CA2223629A1 - Therapeutic use of d-threo-methylphenidate - Google Patents
Therapeutic use of d-threo-methylphenidate Download PDFInfo
- Publication number
- CA2223629A1 CA2223629A1 CA002223629A CA2223629A CA2223629A1 CA 2223629 A1 CA2223629 A1 CA 2223629A1 CA 002223629 A CA002223629 A CA 002223629A CA 2223629 A CA2223629 A CA 2223629A CA 2223629 A1 CA2223629 A1 CA 2223629A1
- Authority
- CA
- Canada
- Prior art keywords
- methylphenidate
- patient
- threo
- treatment
- susceptible
- 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.)
- Abandoned
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
Abstract
A method for the treatment of a human patient having a condition susceptible to treatment with methylphenidate, and wherein the patient exhibits or is susceptible to hepatic dysfunction, comprises the administration of d-threo-methylphenidate.
Description
T~APEUTIC USE OF d-t~rec il~l~Y~Nl~ATE
Field of the Invention This invention relates to new therapeutic uses of d-threo-methylphenidate (abbreviated herein as dtmp).
Back4Lol~rd o~ ~he Invention 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 a~ ; n; ~tered 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 al~ ; n; ~tered in a sustained-release formulation. For example, a coated tablet comprising racemic methylph~nidate is administered, with a view to maint~;nin~ a therapeutically-effective level of the drug. This formulation does not always provide a reproducible or a sustained effect.
Roberts et al, Life Sci. 55:269-281 (1994), found that racemic methylphenidate caused hepatic dysfunction in the mouse, manifest as elevated liver enzyme levels and/or coagulative necrosis, on morphological investigation of the liver. Also, the National Toxicity P~o~amme (NTP TR439) of the USA recently (1995) found that racemic methylph~n;date caused, in the mouse, hepatocellular and centri-lobular hypertrophy, formation of foci of damaged cells and hepatic tumours.
Mehta et al, J. Clin. Gastroenterol. 6:149-151 (1984), report hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride. Goodman, New York State Journal of Medicine 72:2339-40 (15 September 1972), reports hepatoxicity due to methylphenidate hydrochloride. Stecyk et al, Annals of Emergency Medicine 14:597/113-599/115 (6 June 1985), report multiple organ failure resulting from intravenous abuse of methylphenidate hydrochloride.
~m~ of the Invention 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 be 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.
Descri~tion 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.
Other advantages of the use of 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~x, a reduced level of active material even when chewed, reduced patient variability, reduced interaction with ltmp or other drugs, and less variability ~etween fed and fasted subjects.
By controlling the nature of the formulation, it is possible to control dissolution in vitro, and thus match or exceed the US National Formulary (NF) drug release profile for methylphenidate hydrochloride. Further, when administered to a healthy subject, a serum level of dtmp can be attained that is at least 50~ of C~x, over a period of at least 8 hours, e.g. 8-16, 8-12 or 8-lO hours. Thus, for example, a shorter release period may be preferred or a different period before the serum level drops below a different p~o~o~Lion of C~x.
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 sust~;ne~-release formulation may be in matrix, coating, reservoir, osmotic, ion-~Ych~nge or density ~Yçh~nge 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. from microparticles to a gel, so that the active ingredient diffuses or permeates out. Ion-based resins may also be used, the active component being released by ionic ~Y~h~ge, and wherein the rate of release can be controlled by using cationic or anionic forms of the drug.
:
It is pre~erred to use 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 circumst~c~C 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 ~l~;ne 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 HePatotoxity in Mice Experiments were carried out to investigate the differing toxicity effects of dtmp and racemic methylphenidate characterised by elevated liver enzyme levels and inst~nr-~C of coagulative necrosis in the liver.
The procedures followed were as described in Roberts et al, supra .
Groups of 21 male 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. ~n; ~l quarters were temperature and humidity controlled with a 12 hour light/dark cycle.
Blood samples were obtained from all An; -ls 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, ~ectioned at a n~ inA~ 5 ~m, stained with haematoxylin and eosin, and examined using light microscopy. The results are tabulated below.
C~ ulld DoseALT LevelsCoagulant (mg/kg~(IU/L) Necrosis Control (water) 0 81 0 Racemate 75 185 2 dtmp 75 76 0 The results show that there is a marked beneficial effect of treatment with dtmp relative to treatment with racemic methyl~nidate~ in that plasma levels of the liver enzyme ~l An i~ 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 methyl rh~ idate~
whereas there were no cases with dtmp. Thus, the results show a marked difference.
Field of the Invention This invention relates to new therapeutic uses of d-threo-methylphenidate (abbreviated herein as dtmp).
Back4Lol~rd o~ ~he Invention 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 a~ ; n; ~tered 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 al~ ; n; ~tered in a sustained-release formulation. For example, a coated tablet comprising racemic methylph~nidate is administered, with a view to maint~;nin~ a therapeutically-effective level of the drug. This formulation does not always provide a reproducible or a sustained effect.
Roberts et al, Life Sci. 55:269-281 (1994), found that racemic methylphenidate caused hepatic dysfunction in the mouse, manifest as elevated liver enzyme levels and/or coagulative necrosis, on morphological investigation of the liver. Also, the National Toxicity P~o~amme (NTP TR439) of the USA recently (1995) found that racemic methylph~n;date caused, in the mouse, hepatocellular and centri-lobular hypertrophy, formation of foci of damaged cells and hepatic tumours.
Mehta et al, J. Clin. Gastroenterol. 6:149-151 (1984), report hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride. Goodman, New York State Journal of Medicine 72:2339-40 (15 September 1972), reports hepatoxicity due to methylphenidate hydrochloride. Stecyk et al, Annals of Emergency Medicine 14:597/113-599/115 (6 June 1985), report multiple organ failure resulting from intravenous abuse of methylphenidate hydrochloride.
~m~ of the Invention 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 be 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.
Descri~tion 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.
Other advantages of the use of 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~x, a reduced level of active material even when chewed, reduced patient variability, reduced interaction with ltmp or other drugs, and less variability ~etween fed and fasted subjects.
By controlling the nature of the formulation, it is possible to control dissolution in vitro, and thus match or exceed the US National Formulary (NF) drug release profile for methylphenidate hydrochloride. Further, when administered to a healthy subject, a serum level of dtmp can be attained that is at least 50~ of C~x, over a period of at least 8 hours, e.g. 8-16, 8-12 or 8-lO hours. Thus, for example, a shorter release period may be preferred or a different period before the serum level drops below a different p~o~o~Lion of C~x.
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 sust~;ne~-release formulation may be in matrix, coating, reservoir, osmotic, ion-~Ych~nge or density ~Yçh~nge 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. from microparticles to a gel, so that the active ingredient diffuses or permeates out. Ion-based resins may also be used, the active component being released by ionic ~Y~h~ge, and wherein the rate of release can be controlled by using cationic or anionic forms of the drug.
:
It is pre~erred to use 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 circumst~c~C 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 ~l~;ne 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 HePatotoxity in Mice Experiments were carried out to investigate the differing toxicity effects of dtmp and racemic methylphenidate characterised by elevated liver enzyme levels and inst~nr-~C of coagulative necrosis in the liver.
The procedures followed were as described in Roberts et al, supra .
Groups of 21 male 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. ~n; ~l quarters were temperature and humidity controlled with a 12 hour light/dark cycle.
Blood samples were obtained from all An; -ls 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, ~ectioned at a n~ inA~ 5 ~m, stained with haematoxylin and eosin, and examined using light microscopy. The results are tabulated below.
C~ ulld DoseALT LevelsCoagulant (mg/kg~(IU/L) Necrosis Control (water) 0 81 0 Racemate 75 185 2 dtmp 75 76 0 The results show that there is a marked beneficial effect of treatment with dtmp relative to treatment with racemic methyl~nidate~ in that plasma levels of the liver enzyme ~l An i~ 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 methyl rh~ idate~
whereas there were no cases with dtmp. Thus, the results show a marked difference.
Claims (9)
1. A method for the treatment of a human patient having a condition susceptible to treatment with methylphenidate, and wherein the patient exhibits or is susceptible to hepatic dysfunction, which comprises the administration of d-threo-methylphenidate substantially free of 1-threo-methylphenidate.
2. A method for the treatment of a human patient having a condition susceptible to treatment with methylphenidate, wherein the patient is or has been exposed to circumstances that cause, or render the patient susceptible to, hepatic dysfunction, which comprises the administration of d-threo-methylphenidate substantially free of 1-threo-methylphenidate.
3. A method according to claim 1 or claim 2, wherein the patient has previously undergone, or is simultaneously undergoing, administration of a therapeutic agent that may cause or render the patient susceptible to hepatic dysfunction.
4. A method according to claim 3, wherein said therapeutic agent is racemic methylphenidate.
5. A method according to claim 1 or claim 2, wherein the patient has previously, or is simultaneously, taking a drug of abuse known to cause liver dysfunction or damage, including alcohol or ecstasy.
6. A method according to any preceding claim, wherein the patient has abnormal levels of at least one liver enzyme.
7. A method according to claim 6, wherein the at least one liver enzyme is CYP2D6 or another P450 cytochrome enzyme.
8. A method according to any preceding claim, wherein the condition is selected from depression, compulsive shopping disorder, narcolepsy, insomnia and attention-deficit hyperactivity disorder.
9. A product containing d-threo-methylphenidate substantially free of 1-threo-methylphenidate, and a therapeutic agent as defined in claim 3, as a combined preparation for simultaneous, separate or sequential use in the treatment of a condition as defined in claim 1 or claim 2 and a condition susceptible to treatment with said therapeutic agent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9514416.8A GB9514416D0 (en) | 1995-07-14 | 1995-07-14 | Therapeutic use |
| GB9514416.8 | 1995-07-14 | ||
| GBGB9605523.1A GB9605523D0 (en) | 1996-03-15 | 1996-03-15 | Therapeutic use |
| GB9605523.1 | 1996-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2223629A1 true CA2223629A1 (en) | 1997-02-06 |
Family
ID=26307400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002223629A Abandoned CA2223629A1 (en) | 1995-07-14 | 1996-07-15 | Therapeutic use of d-threo-methylphenidate |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0839038A1 (en) |
| JP (1) | JPH11509227A (en) |
| AU (1) | AU702801B2 (en) |
| CA (1) | CA2223629A1 (en) |
| WO (1) | WO1997003672A1 (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6486177B2 (en) | 1995-12-04 | 2002-11-26 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
| US6355656B1 (en) | 1995-12-04 | 2002-03-12 | Celgene Corporation | Phenidate drug formulations having diminished abuse potential |
| 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 |
| US5837284A (en) | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
| US5733756A (en) * | 1996-01-05 | 1998-03-31 | Celgene Corporation | Lactams and processes for stereoselective enrichment of lactams, amides, and esters |
| US6962997B1 (en) | 1997-05-22 | 2005-11-08 | Celgene Corporation | Process and intermediates for resolving piperidyl acetamide steroisomers |
| DK1126826T6 (en) | 1998-11-02 | 2019-06-24 | Alkermes Pharma Ireland Ltd | Multiparticulate modified release of 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 |
| 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 |
| 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 |
| NZ529928A (en) | 1999-10-29 | 2005-10-28 | Euro Celtique Sa | Controlled release hydrocodone formulations |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| KR101045144B1 (en) | 2000-10-30 | 2011-06-30 | 유로-셀티크 소시에떼 아노뉨 | Controlled release hydrocodone formulations |
| 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 |
| ES2703874T3 (en) | 2004-08-23 | 2019-03-12 | Pejo Iserlohn Heilmittel Und Diaet Gmbh & Co Kg | Psychostimulant containing a pharmaceutical composition |
| US8709477B2 (en) | 2009-08-13 | 2014-04-29 | Kremers Urban Pharmaceuticals, Inc` | Pharmaceutical dosage form |
| WO2014174387A1 (en) | 2013-03-29 | 2014-10-30 | Wockhardt Limited | Modified release pharmaceutical compositions of dexmethylphenidate or salts thereof |
| CA2936741C (en) | 2014-10-31 | 2018-11-06 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
| US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
-
1996
- 1996-07-15 WO PCT/GB1996/001689 patent/WO1997003672A1/en not_active Application Discontinuation
- 1996-07-15 AU AU64660/96A patent/AU702801B2/en not_active Ceased
- 1996-07-15 CA CA002223629A patent/CA2223629A1/en not_active Abandoned
- 1996-07-15 EP EP96924082A patent/EP0839038A1/en not_active Withdrawn
- 1996-07-15 JP JP9506411A patent/JPH11509227A/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP0839038A1 (en) | 1998-05-06 |
| JPH11509227A (en) | 1999-08-17 |
| WO1997003672A1 (en) | 1997-02-06 |
| AU702801B2 (en) | 1999-03-04 |
| AU6466096A (en) | 1997-02-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |