Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-04-17
2001-02-27
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S422000, C424S423000, C424S436000, C424S449000, C424S451000, C424S455000, C424S457000, C424S464000, C424S465000, C424S468000, C424S472000, C424S473000, C424S489000, C424S490000, C424S483000, C424S484000, C424S485000, C424S486000, C424S487000, C424S488000, C514S770000, C514S772200, C514S772300, C514S773000, C514S777000, C514S781000, C514S782000, C514S783000, C514S784000, C514S785000, C514S786000, C514S787000
Reexamination Certificate
active
06194000
ABSTRACT:
The present invention relates to pharmaceutical compositions and is particularly concerned with pharmaceutical compositions containing N-methyl-D-aspartate (NMDA) receptor antagonists and their use in the treatment of pain.
BACKGROUND OF THE INVENTION
The amino acid glutamate is an excitatory neurotransmitter that is an agonist at many post-synaptic terminals of the central nervous system. The glutamate receptor complex is termed the NMDA receptor and is a potential target for therapeutic drugs. This receptor incorporates an ion channel complex which is novel because it is gated by both dual ligand binding (glutamate and glycine) and membrane voltage. Because of the novel requirements for activation, it is believed that the NMDA receptor complex plays only a minor role in routine synaptic transmission. However, the receptor complex may be activated following repeated afferent stimuli as occurs during trauma such as surgery. Repeated stimuli cause a temporal summation of C-fibre-mediated responses of dorsal horn nociceptive neurones; this phenomenon, increased output to a constant input, is known as wind-up.
Studies indicate that activation of the NMDA receptor complex in the spinal dorsal horn leads to increased spontaneous neural discharge, expanded receptive fields and exaggerated responses to afferent input. These neural mechanisms may be expressed physically as hyperalgesia (increased pain sensation) and allodynia (pain arising from a stimulus that is not normally painful).
Opioids, through their ability to inhibit release of primary afferent neurotransmitters or to inhibit interneurons early in nociceptive pathways, initially reduce or block C-fibre inputs to the deeper dorsal horn nociceptive neurones. However, as the peripheral stimulation continues, wind-up breaks through the input inhibition and the neurones start to respond. Thus at moderate doses, opioids delay the onset of wind-up without inhibiting the process itself.
By contrast, NMDA receptor antagonists have no effect on the initial inputs to the cells but diminish or abolish wind-up and convert the potentiated response to a normal response.
We have found that a particularly effective composition for the administration of an NMDA receptor antagonist to diminish or abolish wind up is one providing both immediate release of an NMDA receptor antagonist and controlled or sustained release of an NMDA receptor antagonist.
NMDA antagonist receptors have also been indicated to be effective in the treatment of Huntington's disease, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, Alzheimer's disease, schizophrenia, motoneurone diseases and CNS and brain injuries resulting from a number of causes including stroke, trauma and neurosurgery.
THE INVENTION
In accordance with one aspect of the present invention there is provided a pharmaceutical composition for the administration of an NMDA receptor antagonist to a human or animal subject, the composition including an NMDA receptor antagonist in an immediate release form in association with an NMDA receptor antagonist in a controlled release form.
The same NMDA receptor antagonist may be used in both the immediate and controlled release forms or they may be different NMDA receptor antagonists.
The composition of the invention is suitable for the treatment of chronic or acute pain, for example to be administered pre-operatively.
Accordingly, the present invention further provides a method for the therapeutic or prophylactic treatment of pain in a human or animal subject, the method including administering to the subject, a composition in accordance with the present invention. The method of the invention may be used to treat chronic or acute pain.
The composition of the invention may be used in the pre-emptive treatment of pain. The various features of novelty which characterize the invention are pointed out with particularity in the claims next to and form a part of the specification. For a better understanding of the invention, its operative advantages and specific objects obtained by its use, reference should be had to the accompanying drawings and descriptive matter in which there is illustrated and described in the preferred embodiment of the invention.
Preferably the NMDA receptor antagonist may be selected from a morphinan such as dextromethorphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilpine, remacemide, iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine, levemopamil, a pharmaceutically acceptable salt or ester thereof, or a metabolic precursor of any of the foregoing.
The formulation may include sufficient NMDA receptor antagonist to provide from about 1-5000 mg/day, typically 1-1000 mg/day and preferably about 100-800 mg/day of the active ingredient. The composition includes an NMDA receptor antagonist in an immediate release form in association with a NMDA receptor antagonist in a controlled release form. The composition may include an amount of NMDA receptor antagonist in the immediate release form of approximately 5% to 90% of the total NMDA receptor antagonist, preferably 10% to 60%. An immediate release NMDA receptor antagonist content of about 15% to 50% is particularly preferred. The controlled release form of the NMDA receptor antagonist may constitute the remainder of the active ingredients.
The composition of the invention may be in a form suitable for oral or rectal administration or for administration by transdermal, intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular means.
The composition of the invention may or may not be in a single dosage form. Preferably the composition is in a single dose form.
The composition may be formulated as an oral dosage form such as a tablet, capsule, a liquid, powder, granule or suspension, an injectable solution, a suppository, implant or transdermal patch.
Preferably the NMDA receptor antagonist is dextromethorphan (DM) or a pharmaceutically acceptable salt thereof. Preferably the dextromethorphan is in the form of dextromethorphan hydrobromide.
The oral form of the pharmaceutical compositions of the invention may be selected from:
1) liquids, for example, suspensions, reconstitutable powders, elixirs, oils, solutions,or emulsions;
2) confectionery, for example, chewing gums, lozenges or candy bars;
3) powders, for example, drug powder, prilled material, coated actives or granulated materials;
4) capsules, for example, soft gelatin, hard gelatin containing, pellets, powders, tablets, granulates, liquids, or combinations of these; said capsules may or may not be coated;
5) tablets, for example, disintegrating, chewable effervescent, matrix, osmotic pumps, prepared by multi-layering, contain coated powders in tablets, tablets in tablets, pellets in tablets etc, said tablets may or may not be coated.
The oral pharmaceutical composition of the invention may be in the form of a “taste-masked” or “taste-neutral” form.
The method of manufacture, components and quantities of components used, depend on the particular pharmaceutical composition being considered.
A suitable immediate release (IR) form of the NMDA receptor antagonist may simply be particles of the antagonist or particles of the antagonist admixed with soluble components for example, sugars (eg sucrose, lactose, fructose, mannitol etc.), polymers (eg polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc), surfactants (sodium lauryl sulphate, chremophor, tweens, spans, pluronics, and the like), insoluble components (microcrystalline cellulose, Ca
3
(PO
4
)
2
, talc, fumed silica, i.e. aerosil® and the like), coating material (examples of suitable coating materials are polyethylene glycol, hydroxypropyl methyl cellulose, wax, fatty acids, etc.), dispersions in suitable material (examples are wax, polymers, pharmaceutically acceptable oils, soluble agents etc) or combinations of the above. These mixtures may be prepared by blending, mixing, dissolution and evaporation, or by using suspensions
Heinicke Grant Wayne
Smith Ian Keith
Cohen & Pontani, Lieberman & Pavane
F.H. Faulding & Co. Limited
Spear James M.
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