT3556349T (enExample)
RU (1) RU2761041C2 (enExample)
WO (1) WO2018111000A1 (enExample)
ZA (1) ZA201903748B (enExample)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI3711758T3 (fi) 2017-11-14 2024-05-13 Sk Biopharmaceuticals Co Ltd Karbamaattiyhdisteen käyttö poissaolokohtauksen tai poissaolokohtausepilepsian ehkäisemiseksi, lievittämiseksi tai hoitamiseksi
MX2021003203A (es) * 2018-09-21 2021-05-27 Sk Biopharmaceuticals Co Ltd Compuesto de carbamato y uso de la formulacion que comprende el mismo en prevenir, aliviar, o tratar trastorno de estres agudo o trastorno de estres post-traumatico.
EP3854392A4 (en) * 2018-09-21 2022-08-17 SK Biopharmaceuticals Co., Ltd. USE OF A CARBAMATE COMPOUND TO PREVENT, RELIEVE OR TREAT CONJUNCTING SEIGES

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008538557A (ja) 2005-04-22 2008-10-30 エスケー ホルディングス カンパニー リミテッド 神経治療アゾール化合物
JP2009510123A (ja) 2005-09-30 2009-03-12 オベーション ファーマシューティカルズ インコーポレイテッド 新規非経口カルバマゼピン製剤

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100204178A1 (en) * 2006-10-02 2010-08-12 James Cloyd Novel parenteral carbamazepine formulation
CN101578103B (zh) * 2006-06-29 2013-09-25 林科杰诺米克斯株式会社 抗生素的注射剂及其给予液
US8343995B2 (en) * 2007-04-27 2013-01-01 Cydex Pharmaceuticals, Inc. Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use
BRPI0924997B1 (pt) 2009-06-22 2024-01-16 Sk Biopharmaceuticals Co., Ltd Método para preparar um composto de éster do ácido 1-aril-2- tetrazoil etil carbâmico
US8404461B2 (en) 2009-10-15 2013-03-26 SK Biopharmaceutical Co. Ltd. Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008538557A (ja) 2005-04-22 2008-10-30 エスケー ホルディングス カンパニー リミテッド 神経治療アゾール化合物
JP2009510123A (ja) 2005-09-30 2009-03-12 オベーション ファーマシューティカルズ インコーポレイテッド 新規非経口カルバマゼピン製剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY，2005年，Vol.31，p.567-575
EPILEPSIA，1995年，Vol.36, No.3，p.255-261
FOOD AND CHEMICAL TOXICOLOGY，2005年，Vol.43，p.1451-1459
JOURNAL OF PHARMACEUTICAL SCIENCES，Vol.85,No.11，1996年11月，p.1142-1169

Also Published As

Publication number Publication date
CN118766839A (zh) 2024-10-15
RU2019121911A (ru) 2021-01-15
BR112019011914A2 (pt) 2019-11-05
CL2019001617A1 (es) 2019-08-23
JP2020502108A (ja) 2020-01-23
IL267192B2 (en) 2023-05-01
IL267192A (enExample) 2019-07-31
RU2019121911A3 (enExample) 2021-03-05
AU2017374450B2 (en) 2023-05-11
WO2018111000A1 (ko) 2018-06-21
US12070447B2 (en) 2024-08-27
MY200159A (en) 2023-12-09
KR102605030B1 (ko) 2023-11-23
MX390841B (es) 2025-03-21
CN110267647A (zh) 2019-09-20
PL3556349T3 (pl) 2022-04-11
IL267192B1 (en) 2023-01-01
PT3556349T (pt) 2021-12-28
US20240374568A1 (en) 2024-11-14
RU2761041C2 (ru) 2021-12-02
EP3556349A4 (en) 2020-07-01
ES2901427T3 (es) 2022-03-22
AU2017374450A1 (en) 2019-07-04
EP3556349A1 (en) 2019-10-23
DK3556349T3 (da) 2022-01-03
ZA201903748B (en) 2020-12-23
KR20190087568A (ko) 2019-07-24
US20190314336A1 (en) 2019-10-17
EP3556349B1 (en) 2021-11-24
CA3046458A1 (en) 2018-06-21
MX2019006939A (es) 2019-09-13

Similar Documents

Publication Publication Date Title
US20240374568A1 (en) Parenteral liquid preparation comprising carbamate compound
JP5565794B2 (ja) ピモベンダン及びシクロデキストリンの錯体を含む液体製剤
CN102802635B (zh) 麻醉药制剂
US20030055023A1 (en) Formulations containing etomidate and a sulfoalkyl ether cyclodextrin
CN1505513A (zh) 注射用西洛他唑水性制剂
CN113271923A (zh) 呋塞米的药物组合物及其用途
JP2023540149A (ja) 抗ウイルス化合物の製剤
JP2011503105A (ja) バルサルタン含有液体組成物
JP2014185161A (ja) シロスタゾールを含むカルボスチリル誘導体の脂肪肝治療剤
JP2018510912A (ja) ポリアニオン性および非イオン性のシクロデキストリン系デンドリマーの医薬組成物およびその使用
JP2009516001A (ja) リポキシゲナーゼ阻害剤とシクロデキストリンとを含む組成物
CA3046458C (en) Parenteral liquid preparation comprising carbamate compound
CN102362855B (zh) 一种伊曲康唑异构体口服溶液
JP5462797B2 (ja) 注射可能なメクリジン製剤および方法
BR112021011744A2 (pt) Formulações orais de branaplam
HK40110938A (zh) 包含氨基甲酸酯化合物的肠胃外液体制剂
HK40015062A (en) Parenteral liquid preparation comprising carbamate compound
BR112019011914B1 (pt) Formulação líquida parenteral, composição injetável, e, método para preparar uma formulação líquida parenteral
CN1137686C (zh) 椎管狭窄的治疗药
JP2005520856A (ja) 貯蔵時に安定なエプレレノン製剤
HK1064056B (en) An aqueous pharmaceutical preparation of cilostazol for parenteral use
HK1242223A1 (zh) 受体酪氨酸激酶抑制剂的稳定且可溶的制剂和其制备方法
RU2006139065A (ru) Композиции с замаскированным вкусом, содержащие сертралин и простой сульфоалкиловый эфир циклодекстрина
CN102716070A (zh) 松属素环糊精或环糊精衍生物包合物

Legal Events

Date Code Title Description
A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20201112

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20211130

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20220225

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20220308

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20220607

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20220621

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20220720

R150 Certificate of patent or registration of utility model

Ref document number: 7110196

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250