WO2014108808A2 - Formulations pharmaceutiques pour le traitement et la prévention de la neuropathologie et de la neurodégénérescence induites par un traumatisme - Google Patents

Formulations pharmaceutiques pour le traitement et la prévention de la neuropathologie et de la neurodégénérescence induites par un traumatisme Download PDF

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WO2014108808A2
WO2014108808A2 PCT/IB2014/000606 IB2014000606W WO2014108808A2 WO 2014108808 A2 WO2014108808 A2 WO 2014108808A2 IB 2014000606 W IB2014000606 W IB 2014000606W WO 2014108808 A2 WO2014108808 A2 WO 2014108808A2
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trauma
cells
progesterone
formulation
lithium
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PCT/IB2014/000606
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English (en)
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WO2014108808A3 (fr
Inventor
James Lorne HENRY
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Henry James Lorne
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the presently disclosed invention and many particular invention embodiments relate to multiple-component formulations, the use of such formulations, and to methods, procedures and combinations thereof to prevent or reduce, or to reduce the risk of, the damage that can otherwise lead to numerous types of
  • Anticonvulsant/antiepileptic compounds suitable for use as components of invention embodiments include, but not exclusively, one or more from the group comprising gabapentin, pregabalin, barbiturates (such as phenobarbital,
  • benzodiazepines such as clozepam, clonazepam, chlorazepate, diazepam, midazolam, lorazepam, and other hypnotic, anxiolytic, anticonvulsant, amnesic compounds
  • bromides such as potassium bromide,
  • carbamates such as felbamate, fluorofelbamate
  • carboxamides such as carbamazepine, oxcarbazepeine, eslicarbazepine acetate
  • fatty acids such as valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide, sec-butyl -prop ylacetamide
  • fructose derivatives such as topiramate
  • hydantoins such as ethotoin, phenytoin, mephenytoin
  • zonisamide zonisamide
  • triazines such as lamotrigine
  • ureas such as pheneturide, phenacemide
  • valproyamides such as valpromide, valoctamide
  • others known and unknown as well as any homolog or derivative or compound acting on or through a receptor, an enzyme or other mechanism upon which an anticonvulsive/antiepileptic can act, as well as any compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by one or more anticonvulsant/antiepileptic compounds, as well as any related slow-release compound.
  • Neurosteroid/neuroactive steroid compounds suitable for use as components of invention embodiments include, but not exclusively, one or more from the group comprising progesterone, progesterone prodrugs, progesterone derivatives, progesterone analogs, and other progesterone compounds such as but not exclusive to
  • allotetrahydro as well as metabolites of neurosteroids and neuroactive steroids, and including any corticoid, glucocorticoid, estrogen compound or any such compound acting on or through a progesterone, corticosteroid, glucocorticoid, estrogen or other neurosteroid receptor or through any other mechanism upon which progesterone, a corticosteroid, a glucocorticoid, an estrogen or other neurosteroid does or can act, as well as any homolog or derivative or compound acting on or through mechanisms that would modify, modulate or affect in any way pathways or processes affected by progesterone, estrogen or any neurosteroid, as well as any related slow-release compound.
  • NK-1 receptor antagonist compounds suitable for use as components of invention embodiments include, but not exclusively, any biologically active compound of one or more from the group comprising aprepitant, fosaprepitant, casopitant, maropitant, vestipitant, CP-99,994, CP-122,721, MK 869, LY 303870, RPR 67580, RPR 100893, L 758298, L 365260, L 733060, GR 205171, CGP 49823, CJ 11974, and others known and unknown, and any compound acting on or through the NK-1 receptor or any other mechanism that involves activation or involvement of the NK-1 receptor or its synthesis, and other chemical entities known and unknown, including any ligand or compound acting on or through an NK-1 receptor or other mechanism upon which substance P, an endogenous ligand for the NK-1 receptor, does or can act, as well as any compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by substance P or the NK-1 receptor,
  • any ligand or homolog or derivative or compound acting on or through an NK- 1 or NK-2 or NK-3 receptor is included in the presently disclosed technology.
  • Lithium-related/lithium-containing compounds suitable for use as components of invention embodiments include, but not exclusively, any biologically active compound of one or more from the group comprising lithium citrate, lithium carbonate, lithium chloride, lithium bromatum and others known and unknown, as well as any compound acting on or through a lithium receptor or other mechanism upon which lithium does or can act, as well as any homolog or derivative or compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by lithium, as well as any related slow-release compound.
  • Numerous compounds can be administered to a subject in any combination or permutation of these classes of compound to practice this invention aimed to reduce or prevent the development or the risk of development of neuropathology as a result of traumatic injury to a subject by administering to a subject in need thereof a multiplicity of compounds by such combinations of any two, any three or any four compounds from the classes of compounds comprising anticonvulsants/antiepileptics,
  • neurosteroids/neuroactive steroids NK-1 receptor antagonists and lithium- related/lithium-containing compounds.
  • NK-1 receptor antagonists NK-1 receptor antagonists and lithium- related/lithium-containing compounds.
  • injury or damage can be to any nerve cell or nerve cells, to any neural support cell as described herein, or to any neural support tissue as described herein.
  • Injury or damage can be to the brain, the brain stem, the cerebellum, the spinal cord, the enteric nervous system and the peripheral nervous system or any other nerve cell.
  • a subject in need of invention embodiments can be an individual who is at risk of injury or damage, an individual who is about to experience an event that has the potential to cause traumatic damage or injury, or an individual who has experienced a trauma as described herein.
  • Embodiments of the invention address unmet or unsolved medical needs including brain injury, central nervous system ischemia, spinal cord injury, enteric nervous system injury, peripheral nerve injury and any other injury that can include or affect nerve cells, neural support cells or neural support tissues.
  • These unmet or unsolved medical needs share the commonness of the potential for lifelong adverse health conditions or disability. They also share the commonness of the void in current medical interventions to reduce or prevent these adverse health conditions or disability.
  • formulations for use in one or more treatments, procedures and methods to prevent the development, or the risk of development, of neuropathology and neurodegeneration sequelae associated with or caused by trauma or neurotrauma to a subject in need, or for the amelioration of the effects caused by trauma to a subject in need are provided.
  • the present technology presents many embodiments of formulations comprising, or consisting essentially of, any two or any three or all four biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when used in combination with the other biologically active compounds, the compounds being selected from a pharmaceutically effective amount of any two or any three or all four of A) at least one biologically active compound selected from the group comprising anticonvulsants and antiepileptics; B) at least one biologically active compound selected from the group comprising neurosteroids and neuroactive steroids; C) at least one biologically active compound selected from the group comprising NK-1 receptor antagonists; and D) at least one biologically active compound selected from the group comprising lithium-containing and lithium-related compounds.
  • Such formulations include, as examples, wherein the at least one anticonvulsant or antiepileptic agent is one or more from the group consisting of gabapentin, pregabalin, barbiturates (such as phenobarbital, methylphenobarbital, metharbital, barbexaclone and other central nervous system depressants), benzodiazepines (such as clozepam, clonazepam, chlorazepate, diazepam, midazolam, lorazepam, and other hypnotic, anxiolytic, anticonvulsant, amnesic compounds), bromides (such as potassium bromide), carbamates (such as felbamate, fluorofelbamate), carboxamides (such as carbamazepine, oxcarbazepine, eslicarbazepine a
  • zonisamide zonisamide
  • triazines such as lamotrigine
  • ureas such as pheneturide, phenacemide
  • valproyamides such as valpromide, valoctamide
  • others known and unknown as well as any homolog or derivative or compound acting on or through a receptor, an enzyme or other mechanism upon which an anticonvulsive/antiepileptic can act, as well as any compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by one or more anticonvulsant/antiepileptic compounds, as well as any related slow-release compound.
  • the present technology provides many embodiments of formulations comprising any two, or any three, or all four, biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when used in combination with the other biologically active compounds, wherein the at least one neurosteroid or neuroactive steroid is one or more compounds selected from the group consisting of progesterone, progesterone prodrugs, progesterone derivatives, progesterone analogues, and other progesterone compounds such as but not exclusive to medroxyprogesterone acetate, megestrol acetate, 17alpha- hydroxyprogesterone, 5alpha-dihydroxyprogesterone, 3alpha,5alpha- trihydroxyprogesterone, 14b-hydroxy progesterone, 17alpha-hydroxyprogesterone caproate, 16-methyl- 17-benzoyloxypregnen-4-en-3,20-dione, hydroxyprogesterone-3-O- carboxymethyloxime
  • pregnenolone (3beta-hydroxypregn-5-en-20-one) , 17cc-hydroxypregnenolone,
  • progesterone 17cc-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, deoxycorticosterone, 11-deoxycortisol, 3 alpha-hydroxy-5 alpha-pregnan-20-one
  • neuroactive androgens including but not limited to androstenedione (the precursor of 3alpha,5alpha-A, or androsterone), androsterone (5alpha-androstan-3alpha-ol-17-one; 3alpha,5alpha-A), 5alpha-dihydrotestosterone (5alpha-DHT) and its metabolite 5alpha- androstane-3alpha,17beta-diol (3alpha,5alpha-Adiol), 3a,17P-dihydroxy-5a-androstane, 3a-hydroxy-5a-androstan-17-one, 3a-hydroxy-5P-androstan-17-one, androst-5-ene- 3p,17P-diol, 3p,17a-dihydroxy-pregn-5-en-20-one (17a-
  • the present technology also provides many embodiments of formulations comprising any two, or any three, or all four, biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when used in combination with the other biologically active compounds, wherein the at least one NK-1 receptor antagonist is one or more from the group consisting of aprepitant, fosaprepitant, casopitant, maropitant, vestipitant, CP- 99,994, CP-122,721, MK 869, LY 303870, RPR 67580, RPR 100893, L 758298, L 365260, L 733060, GR 205171, CGP 49823, CJ 11974, and others known and unknown, and any compound acting on or through the NK- 1 receptor or any other mechanism that involves activation or involvement of the NK-1 receptor or its synthesis, and other chemical entities known and unknown, including any ligand or compound acting on or through an NK-1 receptor or other mechanism upon which substance P, an end
  • any ligand or homolog or derivative or compound acting on or through an NK-1 or NK-2 or NK-3 receptor, including receptor isoforms, or related mechanism as well as any ligand that occupies, activates or deactivates these receptors, is included in the presently disclosed technology.
  • embodiments of the present technology include many embodiments of formulations comprising any two or any three or all four biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when used in combination with the other biologically active compounds, wherein the at least one lithium-containing/lithium-related agent is one or more from the group consisting of lithium carbonate, lithium citrate, lithium chloride, lithium bromatum and others known and unknown, as well as any compound acting on or through a lithium receptor or other mechanism upon which lithium does or can act, as well as any homolog or derivative or compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by lithium, as well as any related slow-release compound.
  • the at least one lithium-containing/lithium-related agent is one or more from the group consisting of lithium carbonate, lithium citrate, lithium chloride, lithium bromatum and others known and unknown, as well as any compound acting on or through a lithium receptor or other mechanism upon which lithium does or can act, as well as any homolog or derivative or compound acting on or through mechanisms that would modify or affect
  • Examples of the many embodiments of formulations, methods and procedures of the present technology are many. These include wherein the formulation consists of any two, or any three, or all four, of the anticonvulsants or antiepileptics, the neurosteroids or neuroactive steroids, the NK-1 receptor antagonists and the lithium-containing or lithium- related compounds, and wherein the formulation is formulated, or adapted and arranged, for administration within 12 hours after the trauma.
  • Such examples also include wherein the formulation consists essentially of any two, or any three, or all four, of the anticonvulsants or antiepileptics, the neurosteroids or neuroactive steroids, the NK-1 receptor antagonists and the lithium-containing or lithium- related compounds, and wherein the formulation is formulated, or adapted and arranged, to be first administered to a mammal in need thereof, within 24 hours after the trauma.
  • the present technology includes formulations consisting essentially of any two, or any three, or all four, of the anticonvulsants or antiepileptics, the neurosteroids or neuroactive steroids, the NK-1 receptor antagonists and the lithium- containing or lithium-related agents, and is formulated, or adapted and arranged, to be first administered as a prophylactic measure within 90 minutes before an expected or potential trauma, and wherein the formulation consists essentially of any two, or any three, or all four, of the anticonvulsant or antiepileptic, the neurosteroid or neuroactive steroid, the NK-1 receptor antagonist and the lithium-containing or lithium-related agent are formulated, or adapted and arranged, for administration within 24 hours of the trauma.
  • the present technology also includes formulations consisting essentially of combinations wherein the anticonvulsants or antiepileptic s, the neurosteroids or neuroactive steroids and the NK-1 receptor antagonists are formulated for administration as a preventive measure within 90 minutes before a possible trauma.
  • embodiments of the present technology include wherein the
  • formulation consists of any two or any three or all four of the anticonvulsant or antiepileptic, the neurosteroid or neuroactive steroid, the NK-1 receptor antagonist and the lithium-containing or lithium-related agent, and is formulated for administration as a precautionary measure within 90 minutes before a possible trauma.
  • Formulations of the present invention include also wherein the formulation comprises a single dosage unit, wherein the formulation is adapted and arranged for administration a plurality of times, such as in some type or types of sequences. These include wherein the formulation is adapted and arranged for administration in one or more dosage units per day, and wherein they are formulated for administration as one or more of tablets, capsules, pills, lozenges or as one or more ingestible or injectable solutions.
  • Consonant with the numerous embodiments of the invention are formulations adapted and arranged, or provided, as examples, for administration via an oral, buccal, mucosal, parenteral, rectal, sub-cutaneous, transdermal, intravenous, intrathecal, intravaginal, nasal, nasal inhalation, pulmonary inhalation, iontophoresis through the skin, iontophoresis through mucosal or buccal membranes, dermal patch, epidural, intracranial, intrapharyngeal, sublingual, intra-articular, intramuscular or a subcutaneous route.
  • the present formulations can be provided in one or more such forms adapted and arranged to be administered to, given to, or taken by, a subject, and may include other ingredients or substances such as excipients, buffers, penetration enhancers, stabilizers, absorption enhancers and carriers.
  • Also consonant with the present formulations are those wherein one or more of the compounds is in the form of one or more of salts, prodrugs, hydrates, derivatives or metabolites of the compound itself, analogues, homologues, compounds acting on or through mechanisms that compounds can act on or through or compounds that modify, modulate or affect in any way pathways or processes affected by compounds or formulations of the invention.
  • the present technology includes numerous combinations, variations and permutations of the many formulations provided within the spirit and scope of the present description.
  • examples of embodiments of the present formulations include wherein the at least one anticonvulsant is gabapentin, in a form adapted and arranged for administration to a mammal in need thereof, wherein the at least one anticonvulsant is pregabalin, in a form adapted and arranged for
  • the at least one anticonvulsant is valproic acid, in a form adapted and arranged for administration to a mammal in need thereof.
  • Exemplary formulation dosage ranges of the present technology include, as examples, wherein the gabapentin is provided in a range of from 5.0 to 9,600 mg, wherein the pregabalin is provided in a range of from 0.5 to 2,400 mg, wherein the valproic acid is provided in a range of from 25 to 4,800 mg.
  • Examples of embodiments of the present formulations include also wherein the at least one neurosteroid is progesterone, in a form adapted and arranged for administration to a mammal in need thereof, wherein the at least one neurosteroid is methylprednisolone, in a form adapted and arranged for administration to a mammal in need thereof, and wherein the at least one neurosteroid is medroxyprogesterone acetate, in a form adapted and arranged for administration to a mammal in need thereof.
  • Exemplary formulation dosage ranges of the present technology include wherein the progesterone is provided in a range of from 0.05 to 1,200 mg, the methylprednisolone, is provided in a range of from 0.02 to 500 mg, wherein the medroxyprogesterone acetate, is provided in a range of from 0.001 to 400 mg.
  • Examples of embodiments of the present formulations include also wherein the at least one NK-1 receptor antagonist is aprepitant, in a form adapted and arranged for administration to a mammal in need thereof, wherein the at least one NK-1 receptor antagonist is vestipitant, in a form adapted and arranged for administration to a mammal in need thereof; wherein the at least one NK-1 receptor antagonist is casopitant, in a form adapted and arranged for administration to a mammal in need thereof.
  • Dosage ranges of the individual two, or three or four components of the present formulations include any which are effective, and especially wherein the aprepitant, is provided in a range of from 0.05 to 750 mg, wherein the vestipitant, is provided in a range of from 0.001 to 200 mg, and wherein the casopitant, is provided in a range of from 0.005 to 1,000 mg.
  • the present formulations include wherein the at least one lithium-containing compound is lithium carbonate, in a form adapted and arranged for administration to a mammal in need thereof; wherein the at least one lithium-containing compound is lithium citrate, in a form adapted and arranged for administration to a mammal in need thereof, and wherein the at least one lithium-containing compound is lithium chloride, in a form adapted and arranged for administration to a mammal in need thereof.
  • embodiments of the present technology include also wherein the lithium carbonate, is provided in a range of from 0.5 to 3,600 mg, wherein the lithium citrate, is provided in a range of from 0.01 to 2,400 mg, and wherein the lithium chloride, is provided in a range of from 3.0 to 3,600 mg.
  • the present technology includes also wherein embodiments of the present formulations are adapted and arranged to treat one or more changes in cellular or tissue structure, function or health, occurring in one or more of the central nervous system, including the brain, the brainstem, the cerebellum and the spinal cord, and the periphery, including the enteric nervous system and the peripheral nervous system, and also wherein they are adapted and arranged to treat one or more selected from the group comprising neuropathy, neuropathology, neurodegeneration and the effects of trauma, and those governed by a balance of neurotrophic/neuroprotective and neurodegenerative
  • the present technology includes also wherein embodiments of the present formulations are adapted and arranged to treat one or more changes governed by neurotrophic and regenerative mechanisms that repair or regenerate nerve cells, neural support cells or neural support tissues.
  • the present technology includes also wherein embodiments of the present formulations are adapted and arranged to treat one or more changes governed by neurodegenerative mechanisms that lead to secondary injury, neuropathology and neurodegeneration, and cell death.
  • the presently disclosed technology also includes wherein embodiments of the present formulations are adapted and arranged to treat neuroprotective mechanisms to prevent or ameliorate neuropathology and neurodegeneration caused by or resulting from trauma.
  • the present formulations can also be adapted and arranged to treat one or more selected from the group comprising physical trauma, chemical trauma, metabolic trauma, medically-related trauma and other trauma, where injury or damage is to at least one nerve, at least one nerve cell, at least one neural support cell or at least one neural support tissue, whether in the central nervous system or in the periphery, and can also be adapted and arranged to treat one or more from the group comprising brain changes resulting short-, medium- or long-term from trauma, including Alzheimer's disease, Parkinson's disease and other disorders where brain trauma is a risk factor.
  • formulations of the invention can be adapted and arranged to treat spinal cord trauma comprising one or more from the group comprising compression, vertebral collapse, cutting wounds, puncture wounds, crush wounds, surgical or medical intervention, and ischemia resulting from loss of blood, insufficient circulation from stoppage or slowing of the heart, or surgical interruption of the blood supply to the spinal cord.
  • formulations of the invention also can be adapted and arranged to treat brain, brainstem and cerebellum trauma including one or more from the group comprising brain injury, ischemia of the central nervous system, physical trauma, chemical trauma, metabolic trauma, trauma from surgical or medical intervention or procedure and other trauma.
  • formulations of the invention can be adapted and arranged to treat enteric nervous system trauma including injury to one or more from the group comprising neurons, progenitor cells, glial cells and interstitial cells of Cajal, cells of Auerbach's myenteric plexus and Meissner's submucosal plexus, as well as neural support cells and neural support tissues, including luminal, lamina limba muscularis mucosal cells, as well as endothelial cells of the vasculature.
  • enteric nervous system trauma including injury to one or more from the group comprising neurons, progenitor cells, glial cells and interstitial cells of Cajal, cells of Auerbach's myenteric plexus and Meissner's submucosal plexus, as well as neural support cells and neural support tissues, including luminal, lamina limbal and muscularis mucosal cells, as well as endothelial cells of the vasculature.
  • formulations of the invention can be adapted and arranged to treat peripheral nerve trauma including one or more from the group comprising sensory nerves, motor nerves, autonomic nerves, nerve cells, neural support cells, such as Schwann cells, myelin cells, satellite cells, as well as neural support tissues such as the vasculature.
  • targets for the present formulations include those adapted and arranged to treat following trauma as an emergency treatment of trauma as would be in the case of unanticipated or accident-related trauma, taken as soon after trauma as possible that may prevent the development of neuropathology and neurodegeneration or the risk of development of neuropathology and neurodegeneration including such conditions as motor vehicle accidents, battlefield injuries, sports injuries, toxic chemical spill and the like, where evidence informs that there is a risk of damage to brain, spinal cord or peripheral nerve.
  • Emergency treatment to prevent secondary injury, neuropathology and neurodegeneration is different from emergency treatment of trauma, where immediate steps are taken to prevent further injury, to stop bleeding, to stabilize the victim and to take life-saving steps.
  • the present formulations, methods and procedures can also be adapted and arranged to treat before trauma as would be in the case of anticipated, potential or purposeful trauma, taken as a pre-exposure prophylaxis measure to reduce the risk of neuropathology in individuals who are about to undergo procedures where there is a risk of trauma, including such conditions as surgery, chemotherapy, radiation therapy and the like, where evidence informs that there is a risk of damage to brain, brain stem, cerebellum, spinal cord, peripheral nerve and/or enteric nerve cells, and wherein prophylaxis treatment for trauma is different from pre- and post-surgical care, where steps are taken to ensure the patient's comfort and rapid recovery from the immediate condition.
  • the present formulations, methods and procedures can also be adapted and arranged to anticipatorily treat before as a precaution in case of an unanticipated or accident-related trauma that may occur, as a pre-exposure precautionary measure taken to reduce the risk of neuropathology in individuals who are about to enter into a situation or condition where there is a great likelihood of trauma, including such conditions as a dangerous military or law enforcement operation or situation, an impending or underway bioterrorism or other attack where neurotoxic chemicals or other agents have been or may have been released.
  • the present formulations can be adapted and arranged to treat any damage, wound, insult, cut, laceration, concussion, lesion, abrasion, contusion, shock, strain, abrupt acceleration, abrupt deceleration, explosion, percussion, metabolic event that causes, results in, brings about, triggers or leads to or can trigger or can lead to secondary injury or damage or change in structure or change in phenotype or change in gene expression or loss of function or altered function or cell death of a nerve cell, a neural support cell or a neural support tissue, as well as to treat physical trauma including vehicle accidents, workplace accidents, sports accidents, falls, burns, radiation, battlefield injuries, concussive injuries, blast injuries, injuries from landmines, injuries from improvised explosive devices, penetrating injuries, non-penetrating injuries or the result of any traumatic event that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue.
  • the present technology can be adapted and arranged to treat chemical trauma including alcohol overdose, drug abuse, stimulant drugs, carbon dioxide poisoning, lead poisoning, copper poisoning, acrylamide and related chemicals, overexposure to certain environmental chemicals such as copper or natural hazards such as insect and other animal venom toxins, herbicides, insecticides, industrial toxic chemicals, bioterrorism chemicals and other chemicals that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue.
  • chemical trauma including alcohol overdose, drug abuse, stimulant drugs, carbon dioxide poisoning, lead poisoning, copper poisoning, acrylamide and related chemicals, overexposure to certain environmental chemicals such as copper or natural hazards such as insect and other animal venom toxins, herbicides, insecticides, industrial toxic chemicals, bioterrorism chemicals and other chemicals that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue.
  • the many embodiments of the invention are adaptable and arrangeable to treat metabolic trauma including, as examples, hypoxia, ischemia, hypoxia, multiple sclerosis, shingles, diabetes, stroke, epileptic or other seizure, post-polio syndrome, HIV/AIDS peripheral neuropathy, subacute posttraumatic myelopathy, and other effects, syndromes and conditions following a type of trauma to the body that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue.
  • metabolic trauma including, as examples, hypoxia, ischemia, hypoxia, multiple sclerosis, shingles, diabetes, stroke, epileptic or other seizure, post-polio syndrome, HIV/AIDS peripheral neuropathy, subacute posttraumatic myelopathy, and other effects, syndromes and conditions following a type of trauma to the body that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue
  • Other exemplary applications of the present technology include those adapted and arranged to treat trauma resulting from medical treatment or medical procedure trauma including injections, surgery, amputation, implantation, laparoscopy, chemotherapy (for example but not exclusively with methotrexate, cisplatin, cytosine arabinose, carmustine, thiotepa among others), radiation therapy, immunosuppressants (for example tacrolimus) and the like, or during a medical procedure that can reduce or impede the blood supply for any period of time and the like.
  • chemotherapy for example but not exclusively with methotrexate, cisplatin, cytosine arabinose, carmustine, thiotepa among others
  • radiation therapy for example tacrolimus
  • immunosuppressants for example tacrolimus
  • Trauma from surgery includes, as examples, laparoscopy, amputation,
  • formulations, methods, procedures and practices for reducing or preventing the development, or the risk of development, of neuropathology as a result of traumatic injury.
  • formulations, methods, procedures and practices contain one or more functions or operations, it will be understood by those within the art that each formulation, method, procedure and practice can be implemented, individually or collectively, within a wide range of many combinations without undue experimentation.
  • formulations according to the inventive subject matter will be formulated for administration to a mammal, and especially to a human, having a condition that is responsive to the administration of such a formulation. Therefore, where contemplated formulation compounds are administered in a
  • contemplated compounds can be formulated in admixture with pharmaceutically acceptable carriers.
  • contemplated compounds can be administered orally as pharmacologically acceptable salts, or intravenously in a physiological saline solution (e.g., buffered to a pH of about 7.2 to 7.5).
  • physiological saline solution e.g., buffered to a pH of about 7.2 to 7.5.
  • Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose.
  • one of ordinary skill in the art may modify the formulations within the teachings of the present disclosure to provide numerous formulations for a particular route of administration.
  • contemplated compounds may be modified to render them more soluble in water or other vehicle that, for example, may be easily accomplished with minor modifications (e.g. salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound or formulation in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in a patient or subject.
  • contemplated compounds may be prepared for delivery in tablet, capsule, pill or solution form, including any form that can deliver a controlled release of these compounds.
  • inactive constituents include, as examples, excipients, binders, coatings, absorption enhancers, penetration enhancers, transport enhancers, stabilizers, chelators, buffers, carriers, clearance modifiers, emulsifying agents, antioxidants, preservatives, sugars, salts, cellulose, dyes, flavoring agents and any other inactive ingredients that are considered generally recognized as safe.
  • prodrug and derivative forms of contemplated compounds may be formed for various purposes, including reduction of toxicity, increasing the organ or target cell specificity, etc.
  • acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds may be advantageous.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to prodrug and other forms to facilitate delivery of active compounds to a target site within the host organism or patient.
  • One of ordinary skill in the art will also take advantage of favorable
  • contemplated compounds may also be metabolized to their biologically active form (e.g., via hydroxylation, glycolsylation, oxidation etc.), and all metabolites of the compounds herein are therefore specifically contemplated.
  • contemplated compounds (and combinations thereof) may be administered in combination with yet further antiviral and/or antibacterial agents.
  • Suitable additional drugs therefore include but are not limited to various antibiotics (e.g., beta-lactam antibiotics, tetracycline antibiotics, oxazine antibiotics, etc.), various antiviral compounds (e.g., polymerase inhibitors), and/or compounds that stimulate the immune system.
  • various antibiotics e.g., beta-lactam antibiotics, tetracycline antibiotics, oxazine antibiotics, etc.
  • various antiviral compounds e.g., polymerase inhibitors
  • inventive technology described herein sometimes illustrates different components contained within, or connected with, different other components. It is to be understood that such descriptions or subject matter are merely exemplary, and that in fact many other descriptions, examples, methods, procedures and practices can be
  • any two or more methods, procedures or practices herein combined to achieve a particular functionality can be seen as “associated with” each other such that the desired functionality is achieved, irrespective of condition, event, injury, damage or pathology components.
  • any two or more components so associated can also be viewed as being “operably connected”, or “operably coupled”, to each other to achieve the desired functionality, and any two or more components capable of being so associated can also be viewed as being “operably couplable”, to each other to achieve the desired functionality.
  • operably couplable include but are not limited to, practices of embodiments of the invention required under different conditions, practices of embodiments of invention requiring different routes or methods of administration, practices of embodiments of invention requiring repeated administration for varying periods of time or logically interacting or logically interactable components to achieve the desired functionality.
  • “formulation” includes, but is not limited to, two compounds selected from gabapentin, progesterone, aprepitant and lithium, three compounds selected from gabapentin, progesterone, aprepitant and lithium or all four compounds selected from gabapentin, progesterone, aprepitant and lithium.
  • formulations, methods, procedures or practices of certain embodiments of the invention include many combinations and permutations thereof with respect to the nature of the individual formulations, and their relative methods, procedures or practices, can vary in operation by the relative methods, procedures or practices.
  • Table 1 provides some examples of dose ranges of drug categories for some particular embodiments of the invention. As such, Table 1 illustrates both the components of the 2-component, 3-component, and 4-component formulation of the invention, and the numerous unspecified formulations, which also fall within the spirit and scope of the invention.

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Abstract

Nouvelles formulations multicomposants, procédures et méthodes d'utilisation de celles-ci pour le traitement de la neurodégénérescence et de la neuropathologie liées à un traumatisme. Les formulations multicomposants selon la présente l'invention comprennent des formes biologiquement actives d'une combinaison quelconque de deux, trois, ou des quatre composants suivants : au moins un neurostéroïde ou stéroïde neuroactif tel que la progestérone ou la progestine de synthèse, au moins un anti-épileptique ou anticonvulsivant tel que la gabapentine, la prégabaline ou l'acide valproïque, au moins un antagoniste du récepteur NK-1, tel qu'aprépitant, casopitant, ou vestipitant, au moins un médicament renfermant du lithium ou apparenté au lithium. Les formulations de l'invention sont conçues ou adaptées pour empêcher ou réduire l'incidence et la sévérité des dommages neurologiques provoquées par un traumatisme, ou le risque de tels dommages. Les formulations, les procédures et les méthodes de l'invention exercent de manière avantageuse à la fois des actions neuroprotectrices pour prévenir ou réduire les lésions secondaires, et des actions neurotrophiques pour réparer et restaurer les cellules et les tissus affectés par le traumatisme, et sont particulièrement utiles pour le traitement de blessures ou de traumatismes causés aux neurones, aux cellules de support des neurones et aux tissus de support des neurones.
PCT/IB2014/000606 2013-01-09 2014-01-07 Formulations pharmaceutiques pour le traitement et la prévention de la neuropathologie et de la neurodégénérescence induites par un traumatisme WO2014108808A2 (fr)

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US11124538B2 (en) 2015-02-20 2021-09-21 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
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