U.S. patent application number 11/852847 was filed with the patent office on 2008-03-13 for composition comprising methylphenidate and another drug.
Invention is credited to Nicholas Robert Pope, Andrew John McGlashan Richards.
Application Number | 20080064724 11/852847 |
Document ID | / |
Family ID | 26307401 |
Filed Date | 2008-03-13 |
United States Patent
Application |
20080064724 |
Kind Code |
A1 |
Richards; Andrew John McGlashan ;
et al. |
March 13, 2008 |
Composition Comprising Methylphenidate and Another Drug
Abstract
A process of treating a subject that is undergoing
methylphenidate therapy and concomitant therapy with another drug
undergoes or interferes with P.sub.450 metabolism wherein the
methylphenidate is d-threo-methylphenidate.
Inventors: |
Richards; Andrew John
McGlashan; (Cambridge, GB) ; Pope; Nicholas
Robert; (Cambridge, GB) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK;A PROFESSIONAL ASSOCIATION
PO BOX 142950
GAINESVILLE
FL
32614-2950
US
|
Family ID: |
26307401 |
Appl. No.: |
11/852847 |
Filed: |
September 10, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10277413 |
Oct 21, 2002 |
7267949 |
|
|
11852847 |
Sep 10, 2007 |
|
|
|
09597384 |
Jun 19, 2000 |
6468504 |
|
|
10277413 |
Oct 21, 2002 |
|
|
|
09106870 |
Jun 29, 1998 |
6113879 |
|
|
09597384 |
Jun 19, 2000 |
|
|
|
08679878 |
Jul 15, 1996 |
5773478 |
|
|
09106870 |
Jun 29, 1998 |
|
|
|
Current U.S.
Class: |
514/317 |
Current CPC
Class: |
A61K 33/00 20130101;
Y10S 514/81 20130101; A61K 45/06 20130101; A61K 31/445 20130101;
A61K 33/00 20130101; A61K 31/4458 20130101; Y10S 514/922 20130101;
A61P 25/00 20180101; Y10S 514/813 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/445 20130101 |
Class at
Publication: |
514/317 |
International
Class: |
A61K 31/445 20060101
A61K031/445; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 14, 1995 |
GB |
9514450.7 |
Apr 23, 1996 |
GB |
9608390.2 |
Claims
1. A method of treating a subject that is undergoing
methylphenidate therapy and concomitant therapy with another drug,
wherein said therapy is for attention-deficit hyperactivity
disorder and said method provides for reduced side effects or
reduced potential for abuse relative to racemic methylphenidate,
said method comprising administering an effective amount of
d-threo-methylphenidate to said subject daily.
2. The method according to claim 1, wherein said
d-threo-methylphenidate and said another drug is formulated for
administration to an adult patient.
3. The method according to claim 1, wherein the dosage of
d-threo-methylphenidate administered to said subject is 5 mg to 60
mg.
4. The method according to claim 1, wherein said
d-threo-methylphenidate is in at least 95% enantiomeric excess
relative to l-threo-methylphenidate.
5. A method for treating a patient having a condition susceptible
to treatment with methylphenidate and also exhibiting or likely to
exhibit other central nervous system disorders, wherein said
condition is attention-deficit disorder or attention-deficit
hyperactivity disorder and said method provides for reduced side
effects or reduced potential for abuse relative to racemic
methylphenidate, said method comprising administering an effective
amount of d-threo-methylphenidate to said patient daily.
6. The method according to claim 5, wherein the dosage of
d-threo-methylphenidate administered to said patient is 5 mg to 60
mg.
7. The method according to claim 5, wherein said
d-threo-methylphenidate is in at least 95% enantiomeric excess
relative to l-threo-methylphenidate.
8. A method for treating a patient having a condition that is
susceptible to treatment with methylphenidate and concomitant
therapy with another drug, wherein said condition is
attention-deficit disorder or attention-deficit hyperactivity
disorder and said method provides for reduced side effects or
reduced potential for abuse relative to racemic methylphenidate,
said method comprising administering an effective amount of
d-threo-methylphenidate to said patient daily.
9. The method according to claim 8, wherein the dosage of
d-threo-methylphenidate administered to said patient is 5 mg to 60
mg.
10. The method according to claim 8, wherein said
d-threo-methylphenidate is in at least 95% eneantiomeric excess
relative to --threo-methylphenidate.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a new composition comprising
methylphenidate and another drug, and also to new ways of using
known drugs including d-threo-methylphenidate (abbreviated herein
as dtmp).
BACKGROUND OF THE INVENTION
[0002] Methylphenidate is a known drug (although it is a controlled
substance) It is used primarily to treat hyperactive children.
[0003] 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 generally thought
that dtmp is the active material, and that its antipode (ltmp) is
metabolised more rapidly.
[0004] Methylphenidate is often administered in conjunction with
other drugs. It is known that the concurrent administration of two
drugs that act or are metabolised through the same metabolic
pathway can block that pathway, leading to drug interaction.
[0005] Racemic methylphenidate is known to interact clinically with
a variety or drugs, such as the tricyclic antidepressants (TCAs),
necessitating reduction in the TCA dosage when co-administered to
prevent drug interaction (Physicians Desk Reference, Guide to Drug
Interactions, 1994).
[0006] It is generally believed that the separate enantiomers of
chiral therapeutic drugs exhibit different toxicological profiles,
with one usually being the main cause of the toxic effects of drug
interactions; see Ariens, Schweiz. Med. Wochenschr. 120(5) 131-134
(1990). The basis for this is that each enantiomer will exhibit
different preferences for the pathways of enzyme metabolism, e,g.
the cytochrome P.sub.450 pathways, and therefore co-administered
drugs are blocked at different sites of metabolism.
SUMMARY OF THE INVENTION
[0007] It has been discovered that, surprisingly, both dtmp and
ltmp similarly inhibit metabolism of other drugs by the cytochrome
P.sub.450 systems, in human microsomes. Further, the racemate is
shown to have a greater inhibitory profile than either of the
enantiomers, suggesting an interaction between the two.
Administration of dtmp, substantially free of ltmp, will
substantially reduce the inhibition of P.sub.450 isczymes. This has
beneficial effects for patients undergoing concurrent
administration of other drugs. To avoid the resultant risk of
drug-drug toxicity, the present invention involves the
administration of that other drug and dtmp. The two drugs used in
this invention may be administered sequentially, concurrently or
simultaneously, by the same or separate means.
[0008] The discovery is based on data showing that, surprisingly,
dtmp administration results in less toxicity in the mouse liver
than racemic methylphenidate, possibly due to less inhibition of
hepatic cytochrome P.sub.450 enzymes. The experiments and data are
summarised below. The invention is thus of particular utility in
that proportion of the population in which the relevant enzymes
have reduced efficiency, or that are receiving the cross-reacting
drugs, e.g. SSRIs, in therapy of, say, anxiety or depression.
DESCRIPTION OF THE INVENTION
[0009] 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.
[0010] As indicated above, the dtmp and other drug may each be
administered independently. The invention is not restricted to any
particular route of administration, and it will be generally
preferred that the respective drugs are administered by their
preferred routes. Thus, the dtmp may be administered by the same
means as racemic methylphenidate, e.g. in a sustained-release
formulation, e.g. a coated tablet. More preferably, the formulation
is as described in the copending Patent Application entitled
"Sustained-Release Formulation of Methylphenidate", filed on the
same date, also assigned to Chiroscience Limited, and claiming
priority from British Patent Application No. 9514451.5. The
relevant content of that Application is incorporated herein by
reference. Advantages of the use of dtmp are also described
therein, and may include linear kinetics within the clinically
relevant dose range, the reduction of exposure to a controlled
substance, reduced side-effects (which include anorexia, insomnia,
stomach ache and headache), reduced hepatotoxicity, reduced abuse
potential, reduced C.sub.max, a reduced level of active material
even when chewed, reduced patient variability, and less variability
between fed and fasted subjects.
[0011] 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 50t of
C.sub.max, over a period of at least 8 hours, e.g. 8-16, 8-12 or
8-10 hours. Thus, for example, a shorter release period may be
preferred or a different period before the serum level drops below
a different proportion of C.sub.max.
[0012] 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.
[0013] 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. 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
exchange, and wherein the rate of release can be controlled by
using cationic or anionic forms of the drug.
[0014] It is preferred 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. Formulations of the invention that provide
improved release characteristics may also be appropriate for the
administration of racemic methylphenidate. Further, many effects,
benefits etc. described herein apply to formulations providing
immediate release. The various effects etc may be due to the use of
dtmp and/or the absence of ltmp.
[0015] The other drug may be administered in admixture with the
methylphenidate. Alternatively, it may be administered in any other
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.
[0016] The dtmp may be administered for its primary utility, i.e.
treating hyperactive children, as a stimulant in cancer patients
treated with narcotic analgesics, or for treating depression (e.g.
in AIDS patients), compulsive shopping disorder, narcolepsy or
hypersomnia. These subject& typically suffer other complaints
requiring medication. The present invention is particularly adapted
to the use of such other drugs, e.g. agents that are adapted to
treat CNS disorders (e.g. depression); such agents may be tricyclic
antidepressants or SSRIs. Thus, the other drug may be one that has
the same mode of action, or which has a similar CNS activity.
Alternatively or in addition, the other drug that is used in the
invention may be any that undergoes the same metabolic degradation
as ltmp, e.g. via the P.sub.450 cytochromes, that interferes with
ltmp metabolism, or that has its metabolism interfered with by
ltmp.
[0017] There are many drugs that may interact with methylphenidate.
Examples include anti-depressants.
[0018] Particular drugs of interest are those whose metabolism is
known to occur via the cytochrome P.sub.450 pathways. For example,
clomipramine, desipramine, indoramin, imipramine, phenformin and
tropisetron undergo aromatic hydroxylation; amiflamine undergoes
N-demethylation; amitriptyline and nortriptyline undergo benzylic
hydroxylation; codeine, dextromethorphan, dihydrocodeine,
hydrocodone, norcodeine and oxycodone undergo o-demethylation;
ethylmorphine undergoes O-de-ethylation; flecainide and
methoxyamphetamine undergo O-dealkylation; methoxyphenamine
undergoes aromatic hydroxylation and N-demethylation; mexiletine
and ondansetron undergo hydroxylation; perhexiline undergoes
aliphatic hydroxylation; and thioridazine undergoes side-chain
sulfoxidation. These are merely examples of drugs that use the
given pathways. Other specific drugs of interest are cinnarizine,
haloperidol, maprotiline, paroxetine and perphenazine.
[0019] Drugs of particular interest that have been seen to interact
with methylphenidate include tricyclic anti-depressants (TCAs) such
as amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, maprotiline, nortriptyline, protriptyline or
trimipramine; monoamine oxidase inhibitors such as phenelzine,
selegeline or tranylcypromine, selective serotonin reuptake
inhibitors (SSRIs) such as fluoxetine, paroxetine or sertraline;
antipsychotics such as haloperidol; anticonvulsants/antiepileptics
such as phenytoin, primidone and diphenylhydantoin; anticoagulants
such as warfarin; and other drugs for which interactions have been
reported such as isocarboxarid, metaramincl, phenylbutazone,
phenylephrine, dopamide, norepinephrine, epinephrine, furazalidone,
physostigmine and lithium.
[0020] It is often the case that a patient, typically a child,
diagnosed as having attention-deficit hyperactivity disorder (ADHD;
this term is used herein to include also attention-deficit
disorder), has concomitant CNS disorders (whether or not diagnosed)
which may require no immediate medication but which indicate the
likelihood of a future need for, say, a SSRI or TCA. The use of
dtmp is indicated, according to this invention, for such a
patient.
[0021] Adverse effects (including cognitive and mood deterioration)
were seen in children treated with a combination of imipramine and
methylphenidate. Lithium significantly reduces the level of
arousal-activation, euphoria-grandiosity, and the total score of
manic-state ratings following methylphenidate challenge.
[0022] Further, of 20 patients treated with tricyclics combined
with methylphenidate, 3 were withdrawn from the trial due to
side-effects. These included dizziness, orthostatic blood pressure
changes, dry mouth, increased anxiety and hypomania. Baclofen at 10
mg/kg produced a uniform block of both methylphenidate-enhanced
activity and stereotypics in rats within 15 to 25 minutes when
administered 10 minutes following methylphenidate. Physostigmine
and nethylphenidate each antagonised the effects of the other in
the treatment of manic patients.
Metabolism of Methylphenidate by Cytochrome P.sub.450
[0023] Experiments were carried out to investigate the effect of
racemic methylphenidate, dtmp and ltmp on the hepatic cytochrome
P.sub.450 pathways. The experimental protocol utilised drugs known
to be characteristically metabolised by a specific P.sub.450
isotype, and measured the corresponding "enzyme activity" (see
results Table, below) in human microsome preparations, by standard
methods; see: [0024] Tolbutamide: Knodell et al, J. Pharmacol. Exp.
Thes. 241(3):1012-1019 (1987); [0025] Mephenytoin: Yasumori et al,
J. Pharmacol. Exp. Thes. 264(1) :89-94 (1993); [0026] Bufuralol:
Kronbach et al, Anal. Biochem. 162:24-32 (1987); and [0027] Lauric
Acid: Okita et al, Methods in Enzymology 206:432-441 (1991).
[0028] The involvement of the particular P.sub.450 isotype was
confirmed using known standard inhibitor compounds (see results
Table), using the indicated inhibitor concentrations.
Methylphenidate, dtmp and ltmp were used at 100 .mu.M.
TABLE-US-00001 Standard Inhibitor & % Inhibition of Enzyme
Activity P.sub.450 Enzyme Concentration Standard Racemic Isozyme
Activity (.mu.M) Inhibitor Methylphenidate dtmp ltmp 2C9
Tolbutamide Sulpha- >90 19 25 34 hydroxylase phenazole (100)
2C19 Mephenytoin Tranyl- 83 44 31 33 hydroxylase cypronine (50) 2D6
Bufuralol Quinidine >90 65 64 41 hydroxylase (10) 2B Lauric acid
Disulfuram 47 <15 <20 <20 11- (10) hydroxylase
[0029] The results show that dtmp and ltmp have surprisingly
similar profiles of inhibitory activity against the enzymes of the
hepatic cytochrome P.sub.450 pathway. Further, racemic
methylphenidate appears more inhibitory of certain enzymes than
either dtmp or ltmp. A reduction in the inhibition of the enzymes
of the P.sub.450 pathway may thus lead to a reduction in drug
interaction.
* * * * *