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WO2000032558A1 - Produit therapeutique et ses utilisations - Google Patents

Produit therapeutique et ses utilisations Download PDF

Info

Publication number
WO2000032558A1
WO2000032558A1 PCT/GB1999/004021 GB9904021W WO0032558A1 WO 2000032558 A1 WO2000032558 A1 WO 2000032558A1 GB 9904021 W GB9904021 W GB 9904021W WO 0032558 A1 WO0032558 A1 WO 0032558A1
Authority
WO
WIPO (PCT)
Prior art keywords
tramadol
enantiomer
product according
treatment
racemic
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.)
Ceased
Application number
PCT/GB1999/004021
Other languages
English (en)
Inventor
Hazel Bardsley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Darwin Discovery Ltd
Original Assignee
Darwin Discovery Ltd
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
Priority claimed from GBGB9826536.6A external-priority patent/GB9826536D0/en
Priority claimed from GBGB9826537.4A external-priority patent/GB9826537D0/en
Priority claimed from GBGB9826535.8A external-priority patent/GB9826535D0/en
Priority to BR9915873-6A priority Critical patent/BR9915873A/pt
Application filed by Darwin Discovery Ltd filed Critical Darwin Discovery Ltd
Priority to AU14001/00A priority patent/AU1400100A/en
Priority to CA002350635A priority patent/CA2350635A1/fr
Priority to KR1020017005443A priority patent/KR20010080364A/ko
Priority to IL14277899A priority patent/IL142778A0/xx
Priority to JP2000585200A priority patent/JP2002531431A/ja
Priority to PL99347542A priority patent/PL347542A1/xx
Priority to EP99973016A priority patent/EP1135361A1/fr
Publication of WO2000032558A1 publication Critical patent/WO2000032558A1/fr
Priority to NO20012738A priority patent/NO20012738L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered 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

Definitions

  • the present invention relates to a novel, non-racemic, form of tramadol, and its use in analgesia.
  • Tramadol ( ⁇ is-2-dimethylaminomethyl-l- (3-methoxy- phenyl)-l-cyclohexanol) is a chiral drug substance which is used as a high-potency analgesic agent.
  • tramadol is currently marketed as the racemate only, there has been considerable interest in the physiological properties associated with its individual enantiomers, namely 1S, 2S- (-) -tramadol and lR, 2R- ⁇ +) -tramadol, the latter being shown below (1) .
  • the present invention is based on the discovery that, by employing certain, non-racemic, proportions of the respective enantiomers of tramadol, the most beneficial therapeutic index, in terms of analgesic efficacy and reduction of side effects (e.g. nausea, vomiting, dizziness, constipation, sedation and others) associated with administration of the racemate, may be achieved.
  • a product comprises a non-racemic mixture of the single enantiomers of tramadol as a combined preparation (kit) for simultaneous, separate or sequential use in the treatment or prevention of pain.
  • a non-racemic mixture of the single enantiomers of tramadol is used in the manufacture of a medicament for the treatment or prevention of pain, and is particularly useful for the treatment of patients disposed to side effects typically associated with the administration of racemic tramadol.
  • the medicament is, however, useful in treating other patient types, as discussed below.
  • a product comprises a non-racemic mixture of the single enantiomers of tramadol and a pharmaceutically-acceptable carrier.
  • the non-racemic mixture for use in the present invention comprises at least 60 wt.% (-) -tramadol. While enantiomerically-pure (-) -tramadol may be useful in achieving analgesia, it is preferred that (-) -tramadol be formulated with at least some (+) -tramadol, as with both enantiomers present the optimal balance between analgesic efficacy and safety is achieved.
  • weight ratios of the two enantiomers lie in the range 10- 40:90-60 (+) -tramadol: (-) -tramadol (+:-), more preferred ratios lie in the range 20-40:80-60 (+:-), and the most preferred ratios lie in the range 30-40:70-60 (+:-) .
  • racemic tramadol preferred non-racemic mixtures are particularly useful in the treatment of patients who are disposed to side effects typically associated with the administration of racemic tramadol.
  • side effects typically observed in the administration of racemic tramadol include blurred vision, drowsiness, somnolence, hallucinations, respiratory depression, and euphoria.
  • the present invention is particularly useful in treating those patients prone to nausea and vomiting. This is because, as is explained in the Example below, (-) -tramadol is believed to modulate the emetic properties of (+)- tramadol, thereby reducing the overall emetic capability of racemic tramadol. This effect can be exploited for maximum benefit using different release profiles for the different enantiomers, as is discussed below.
  • the present invention is also believed to be particularly suited to the treatment of patients exhibiting abnormal CYP2D6 liver enzyme activity.
  • the CYP2D6 gene encoding sparteine oxygenase is highly polymorphic, and an ever-increasing number of mutations are being identified.
  • the wild-type gene is CYP2D6*1A. Any person not having the wild-type gene can be categorised as exhibiting abnormal enzyme activity. The precise nature of any particular mutation determines the degree to which a patient exhibits abnormal enzyme activity. Thus, by applying simple laboratory genetic analysis techniques it is possible to ascertain the approximate rate at which (+) -tramadol will be metabolised by a particular patient, and therefore how rapid and effective analgesia will be.
  • mixtures comprising a very high proportion of (-) -tramadol may be used, for example weight ratios in the range 0-10:100-90 (+:-), with patients particularly disposed to side effects associated with racemic tramadol.
  • Another option is to employ a more even balance of the two enantiomers, with the more efficacious (+) -enantiomer in excess, for instance weight ratios in the range 60-80:40-20 (+:-), typically 60-70:40- 30 (+:-).
  • Such ratios may be useful in treating patients not particularly disposed to side effects associated with racemic tramadol, or where analgesic efficacy is of primary importance.
  • Administration of (-) -tramadol before or at a faster rate than (+) -tramadol would, however, still be beneficial in reducing side effects.
  • a further aspect of the present invention is the use of a non-racemic mixture of the single enantiomers of tramadol in the manufacture of a medicament for the prevention or treatment of migraine.
  • the amount of non-racemic tramadol administered to any particular patient will depend upon the patient and the conditions for which the non-racemic tramadol is administered, and on whether non-racemic tramadol is to be used in prophylaxis or in therapy.
  • Suitable amounts for administration are readily derivable by the skilled person.
  • the different enantiomers of tramadol may be administered simultaneously, separately or sequentially. They may be formulated for either immediate or controlled release, or a combination of the two, or for release at different rates, or at different times.
  • Preferred modes of administration release (-) -tramadol before or at a faster rate than (+) -tramadol, so as to optimise the effect of (-) -tramadol on the emetic properties of (+) -tramadol.
  • situations may be envisaged, where the reverse may be required, and it is desired to administer (+)- tramadol before or at a faster rate than (-) -tramadol.
  • a particularly preferred mode of administration is with (-) -tramadol in immediate release form and (+)- tramadol in controlled release form, by employing a combination of immediate and controlled release technologies, as described in WO-A-9840053 , the contents of which are incorporated herein by way of reference. It is envisaged that a dosage form of this type may be particularly beneficial in achieving rapid analgesia without the concomitant side effects associated with administration of racemic tramadol.
  • a number of different types of dosage form can be envisaged for the non-racemic mixtures of the present invention, for administration by a variety of routes, e.g. oral, rectal, transdermal, nasal, ophthalmic, pormonary and injectable (subcutaneous or intravenous) .
  • Suitable dosage forms include, for example, tablets, suppositories, capsules, e.g. containing multiparticulates, patches, polymer implants, aerosols, liposomes or microparticulates for injection, and any other conventional dosage form. Particularly preferred dosage forms are described in WO-A-9840053.
  • a bilayered tablet is particularly preferred, including (-) -tramadol for immediate release in one layer and (+) -tramadol for controlled release in another layer.
  • the results upon which the present invention are based are reported in the following Example.
  • the objective was to identify the optimal range of enantiomeric ratios capable of providing the most beneficial therapeutic index, in terms of both analgesic efficacy and reduction of the nausea and vomiting associated with racemic tramadol.
  • test substances Different amounts of each of the test substances were orally administered to rats, using a constant dose volume of 10 ml/kg.
  • 0.1 ml of a 20% w/v suspension of Brewer's yeast in saline was injected subcutaneously into the plantar surface of the right hand paw of each rat to induce hyper-algesia.
  • the left hind paw was similarly injected with 0.1 ml saline, as a control.
  • Measurements of pressure tolerated were taken from the left (non-inflamed) and right (inflamed) paws 30 minutes after administration of the test substance.
  • (+) -tramadol is seen to be non-emetic at doses of up to 200 mg/kg.
  • (+) -tramadol induces nausea in 75% of ferrets at 50 mg/kg, while the racemate causes nausea in 25% of animals at 100 mg/kg.
  • the racemate is a 50:50 mixture of the two enantiomers it is seen to induce less nausea than would be expected based on its content of (+)- enantiomer. This disparity can be explained by the ability of the (-) -enantiomer to modulate emesis associated with the (+) -enantiomer.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se base sur une découverte selon laquelle en employant certaines proportions non racémiques des différents énantiomères du tramadol, on pouvait, en association avec le racémate, obtenir les index thérapeutiques les plus bénéfiques en terme d'efficacité analgésique et de réduction des effets secondaires (par exemple nausée, vomissements, vertiges, constipation, sédation et autres).
PCT/GB1999/004021 1998-12-02 1999-12-02 Produit therapeutique et ses utilisations Ceased WO2000032558A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP99973016A EP1135361A1 (fr) 1998-12-02 1999-12-02 Produit therapeutique et ses utilisations
PL99347542A PL347542A1 (en) 1998-12-02 1999-12-02 Therapeutic product and its use
JP2000585200A JP2002531431A (ja) 1998-12-02 1999-12-02 治療用製品およびその使用
BR9915873-6A BR9915873A (pt) 1998-12-02 1999-12-02 Produto terapêutico e seu uso
AU14001/00A AU1400100A (en) 1998-12-02 1999-12-02 Therapeutic product and its use
CA002350635A CA2350635A1 (fr) 1998-12-02 1999-12-02 Produit therapeutique et ses utilisations
KR1020017005443A KR20010080364A (ko) 1998-12-02 1999-12-02 치료제 및 그 용도
IL14277899A IL142778A0 (en) 1998-12-02 1999-12-02 Therapeutic product and its use
NO20012738A NO20012738L (no) 1998-12-02 2001-06-01 Terapeutiske produkter og anvendelse derav

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GBGB9826536.6A GB9826536D0 (en) 1998-12-02 1998-12-02 Therapeutic product and its use
GB9826535.8 1998-12-02
GBGB9826535.8A GB9826535D0 (en) 1998-12-02 1998-12-02 Therapeutic product and its use
GBGB9826537.4A GB9826537D0 (en) 1998-12-02 1998-12-02 Therapeutic product and its use
GB9826537.4 1998-12-02
GB9826536.6 1998-12-02

Publications (1)

Publication Number Publication Date
WO2000032558A1 true WO2000032558A1 (fr) 2000-06-08

Family

ID=27269570

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/004021 Ceased WO2000032558A1 (fr) 1998-12-02 1999-12-02 Produit therapeutique et ses utilisations

Country Status (12)

Country Link
EP (1) EP1135361A1 (fr)
JP (1) JP2002531431A (fr)
KR (1) KR20010080364A (fr)
CN (1) CN1329590A (fr)
AU (1) AU1400100A (fr)
BR (1) BR9915873A (fr)
CA (1) CA2350635A1 (fr)
HU (1) HUP0104420A2 (fr)
IL (1) IL142778A0 (fr)
NO (1) NO20012738L (fr)
PL (1) PL347542A1 (fr)
WO (1) WO2000032558A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297286B1 (en) 1999-11-09 2001-10-02 Darwin Discovery, Ltd. Therapeutic use and formulation
WO2002028383A1 (fr) * 2000-10-03 2002-04-11 Penwest Pharmaceuticals Company Systeme d'administration pour plusieurs principes actifs pharmaceutiques a des vitesses differentes de liberation
WO2002066026A3 (fr) * 2001-02-21 2002-11-07 Gruenenthal Gmbh Medicament a base de tramadol
US6780891B2 (en) 2001-11-30 2004-08-24 Sepracor Inc. Tramadol analogs and uses thereof
WO2008100933A2 (fr) 2007-02-12 2008-08-21 Dmi Biosciences, Inc. Réduction des effets secondaires du tramadol
US8962019B2 (en) 2005-09-09 2015-02-24 Angelini Pharma, Inc. Sustained drug release composition
WO2018219977A1 (fr) * 2017-05-31 2018-12-06 Metys Pharmaceuticals AG Compositions synergiques comprenant (r)-dimiracetam (1) et (s)-dimiracetam (2) dans un rapport non racémique
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2470011C2 (ru) * 2007-05-31 2012-12-20 Сепракор Инк. Циклоалкиламины, содержащие в качестве заместителя фенил, как ингибиторы обратного захвата моноаминов
JP2022510362A (ja) * 2018-12-04 2022-01-26 メティス ファーマシューティカルズ アクチェンゲゼルシャフト Ｒ－２－（置換スルホニル）－ヘキサヒドロ－ピロロ［１，２－ａ］ピラジン－６（２Ｈ）－オンとＳ－２－（置換スルホニル）－ヘキサヒドロ－ピロロ［１，２－ａ］ピラジン－６（２Ｈ）－オンを非ラセミ比で含む相乗的組成物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5204116A (en) * 1991-05-01 1993-04-20 Alza Corporation Dosage form providing immediate therapy followed by prolonged therapy
WO1998040053A1 (fr) * 1997-03-11 1998-09-17 Darwin Discovery Limited Formes galeniques comprenant des parties separees d'enantiomeres r et s
WO1999042095A1 (fr) * 1998-02-21 1999-08-26 Asta Medica Ag Combinaisons pharmaceutiques contenant du tramadol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5204116A (en) * 1991-05-01 1993-04-20 Alza Corporation Dosage form providing immediate therapy followed by prolonged therapy
WO1998040053A1 (fr) * 1997-03-11 1998-09-17 Darwin Discovery Limited Formes galeniques comprenant des parties separees d'enantiomeres r et s
WO1999042095A1 (fr) * 1998-02-21 1999-08-26 Asta Medica Ag Combinaisons pharmaceutiques contenant du tramadol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FRANKUS E ET AL: "UEBER DIE ISOMERENTRENNUNG, STRUKTURAUFKLAERUNG UND PHARMAKOLOGISCHE CHARAKTERISIERUNG VON 1-(M-METHOXYPHENYL)-2 -(DIMETHYLAMINOMETHYL)-CY CLOHEXAN-1-OL. ON SEPARARION OF ISOMERS, STRUCTURAL ELUCIDATION AND PHARMACOLOGICAL CHARACTERIZATION OF 1 -(M-METHOXYPHENYL)-2-(DIMETHYLA MINOMETHYL)-CYCLOHEXAN-", ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, vol. 28, no. 1A, 1 January 1978 (1978-01-01), pages 114 - 121, XP000644506, ISSN: 0004-4172 *
POULSEN L ET AL: "THE HYPOALGESIC EFFECT OF TRAMADOL IN RELATION TO CYP2D6", CLINICAL PHARMACOLOGY & THERAPEUTICS,US,ST LOUIS, MO, vol. 60, no. 6, 1 December 1996 (1996-12-01), pages 636 - 644, XP000891863 *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034125A3 (fr) * 1999-11-09 2002-07-11 Darwin Discovery Ltd Utilisation et formulation therapeutiques
US6297286B1 (en) 1999-11-09 2001-10-02 Darwin Discovery, Ltd. Therapeutic use and formulation
AU2001294979B2 (en) * 2000-10-03 2007-03-29 Penwest Pharmaceuticals Company Delivery system for multi-pharmaceutical active materials at various release rates
WO2002028383A1 (fr) * 2000-10-03 2002-04-11 Penwest Pharmaceuticals Company Systeme d'administration pour plusieurs principes actifs pharmaceutiques a des vitesses differentes de liberation
JP2004513091A (ja) * 2000-10-03 2004-04-30 ペンウェスト　ファーマシューティカルズ　カンパニー 異なる速度の複数の医薬活性成分の送達系
US7611730B2 (en) 2001-02-21 2009-11-03 Grunenthal Gmbh Tramadol-based medicament
WO2002066026A3 (fr) * 2001-02-21 2002-11-07 Gruenenthal Gmbh Medicament a base de tramadol
US6780891B2 (en) 2001-11-30 2004-08-24 Sepracor Inc. Tramadol analogs and uses thereof
US8962019B2 (en) 2005-09-09 2015-02-24 Angelini Pharma, Inc. Sustained drug release composition
US9439866B2 (en) 2005-09-09 2016-09-13 Angelini Pharma, Inc. Trazodone composition for once a day administration
WO2008100933A2 (fr) 2007-02-12 2008-08-21 Dmi Biosciences, Inc. Réduction des effets secondaires du tramadol
EP2486921A1 (fr) 2007-02-12 2012-08-15 DMI Biosciences, Inc. Réduciton Des Effets Secondaires Du Tramadol
JP2020521816A (ja) * 2017-05-31 2020-07-27 メティス ファーマシューティカルズ アクチェンゲゼルシャフト （ｒ）−ジミラセタム（１）と（ｓ）−ジミラセタム（２）を非ラセミ比で含む相乗的組成物
WO2018219977A1 (fr) * 2017-05-31 2018-12-06 Metys Pharmaceuticals AG Compositions synergiques comprenant (r)-dimiracetam (1) et (s)-dimiracetam (2) dans un rapport non racémique
JP7157471B2 (ja) 2017-05-31 2022-10-20 メティス ファーマシューティカルズ アクチェンゲゼルシャフト （ｒ）－ジミラセタム（１）と（ｓ）－ジミラセタム（２）を非ラセミ比で含む相乗的組成物
JP2021073171A (ja) * 2017-05-31 2021-05-13 メティス ファーマシューティカルズ アクチェンゲゼルシャフト （ｒ）−ジミラセタム（１）と（ｓ）−ジミラセタム（２）を非ラセミ比で含む相乗的組成物
EP3735971A1 (fr) * 2017-05-31 2020-11-11 Metys Pharmaceuticals AG Compositions synergiques comprenant (r)-dimiracetam (1) et (s)-dimiracetam (2) selon un ratio non racémique
US10738054B2 (en) 2017-05-31 2020-08-11 Metys Pharmaceuticals AG Synergistic compositions comprising (R)-dimiracetam (1) and (S)-dimiracetam (2) in a non-racemic ratio
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US12161623B2 (en) 2017-12-05 2024-12-10 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US12161758B2 (en) 2019-06-04 2024-12-10 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

Also Published As

Publication number Publication date
JP2002531431A (ja) 2002-09-24
PL347542A1 (en) 2002-04-08
CA2350635A1 (fr) 2000-06-08
NO20012738D0 (no) 2001-06-01
CN1329590A (zh) 2002-01-02
HUP0104420A2 (en) 2002-08-28
EP1135361A1 (fr) 2001-09-26
AU1400100A (en) 2000-06-19
NO20012738L (no) 2001-06-01
BR9915873A (pt) 2001-08-21
IL142778A0 (en) 2002-03-10
KR20010080364A (ko) 2001-08-22

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