WO1997003672A1 - USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE - Google Patents

USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE Download PDF

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Publication number
WO1997003672A1
WO1997003672A1 PCT/GB1996/001689 GB9601689W WO9703672A1 WO 1997003672 A1 WO1997003672 A1 WO 1997003672A1 GB 9601689 W GB9601689 W GB 9601689W WO 9703672 A1 WO9703672 A1 WO 9703672A1
Authority
WO
WIPO (PCT)
Prior art keywords
methylphenidate
patient
treatment
susceptible
threo
Prior art date
Application number
PCT/GB1996/001689
Other languages
English (en)
Inventor
Ruth Elizabeth Wills
Nicholas Robert Pope
Original Assignee
Chiroscience Limited
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 GBGB9514416.8A external-priority patent/GB9514416D0/en
Priority claimed from GBGB9605523.1A external-priority patent/GB9605523D0/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to JP9506411A priority Critical patent/JPH11509227A/ja
Priority to EP96924082A priority patent/EP0839038A1/fr
Priority to AU64660/96A priority patent/AU702801B2/en
Publication of WO1997003672A1 publication Critical patent/WO1997003672A1/fr

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • 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

Definitions

  • This invention relates to new therapeutic uses of d-threo-methylphenidate (abbreviated herein as dtmp) .
  • dtmp d-threo-methylphenidate
  • Methylphenidate is a known drug. It is used primarily to treat hyperactive children. It may have to be administered over a prolonged period of time, and is a controlled substance. Methylphenidate is a chiral molecule. The properties of the enantiomers have been investigated to some extent, although the drug is still administered as the racemate. It is generaly thought that dtmp is the active material, and that its antipode (ltmp) is metabolised more rapidly. Methylphenidate is often administered in a sustained- release formulation. For example, a coated tablet comprising racemic methylphenidate is administered, with a view to maintaining a therapeutically-effective level of the drug. This formulation does not always provide a reproducible or a sustained effect.
  • This invention is based on the discovery that dtmp can satisfactorily be used to treat human patients exhibiting or susceptible to hepatic dysfunction, or to reduce the likelihood of such symptoms occurring.
  • dtmp may also oe used instead of the racemate in therapy involving the use of other drugs that have effects likely to be exacerbated by use of the racemate. Such effects may include hepatic dysfunction.
  • the patient may be an adult, e.g. in the treatment of compulsive shopping disorder or narcolepsy, or a child, e.g. a pre-pubertal child suffering from attention-deficit hyperactivity disorder (which, for the purposes of this specification, includes attention-deficit disorder) .
  • the discovery is based on the finding that, in an animal model, dtmp is surprisingly less hepatotoxic than racemic methylphenidate. Description of the Invention
  • the dtmp that is used in this invention is substantially free of ltmp, e.g. in an enantiomeric excess (ee) of at least 70%, preferably at least 90%, and more preferably at least 95%.
  • the dtmp may be substantially enantiopure. It may be used in the form of any suitable salt, e.g. the hydrochloride.
  • the dtmp may be administered by the same means as is known for racemic methylphenidate, in a sustained-release formulation, e.g. a coated tablet. It may be administered in any other conventional sustained-release formulation, via any suitable route of administration. Conventional dosing parameters may be adopted, i.e. those which are known to or adapted to the practice of those skilled in the art. For example, the daily dosage of dtmp may be 5 to 60 mg, but will be chosen according to the age, weight and health of the subject, and other factors that are routinely considered by the man skilled in the art.
  • dtmp may include the reduction of exposure to a controlled substance, reduced side-effects (which include anorexia, insomnia, stomach ache and headache) , reduced abuse potential, reduced C ⁇ , a reduced level of active material even when chewed, reduced patient variability, reduced interaction with ltmp or other drugs, and less variability between fed and fasted subjects.
  • a serum level of dtmp can be attained that is at least 50% of C ⁇ )ax , over a period of at least 8 hours, e.g. 8-16, 8-12 or 8-10 hours.
  • a shorter release period may be preferred or a different period before the serum level drops below a different proportion of C MX .
  • the serum level may be also controlled so that it remains high during the day, after taking a dosage in the morning, and is reduced in the evening, before it can have any undesirable effect on sleeping patterns.
  • a formulation of the invention may be a unit dosage such as a tablet, capsule or suspension.
  • a sustained- release formulation may be in matrix, coating, reservoir, osmotic, ion-exchange or density exchange form. It may comprise a soluble polymer coating which is dissolved or eroded, after administration. Alternatively, there may be an insoluble coating, e.g. of a polymer, through which the active ingredient permeates, as from a reservoir, diffuses, e.g. through a porous matrix, or undergoes osmotic exchange.
  • a further option for a sustained-release formulation involves density exchange, e.g. in the case where the formulation alters on administration, e.g.
  • a formulation in this invention that is resistant to chewing, e.g. micronised particles that are individually coated and which do not immediately release the active component on chewing, or possibly even actively discourage chewing by their consistency.
  • Many effects, benefits etc. described herein apply also to formulations providing immediate release. The various effects etc. may be due to the use of dtmp and/or the absence of ltmp.
  • Various circumstances may cause hepatic dysfunction, or render a patient susceptible to such a problem. Such circumstances include the administration of a therapeutic agent in which liver dysfunction, is a side-effect, or the taking of drugs of abuse known to cause liver dysfunction, e.g. alcohol or ecstasy.
  • Hepatic dysfunction may be evident in terms of interference with enzyme function, or changes in the levels of certain enzymes such as alanine aminotransferase (ALT) , or in terms of gross alterations such as cirrhosis or cancer of the liver. Hepatic dysfunction can be determined by the skilled man, as may be susceptibility or predisposition to such dysfunction. Methylphenidate-Induced Hepatotoxitv in Mice
  • mice of the Crl:CD-l(ICR)BR strain were given a single intraperitoneal dose of the compounds in a saline solution with an injection volume of 10 ml/kg body weight.
  • the animals were housed in groups of three in polypropylene cages with a steel mesh floor in a single, exclusive room, air conditioned to provide a minimum of 15 air changes/hour. Animal quarters were temperature and humidity controlled with a 12 hour light/dark cycle. Blood samples were obtained from all animals at 16 hours after dosing for determination of serum alanine aminotransferase (ALT) activity. The results are tabulated below.
  • Livers were removed 24 hours after dosing and preserved in fixative of 10% neutral buffered formalin for histopathological examination.
  • the livers were embedded in paraffin wax, sectioned at a nominal 5 ⁇ m, stained with haematoxylin and eosin, and examined using light microscopy. The results are tabulated below.
  • results show that there is a marked beneficial effect of treatment with dtmp relative to treatment with racemic methylphenidate, in that plasma levels of the liver enzyme alanine aminotransferase were not increased.
  • the histopathology data further support the finding that dtmp treatment has beneficial advantages over treatment with the racemate. Coagulant necrosis was detected in two animals out of 21 in the group receiving racemic methylphenidate, whereas there were no cases with dtmp. Thus, the results show a marked difference.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Méthode de traitement d'un sujet humain dont l'état est susceptible d'être traité au méthylphénidate, lorsque le patient présente un dysfonctionnement hépatique ou est sujet à ce type de dysfonctionnement, consistant à administrer du d-thréo-méthylphénidate.
PCT/GB1996/001689 1995-07-14 1996-07-15 USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE WO1997003672A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9506411A JPH11509227A (ja) 1995-07-14 1996-07-15 ｄ−トレオ−メチルフェニデートの治療的使用
EP96924082A EP0839038A1 (fr) 1995-07-14 1996-07-15 USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE
AU64660/96A AU702801B2 (en) 1995-07-14 1996-07-15 Therapeutic use of D-threo-methylphenidate

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9514416.8A GB9514416D0 (en) 1995-07-14 1995-07-14 Therapeutic use
GB9605523.1 1996-03-15
GBGB9605523.1A GB9605523D0 (en) 1996-03-15 1996-03-15 Therapeutic use
GB9514416.8 1996-03-15

Publications (1)

Publication Number Publication Date
WO1997003672A1 true WO1997003672A1 (fr) 1997-02-06

Family

ID=26307400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/001689 WO1997003672A1 (fr) 1995-07-14 1996-07-15 USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE

Country Status (5)

Country Link
EP (1) EP0839038A1 (fr)
JP (1) JPH11509227A (fr)
AU (1) AU702801B2 (fr)
CA (1) CA2223629A1 (fr)
WO (1) WO1997003672A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5733756A (en) * 1996-01-05 1998-03-31 Celgene Corporation Lactams and processes for stereoselective enrichment of lactams, amides, and esters
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US5922736A (en) * 1995-12-04 1999-07-13 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
US6228398B1 (en) 1998-11-02 2001-05-08 Elan Corporation, Plc Multiparticulate modified release composition
US6355656B1 (en) 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
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
US6486177B2 (en) 1995-12-04 2002-11-26 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US6635284B2 (en) 1995-12-04 2003-10-21 Celegene Corporation Delivery of multiple doses of medications
US6673367B1 (en) 1998-12-17 2004-01-06 Euro-Celtique, S.A. Controlled/modified release oral methylphenidate formulations
US6913768B2 (en) 2002-09-24 2005-07-05 Shire Laboratories, Inc. Sustained release delivery of amphetamine salts
US7083808B2 (en) 1998-12-17 2006-08-01 Euro-Celtique S.A. Controlled/modified release oral methylphenidate formulations
US7459560B2 (en) 1997-05-22 2008-12-02 Celgene Corporation Processes and intermediates for resolving piperidyl acetamide stereoisomers
EP2036546A1 (fr) 2004-08-23 2009-03-18 PEJO Iserlohn Heilmittel-und Diät-GmbH & Co.KG Psychostimulant contenant une composition pharmaceutique
AU2005237538B2 (en) * 2004-04-26 2011-01-06 Celgene Corporation Methods of diminishing co-abuse potential
US8709477B2 (en) 2009-08-13 2014-04-29 Kremers Urban Pharmaceuticals, Inc` Pharmaceutical dosage form
WO2014174387A1 (fr) 2013-03-29 2014-10-30 Wockhardt Limited Compositions pharmaceutiques à libération modifiée de dexméthylphénidate ou de sels de celui-ci
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AOYAMA ET AL: "PHARMACOKINETICS OF (+)-THREO-METHYLPHENIDATE ENANTIOMER IN PATIENTS WITH HYPERSOMNIA", CLINICAL PHARMACOLOGY AND THERAPEUTICS, vol. 55, no. 3, March 1993 (1993-03-01), USA, XP000602459 *
ECKERMANN ET AL: "ENANTIOSELECTIVE BEHAVIORAL EFFECTS OF THREO-METHYLPHENIDATE IN RATS", PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOR, vol. 40, no. 4, December 1991 (1991-12-01), USA, pages 875 - 880, XP000602558 *
PATRICK ET AL: "PHARMACOLOGY OF THE ENANTIOMERS OF THREO-METHYLPHENIDATE", J. PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 241, no. 1, April 1987 (1987-04-01), USA, pages 152 - 158, XP000602559 *
TYNDALE ET AL: "NEURONAL CYTOCHROME P450IID1 (DEBRISOQUINE/SPARTEINE-TYPE): POTENT INHIBITION OF ACTIVITY BY (-)-COCAINE AND NUCLEOTIDE SEQUENCE INDENTITY TO HUMAN HEPATIC P450 GENE CYP2D6.", MOLECULAR PHARMACOLOGY, vol. 40, no. 1, July 1991 (1991-07-01), USA, pages 63 - 68, XP000602574 *

Cited By (79)

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US6528530B2 (en) 1995-12-04 2003-03-04 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with d-threo methylphenidate
US5922736A (en) * 1995-12-04 1999-07-13 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US6635284B2 (en) 1995-12-04 2003-10-21 Celegene Corporation Delivery of multiple doses of medications
US7115631B2 (en) 1995-12-04 2006-10-03 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US6255325B1 (en) 1995-12-04 2001-07-03 Celgene Corporation Chronic, bolus administration of D-threo methylphenidate
US6355656B1 (en) 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US7431944B2 (en) 1995-12-04 2008-10-07 Celgene Corporation Delivery of multiple doses of medications
US6602887B2 (en) * 1995-12-04 2003-08-05 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US6486177B2 (en) 1995-12-04 2002-11-26 Celgene Corporation Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US5733756A (en) * 1996-01-05 1998-03-31 Celgene Corporation Lactams and processes for stereoselective enrichment of lactams, amides, and esters
US7459560B2 (en) 1997-05-22 2008-12-02 Celgene Corporation Processes and intermediates for resolving piperidyl acetamide stereoisomers
EP1032389A1 (fr) * 1997-09-29 2000-09-06 Celgene Corporation Administration de longue duree en bolus de d-threo methylphenidate
EP1032389A4 (fr) * 1997-09-29 2002-07-03 Celgene Corp Administration de longue duree en bolus de d-threo methylphenidate
US6228398B1 (en) 1998-11-02 2001-05-08 Elan Corporation, Plc Multiparticulate modified release composition
EP2020229A1 (fr) 1998-11-02 2009-02-04 Elan Pharma International Limited Composition à libération modifiée multi particules
US6730325B2 (en) 1998-11-02 2004-05-04 Elan Corporation, Plc Multiparticulate modified release composition
US6793936B2 (en) 1998-11-02 2004-09-21 Elan Corporation, Plc Multiparticulate modified release composition
US6902742B2 (en) 1998-11-02 2005-06-07 Elan Corporation, Plc Multiparticulate modified release composition
US8119163B2 (en) 1998-11-02 2012-02-21 Alkermes Pharma Ireland Limited Nanoparticulate and controlled release compositions comprising cefditoren
US7438930B2 (en) 1998-12-17 2008-10-21 Purdue Pharma Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US10039719B2 (en) 1998-12-17 2018-08-07 Rhodes Pharmaceuticals L.P. Methods of treating attention deficit hyperactivity disorder
US7247318B2 (en) 1998-12-17 2007-07-24 Purdue Pharma Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US10463624B2 (en) 1998-12-17 2019-11-05 Rhodes Pharmaceuticals L.P. Controlled release formulations
US9066869B2 (en) 1998-12-17 2015-06-30 Purdue Pharma Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US6673367B1 (en) 1998-12-17 2004-01-06 Euro-Celtique, S.A. Controlled/modified release oral methylphenidate formulations
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
US7083808B2 (en) 1998-12-17 2006-08-01 Euro-Celtique S.A. Controlled/modified release oral methylphenidate formulations
US10022330B2 (en) 1998-12-17 2018-07-17 Rhodes Pharmaceuticals L.P. Methods of preparing oral controlled release formulations
US9801823B2 (en) 1998-12-17 2017-10-31 Rhodes Pharmaceuticals L.P. Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US8580310B2 (en) 1998-12-17 2013-11-12 Purdue Pharma Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations
US9949931B2 (en) 1998-12-17 2018-04-24 Rhodes Pharmaceuticals L.P. Methods of treating attention deficit hyperactivity disorder
US6395752B1 (en) * 1999-03-04 2002-05-28 Pharmaquest Limited Method of treating depression using 1-threo-methylphenidate
US6127385A (en) * 1999-03-04 2000-10-03 Pharmaquest Limited Method of treating depression using l-threo-methylphenidate
US9675611B1 (en) 1999-10-29 2017-06-13 Purdue Pharma L.P. Methods of providing analgesia
US9278074B2 (en) 1999-10-29 2016-03-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
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US9056107B1 (en) 1999-10-29 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
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Also Published As

Publication number Publication date
CA2223629A1 (fr) 1997-02-06
EP0839038A1 (fr) 1998-05-06
AU6466096A (en) 1997-02-18
AU702801B2 (en) 1999-03-04
JPH11509227A (ja) 1999-08-17

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