HRP20200432T1 - Oblik za kombinacijsko doziranje antagonista mu opioidnog receptora i opioidnog sredstva - Google Patents

Oblik za kombinacijsko doziranje antagonista mu opioidnog receptora i opioidnog sredstva Download PDF

Info

Publication number
HRP20200432T1
HRP20200432T1 HRP20200432TT HRP20200432T HRP20200432T1 HR P20200432 T1 HRP20200432 T1 HR P20200432T1 HR P20200432T T HRP20200432T T HR P20200432TT HR P20200432 T HRP20200432 T HR P20200432T HR P20200432 T1 HRP20200432 T1 HR P20200432T1
Authority
HR
Croatia
Prior art keywords
dosage form
weight
solid
axelopran
opioid analgesic
Prior art date
Application number
HRP20200432TT
Other languages
English (en)
Inventor
Shaoling Li
Manshiu Leung
Hao Zhang
Venkat R. Thalladi
Yun Mo
Original Assignee
Theravance Biopharma R&D Ip, Llc
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 Theravance Biopharma R&D Ip, Llc filed Critical Theravance Biopharma R&D Ip, Llc
Publication of HRP20200432T1 publication Critical patent/HRP20200432T1/hr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/439Heterocyclic 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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/468-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/282Organic compounds, e.g. fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/2853Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893Tablet coating processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (16)

1. Čvrsti pripravak, naznačen time, da taj pripravak sadržava: (a) između 50 % i 95 % težinskih udjela akselopran sulfata, (b) između 5 % i 50 % težinskih udjela polivinil alkohola, (c) između 0 % i 45 % težinskih udjela polietilen glikola 3350, i (d) između 0 % i 10 % težinskog udjela askorbinske kiseline.
2. Čvrsti pripravak u skladu s patentnim zahtjevom 1, naznačen time, da je akselopran sulfat u kristalnom obliku.
3. Čvrsti pripravak u skladu s patentnim zahtjevom 1 ili patentnim zahtjevom 2, naznačen time, da taj pripravak sadržava: (a) između 50 % i 70 % težinskih udjela akselopran sulfata, (b) između 10 % i 50 % težinskih udjela polivinil alkohola, (c) između 5 % i 30 % težinskih udjela polietilen glikola 3350, i (d) između 0,5 % i 10 % težinskih udjela askorbinske kiseline.
4. Čvrsti pripravak u skladu s patentnim zahtjevom 1 ili zahtjevom 2, naznačen time, da taj pripravak sadržava: (a) između 50 % i 70 % težinskih udjela akselopran sulfata, (b) između 12 % i 25 % težinskih udjela polivinil alkohola (c) između 12 % i 25 % težinskih udjela polietilen glikola 3350, i (d) između 2 % i 6 % težinskih udjela askorbinske kiseline.
5. Kombinirani oblik doziranja, naznačen time, da sadržava: čvrsti oblik doziranja koji sadržava opioidno analgetsko sredstvo i dio s trenutačnim oslobađanjem, pri čemu dio s trenutačnim oslobađanjem sadržava čvrsti pripravak u skladu s bilo kojim patentnim zahtjevom od 1 do 4 i predstavlja sloj premaza lijeka na čvrstom obliku doziranja.
6. Kombinirani oblik doziranja u skladu s patentnim zahtjevom 5, naznačen time, da je opioidni analgetik u formulaciji s modificiranim otpuštanjem.
7. Kombinirani oblik doziranja u skladu s patentnim zahtjevom 6, naznačen time, da nadalje sadržava donji sloj premaza između vanjskog premaza lijeka i krutog oblika doziranja koji sadržava opioidni analgetski agens i pri čemu vanjski premaz lijeka sadržava akselopran sulfat u kristalnom obliku, a dodatno sadržava i film koji tvori polimer i plastifikator.
8. Kombinirani oblik doziranja u skladu s patentnim zahtjevom 7, naznačen time, da donji sloj premaza sadržava polivinil alkohol i polietilen glikol.
9. Kombinirani oblik doziranja u skladu s bilo kojim od patentnih zahtjeva 5 do 8, naznačen time, da je opioidno analgetsko sredstvo oksikodon ili oksimorfon.
10. Kombinirani oblik doziranja u skladu s patentnim zahtjevom 5, naznačen time, da sloj vanjskog premaza lijeka sadržava akselopran sulfat u kristalnom obliku i nadalje sadržava polimer koji tvori film te plastifikator; oblik doziranja koji dodatno sadržava donji sloj premaza, pri čemu se donji sloj premaza sastoji od polivinil alkohola i polietilen glikola; pri čemu je opioidni analgetski agens oksikodon ili oksimorfon; pri čemu sloj vanjskog premaza lijeka sadržava: (a) između 50 % i 70 % težinskih udjela akselopran sulfata, (b) između 12 % i 25 % težinskih udjela polivinil alkohola, (c) između 12 % i 25 % težinskih udjela polietilen glikola 3350, i (d) između 2 % i 6 % težinskih udjela askorbinske kiseline.
11. Kombinirani oblik doziranja u skladu s patentnim zahtjevom 10, naznačen time, da oblik doziranja osigurava in vitro brzinu otpuštanja akseloprana u razdoblju kraćem od jednog sata i in vitro brzinu otpuštanja opioidnog analgetskog sredstva do 12 sati.
12. Vodena otopina, naznačena time, da u njoj nevodene komponente otopine sadržavaju komponente (a), (b), (c) i (d) kako je definirano u skladu s bilo kojim od patentnih zahtjeva 1, 3 i 4.
13. Postupak pripreme kombiniranog oblika doziranja u skladu s bilo kojim patentnim zahtjevom od 5 do 11, naznačen time, da postupak uključuje: (a) pripremanje opioidnog analgetskog sredstva u čvrstom obliku doziranja i (b) oblaganje krutog oblika doziranja vodenom otopinom u skladu s patentnim zahtjevom 12.
14. Postupak u skladu s patentnim zahtjevom 13, naznačen time, da nadalje obuhvaća oblaganje opioidnog krutog oblika doziranja donjim slojem premaza koji sadržava polivinil alkohol i polietilen glikol na opioidni čvrsti oblik doziranja prije nanošenja sloja premaza lijeka koji sadržava akselopran.
15. Postupak u skladu s patentnim zahtjevom 13, naznačen time, da je akselopran sulfat sadržan u kombiniranom obliku doziranja u kristalnom obliku, a postupak nadalje uključuje korak (c): (c) izlaganje obloženog krutog oblika doziranja na između 70 % i 86 % relativne vlage, pri temperaturi između 20 °C i 45 °C dok se akselopran sulfat ne pretvori u kristalni oblik.
16. Pripravak u skladu s bilo kojim patentnim zahtjevom od 5 do 11, naznačen time, da se upotrebljava za liječenje boli kod sisavca ili za ublažavanje gastrointestinalnih nuspojava opioidne analgetske terapije.
HRP20200432TT 2015-04-02 2020-03-17 Oblik za kombinacijsko doziranje antagonista mu opioidnog receptora i opioidnog sredstva HRP20200432T1 (hr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562141981P 2015-04-02 2015-04-02
EP16718062.9A EP3277278B1 (en) 2015-04-02 2016-03-31 Combination dosage form of a mu opioid receptor antagonist and an opioid agent
PCT/US2016/025176 WO2016161069A1 (en) 2015-04-02 2016-03-31 Combination dosage form of a mu opioid receptor antagonist and an opioid agent

Publications (1)

Publication Number Publication Date
HRP20200432T1 true HRP20200432T1 (hr) 2020-06-12

Family

ID=55806767

Family Applications (1)

Application Number Title Priority Date Filing Date
HRP20200432TT HRP20200432T1 (hr) 2015-04-02 2020-03-17 Oblik za kombinacijsko doziranje antagonista mu opioidnog receptora i opioidnog sredstva

Country Status (26)

Country Link
US (4) US20160287573A1 (hr)
EP (1) EP3277278B1 (hr)
JP (2) JP6713483B2 (hr)
KR (1) KR20170132325A (hr)
CN (1) CN107820424B (hr)
AU (1) AU2016243691A1 (hr)
BR (1) BR112017021120A2 (hr)
CA (1) CA2980328A1 (hr)
CY (1) CY1122828T1 (hr)
DK (1) DK3277278T3 (hr)
ES (1) ES2774473T3 (hr)
HK (1) HK1247105A1 (hr)
HR (1) HRP20200432T1 (hr)
HU (1) HUE048785T2 (hr)
IL (1) IL254593A0 (hr)
LT (1) LT3277278T (hr)
ME (1) ME03671B (hr)
MX (1) MX2017012474A (hr)
PH (1) PH12017501767A1 (hr)
PL (1) PL3277278T3 (hr)
PT (1) PT3277278T (hr)
RS (1) RS60074B1 (hr)
RU (1) RU2017134794A (hr)
SI (1) SI3277278T1 (hr)
TW (1) TW201642856A (hr)
WO (1) WO2016161069A1 (hr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT3277278T (lt) 2015-04-02 2020-03-25 Theravance Biopharma R&D Ip, Llc Kombinuota vaisto forma mu opioidinio receptoriaus antagonisto ir opioidinio agento
EP3666261A4 (en) 2017-08-08 2020-08-05 Mitsubishi Chemical Corporation PHARMACEUTICAL TABLET AND METHOD FOR MANUFACTURING THEREOF

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1041987T3 (da) 1997-12-22 2006-08-21 Euro Celtique Sa Oral farmaceutisk doseringsform omfattende en kombination af en opioid-agonist og naltrexon
US6419960B1 (en) 1998-12-17 2002-07-16 Euro-Celtique S.A. Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US6451806B2 (en) 1999-09-29 2002-09-17 Adolor Corporation Methods and compositions involving opioids and antagonists thereof
AR029538A1 (es) * 2000-07-06 2003-07-02 Wyeth Corp Composiciones farmaceuticas de agentes estrogenicos
US7842307B2 (en) 2001-08-06 2010-11-30 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent
PT1414451E (pt) * 2001-08-06 2009-07-31 Euro Celtique Sa Formulações agonistas de opióides com antagonista libertável e sequestrado
CA2510465A1 (en) * 2002-12-18 2004-07-08 Pain Therapeutics Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats
US20050013863A1 (en) 2003-07-18 2005-01-20 Depomed, Inc., A Corporation Of The State Of California Dual drug dosage forms with improved separation of drugs
AU2004314693B2 (en) 2003-09-26 2011-04-07 Alza Corporation Drug coating providing high drug loading and methods for providing the same
TWI415635B (zh) 2004-05-28 2013-11-21 必治妥施貴寶公司 加衣錠片調製物及製備彼之方法
US7446114B2 (en) * 2005-03-02 2008-11-04 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
CN101395154B (zh) * 2006-03-01 2011-01-19 施万制药 作为μ阿片受体拮抗剂的8-氮杂双环[3.2.1]辛烷化合物
MY145633A (en) 2006-03-01 2012-03-15 Theravance Inc 8-azabicyclo[3.2.1]octane compounds as mu opioid receptor antagonists
CN101500542A (zh) * 2006-07-11 2009-08-05 共有药物有限公司 控释制剂
TWI409067B (zh) 2007-02-28 2013-09-21 Theravance Inc 8-氮雜雙環〔3.2.1〕辛烷化合物之結晶型
TWI415850B (zh) 2007-07-20 2013-11-21 Theravance Inc 製備mu類鴉片受體拮抗劑之中間物的方法
WO2009137672A1 (en) * 2008-05-07 2009-11-12 Salix Pharmaceuticals, Ltd. Methods of treating bowel disease by administering a bowel cleanser and an antibiotic
EP2210595A1 (en) 2009-01-14 2010-07-28 LEK Pharmaceuticals d.d. Active coating of pharmaceutical dosage forms
KR101783945B1 (ko) * 2009-05-12 2017-10-10 비피에스아이 홀딩스, 엘엘씨. 향상된 수분차단 속방출형 필름의 코팅 시스템 및 이에 의하여 코팅된 기재
IT1398930B1 (it) * 2010-03-24 2013-03-28 Molteni & C Formulazioni farmaceutiche bistrato contenenti agonisti ed antagonisti oppioidi.
AU2011295837B2 (en) * 2010-09-03 2015-06-18 Astrazeneca Uk Limited Drug formulations using water soluble antioxidants
JP2014504639A (ja) 2011-02-01 2014-02-24 ブリストル−マイヤーズ スクイブ カンパニー アミン化合物を含む医薬製剤
US9339489B2 (en) * 2013-03-15 2016-05-17 Aprecia Pharmaceuticals Company Rapid disperse dosage form containing levetiracetam
LT3277278T (lt) 2015-04-02 2020-03-25 Theravance Biopharma R&D Ip, Llc Kombinuota vaisto forma mu opioidinio receptoriaus antagonisto ir opioidinio agento

Also Published As

Publication number Publication date
KR20170132325A (ko) 2017-12-01
WO2016161069A1 (en) 2016-10-06
US10946009B2 (en) 2021-03-16
US20180050028A1 (en) 2018-02-22
US10369142B2 (en) 2019-08-06
EP3277278A1 (en) 2018-02-07
US20210161884A1 (en) 2021-06-03
ES2774473T3 (es) 2020-07-21
CN107820424A (zh) 2018-03-20
PT3277278T (pt) 2020-04-16
PL3277278T3 (pl) 2020-07-27
ME03671B (me) 2020-10-20
BR112017021120A2 (pt) 2018-07-03
LT3277278T (lt) 2020-03-25
JP2020073583A (ja) 2020-05-14
CN107820424B (zh) 2020-07-28
EP3277278B1 (en) 2020-01-08
PH12017501767A1 (en) 2018-06-11
RS60074B1 (sr) 2020-05-29
AU2016243691A1 (en) 2017-10-12
US20190321350A1 (en) 2019-10-24
JP2018513138A (ja) 2018-05-24
SI3277278T1 (sl) 2020-04-30
US11452723B2 (en) 2022-09-27
JP6713483B2 (ja) 2020-06-24
DK3277278T3 (da) 2020-04-06
CY1122828T1 (el) 2021-05-05
CA2980328A1 (en) 2016-10-06
IL254593A0 (en) 2017-11-30
MX2017012474A (es) 2018-01-11
HUE048785T2 (hu) 2020-08-28
TW201642856A (zh) 2016-12-16
RU2017134794A (ru) 2019-04-04
US20160287573A1 (en) 2016-10-06
HK1247105A1 (zh) 2018-09-21

Similar Documents

Publication Publication Date Title
JP2014218522A5 (hr)
JP2016510019A5 (hr)
HRP20200432T1 (hr) Oblik za kombinacijsko doziranje antagonista mu opioidnog receptora i opioidnog sredstva
AR070863A1 (es) Preparacion solida de desintegracion oral y metodo para suprimir la ruptura de los granulos finos durante la produccion de un comprimido
NZ705578A (en) Coated pharmaceutical composition containing regorafenib
DE602007010254D1 (de) Feste dosierungsform mit einem wirkstoff mit unterdrücktem geschmack
RS53363B (en) ORAL PHARMACEUTICAL TABLETS FOR THE CONTROLLED MESALAZINE RELEASE AND THE PROCESS OF OBTAINING THEM
WO2010010257A3 (fr) Medicaments appetissants a administration orale sous forme solide pour la prevention et/ou le traitement de l'insuffisance cardiaque chez les animaux
MX2021016109A (es) Metodos y composiciones particularmente para el tratamiento del trastorno por deficit de atencion.
JP2014534197A5 (hr)
EP2823819A4 (en) PHARMACEUTICAL COMPOSITION CONTAINING OLEANOLIC ACID ACETATE AS AN ACTIVE INGREDIENT FOR THE PREVENTION OR TREATMENT OF MEDIATED DISEASE BY TLR OR IL-6
HRP20161340T1 (hr) Formulacije darunavira
JP2013517304A5 (hr)
IL251413B2 (en) Composition of injectable buprenorphine
HRP20210068T1 (hr) Opioidne formulacije
EA201690005A1 (ru) Состав с модифицированной кинетикой высвобождения
HRP20220271T1 (hr) Čvrsti oralni pripravci sa sporim otpuštanjem
WO2013017910A8 (en) Extended release pharmaceutical compositions containing paliperidone
CN104434799A (zh) 聚六亚甲基胍喷雾剂及其制备方法
WO2016091805A3 (de) Naloxon-monopräparat und mehrschichttablette
JP2016539112A5 (hr)
RU2015143891A (ru) Фармацевтические составы тамсулозина или его солей
PH12014502609A1 (en) Mutilayer coating form of orally administered pharmaceutical composition containing omega-3 fatty acid or alkyl ester thereof and statin based drug
MX359887B (es) Composicion masticable para administracion oral y proceso para preparar la misma.
JP2018513138A5 (hr)