CA2235071A1 - Analgesic immediate and controlled release pharmaceutical composition - Google Patents
Analgesic immediate and controlled release pharmaceutical composition Download PDFInfo
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- CA2235071A1 CA2235071A1 CA 2235071 CA2235071A CA2235071A1 CA 2235071 A1 CA2235071 A1 CA 2235071A1 CA 2235071 CA2235071 CA 2235071 CA 2235071 A CA2235071 A CA 2235071A CA 2235071 A1 CA2235071 A1 CA 2235071A1
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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.
Accordingly, 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 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 NMDA receptor antagonist may be selected from a morphinan such as dextromethorphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilpine, remacemide, lamotrigine, 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.
Accordingly, 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 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 NMDA receptor antagonist may be selected from a morphinan such as dextromethorphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilpine, remacemide, lamotrigine, 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.
Description
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU!)6~'~D~'Q
,~n~ sjC; ~ and controlled release pharm~e--tical c~ ilion ~ The present invention relates to pharmaceutical compositions and is particularly s concerned with pharmaceutical compositions containing N-methyl-D-aspartate (NMDA) receptor antagonists and their use in the treatment of pain.
The amino acid glul~",ate is an excitatory neurotransmitter that is an agonist at many post-synaptic terminals of the central nervous system. The glutamate 0 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 (gluLalnale 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 S 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 su~n,nalion 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 25 (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.
~ 30 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.
~ CA 0223~071 1998-04-16 PC~l~U 9 6 / (3 0 6 ~ ~3 7~ E ~ E I '~ d ~, .J ~g~7 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.
s 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 bothimmediate release of an NMDA receptor antagonist and controlled or sustained release of an NMDA receptor antagonist.
0 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.
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 for the treatment of pain, the composition including an NMDA receptor antagonist in an immediate release form in 20 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.
25 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 for the treatment of30 pain, 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.
HEET
~F~/A~J
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU~ U-~'8 The composition of the invention may be used in the pre-emptive treatment of pain. ~~
Preferably the NMDA receptor antagonist may be setected from a morphinan s such as dexl~u",ell,orphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilpine, remacemide, lamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine, levemopamil, a pharmaceutically acceptable salt or ester thereof, or a metabolic precursor ofany 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 5 antagonist in a controlled release form. The composition may include an amountof 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 20 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, 30 capsule, a liquid, powder, granule or suspension, an injectable solution, a suppository, implant or transdermal patch CA 0223~071 1998-04-16 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 pharlmaceutical compositions of the invention may be selected from:
1) liquids, for example, suspensions, reconstitutable powders, elixirs, oils, solutions,or emulsions;
,~n~ sjC; ~ and controlled release pharm~e--tical c~ ilion ~ The present invention relates to pharmaceutical compositions and is particularly s concerned with pharmaceutical compositions containing N-methyl-D-aspartate (NMDA) receptor antagonists and their use in the treatment of pain.
The amino acid glul~",ate is an excitatory neurotransmitter that is an agonist at many post-synaptic terminals of the central nervous system. The glutamate 0 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 (gluLalnale 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 S 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 su~n,nalion 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 25 (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.
~ 30 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.
~ CA 0223~071 1998-04-16 PC~l~U 9 6 / (3 0 6 ~ ~3 7~ E ~ E I '~ d ~, .J ~g~7 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.
s 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 bothimmediate release of an NMDA receptor antagonist and controlled or sustained release of an NMDA receptor antagonist.
0 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.
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 for the treatment of pain, the composition including an NMDA receptor antagonist in an immediate release form in 20 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.
25 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 for the treatment of30 pain, 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.
HEET
~F~/A~J
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU~ U-~'8 The composition of the invention may be used in the pre-emptive treatment of pain. ~~
Preferably the NMDA receptor antagonist may be setected from a morphinan s such as dexl~u",ell,orphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilpine, remacemide, lamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine, levemopamil, a pharmaceutically acceptable salt or ester thereof, or a metabolic precursor ofany 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 5 antagonist in a controlled release form. The composition may include an amountof 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 20 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, 30 capsule, a liquid, powder, granule or suspension, an injectable solution, a suppository, implant or transdermal patch CA 0223~071 1998-04-16 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 pharlmaceutical 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;
20 5) tablets, for example, disintegrating, chewable effervescent, matrix, osmotic pumps, prepared by multi-layering, contain coated powders in tablets, tablets intablets, 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 2~; "taste-masked" or "taste-neutral" form.
The method of manufacture, components and quantities of components used, depend on the particular pharmaceutical composition being considered.
30 A suitable immediate release (IR) form of the NMDA receptor antagonist may simply be particles of the antagonist or ~articles of the antagonist admixed with soluble components for example, sugars (eg sucrose, lactose, fructose, mannitol CA 0223~071 1998-04-16 5 PCT/AU9G/OOf~8 etc.), polymers (eg polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc), sùrfactants (sodium lauryl sulphate, chremophor, tweens,spans, pluronics, and the like), insoluble components (microcrystalline cellulose, Ca3 (PO4)2, talc, aerosol and the like), coating material (examples of suitable 5 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 etc. These mixtures may be deposited on o inert cores, wet massed and extruded, granulated, spray dried, etc. These mixtures or processed mixtures may be used in suspensions, filled into capsules,tabletted, filled into sachets, used in confectionery and so on.
The controlled release may be a sustained release or delayed/modified release.
A c~ntrolled-release dosage form as defined in US Pharmacopeia XXII includes extended release dosage forms which allow at least a twofold reduction in dosingfrequency as compared to the drug presented as a conventional dosage form and delayed release dosage forms which release the drug at a time other than 20 promptly after administration.
A core used herein the description contains the active ingredient and other carriers and excipients, fillers, stablising agents, binders, core seeds or colourants. The active may be present in amounts of approximately 0.1 to 95%
2s by weight based on the weight of the total core element. Preferably the active is present in amounts of 10 to 80% by weight based on the weight of the total core element. The core may be 200 to 170011 in diameter.
.
A pellet is a coated core, the coating being any suitable coating.
Preferably, the controlled release component is a sustained (or extended) release form.
CA 0223~071 1998-04-16 WO 97tl4415 PCT/AU~)6/00~58 A suitable sustained release (SR) form of the NMDA receptor antagonist may be a matrix tablet composition. Suitable matrix forming materials are waxes (eg.
carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, fatty s alcohols), oils, hardened oils or fats (eg. hardened rapeseed oil, castor oil, beef tallow, palm oil, soya bean oil), polymers (eg. hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, polyethylene glycol) and other excipients known to those familiar with the art. Other suitable matrix tabletting materials are rnicrocrystalline cellulose, powdered cellulose, 0 hydroxypropyl cellulose, ethyl cellulose, with other carriers, fillers, and excipients known to those familiar with the art. SR tablets may contain granulates, coated powders, pellets, or be multi-layered and the finished tablet may be coated or uncoated.
15 Suitable coating materials to prepare SR products are any pharmaceutically acceptable polymer such as ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, 20 and monomeric materials such as sugars including lactose, sucrose, fructose and mannitol, salts including sodium chloride, potassium chloride and derivatives, organic acids including fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof, enteric polymers including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate 25 phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups. These polymers may be applied as solutions or latexes. Other barriers may be used such as waxes.
The coating composition may or may not be plasticised according to the 30 properties of the coating blend such as the glass transition temperature of the main component or mixture of components or the solvent used for applying the coating compositions. Suitabie plasticises can be added from 0 to 50% by weight CA 0223~071 1998-04-16 WO 97/14415 PCT/AU9GhJ~r8 of the coating composition and at ieast one may be selected from diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides,castor oil and the like.
s Cores containing active may be coated directly to produce a SR dose, or tablets or capsules containing active may be coated.
A suitable SR form of NMDA receptor antagonist may be an osmotic pump, or combinations of the above.
These IR or SR forms may be made by prilling, spray drying, pan coating, melt granulation, granulation, wurster coating, tangential coating, top spray, tabletting, extruding, coacervation and the like.
S The particle sizes of the IR and SR components in the dosage form depends on the-technology used. The particle sizes could range from submicron to 500 ~m forpowder technologies (mixtures, spray drying, dispersions etc), 5-1700 ~lm for coating technologies (wurster, top spray, bottom spray, spray drying, extrusion,layering etc), to 1 40mm for tabletting technologies.
The IR and SR forms of the NMDA receptor antagonist are then combined into a single dosage such that the amount of NMDA receptor antagonist in the composition of the invention is in the range of about 1 - 5000 mg typically, 1 mg to 1000 mg, and preferably 100 mg to 800 mg. The composition including an NMDA
25 receptor antagonist in an immediate release form in association with a NMDQ
receptor antagonist in a controlled release form may include an amount of NMDA
receptor antagonist in the immediate release form of approximately 5% to 90% of the composition of the invention, preferably 10% to 60%. An immediate release NMDA receptor antagonist content of about 15% to 50% is particularly preferred.
30 The controlled release form of the NMDA receptor antagonist may constitute the remainder of the active ingredient.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU~G~'(; ~ ~58 As a result the final composition provides an amount of NMDA receptor antagonist for immediaté release following administration and an additional amount of NMDA receptor antagonist for sustained release. The SR component is preferably aimed at reducing the dosage interval from 3 to 6 times daily to 1 or 2 5 times daily.
The composition of the invention may exhibit more than one peak in the plasma concentration/time curve in any one dosing interval depending on the particular NMDA receptor antagonist(s) used, the relative amounts of the IR and SR
0 components, and the dissolution properties of the SR component.
The following non-limiting example illustrates the uses of the components listedabove in producing a composition in accordance with the invention.
5 Where the composition of the invention is in the form of a pellet product, thepeltets may be presented in a sachet, capsule or tablet. The non limiting example below describes pellets (particle sizes 200 - 1 700~Lm) in a capsule. All the quoted ranges are %w/w.
20 A plurality of elements containing the active ingredients (cores) are prepared by extrusion/marumerisation, or layering the active (or blend of active with other excipients) onto inert carriers by various processes. The cores themselves couldbe IR or SR depending on the materials and method of manufacture. The cores may contain the drug at the required potency according to the particular NMDA
2~; dose (mg), required size and presentation, and subsequent processes (coatingetc.) The cores may contain drugs in the range 0.1-100% depending on the required dose, potency, manufacturing method, and properties.
An extruded core would typically include a carrier such as microcrystalline 30 cellulose in the range ~-99.9%, a binder such as hydroxypropyl cellulose in the range 0-50%, a filler such as lactose in the range 0-50% and other excipients. An extruded core may only contain drug and binder.
CA 0223~071 1998-04-16 _ g _ An extruded core with SR properties would typically contain a swelling/gelling polymer such as hydroxypropyl cellulose in the range 0-50% or a hydrophobic material such as cetylalcohol in the range 10-90% with the drug. A layered core 5 would contain an inert carrier such as a sugar sphere in the range 10-90% with a binder in the range 0.1-50 % with the drug. The core may or may not contain fillers, solubilisers and other additives. The binder may be chosen to achieve IR
(hydroxypropyl cellulose, hydroxypropyl methyl cellulose etc), or SR (ethyl cellulose, cellulose acetate butyrate etc), or delayed/modified release (ie enteric 10 ~inding materials such as hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate etc).
A portion of the final dosage form may be IR cores made by the above described processes. Alternatively the IR cores may be coated with a rapidly disintegrating 5 or dissolving coat for aesthetic, handling, or stability purposes. Suitable materials are polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, polymethacrylates containing free amino groups, each may be with or without plasticisers, and with or without an antitack agent or filler. An addition of about 3% of the weight of the core as coating material is generally 20 regarded as providing a continuous coat for this size range.
The SR portion of the dose may be provided by a SR core as described above, a SR core which is further modified by overcoating, or an IR core which is modified by overcoating. The IR and SR NMDA receptor antagonist need not be the same 2s active, nor are the IR or SR components of a dose themselves limited to just one active.
A typical coating composition for making the SR component would contain an insoluble matrix polymer in amounts approximately 15 - 85% by weight of the 30 coating composition and a water soluble material in an amount of approximately 15 - 85% by weight of the coating composition . Optionally an enteric polymer inamounts from 0 to 100% by weight of the coating composition may be used or CA 0223~07l l998-04-l6 included. Suitable insoluble matrix polymers include ethyl cellulose, cellulose acetate butyrate, cellul~ose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers. Suitable water soluble materials include polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such as sugars (eg lactose, sucrose, fructose, mannitol and the like), salts (eg. sodium chloride, potassium chloride and the like), organic acids (eg. fumaric acid, succinic acid, lactic acid, tartaric acid and the like) and mixtures thereof. Suitable enteric polymers include hydroxypropyl methyl 10 cellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, polymethacrylates containing carboxyl groups, and the like.
The coating composition may or may not be plasticised according to the properties of the coating blend such as the glass transition temperature of the màin component or mixture of components or the solvent used for applying the coating compositions. Suitable plasticisers can be added from 0 to 50% by weightof the coating composition and at least one may be selected from diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides,20 acetylated citrate esters, dibutylsebacate, castor oil and the like.
The coating composition may or may not include a filler. The filler may comprise 0 to approximately 200% by weight based on the total weight of the coating composition and may be an insoluble material such as silicon dioxide, titanium 25 dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, polacrilin potassium, and the like.
The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. Where solutions are applied the solvent30 is present in amounts from approximate by 25-99% by weight preferably 85-97%
by weight based on the total weight of dissolved solids. Suitable solvents are water, lower alcohol, lower chlorinated hydrocarbons, ketones or mixtures thereof.
-CA 0223~071 1998-04-16 WO 97/1~1415 PCT/AU96/00658 Where latexes are applied, the solvent is present in amounts from approximately 25 - 97% by weight, preferably 60-97% based on the quantity of polymeric material in the latex. The solvent may be predominantly water.
s A suitable tablet formulation may be of a swelling/gelling polymer such as L-hydroxypropyl cellulose admixed with a filler such as MCC and the drug. The tablet excipients rnay or may not be processed ie. spray dried together, prior to use in tabletting. The mixture may be compressed directly, or granulated prior to compression. Matrix tablets of this type often exhibit a rapid initial release until the 10 polymers swell and gel, which induces SR for the remainder of the drug.
The quantity of IR and duration of SR can be varied by altering the quantities of the excipients used. If the IR component is not large enough, a quantity of drugcan be included in a rapidly dissolving outer coat of polymers such as PEG or hydroxypropyl methyl cellulose. A typical matrix tablet would contain the swellinglgelling polymer in amounts from approximately 15 to 70% by weight based on the total weight of the tablet and filler in amounts from approximately 15 to 70% by weight based on the total weight of the tablet. Additional fillers may be included in amounts from approximately 0 - 60% by weight based on the total 20 weight of the tablet. These may be soluble materials such as lactose, mannitol, sorbitol and the like, or insoluble materials such as tribasic calcium phosphatepowdered cellulose or any of the various starches (corn, wheat, potato etc.) Additionally, the tablets may contain a lubricant in an amount from 0-8% by weight based on the total weight of the tablet. Lubricants may be selected from 25 metal stearates, stearic acid, hydrogenated oils, such as soya bean oil or castor oil, sodium stearyl fumarate, polytetrafluoroethylene, talc and the like. The tablets may be coated for aesthetic, handling or stability purposes, or to increase the quantity of the IR portion of the drug. In this latter case the drug is dissolved or suspended in the coating solution and sprayed onto the tablets until the desired30 quantity of drug has been added. Suitable coating materials include polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sugar, waxes, or mixtures of these. The material may be CA 0223~07l l998-04-l6 added to any desired thickness but weight gains in the range 1-20% are typical, preferably 2-10%, more~preferably 2-5%. The coat may or may not be plasticised.
A plasticiser may be present in amounts from about 0-50% by weight based on the total weight of the tablet of the coating material. Examples of plasticisers are 5 diethyl phthalate, citrate esters, acetylated citrate esters, polyethylene glycol, glycerol, dibutylsebacate, acetylated monoglycerides, castor oil and the like).
The coating composition may include an antitack agent such as talc, kaolin, titanium dioxide, silicon dioxide, alumina, starch, polacrilin potassium, 10 microcrystalline cellulose or the like).
The coating materials may be applied to the drug particles, processed drug particles (ie. cores, granules), finished tablets, or finished capsules.
The coating composition may or may not include a filler. The filler may comprise 0 to~approximately 200% by weight based on the total weight of the coating composition and may be an insoluble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, microcrystalline cellulose, polacrilin potassium.
The coat may contain other ingredients such as dyes and waxes.
The coat may be applied as a solution or suspension from aqueous or organic solvents solution concentration in equipment familiar to these skilled in the art.
25 The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. Where solutions are applied the solventis present in amounts from approximate by 25-99% by weight preferably 85-97%
by weight based on the total weight of dissolved solids. Suitable solvents are water, go lower alcohols, lower chlorinated hydrocarbons, ketones, or mixtures 30 thereof. Where latexes are applied, the solvent is present in amounts from approximately 25 - 97% by weight, preferably 60-97% based on the quantity of polymeric material in the latex. The solvent may be predominantly water.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU96/Ob658 Alternatively the SR component of a tablet may be provided in the form of SR
pellets and the IR component may be included in the body of the tablet. Such a tablet disintegrates to release the IR drug and the SR pellets. Pellets may be s present in amounts from 1 - 60% by weight of the tablet, preferably 5 -50% more preferably 5 40%. Suitable matrix materials for tablets of this type are microcrystalline cellulose, starches and the like.
The immediate release form of the NMDA receptor antagonist may be presented 10 in a fast dissolving dosage form. The immediate release form may be in the form of a solid or molecular dispersion of the active within a polymer matrix. The polymer matrix may be selected from biologically acceptable polymer such as a cellulose ether, for example ethyl cellulose, or cellulose ester, for example cellulose acetate butyrate etc. The immediate release form may simply be 15 particles of the antagonist or the antagonist deposited on a core containing the antagonist.
The composition of the invention, where it is in a tablet or like form, may include the two forms of the NMDA receptor antagonist as separate components, for 20 example, in a multi-layer tablet, wherein one or more layer include the NMDA
receptor antagonist in an immediate release form with one or more layers of the NMDA receptor antagonist in a controlled release form. Alternatively the composition of the invention may be in the form of a tablet wherein the immediate release forms the shell and the controlled release form constitutes the core.
Alternatively, the two forms of the NMDA receptor antagonist may be dispersed throughout the tablet.
The composition of the invention may be produced by providing a core containing 30 the NMDA receptor antagonist controlled release component coated with an enteric or delayed release coating. The core can be in the form of beads compressed to a tablet. The coated core may then be compressed into tablets CA 0223~,071 1998-04-16 along with a powder mixture containing additional NMDA receptor antagonist or filled in combination with uncoated NMDA receptor antagonist into a capsule shell. As a result, the final composition provides an amount of NMDA receptor antagonist for immediate release following administration and an additional s amount of NMDA receptor antagonist for controlled release.
The controlled release form of the NMDA receptor antagonist is such as to provide sustained release of the antagonist. Preferably the controlled or sustained release form provides a therapeutic effect over a period greater than o about 6 hours. More preferably the sustained therapeutic effect is greater than about 8 hours. A sustainecll therapeutic effect period of 8 to 24 hours being especially preferred. The SR component of the controlled release composition is aimed at reducing the dosage interval from 3 to 6 times daily to 1 to 2 times daily.
15 The controlled release form of the antagonist may be coated beads or granules of the- NMDA receptor antagonist. The coated antagonist may be combined with uncoated or lightly coated antagonist to provide a composition of the present invention. The term "lightly coated" as used in the description means a rapidly disintegrating coating for aesthetic, handling or stability purposes. These then20 may be filled into capsules or formed into tablets. Microencapsulation may also be used to produce the controlled release form of the NMDA receptor antagonist.
The coating or matrix material may be any suitable material. The coating or matrix material may be a polymer or a wax. The wax may be selected from any suitable 25 wax or wax-like material including natural oil and fat and hardened oils such as hardened rapeseed oil, hardened castor oil, hardened beef tallow, palm oils and the like; waxes such as carnauba wax, bees wax, paraffin wax, ceresine wax, shellac wax or a fatty acid.
30 The present invention also provides a kit including a plurality of unit dosage forms, in a container or the like, the container including indicia indicative of a CA 0223S07l l998-04-l6 WO 97/14415 PCT/AU9Gi'UQ~S8 dosage regimen, at least one of the unit dosages being in the form of a pharmaceutical composition in accordance with the present invention.
The kit may further include unit dosages which provide immediate and controlled 5 release of one or more actives such as an NMDA receptor antagonist. The kit - may also include instructions for use of the kit.
Throughout the claims and description of this specification, the word "comprise"and variations of the word, such as "comprising" and "comprises", is not intended 10 to exclude other additives, components, integers and steps.
The present invention will now be more fully described with reference to the accompanying example. It should be understood, however that the following description is illustrative only and should not be taken in any way as a restriction 15 on the generality of the invention as specified above.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU!)G/(. ~;''~
FI~URES
Figure 1: Dissolution rate of Sustained Release Dextromethorphan capsules A DEXTROMETHORPHAN DISSOLUTION PROFILE
BACKGROUND
10 Dextromethorphan (DM) is an NMDA recpetor which has been in clinical use for many years. Pharmacokinetic data suggest that after a normal 60mg dose the absorption of the drug is quite rapid, reaching maximum plasma levels in 1 to 2 hours. However, the bioavailability of the drug is quite low, probably because of extensive first-pass hepatic metabolism. Once absorbed, DM is converted in the 15 body to a metabolite (dextrophan) which is reported to be pharmacologically acttve. Both the parent and the metabolite have short half-lives (2 to 4 hours).
Since DM and the active metabolite have short half-lives, a controlled release formulation will be useful to provide up to 24 hour delivery of this NMDA receptor 20 antagonist from a single dose.
METHOD
a) PRODUCTION OF DE:lCTROMETHORPHAN CAPSULES
Dextromethorphan capsules were prepared according to the following and dissolution profiles were determined on the capsules.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU96/0~658 (i) Granulating Dextromethorphan Solution Inqredient % (WNV) Ethanol 96 PC/BP 95.0 sHydroxy Propyl Cellulose BP/NF 5.0 Ethanol 96 PC/BP was added to a container. To this, Hydroxy Propyl Cellulose BP/NF was added while shear stirring. The solution was left to stir until all of the polymer was dissolved.
(ii) Coating Solutions Formulation 1 S Inqredient % (WNV) Ethanol 96 PC/BP 95.0 Hydroxy Propyl Methyl Cellulose BP/USP 603 2.0 Ethyl Cellulose N50 3.0 Ethanol 96 PC/BP and Hydroxy Propyl Methyl Cellulose BP/USP 603 were shear stirred. After the HPMC had dissolved, Ethyl Cellulose N50 was shear stirred into the solution. The solution was shear stirred until the Ethyl Cellulose had completely dissolved.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU9Gf~
Formulation 2 Ingredient % (WNV) Ethanol 96 PC/BP 93.43 s Diethyl Phthalate BP/USP 0.65 Methacrylic Acid Copolymer NF, Type C Powder 1.05 Ethyl Cellulose N50 3.59 Poly Ethylene Glycol (6000) I~IF 1.28 o The above ingredients were combined with stirring to produce Coating Formulation 2.
(iii) Dextromethorphan Cores Dextromethorphan Cores Parlt 1 The cores containing dextromethorphan were produced in a fluid bed coater at the following conditions:
Inlet Air Temperature: 50~C
20 AirFlow: 80 m3/hr Two sets of dextromethorphan containing cores were produced; one with dextromethorphan potency of 57.75% and one with a potency of 80%. Both cores were made in a fluid bed coater with the ingredients listed below using 25 standard methods known to those skilled in the art. The particle size range of the final cores was 710-1400 microns for the low potency cores and 1000-1700 microns for the high potency cores. In order that the desired capsule size wouldbe used, the high potency cores were used in the next part of the process.
CA 0223~071 1998-04-16 lngredient % (WNV)TypicalAmounts (kg) Ethanol 96 PCIBP ~ - 0.200 Dextromethorphan Granulating Solution 43.82 1.560 Dextromethorphan HBr 33.71 1.200 s Sugar Spheres 30-35 Mesh 22.47 0.800 Theoretical Potency at the end of Dextromethorphan Core Part 1 is 57.75%.
Dextromethorphan Core Part 2 The cores containing dextromethorphan were produced in a fluid bed coated at the following operating conditions:
Inlet Air Temperature: 50~C
Air Flow: 80 m3/hr -Ingredient % (WNV) TvPical Amounts (kg) Ethanol 96 PCIBP - 0.200 Dextromethorphan Granulating Solution 43.82 1.560 Dextromethorphan HBr 33.71 1.200 Dextromethorphan Cores Part 1 22.47 0.800 Theoretical potency at the end of Dextromethorphan Core Part 2 is 80%.
25 The final core will have the following composition.
Ingredient % (WN~) Dextromethorphan HBr 79.98 Hydroxy Propyl Cellulose BPINF 5.20 Sugar Spheres (30-35) Mesh 14.82 CA 0223~071 1998-04-16 (iv) De,~l,c"l,cthorphan Pellets The high potency dextromethorphan cores were dispensed with one of thecoating formulations and talc in a fluid bed coater to produce the pellets. The s process was run with the two different coating formulations and two different theoretical polymer coat weights (TPCW) were produced with Coating formulation 1. The conditions in the fluid bed coater are as follows:
Inlet Air Temperature: 50~C
o AirFlow: 80 m3/hr Dew Point: 0~C
The pellets were produced by standard coating methods well known to those skilled in the art. The final pellets within the size range 1000-1700 microns were retained.
-Aim Product for A6-048 A1 (8% Theoretical Polymer Coat Weight (TPCW)). A6-048 A1, A6-052 A2, and A6-048 A2 are batch numbers used to identify different pellet compositions.
Ingredient % (WN\I)TypicalAmounts (kq) Ethanol 96 PC/BP - 0.2000 Coating Formulation 1 62.51 1.7400 Talc Purified Micronised BP/USP 1.56 0.0435 Dextromethorphan Cores 35.93 1.0000 CA 0223~071 1998-04-16 Aim Product for A6-052 A2 (10% Theoretical Polymer Coat Weight (TPCV\~
In~redient % (WNV) Typical Amounts (kg) Ethanol 96 PC/BP - 0.2000 s Coating Formulation 2 67.80 Talc Purified Micronised BP/USP 1.69 0.0555 Dextromethorphan Cores 30.51 1.0000 The resulting Dextromethorphan Pellets have an excipient breakdown as follows.
DextromethorPhan Pellet A6-052 A2 (10% TPCW) Ingredient % (WN\~) Dextromethorphan HBr 68.56 Hydroxy Propyl Cellulose BP/NF 4.46 Sugar Spheres (30-35) Mesh 12.70 Ethyl Cellulose N50 5.20 Diethyl Phthalate BP/USP 0.94 Methacrylic Acid Copolymer NF, Type C Powder 1.52 20 Poly Ethylene Glycol (6000) NF 1.86 Talc Purified Micronised BP/USP 4.76 Dextro Pellet A6-048 A1 (8% TPCW) 25 Ingredient % (WN\I) Dextromethorphan HBr 70.75 Hydroxy Propyl Cellulose BP/NF 4.60 Sugar Spheres (30-35) Mesh 13.11 Hydroxy Propyl Methyl Cellulose BP/USP 603 3.08 Ethyl Cellulose N50 4.61 Talc Purified Micronised BP/USP 3.85 CA 0223~071 1998-04-16 Dextro Pellet A6-048-A2 has a 10% TPCW with the same extract coating solution.
(v) Capsules 5 Capsules were filled by blending cores with pellets. Each size 0, natural / natural capsule contained 250 mg of dextromethorphan. The ratio of core ADS
equivalent to pellet ADS equivalent was 25t75. This meant that 62.5 mg of dextromethorphan was contained in the immediate release cores, and 187.5 mg of dextromethorphan was contained in the controlled release pellets. The 10 potencies of each of the cores and pellets was determined by UV assay.
b) MEASUREMENT OF DISSOLUTION OF DEXTROMETHORPHAN
CAPSULES
5 Dissolution was measured using USPXXIII apparatus and method for dissolution ~711~, apparatus 1. The analysis measures the UV absorbance of dextromethorphan at 278nm.
RESULTS
DISSOLUTION PROFILE OF DEXTROMETHORPHAN CAPSULES
Dissoiution of the dextromethorphan capsules was measured according to the parameters above. The theoretical dissolution profile is compared with actual 25 dissolution profile in Table 2 and shown in Figure 1. An aim dissolution profile was established with reference to the pharmacokinetic parameters, derived from the literature of immediate release dextromethorphan.
WO 97/1441~i PCT/AU96~ '8 TABLE 2: AIM AND ACTUAL DISSOLUTION
Aim Actual Time (hours) % Released + 20% limit A6-048 A1 A6-048 A2 A6-052 A2 0.5 27.5 22-33 25.8 24.9 26.7 1 30 24-36 28.0 26.5 27.8 2 35 28-42 33.3 29.5 31.5 4 45 36-54 43.8 36.3 42.2 6 55 44-66 55.2 44.4 53.2 8 65 52-78 66.8 53.3 64.1 12 85 68-100 87.9 71.8 82.0 16 100 >80 99.6 87.7 94.3 Finally, it is to be understood that various other modifications and/or alterations 5 may be made without departing from the spirit of the present invention as outlined herein.
20 5) tablets, for example, disintegrating, chewable effervescent, matrix, osmotic pumps, prepared by multi-layering, contain coated powders in tablets, tablets intablets, 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 2~; "taste-masked" or "taste-neutral" form.
The method of manufacture, components and quantities of components used, depend on the particular pharmaceutical composition being considered.
30 A suitable immediate release (IR) form of the NMDA receptor antagonist may simply be particles of the antagonist or ~articles of the antagonist admixed with soluble components for example, sugars (eg sucrose, lactose, fructose, mannitol CA 0223~071 1998-04-16 5 PCT/AU9G/OOf~8 etc.), polymers (eg polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc), sùrfactants (sodium lauryl sulphate, chremophor, tweens,spans, pluronics, and the like), insoluble components (microcrystalline cellulose, Ca3 (PO4)2, talc, aerosol and the like), coating material (examples of suitable 5 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 etc. These mixtures may be deposited on o inert cores, wet massed and extruded, granulated, spray dried, etc. These mixtures or processed mixtures may be used in suspensions, filled into capsules,tabletted, filled into sachets, used in confectionery and so on.
The controlled release may be a sustained release or delayed/modified release.
A c~ntrolled-release dosage form as defined in US Pharmacopeia XXII includes extended release dosage forms which allow at least a twofold reduction in dosingfrequency as compared to the drug presented as a conventional dosage form and delayed release dosage forms which release the drug at a time other than 20 promptly after administration.
A core used herein the description contains the active ingredient and other carriers and excipients, fillers, stablising agents, binders, core seeds or colourants. The active may be present in amounts of approximately 0.1 to 95%
2s by weight based on the weight of the total core element. Preferably the active is present in amounts of 10 to 80% by weight based on the weight of the total core element. The core may be 200 to 170011 in diameter.
.
A pellet is a coated core, the coating being any suitable coating.
Preferably, the controlled release component is a sustained (or extended) release form.
CA 0223~071 1998-04-16 WO 97tl4415 PCT/AU~)6/00~58 A suitable sustained release (SR) form of the NMDA receptor antagonist may be a matrix tablet composition. Suitable matrix forming materials are waxes (eg.
carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, fatty s alcohols), oils, hardened oils or fats (eg. hardened rapeseed oil, castor oil, beef tallow, palm oil, soya bean oil), polymers (eg. hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, polyethylene glycol) and other excipients known to those familiar with the art. Other suitable matrix tabletting materials are rnicrocrystalline cellulose, powdered cellulose, 0 hydroxypropyl cellulose, ethyl cellulose, with other carriers, fillers, and excipients known to those familiar with the art. SR tablets may contain granulates, coated powders, pellets, or be multi-layered and the finished tablet may be coated or uncoated.
15 Suitable coating materials to prepare SR products are any pharmaceutically acceptable polymer such as ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, 20 and monomeric materials such as sugars including lactose, sucrose, fructose and mannitol, salts including sodium chloride, potassium chloride and derivatives, organic acids including fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof, enteric polymers including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate 25 phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups. These polymers may be applied as solutions or latexes. Other barriers may be used such as waxes.
The coating composition may or may not be plasticised according to the 30 properties of the coating blend such as the glass transition temperature of the main component or mixture of components or the solvent used for applying the coating compositions. Suitabie plasticises can be added from 0 to 50% by weight CA 0223~071 1998-04-16 WO 97/14415 PCT/AU9GhJ~r8 of the coating composition and at ieast one may be selected from diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides,castor oil and the like.
s Cores containing active may be coated directly to produce a SR dose, or tablets or capsules containing active may be coated.
A suitable SR form of NMDA receptor antagonist may be an osmotic pump, or combinations of the above.
These IR or SR forms may be made by prilling, spray drying, pan coating, melt granulation, granulation, wurster coating, tangential coating, top spray, tabletting, extruding, coacervation and the like.
S The particle sizes of the IR and SR components in the dosage form depends on the-technology used. The particle sizes could range from submicron to 500 ~m forpowder technologies (mixtures, spray drying, dispersions etc), 5-1700 ~lm for coating technologies (wurster, top spray, bottom spray, spray drying, extrusion,layering etc), to 1 40mm for tabletting technologies.
The IR and SR forms of the NMDA receptor antagonist are then combined into a single dosage such that the amount of NMDA receptor antagonist in the composition of the invention is in the range of about 1 - 5000 mg typically, 1 mg to 1000 mg, and preferably 100 mg to 800 mg. The composition including an NMDA
25 receptor antagonist in an immediate release form in association with a NMDQ
receptor antagonist in a controlled release form may include an amount of NMDA
receptor antagonist in the immediate release form of approximately 5% to 90% of the composition of the invention, preferably 10% to 60%. An immediate release NMDA receptor antagonist content of about 15% to 50% is particularly preferred.
30 The controlled release form of the NMDA receptor antagonist may constitute the remainder of the active ingredient.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU~G~'(; ~ ~58 As a result the final composition provides an amount of NMDA receptor antagonist for immediaté release following administration and an additional amount of NMDA receptor antagonist for sustained release. The SR component is preferably aimed at reducing the dosage interval from 3 to 6 times daily to 1 or 2 5 times daily.
The composition of the invention may exhibit more than one peak in the plasma concentration/time curve in any one dosing interval depending on the particular NMDA receptor antagonist(s) used, the relative amounts of the IR and SR
0 components, and the dissolution properties of the SR component.
The following non-limiting example illustrates the uses of the components listedabove in producing a composition in accordance with the invention.
5 Where the composition of the invention is in the form of a pellet product, thepeltets may be presented in a sachet, capsule or tablet. The non limiting example below describes pellets (particle sizes 200 - 1 700~Lm) in a capsule. All the quoted ranges are %w/w.
20 A plurality of elements containing the active ingredients (cores) are prepared by extrusion/marumerisation, or layering the active (or blend of active with other excipients) onto inert carriers by various processes. The cores themselves couldbe IR or SR depending on the materials and method of manufacture. The cores may contain the drug at the required potency according to the particular NMDA
2~; dose (mg), required size and presentation, and subsequent processes (coatingetc.) The cores may contain drugs in the range 0.1-100% depending on the required dose, potency, manufacturing method, and properties.
An extruded core would typically include a carrier such as microcrystalline 30 cellulose in the range ~-99.9%, a binder such as hydroxypropyl cellulose in the range 0-50%, a filler such as lactose in the range 0-50% and other excipients. An extruded core may only contain drug and binder.
CA 0223~071 1998-04-16 _ g _ An extruded core with SR properties would typically contain a swelling/gelling polymer such as hydroxypropyl cellulose in the range 0-50% or a hydrophobic material such as cetylalcohol in the range 10-90% with the drug. A layered core 5 would contain an inert carrier such as a sugar sphere in the range 10-90% with a binder in the range 0.1-50 % with the drug. The core may or may not contain fillers, solubilisers and other additives. The binder may be chosen to achieve IR
(hydroxypropyl cellulose, hydroxypropyl methyl cellulose etc), or SR (ethyl cellulose, cellulose acetate butyrate etc), or delayed/modified release (ie enteric 10 ~inding materials such as hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate etc).
A portion of the final dosage form may be IR cores made by the above described processes. Alternatively the IR cores may be coated with a rapidly disintegrating 5 or dissolving coat for aesthetic, handling, or stability purposes. Suitable materials are polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, polymethacrylates containing free amino groups, each may be with or without plasticisers, and with or without an antitack agent or filler. An addition of about 3% of the weight of the core as coating material is generally 20 regarded as providing a continuous coat for this size range.
The SR portion of the dose may be provided by a SR core as described above, a SR core which is further modified by overcoating, or an IR core which is modified by overcoating. The IR and SR NMDA receptor antagonist need not be the same 2s active, nor are the IR or SR components of a dose themselves limited to just one active.
A typical coating composition for making the SR component would contain an insoluble matrix polymer in amounts approximately 15 - 85% by weight of the 30 coating composition and a water soluble material in an amount of approximately 15 - 85% by weight of the coating composition . Optionally an enteric polymer inamounts from 0 to 100% by weight of the coating composition may be used or CA 0223~07l l998-04-l6 included. Suitable insoluble matrix polymers include ethyl cellulose, cellulose acetate butyrate, cellul~ose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers. Suitable water soluble materials include polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such as sugars (eg lactose, sucrose, fructose, mannitol and the like), salts (eg. sodium chloride, potassium chloride and the like), organic acids (eg. fumaric acid, succinic acid, lactic acid, tartaric acid and the like) and mixtures thereof. Suitable enteric polymers include hydroxypropyl methyl 10 cellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, polymethacrylates containing carboxyl groups, and the like.
The coating composition may or may not be plasticised according to the properties of the coating blend such as the glass transition temperature of the màin component or mixture of components or the solvent used for applying the coating compositions. Suitable plasticisers can be added from 0 to 50% by weightof the coating composition and at least one may be selected from diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides,20 acetylated citrate esters, dibutylsebacate, castor oil and the like.
The coating composition may or may not include a filler. The filler may comprise 0 to approximately 200% by weight based on the total weight of the coating composition and may be an insoluble material such as silicon dioxide, titanium 25 dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, polacrilin potassium, and the like.
The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. Where solutions are applied the solvent30 is present in amounts from approximate by 25-99% by weight preferably 85-97%
by weight based on the total weight of dissolved solids. Suitable solvents are water, lower alcohol, lower chlorinated hydrocarbons, ketones or mixtures thereof.
-CA 0223~071 1998-04-16 WO 97/1~1415 PCT/AU96/00658 Where latexes are applied, the solvent is present in amounts from approximately 25 - 97% by weight, preferably 60-97% based on the quantity of polymeric material in the latex. The solvent may be predominantly water.
s A suitable tablet formulation may be of a swelling/gelling polymer such as L-hydroxypropyl cellulose admixed with a filler such as MCC and the drug. The tablet excipients rnay or may not be processed ie. spray dried together, prior to use in tabletting. The mixture may be compressed directly, or granulated prior to compression. Matrix tablets of this type often exhibit a rapid initial release until the 10 polymers swell and gel, which induces SR for the remainder of the drug.
The quantity of IR and duration of SR can be varied by altering the quantities of the excipients used. If the IR component is not large enough, a quantity of drugcan be included in a rapidly dissolving outer coat of polymers such as PEG or hydroxypropyl methyl cellulose. A typical matrix tablet would contain the swellinglgelling polymer in amounts from approximately 15 to 70% by weight based on the total weight of the tablet and filler in amounts from approximately 15 to 70% by weight based on the total weight of the tablet. Additional fillers may be included in amounts from approximately 0 - 60% by weight based on the total 20 weight of the tablet. These may be soluble materials such as lactose, mannitol, sorbitol and the like, or insoluble materials such as tribasic calcium phosphatepowdered cellulose or any of the various starches (corn, wheat, potato etc.) Additionally, the tablets may contain a lubricant in an amount from 0-8% by weight based on the total weight of the tablet. Lubricants may be selected from 25 metal stearates, stearic acid, hydrogenated oils, such as soya bean oil or castor oil, sodium stearyl fumarate, polytetrafluoroethylene, talc and the like. The tablets may be coated for aesthetic, handling or stability purposes, or to increase the quantity of the IR portion of the drug. In this latter case the drug is dissolved or suspended in the coating solution and sprayed onto the tablets until the desired30 quantity of drug has been added. Suitable coating materials include polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sugar, waxes, or mixtures of these. The material may be CA 0223~07l l998-04-l6 added to any desired thickness but weight gains in the range 1-20% are typical, preferably 2-10%, more~preferably 2-5%. The coat may or may not be plasticised.
A plasticiser may be present in amounts from about 0-50% by weight based on the total weight of the tablet of the coating material. Examples of plasticisers are 5 diethyl phthalate, citrate esters, acetylated citrate esters, polyethylene glycol, glycerol, dibutylsebacate, acetylated monoglycerides, castor oil and the like).
The coating composition may include an antitack agent such as talc, kaolin, titanium dioxide, silicon dioxide, alumina, starch, polacrilin potassium, 10 microcrystalline cellulose or the like).
The coating materials may be applied to the drug particles, processed drug particles (ie. cores, granules), finished tablets, or finished capsules.
The coating composition may or may not include a filler. The filler may comprise 0 to~approximately 200% by weight based on the total weight of the coating composition and may be an insoluble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, microcrystalline cellulose, polacrilin potassium.
The coat may contain other ingredients such as dyes and waxes.
The coat may be applied as a solution or suspension from aqueous or organic solvents solution concentration in equipment familiar to these skilled in the art.
25 The coating composition may be applied as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. Where solutions are applied the solventis present in amounts from approximate by 25-99% by weight preferably 85-97%
by weight based on the total weight of dissolved solids. Suitable solvents are water, go lower alcohols, lower chlorinated hydrocarbons, ketones, or mixtures 30 thereof. Where latexes are applied, the solvent is present in amounts from approximately 25 - 97% by weight, preferably 60-97% based on the quantity of polymeric material in the latex. The solvent may be predominantly water.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU96/Ob658 Alternatively the SR component of a tablet may be provided in the form of SR
pellets and the IR component may be included in the body of the tablet. Such a tablet disintegrates to release the IR drug and the SR pellets. Pellets may be s present in amounts from 1 - 60% by weight of the tablet, preferably 5 -50% more preferably 5 40%. Suitable matrix materials for tablets of this type are microcrystalline cellulose, starches and the like.
The immediate release form of the NMDA receptor antagonist may be presented 10 in a fast dissolving dosage form. The immediate release form may be in the form of a solid or molecular dispersion of the active within a polymer matrix. The polymer matrix may be selected from biologically acceptable polymer such as a cellulose ether, for example ethyl cellulose, or cellulose ester, for example cellulose acetate butyrate etc. The immediate release form may simply be 15 particles of the antagonist or the antagonist deposited on a core containing the antagonist.
The composition of the invention, where it is in a tablet or like form, may include the two forms of the NMDA receptor antagonist as separate components, for 20 example, in a multi-layer tablet, wherein one or more layer include the NMDA
receptor antagonist in an immediate release form with one or more layers of the NMDA receptor antagonist in a controlled release form. Alternatively the composition of the invention may be in the form of a tablet wherein the immediate release forms the shell and the controlled release form constitutes the core.
Alternatively, the two forms of the NMDA receptor antagonist may be dispersed throughout the tablet.
The composition of the invention may be produced by providing a core containing 30 the NMDA receptor antagonist controlled release component coated with an enteric or delayed release coating. The core can be in the form of beads compressed to a tablet. The coated core may then be compressed into tablets CA 0223~,071 1998-04-16 along with a powder mixture containing additional NMDA receptor antagonist or filled in combination with uncoated NMDA receptor antagonist into a capsule shell. As a result, the final composition provides an amount of NMDA receptor antagonist for immediate release following administration and an additional s amount of NMDA receptor antagonist for controlled release.
The controlled release form of the NMDA receptor antagonist is such as to provide sustained release of the antagonist. Preferably the controlled or sustained release form provides a therapeutic effect over a period greater than o about 6 hours. More preferably the sustained therapeutic effect is greater than about 8 hours. A sustainecll therapeutic effect period of 8 to 24 hours being especially preferred. The SR component of the controlled release composition is aimed at reducing the dosage interval from 3 to 6 times daily to 1 to 2 times daily.
15 The controlled release form of the antagonist may be coated beads or granules of the- NMDA receptor antagonist. The coated antagonist may be combined with uncoated or lightly coated antagonist to provide a composition of the present invention. The term "lightly coated" as used in the description means a rapidly disintegrating coating for aesthetic, handling or stability purposes. These then20 may be filled into capsules or formed into tablets. Microencapsulation may also be used to produce the controlled release form of the NMDA receptor antagonist.
The coating or matrix material may be any suitable material. The coating or matrix material may be a polymer or a wax. The wax may be selected from any suitable 25 wax or wax-like material including natural oil and fat and hardened oils such as hardened rapeseed oil, hardened castor oil, hardened beef tallow, palm oils and the like; waxes such as carnauba wax, bees wax, paraffin wax, ceresine wax, shellac wax or a fatty acid.
30 The present invention also provides a kit including a plurality of unit dosage forms, in a container or the like, the container including indicia indicative of a CA 0223S07l l998-04-l6 WO 97/14415 PCT/AU9Gi'UQ~S8 dosage regimen, at least one of the unit dosages being in the form of a pharmaceutical composition in accordance with the present invention.
The kit may further include unit dosages which provide immediate and controlled 5 release of one or more actives such as an NMDA receptor antagonist. The kit - may also include instructions for use of the kit.
Throughout the claims and description of this specification, the word "comprise"and variations of the word, such as "comprising" and "comprises", is not intended 10 to exclude other additives, components, integers and steps.
The present invention will now be more fully described with reference to the accompanying example. It should be understood, however that the following description is illustrative only and should not be taken in any way as a restriction 15 on the generality of the invention as specified above.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU!)G/(. ~;''~
FI~URES
Figure 1: Dissolution rate of Sustained Release Dextromethorphan capsules A DEXTROMETHORPHAN DISSOLUTION PROFILE
BACKGROUND
10 Dextromethorphan (DM) is an NMDA recpetor which has been in clinical use for many years. Pharmacokinetic data suggest that after a normal 60mg dose the absorption of the drug is quite rapid, reaching maximum plasma levels in 1 to 2 hours. However, the bioavailability of the drug is quite low, probably because of extensive first-pass hepatic metabolism. Once absorbed, DM is converted in the 15 body to a metabolite (dextrophan) which is reported to be pharmacologically acttve. Both the parent and the metabolite have short half-lives (2 to 4 hours).
Since DM and the active metabolite have short half-lives, a controlled release formulation will be useful to provide up to 24 hour delivery of this NMDA receptor 20 antagonist from a single dose.
METHOD
a) PRODUCTION OF DE:lCTROMETHORPHAN CAPSULES
Dextromethorphan capsules were prepared according to the following and dissolution profiles were determined on the capsules.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU96/0~658 (i) Granulating Dextromethorphan Solution Inqredient % (WNV) Ethanol 96 PC/BP 95.0 sHydroxy Propyl Cellulose BP/NF 5.0 Ethanol 96 PC/BP was added to a container. To this, Hydroxy Propyl Cellulose BP/NF was added while shear stirring. The solution was left to stir until all of the polymer was dissolved.
(ii) Coating Solutions Formulation 1 S Inqredient % (WNV) Ethanol 96 PC/BP 95.0 Hydroxy Propyl Methyl Cellulose BP/USP 603 2.0 Ethyl Cellulose N50 3.0 Ethanol 96 PC/BP and Hydroxy Propyl Methyl Cellulose BP/USP 603 were shear stirred. After the HPMC had dissolved, Ethyl Cellulose N50 was shear stirred into the solution. The solution was shear stirred until the Ethyl Cellulose had completely dissolved.
CA 0223~071 1998-04-16 WO 97/14415 PCT/AU9Gf~
Formulation 2 Ingredient % (WNV) Ethanol 96 PC/BP 93.43 s Diethyl Phthalate BP/USP 0.65 Methacrylic Acid Copolymer NF, Type C Powder 1.05 Ethyl Cellulose N50 3.59 Poly Ethylene Glycol (6000) I~IF 1.28 o The above ingredients were combined with stirring to produce Coating Formulation 2.
(iii) Dextromethorphan Cores Dextromethorphan Cores Parlt 1 The cores containing dextromethorphan were produced in a fluid bed coater at the following conditions:
Inlet Air Temperature: 50~C
20 AirFlow: 80 m3/hr Two sets of dextromethorphan containing cores were produced; one with dextromethorphan potency of 57.75% and one with a potency of 80%. Both cores were made in a fluid bed coater with the ingredients listed below using 25 standard methods known to those skilled in the art. The particle size range of the final cores was 710-1400 microns for the low potency cores and 1000-1700 microns for the high potency cores. In order that the desired capsule size wouldbe used, the high potency cores were used in the next part of the process.
CA 0223~071 1998-04-16 lngredient % (WNV)TypicalAmounts (kg) Ethanol 96 PCIBP ~ - 0.200 Dextromethorphan Granulating Solution 43.82 1.560 Dextromethorphan HBr 33.71 1.200 s Sugar Spheres 30-35 Mesh 22.47 0.800 Theoretical Potency at the end of Dextromethorphan Core Part 1 is 57.75%.
Dextromethorphan Core Part 2 The cores containing dextromethorphan were produced in a fluid bed coated at the following operating conditions:
Inlet Air Temperature: 50~C
Air Flow: 80 m3/hr -Ingredient % (WNV) TvPical Amounts (kg) Ethanol 96 PCIBP - 0.200 Dextromethorphan Granulating Solution 43.82 1.560 Dextromethorphan HBr 33.71 1.200 Dextromethorphan Cores Part 1 22.47 0.800 Theoretical potency at the end of Dextromethorphan Core Part 2 is 80%.
25 The final core will have the following composition.
Ingredient % (WN~) Dextromethorphan HBr 79.98 Hydroxy Propyl Cellulose BPINF 5.20 Sugar Spheres (30-35) Mesh 14.82 CA 0223~071 1998-04-16 (iv) De,~l,c"l,cthorphan Pellets The high potency dextromethorphan cores were dispensed with one of thecoating formulations and talc in a fluid bed coater to produce the pellets. The s process was run with the two different coating formulations and two different theoretical polymer coat weights (TPCW) were produced with Coating formulation 1. The conditions in the fluid bed coater are as follows:
Inlet Air Temperature: 50~C
o AirFlow: 80 m3/hr Dew Point: 0~C
The pellets were produced by standard coating methods well known to those skilled in the art. The final pellets within the size range 1000-1700 microns were retained.
-Aim Product for A6-048 A1 (8% Theoretical Polymer Coat Weight (TPCW)). A6-048 A1, A6-052 A2, and A6-048 A2 are batch numbers used to identify different pellet compositions.
Ingredient % (WN\I)TypicalAmounts (kq) Ethanol 96 PC/BP - 0.2000 Coating Formulation 1 62.51 1.7400 Talc Purified Micronised BP/USP 1.56 0.0435 Dextromethorphan Cores 35.93 1.0000 CA 0223~071 1998-04-16 Aim Product for A6-052 A2 (10% Theoretical Polymer Coat Weight (TPCV\~
In~redient % (WNV) Typical Amounts (kg) Ethanol 96 PC/BP - 0.2000 s Coating Formulation 2 67.80 Talc Purified Micronised BP/USP 1.69 0.0555 Dextromethorphan Cores 30.51 1.0000 The resulting Dextromethorphan Pellets have an excipient breakdown as follows.
DextromethorPhan Pellet A6-052 A2 (10% TPCW) Ingredient % (WN\~) Dextromethorphan HBr 68.56 Hydroxy Propyl Cellulose BP/NF 4.46 Sugar Spheres (30-35) Mesh 12.70 Ethyl Cellulose N50 5.20 Diethyl Phthalate BP/USP 0.94 Methacrylic Acid Copolymer NF, Type C Powder 1.52 20 Poly Ethylene Glycol (6000) NF 1.86 Talc Purified Micronised BP/USP 4.76 Dextro Pellet A6-048 A1 (8% TPCW) 25 Ingredient % (WN\I) Dextromethorphan HBr 70.75 Hydroxy Propyl Cellulose BP/NF 4.60 Sugar Spheres (30-35) Mesh 13.11 Hydroxy Propyl Methyl Cellulose BP/USP 603 3.08 Ethyl Cellulose N50 4.61 Talc Purified Micronised BP/USP 3.85 CA 0223~071 1998-04-16 Dextro Pellet A6-048-A2 has a 10% TPCW with the same extract coating solution.
(v) Capsules 5 Capsules were filled by blending cores with pellets. Each size 0, natural / natural capsule contained 250 mg of dextromethorphan. The ratio of core ADS
equivalent to pellet ADS equivalent was 25t75. This meant that 62.5 mg of dextromethorphan was contained in the immediate release cores, and 187.5 mg of dextromethorphan was contained in the controlled release pellets. The 10 potencies of each of the cores and pellets was determined by UV assay.
b) MEASUREMENT OF DISSOLUTION OF DEXTROMETHORPHAN
CAPSULES
5 Dissolution was measured using USPXXIII apparatus and method for dissolution ~711~, apparatus 1. The analysis measures the UV absorbance of dextromethorphan at 278nm.
RESULTS
DISSOLUTION PROFILE OF DEXTROMETHORPHAN CAPSULES
Dissoiution of the dextromethorphan capsules was measured according to the parameters above. The theoretical dissolution profile is compared with actual 25 dissolution profile in Table 2 and shown in Figure 1. An aim dissolution profile was established with reference to the pharmacokinetic parameters, derived from the literature of immediate release dextromethorphan.
WO 97/1441~i PCT/AU96~ '8 TABLE 2: AIM AND ACTUAL DISSOLUTION
Aim Actual Time (hours) % Released + 20% limit A6-048 A1 A6-048 A2 A6-052 A2 0.5 27.5 22-33 25.8 24.9 26.7 1 30 24-36 28.0 26.5 27.8 2 35 28-42 33.3 29.5 31.5 4 45 36-54 43.8 36.3 42.2 6 55 44-66 55.2 44.4 53.2 8 65 52-78 66.8 53.3 64.1 12 85 68-100 87.9 71.8 82.0 16 100 >80 99.6 87.7 94.3 Finally, it is to be understood that various other modifications and/or alterations 5 may be made without departing from the spirit of the present invention as outlined herein.
Claims (47)
1. An analgesic pharmaceutical composition for the administration of an NMDA receptor antagonist to a human or animal subject for the treatment of pain,the composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up.
2. An analgesic pharmaceutical composition according to claim 1 in a unit dosage form.
3. An analgesic pharmaceutical composition according to claim 1 providing an NMDA receptor antagonist to a human or animal subject such that the NMDA
receptor antagonist is in the range of from about 1 to 5000 mg.
receptor antagonist is in the range of from about 1 to 5000 mg.
4. An analgesic pharmaceutical composition according to claim 3 providing an NMDA receptor antagonist to a human or animal subject such that the NMDA
receptor antagonist is in the range of from about 1 to 1000 mg.
receptor antagonist is in the range of from about 1 to 1000 mg.
5. An analgesic pharmaceutical composition according to claim 4 providing an NMDA receptor antagonist to a human or animal subject such that the NMDA
receptor antagonist is in the range of from about 100 to 800 mg.
receptor antagonist is in the range of from about 100 to 800 mg.
6. An analgesic pharmaceutical composition according to any one of claims 1-5 wherein an NMDA receptor antagonist in the immediate release form comprises 5% to 90% of the total weight of the NMDA receptor antagonist.
7. An analgesic pharmaceutical composition according to claim 6 wherein the NMDA receptor antagonist in the immediate release form comprises 10%-60% of the total weight of the NMDA receptor antagonist.
8. An analgesic pharmaceutical composition according to claim 6 or 7 wherein the NMDA receptor antagonist in the immediate release form comprises 15%-50% of the total weight of the NMDA receptor antagonist.
9. An analgesic pharmaceutical composition according to claim 1, including an NMDA receptor antagonist in an immediate release form in a single dosage form combined with an NMDA receptor antagonist in a sustained released form.
10. An analgesic pharmaceutical composition according to claim 9 wherein a portion of the NMDA receptor antagonist is immediately released following administration and a portion is sustained released to provide therapeutic effectover a period of greater than 6 hours.
11. An analgesic pharmaceutical composition according to claim 10 wherein the therapeutic effect is provided over a period of 8 to 24 hours.
12. An analgesic pharmaceutical composition according to claim 11 wherein the therapeutic effect is provided over a period of 8 to 12 hours.
13. An analgesic pharmaceutical composition according to claim 12 wherein the therapeutic effect is provided over a period of 12 to 24 hours.
14. An analgesic pharmaceutical composition according to any one of claims 1 to 13 wherein the NMDA receptor antagonist in the immediate release or sustained release form is the same or different.
15. An analgesic pharmaceutical composition according to any one of claims 1 to 14 wherein the immediate release or sustained release form are in a form selected from the group including active cores comprising active; tablets;
multi-Layered tablets; capsules containing active cores, either coated or uncoated;
liquids; powder; granules or pellets, either coated or uncoated; suspensions; aninjectable solution; a suppository; implant; transdermal patch; or osmotic pump.
multi-Layered tablets; capsules containing active cores, either coated or uncoated;
liquids; powder; granules or pellets, either coated or uncoated; suspensions; aninjectable solution; a suppository; implant; transdermal patch; or osmotic pump.
16. An analgesic pharmaceutical composition according to claim 15 wherein the immediate release and sustained release form of the NMDA receptor antagonist are separate components in a multi-layer tablet wherein one or more layers include the NMDA receptor antagonist in an immediate release form and one or more layers include the NMDA receptor antagonist in a sustained release form.
17. An analgesic pharmaceutical composition according to claim 16 wherein the immediate release and sustained release forms of the NMDA receptor antagonist are dispersed throughout a tablet.
18. An analgesic pharmaceutical composition according to claim 15 wherein the immediate release and sustained release form of the NMDA receptor antagonist are separate components in a capsule wherein one or more components include the NMDA receptor antagonist in an immediate release form and one or more components include the NMDA receptor antagonist in a sustained release form.
19. An analgesic pharmaceutical composition according to claim 18 wherein one or more of the components are active cores or pellets and wherein the activecores are uncoated or coated for immediate or sustained release of the active and wherein the pellets are coated for sustained release of the active.
20. An analgesic pharmaceutical composition according to claims 18 or 19 comprising a blend of cores and pellets wherein a ratio of cores to pellets is 25/75.
21. An analgesic pharmaceutical composition according to any one of claims 1 to 20 wherein the NMDA receptor antagonist is a morphinan selected from the group including dextromethorphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilpine, remacemide, lamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine, levemopamil, a pharmaceutically acceptable salt or ester thereof, or a metabolicprecursor of any of the foregoing.
22. An analgesic pharmaceutical composition according to claim 21 wherein the NMDA receptor antagonist is dextromethorphan (DM) or a pharmaceutically acceptable salt.
23. An analgesic pharmaceutical composition according to claim 22 wherein the NMDA receptor antagonist is dextromethorphan hydrobromide.
24. An analgesic pharmaceutical composition for the administration of dextromethorphan to a human or animal subject for the treatment of pain, the composition being in a unit dosage form and including dextromethorphan in an immediate release form combined with dextromethorphan in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up, wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37°C is between 22% and 33% (by weight) dextromethorphan released after 0.5 hour, between 24% and 36% (by weight) dextromethorphan released after 1 hour, between 28% and 42%
(by weight) dextromethorphan released after 2 hours, between 36% and 54% (by weight) dextromethorphan released after 4 hours, between 44% and 66% (by weight) dextromethorphan released after 6 hours, between 52% and 78% (by weight) dextromethorphan released after 8 hours, between 68% and 100% (by weight) dextromethorphan released after 12 hours, and greater than 80% (by weight) dextromethorphan released after 16 hours.
(by weight) dextromethorphan released after 2 hours, between 36% and 54% (by weight) dextromethorphan released after 4 hours, between 44% and 66% (by weight) dextromethorphan released after 6 hours, between 52% and 78% (by weight) dextromethorphan released after 8 hours, between 68% and 100% (by weight) dextromethorphan released after 12 hours, and greater than 80% (by weight) dextromethorphan released after 16 hours.
25. An analgesic pharmaceutical composition according to any one of claims 1 to 24 wherein the immediate release forms of the NMDA receptor antagonist are particles of the antagonist or particles of the antagonist admixed with soluble components selected from the group including sugars including sucrose, lactose, fructose, mannitol; polymers including polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; surfactants including sodium lauryl sulphate, chremophor, tweens, spans, pluronics; insoluble components including microcrystalline cellulose, Ca3(PO4)2, talc, aerosol; coating material includingpolyethylene glycol, hydroxypropyl methyl cellulose, wax, fatty acids; dispersins in suitable material including wax, polymers, pharmaceutically acceptable oils, soluble agents or combinations thereof.
26. An analgesic pharmaceutical composition according to any one of claims 1 to 25 wherein the sustained release form of the NMDA receptor antagonist is in amatrix composition selected from the group including waxes including carnauba, bees wax, paraffin wax, ceresine, shellac, fatty acids, fatty alcohols; oils, hardened oils or fats including hardened rapeseed oil, castor oil, beef tallow, palm oil, soya bean oil; insoluble matrix polymers including ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers; water soluble matrix materials including polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials including sugars including lactose, sucrose, fructose, mannitol, salts including sodium chloride, potassium chloride, organic acids including fumaric acid, succinic acid, lactic acid, tartaric acid and mixtures thereof.
27. An analgesic pharmaceutical composition according to claim 26 further including an enteric polymer selected from the group including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups or combinations thereof.
28. An analgesic pharmaceutical composition according to claim 27 wherein the composition further includes a binder selected from the group including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate butyrate, or enteric binding materials such as hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate or combinations thereof.
29. An analgesic pharmaceutical composition according to any one of claims 1 to 28 wherein the immediate release or sustained release forms are coated with apharmaceutically acceptable coating composition comprising ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such as sugars including lactose, sucrose, fructose and mannitol, salts including sodium chloride, potassium chloride and derivatives, organic acids including fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof, enteric polymers including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.
30. An analgesic pharmaceutical composition according to claim 29 wherein the coating composition includes from 0 to 50% by weight of a plasticiser selected from the group including silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, polacrilin potassium, or any combination thereof.
31. An analgesic pharmaceutical composition according to claim 30 further including 0 to 200% w/w of a filler selected from the group including silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, microcrystalline cellulose, polacrilin potassium, or any combination thereof.
32. An analgesic pharmaceutical composition according to claim 31 further comprising a swelling/gelling polymer selected from the group including hydroxypropyl cellulose in the range 0-50% w/w or a hydrophobic material such as cetylalcohol in the range 10-90% w/w.
33. An analgesic pharmaceutical composition according to any one of claims 1 to 32 in a form suitable for oral or rectal administration or for administration by transdermal, intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular means.
34. A method of preparing an analgesic pharmaceutical composition for the administration of an NMDA receptor antagonist to a human or animal subject for the treatment of pain, the composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up, said method including:
providing a matrix or coated core containing an NMDA receptor antagonist to provide sustained release of a NMDA receptor antagonist;
providing a mixture containing a NMDA receptor antagonist to provide an immediate release of a NMDA receptor antagonist; and combining the matrix or coated core with the mixture.
providing a matrix or coated core containing an NMDA receptor antagonist to provide sustained release of a NMDA receptor antagonist;
providing a mixture containing a NMDA receptor antagonist to provide an immediate release of a NMDA receptor antagonist; and combining the matrix or coated core with the mixture.
35. A method according to claim 34 wherein the matrix core is a matrix composition selected from the group including waxes including carnauba, bees wax, paraffin wax, ceresine, shellac, fatty acids, fatty alcohols; oils, hardened oils or fats including hardened rapeseed oil, castor oil, beef tallow, palm oil, soyabean oil; insoluble matrix polymers including ethyl cellulose, cellulose acetatebutyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers; water soluble matrix materials including polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials including sugars including lactose, sucrose, fructose, mannitol, salts including sodium chloride, potassium chloride, organic acids including fumaric acid, succinic acid, lactic acid, tartaric acid and mixtures thereof.
36. A method according to claim 34 wherein the coated core is a core of NMDA receptor antagonist coated with a pharmaceutically acceptable polymer including diffusion barrier polymers with or without porosity enhancers selected from the group including ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other pharmaceutically acceptable polymers, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such as sugars including lactose, sucrose, fructose and mannitol, salts including sodium chloride, potassium chloride and derivatives, organic acids including fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof, enteric polymers including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.
37. A method according to claim 34 wherein the core and the mixture are combined and compressed into a tablet form and wherein the core and the mixture are dispersed throughout the tablet form.
38. A method according to claim 34 wherein the core and the mixture are combined and compressed into a tablet form such that the core and the mixture form a multilayer tablet form.
39. A method according to claim 34 wherein the core and the mixture are combined into a capsule.
40. A method for the therapeutic or prophylactic treatment of pain related to wind-up in a human or animal subject, the method including administering to the subject an analgesic pharmaceutical composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustainedrelease form being present in sufficient amounts to diminish or abolish wind-up.
41. A method according to claim 40 wherein the analgesic pharmaceutical composition is in a unit dosage form.
42. A method according to claim 40 for the treatment of chronic or acute pain.
43. A method according to claim 42 wherein the analgesic pharmaceutical composition is administered pre-operatively.
44 A method according to claim 40 wherein the pain is related to hyperalgesia or alkodynia.
45. A method for the treatment of Huntington's disease amyotrophic lateral sclerosis (ALS), AlDS-related dementia, Alzheimer's disease, schizophrenia, motoneurone diseases and CNS and brain injuries resulting from a number of causes including trauma, stroke and neurosurgery in a human or animal subject, the method including administering to the subject an analgesic pharmaceutical composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up.
46. A kit including a plurality of unit dosage forms, in a container or the like, the container including indicia indicative of a dosage regimen, at least one of the unit dosages being in the form of a pharmaceutical composition according to any one of claims 1 to 33.
47. A kit according to claim 45 further including instructions and unit dosage forms providing immediate release and sustained release of NMDA receptor antagonist.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPN6057 | 1995-10-19 | ||
| AUPN6057A AUPN605795A0 (en) | 1995-10-19 | 1995-10-19 | Analgesic pharmaceutical composition |
| PCT/AU1996/000658 WO1997014415A1 (en) | 1995-10-19 | 1996-10-18 | Analgesic immediate and controlled release pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2235071A1 true CA2235071A1 (en) | 1997-04-24 |
Family
ID=29402805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2235071 Abandoned CA2235071A1 (en) | 1995-10-19 | 1996-10-18 | Analgesic immediate and controlled release pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2235071A1 (en) |
-
1996
- 1996-10-18 CA CA 2235071 patent/CA2235071A1/en not_active Abandoned
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