EP0839038A1 - USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE - Google Patents

USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE

Info

Publication number
EP0839038A1
EP0839038A1 EP96924082A EP96924082A EP0839038A1 EP 0839038 A1 EP0839038 A1 EP 0839038A1 EP 96924082 A EP96924082 A EP 96924082A EP 96924082 A EP96924082 A EP 96924082A EP 0839038 A1 EP0839038 A1 EP 0839038A1
Authority
EP
European Patent Office
Prior art keywords
methylphenidate
patient
treatment
susceptible
threo
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.)
Withdrawn
Application number
EP96924082A
Other languages
German (de)
English (en)
Inventor
Ruth Elizabeth Wills
Nicholas Robert Pope
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
Chiroscience 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 GBGB9514416.8A external-priority patent/GB9514416D0/en
Priority claimed from GBGB9605523.1A external-priority patent/GB9605523D0/en
Application filed by Chiroscience Ltd filed Critical Chiroscience Ltd
Publication of EP0839038A1 publication Critical patent/EP0839038A1/fr
Withdrawn legal-status Critical Current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
    • A61K31/33—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)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (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.
EP96924082A 1995-07-14 1996-07-15 USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE Withdrawn EP0839038A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB9514416.8A GB9514416D0 (en) 1995-07-14 1995-07-14 Therapeutic use
GB9514416 1995-07-14
GB9605523 1996-03-15
GBGB9605523.1A GB9605523D0 (en) 1996-03-15 1996-03-15 Therapeutic use
PCT/GB1996/001689 WO1997003672A1 (fr) 1995-07-14 1996-07-15 USAGE THERAPEUTIQUE DU d-threo-METHYLPHENIDATE

Publications (1)

Publication Number Publication Date
EP0839038A1 true EP0839038A1 (fr) 1998-05-06

Family

ID=26307400

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96924082A Withdrawn EP0839038A1 (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)

Families Citing this family (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
US5922736A (en) * 1995-12-04 1999-07-13 Celegene Corporation Chronic, bolus administration of D-threo methylphenidate
US5908850A (en) * 1995-12-04 1999-06-01 Celgene Corporation Method of treating attention deficit disorders with 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
US5837284A (en) 1995-12-04 1998-11-17 Mehta; Atul M. Delivery of multiple doses of medications
US6355656B1 (en) 1995-12-04 2002-03-12 Celgene Corporation Phenidate drug formulations having diminished abuse potential
US6962997B1 (en) 1997-05-22 2005-11-08 Celgene Corporation Process and intermediates for resolving piperidyl acetamide steroisomers
CA2348871C (fr) 1998-11-02 2009-04-14 John G. Devane Composition a liberation modifiee multiparticulaire
US7083808B2 (en) 1998-12-17 2006-08-01 Euro-Celtique S.A. Controlled/modified release oral methylphenidate formulations
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
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
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
ATE526950T1 (de) 1999-10-29 2011-10-15 Euro Celtique Sa Hydrocodon-formulierungen mit gesteuerter freisetzung
EP2283829A1 (fr) 2000-10-30 2011-02-16 Euro-Celtique S.A. Formulations d'hydrocodone à liberation lente
US6913768B2 (en) 2002-09-24 2005-07-05 Shire Laboratories, Inc. Sustained release delivery of amphetamine salts
US20050239830A1 (en) * 2004-04-26 2005-10-27 Vikram Khetani Methods of diminishing co-abuse potential
CA2617941C (fr) 2004-08-23 2012-07-24 Pejo Iserlohn Heilmittel Und Diaet Gmbh & Co. Kg Psychostimulant contenant une composition pharmaceutique
US8709477B2 (en) 2009-08-13 2014-04-29 Kremers Urban Pharmaceuticals, Inc` Pharmaceutical dosage form
EP2994112A1 (fr) 2013-03-29 2016-03-16 Wockhardt Limited Compositions pharmaceutiques à libération modifiée de dexméthylphénidate ou de sels de celui-ci
CA2936741C (fr) 2014-10-31 2018-11-06 Purdue Pharma Methodes et compositions destinees au traitement du trouble de deficit d'attention
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 (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9703672A1 *

Also Published As

Publication number Publication date
AU702801B2 (en) 1999-03-04
CA2223629A1 (fr) 1997-02-06
AU6466096A (en) 1997-02-18
WO1997003672A1 (fr) 1997-02-06
JPH11509227A (ja) 1999-08-17

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