SG10201704858PA - Formulations and methods for vaginal delivery of antiprogestins - Google Patents

Formulations and methods for vaginal delivery of antiprogestins

Info

Publication number
SG10201704858PA
SG10201704858PA SG10201704858PA SG10201704858PA SG10201704858PA SG 10201704858P A SG10201704858P A SG 10201704858PA SG 10201704858P A SG10201704858P A SG 10201704858PA SG 10201704858P A SG10201704858P A SG 10201704858PA SG 10201704858P A SG10201704858P A SG 10201704858PA
Authority
SG
Singapore
Prior art keywords
antiprogestins
formulations
methods
vaginal delivery
vaginal
Prior art date
Application number
SG10201704858PA
Other languages
English (en)
Inventor
Joseph S Podolski
Kuang Hsu
Original Assignee
Repros Therapeutics Inc
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=48614182&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=SG10201704858P(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Repros Therapeutics Inc filed Critical Repros Therapeutics Inc
Publication of SG10201704858PA publication Critical patent/SG10201704858PA/en

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Reproductive Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
SG10201704858PA 2012-05-31 2013-05-30 Formulations and methods for vaginal delivery of antiprogestins SG10201704858PA (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US201261653674P 2012-05-31 2012-05-31

Publications (1)

Publication Number Publication Date
SG10201704858PA true SG10201704858PA (en) 2017-07-28

Family

ID=48614182

Family Applications (2)

Application Number Title Priority Date Filing Date
SG11201407397WA SG11201407397WA (en) 2012-05-31 2013-05-30 Formulations and methods for vaginal delivery of antiprogestins
SG10201704858PA SG10201704858PA (en) 2012-05-31 2013-05-30 Formulations and methods for vaginal delivery of antiprogestins

Family Applications Before (1)

Application Number Title Priority Date Filing Date
SG11201407397WA SG11201407397WA (en) 2012-05-31 2013-05-30 Formulations and methods for vaginal delivery of antiprogestins

Country Status (22)

Country Link
US (1) US10328022B2 (cs)
EP (1) EP2854763B1 (cs)
JP (1) JP6341910B2 (cs)
KR (1) KR102127348B1 (cs)
CN (1) CN104334158B (cs)
AU (1) AU2013267359C1 (cs)
BR (1) BR112014029131B1 (cs)
CA (1) CA2872644A1 (cs)
CL (1) CL2014003232A1 (cs)
CO (1) CO7141411A2 (cs)
CR (1) CR20140567A (cs)
EA (1) EA030444B1 (cs)
ES (1) ES2701400T3 (cs)
IL (1) IL235450B (cs)
IN (1) IN2014DN10548A (cs)
MX (2) MX382986B (cs)
NZ (1) NZ702467A (cs)
PH (1) PH12014502516A1 (cs)
SG (2) SG11201407397WA (cs)
UA (1) UA114106C2 (cs)
WO (1) WO2013181449A1 (cs)
ZA (1) ZA201408262B (cs)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20211377T1 (hr) 2011-11-23 2022-01-07 Therapeuticsmd, Inc. Prirodne kombinirane hormonske supstitucijske formulacije i terapije
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
MX384159B (es) * 2014-05-05 2025-03-14 Repros Therapeutics Inc Formulaciones y métodos para el suministro vaginal de antiprogestinas.
MX2016014281A (es) 2014-05-22 2017-02-22 Therapeuticsmd Inc Formulaciones y terapias de reemplazo de combinación de hormonas naturales.
US11623008B2 (en) 2014-08-20 2023-04-11 Professional Compounding Centers Of America Excipient compositions for mucoadhesive pharmaceutical compositions including a synergistic combination of amylopectin, pullulan, hyaluronic acid, and xyloglucan
EP3209282A4 (en) * 2014-10-20 2018-05-23 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
EP3025709B1 (en) 2014-11-27 2020-09-30 Capsugel Belgium NV Dosage form articles for external mucosal applications
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
MX2018011705A (es) 2016-04-01 2019-06-10 Therapeuticsmd Inc Composicion farmaceutica de hormona esteroide.
WO2017173044A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd Inc. Steroid hormone compositions in medium chain oils
EP3610028A1 (en) 2017-04-14 2020-02-19 Capsugel Belgium NV Process for making pullulan
EP4585211A2 (en) * 2017-04-14 2025-07-16 Capsugel Belgium NV Pullulan capsules

Family Cites Families (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2377418A1 (fr) 1977-01-13 1978-08-11 Roussel Uclaf Nouveaux derives steroides 4,9-dieniques 11b-substitues, leur procede de preparation et leur application comme medicaments
FR2521565B1 (fr) 1982-02-17 1985-07-05 Dior Sa Parfums Christian Melange pulverulent de constituants lipidiques et de constituants hydrophobes, procede pour le preparer, phases lamellaires lipidiques hydratees et procede de fabrication, compositions pharmaceutiques ou cosmetiques comportant des phases lamellaires lipidiques hydratees
FR2522328B1 (fr) 1982-03-01 1986-02-14 Roussel Uclaf Nouveaux produits derives de la structure 3-ceto 4,9 19-nor steroides, leur procede de preparation et leur application comme medicaments
FR2534487B1 (fr) 1982-10-15 1988-06-10 Dior Christian Parfums Procede d'homogeneisation de dispersions de phases lamellaires lipidiques hydratees, et suspensions obtenues par ce procede
DE3237814A1 (de) * 1982-10-12 1984-04-12 Warner-Lambert Co., 07950 Morris Plains, N.J. Wasserfreie emulsionen und verwendung derselben
EP0501523B1 (en) 1983-11-14 1997-04-09 Columbia Laboratories, Inc. Bioadhesive compositions
FR2598421B1 (fr) 1986-05-06 1988-08-19 Roussel Uclaf Nouveaux produits 19-nor ou 19-nor d-homo steroides substitues en position 11b par un radical phenyle portant un radical alkynyle, leur procede de preparation, leur application comme medicaments et les compositions les renfermant
US4954490A (en) 1988-06-23 1990-09-04 Research Triangle Institute 11 β-substituted progesterone analogs
US5077211A (en) 1988-07-06 1991-12-31 Applied Genetics, Inc. Purification and administration of dna repair enzymes
US5468741A (en) 1993-05-28 1995-11-21 The Regents Of The University Of California Use of low levels of mifepristone to treat leiomyomata
US5543150A (en) 1993-09-15 1996-08-06 Columbia Laboratories, Inc. Method of progesterone delivery and affect thereof
IL112778A0 (en) * 1994-03-04 1995-05-26 Merck & Co Inc Substituted heterocycles, their preparation and pharmaceutical compositions containing them
DE4426601A1 (de) 1994-07-27 1996-02-01 Schering Ag Verwendung eines Kombinationsproduktes enthaltend einen kompetitiven Progesteronantagonisten und ein Gestagen zur Herstellung eines Arzneimittels zur Behandlung der Endometriose oder des Leiomyomata uteri
CA2186953C (en) 1995-02-02 2009-11-10 Kristof Chwalsz Progesterone antagonists for the production of pharmaceutical agents for the treatment of dysfunctional uterine bleeding
GB9522403D0 (en) * 1995-11-01 1996-01-03 Hoechst Roussel Ltd Intravaginal drug delivery device
US6900193B1 (en) 1996-05-01 2005-05-31 The United States Of America As Represented By The Department Of Health And Human Services Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents
ES2152671T3 (es) 1996-05-01 2001-02-01 Us Gov Health & Human Serv Derivados de progesterona sustituidos en posicion 21 como nuevos agentes antiprogestacionales.
WO1998008471A1 (en) 1996-08-30 1998-03-05 The Population Council, Inc. Vaginal application mifepristone
US6682174B2 (en) 1998-03-25 2004-01-27 Silverbrook Research Pty Ltd Ink jet nozzle arrangement configuration
US20050070516A1 (en) 1997-10-28 2005-03-31 Vivus Inc. As-needed administration of an androgenic agent to enhance female desire and responsiveness
US6020328A (en) 1998-03-06 2000-02-01 Research Triangle Institute 20-keto-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties
EP1008443A1 (de) 1998-12-08 2000-06-14 Alusuisse Technology & Management AG Sterilisierbarer Folienverbund für Verpackungszwecke
US6740645B1 (en) 1999-09-03 2004-05-25 Research Triangle Institute 17β-acyl-17α-propynyl-11β-(cyclic amino) aryl steroids and their derivatives having antagonist hormonal properties
AR025609A1 (es) * 1999-09-13 2002-12-04 Hoffmann La Roche Formulaciones lipidas solidas
UA74168C2 (uk) 1999-10-05 2005-11-15 Коламбіа Леборетеріс (Бермуда) Лімітед Лікування ендометріозу або безпліддя, або покращення плідності та застосування бета-адренергічного агоніста для виробництва лікарського засобу
ES2546291T3 (es) 2000-03-17 2015-09-22 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services 17-Alfa-sustituida, 11-beta-sustituida-4-arilo y 21-sustituida 19-norpregnadienodionas como agentes antiprogestacionales
IN191020B (cs) 2000-03-28 2003-09-13 Dabur Res Foundation
IL154975A0 (en) 2000-10-18 2003-10-31 Schering Ag Use of antiprogestins for prophylaxis and treatment of hormone-dependent diseases
US7759360B2 (en) 2001-07-09 2010-07-20 Repros Therapeutics Inc. Methods and materials for the treatment of testosterone deficiency in men
WO2003020210A2 (en) 2001-08-29 2003-03-13 Umd, Inc. Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy
JP2003143474A (ja) 2001-11-02 2003-05-16 Matsushita Electric Ind Co Ltd 映像信号処理システム
US7417013B2 (en) 2002-05-01 2008-08-26 Mcneil-Ppc, Inc. Warming and nonirritating lubricant compositions and method of comparing irritation
US7833545B2 (en) 2003-04-29 2010-11-16 The General Hospital Corporation Methods and devices for the sustained release of multiple drugs
EP1593376A1 (en) 2004-05-04 2005-11-09 Warner-Lambert Company LLC Improved pullulan capsules
WO2006010097A2 (en) 2004-07-09 2006-01-26 The Population Council, Inc. Sustained release compositions containing progesterone receptor modulators
GT200500185A (es) 2004-08-09 2006-04-10 Moduladores del receptor de progesterona que comprenden derivados de pirrol-oxindol y sus usos
KR20070114187A (ko) 2005-03-22 2007-11-29 레프로스 쎄라피우틱스 아이엔씨. 트랜스-클로미펜의 투약 방법
EP1874732A1 (en) 2005-04-20 2008-01-09 Pfizer Limited Pyrazole derivatives as progesterone receptor antagonists
DE102005030294A1 (de) 2005-06-24 2007-01-04 Schering Ag Nichtsteroidale Progesteronrezeptor-Modulatoren
WO2007038796A1 (en) * 2005-09-29 2007-04-05 Repros Therapeutics Inc. Formulations with improved bioavailability, comprising a steroid derivative and a polyglycolysed glyceride
CN1846703A (zh) 2006-02-13 2006-10-18 程定超 米非司酮阴道给药制剂及其组成和制备方法
US8173626B2 (en) 2006-03-08 2012-05-08 Danco Laboratories Llc Methods, dosing regimens and medications using anti-progestational agents for the treatment of disorders
JP2008012281A (ja) * 2006-06-05 2008-01-24 Koritsu Shoji:Kk 挿入補助器具
KR20070116538A (ko) * 2006-06-05 2007-12-10 유겐가이샤 코리츠 쇼지 삽입 보조 기구
CZ300424B6 (cs) * 2006-06-20 2009-05-13 Pliva - Lachema A. S. Farmaceutická kompozice pro perorální podání
KR20090067198A (ko) 2006-10-24 2009-06-24 레프로스 쎄라피우틱스 아이엔씨. 자궁내막 증식을 억제하는 조성물과 방법
US8105625B2 (en) * 2007-04-05 2012-01-31 University Of Kansas Rapidly dissolving pharmaceutical compositions comprising pullulan
ES2575554T3 (es) 2007-04-20 2016-06-29 Preglem S.A. Moduladores selectivos de progesterona en el tratamiento de la hemorragia uterina
DK2197415T3 (da) 2007-09-20 2014-05-26 Lapidot Medical Imp And Marketing Ltd Sammensætninger og midler til at behandle uterusleiomyomer, leiomyom, myom, uterusfibroid, endometriose, adenomyose og beslægtede forstyrrelser med mifepriston
TWI477276B (zh) * 2008-04-28 2015-03-21 Repros Therapeutics Inc 抗黃體素給藥方案
WO2011039680A1 (en) * 2009-09-29 2011-04-07 Koninklijke Philips Electronics N.V. Intrauterine electronic capsule for administering a substance
UA113283C2 (xx) 2010-12-23 2017-01-10 19-норстероїди і їх застосування для лікування прогестеронзалежних станів
DE202011110355U1 (de) 2011-03-09 2014-01-15 Arstat, Inc. Behandlung von Uterusmyomen durch intravaginale Verabreichung einer niedrigen Dosis eines selektiven Progesteronrezeptormodulators, eines Antigestagens oder eines Antigestagen-Wirkstoffes
UA113291C2 (xx) 2011-08-04 2017-01-10 Метаболіти транскломіфену і їх застосування

Also Published As

Publication number Publication date
CN104334158B (zh) 2018-08-10
CR20140567A (es) 2015-03-09
CN104334158A (zh) 2015-02-04
MX2014014054A (es) 2015-02-12
PH12014502516B1 (en) 2015-01-12
EP2854763B1 (en) 2018-09-26
KR102127348B1 (ko) 2020-06-29
NZ702467A (en) 2016-07-29
AU2013267359C1 (en) 2016-09-29
ES2701400T3 (es) 2019-02-22
MX382986B (es) 2025-03-13
JP6341910B2 (ja) 2018-06-13
JP2015518052A (ja) 2015-06-25
KR20150014928A (ko) 2015-02-09
BR112014029131B1 (pt) 2021-03-09
AU2013267359A1 (en) 2014-11-20
BR112014029131A2 (pt) 2018-05-29
MX2019003467A (es) 2019-06-06
EP2854763A1 (en) 2015-04-08
CL2014003232A1 (es) 2015-03-13
MX363640B (es) 2019-03-28
SG11201407397WA (en) 2014-12-30
IN2014DN10548A (cs) 2015-08-21
EA201492290A1 (ru) 2015-03-31
US20150111862A1 (en) 2015-04-23
EA030444B1 (ru) 2018-08-31
UA114106C2 (xx) 2017-04-25
CO7141411A2 (es) 2014-12-12
PH12014502516A1 (en) 2015-01-12
IL235450B (en) 2020-02-27
CA2872644A1 (en) 2013-12-05
IL235450A0 (en) 2014-12-31
HK1206622A1 (en) 2016-01-15
AU2013267359B2 (en) 2016-05-26
WO2013181449A1 (en) 2013-12-05
ZA201408262B (en) 2015-12-23
US10328022B2 (en) 2019-06-25

Similar Documents

Publication Publication Date Title
IL235450A0 (en) Formulations and methods for administering antiprogestins through the vagina
IL239557B (en) Microarray for providing therapeutic material and methods for use
SMT202100528T1 (it) Lipidi per formulazioni di rilascio di agente terapeutico
IL237462B (en) Delivery devices and methods for skin tightening
EP2643045A4 (en) THERAPEUTIC PROCESSES AND COMPOSITIONS FOR SOLID FORM DELIVERY
ZA201401143B (en) Capsule formulation comprising montelukast and levocetirizine
IL242545B (en) Compositions and methods for administering hydrophobic active substances
IL235768A0 (en) Pharmaceutical preparations and treatment of inflammation of the nipples
IL235831A0 (en) A new dosage form and formulation of aveditrol
IL238274A0 (en) Methods and preparations for local increase of body fat
IL236791A0 (en) Compositions and methods for producing the compositions for use in colon emptying
EP2790637A4 (en) VAGINAL DRUG DELIVERY DEVICES AND METHODS OF MANUFACTURING THE SAME
ZA201500459B (en) Pharmaceutical formulation for reducing frequency of urination and method of use thereof
IL248621A0 (en) Formulations and methods for vaginal administration of antiprogestins
EP2763716A4 (en) SOLID MEDICATION ADMINISTRATION APPARATUS, FORMULATIONS AND METHODS OF USE
EP2846839A4 (en) FORMULATIONS FOR THE ADMINISTRATION OF ACTIVE PRINCIPLES
GB201012660D0 (en) Inhaler and formulation