# US 2014/0194394 A1 · Two-component formulations, methods and procedures to prevent or reduce trauma-induced neuropathology and neurodegeneration > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0194394 A1 - Document ID: US20140194394A1 - Status: Published application - Kind: A1 - Application number: 14/055,604 - Filed: 2013-10-16 - Published: 2014-07-10 - Earliest claimed: 2013-01-09 - Inventors: James Lorne Henry - Web page: https://patentgrep.com/patent/US20140194394A1 ## CPC - A61K 33/14: Alkali metal chlorides; Alkaline earth metal chlorides - A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) - A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid - A61K 31/195: having an amino group - A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) - A61K 31/20: having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids - A61K 31/205: Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine - A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) - A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin - A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol - A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone - A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone - A61K 33/00: Medicinal preparations containing inorganic active ingredients - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/02: for peripheral neuropathies - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract Novel two-component formulations, procedures and methods for use in treating neuropathology incident to trauma are provided. Two-component formulations of the invention comprise biologically active forms of at least one neurosteroid or neuroactive steroid, such as progesterone or synthetic progestin, and at least one anti-epileptic or anticonvulsant, such as gabapentin. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by trauma. Formulations, procedures and methods of the invention advantageously effect both neuroprotective actions to prevent or reduce secondary injuries, and neurotrophic actions to repair and restore cells and tissues affected by the trauma, and are especially useful in treating neurological trauma, such as those caused by sports injuries, chemical weapons, vehicle collisions and improvised explosive devices in combat. ## Claims ### Claim 1 (canceled) ### Claim 2 (canceled) ### Claim 3 (canceled) ### Claim 4 (canceled) ### Claim 5 (canceled) ### Claim 6 (canceled) ### Claim 7 (canceled) ### Claim 8 (canceled) ### Claim 9 (canceled) ### Claim 10 (canceled) ### Claim 11 (canceled) ### Claim 12 (canceled) ### Claim 13 (canceled) ### Claim 14 (canceled) ### Claim 15 (canceled) ### Claim 16 A method for one or more of preventing, reducing the effects of, or reducing the risk of development of, neuropathology incident to trauma, the method comprising the steps or actions of A. providing a formulation adapted for the prevention of the development of neuropathology, wherein the formulation comprises two biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other biologically active compound, the two compounds respectively comprising a formulation comprising a pharmaceutically effective amount of: i. at least one biologically active compound from the group comprising anticonvulsants and antiepileptic drugs, wherein the anticonvulsant or antiepileptic is at east one form of gabapentin; and ii. at least one biologically active compound from the group comprising neurosteroids and neuroactive steroids, wherein the neurosteroid or neuroactive steroid is at least one form of progesterone or synthetic progestin; wherein the formulation is in a form adapted and arranged for administration to a mammal in need thereof, such that the development, or the risk of development, of neuropathology is reduced, lessened, attenuated or prevented, and B. administering the formulation to a mammal in need thereof. ### Claim 17 (depends on 16) The method of claim 16, wherein Step B is effected with respect to time in relation to one or more of i.) the onset of the trauma, ii.) in anticipation of a possible or potential trauma, iii.) during the trauma, and iv.) during a period of recovery from the trauma. ### Claim 18 (depends on 16) The method of claim 16, wherein the at least one form of anticonvulsant/antiepileptic is gabapentin, and the at least one form of neurosteroid/neuroactive steroid is at least one form of progesterone or synthetic progestin. ### Claim 19 (depends on 16) The method of claim 16, wherein the formulation is first administered within two hours after the trauma. ### Claim 20 (depends on 16) The method of claim 16, wherein the formulation is first administered within 24 hours after the onset of the trauma. ### Claim 21 (depends on 16) The method of claim 16, wherein the formulation is first administered preventively or prophylactically within 6 hours before the expected onset or the expected end of the trauma. ### Claim 22 (depends on 16) The method of claim 16, wherein the formulation is administered additionally one, or a plurality of, times after the formulation is first administered. ### Claim 23 (depends on 16) The method of claim 16, wherein the formulation is administered one, or a plurality of times as a sustaining dose as needed. ### Claim 24 (depends on 16) The method of claim 16, wherein the at least one form of gabapentin is provided in a dosage range of from about 5.0 mg to about 9,600 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 0.05 mg to about 1,200 mg. ### Claim 25 (depends on 16) The method of claim 16, wherein the at least one form of gabapentin is provided in a dosage range of from about 50 mg to about 4,800 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 5 mg to about 600 mg. ### Claim 26 (depends on 16) The method of claim 16, wherein the at least one form of gabapentin is provided in a dosage range of from about 100 mg to about 2,400 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 50 mg to about 450 mg. ### Claim 27 (depends on 16) The method of claim 16, wherein the at least one form of gabapentin is provided in a dosage range of from about 200 mg to about 600 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 100 mg to about 300 mg. ### Claim 28 A pharmaceutical formulation adapted for the prevention of the development of neuropathology incident to traumatic brain injury, or for the amelioration of the effects caused by traumatic brain injury to a subject, the formulation comprising two biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other biologically active compound, the formulation comprising a pharmaceutically effective amount of: A) at least one biologically active compound selected from the group consisting of anticonvulsants and antiepileptics, wherein the at least one anticonvulsants and antiepileptics are one or more compounds selected from the group consisting of gabapentin, pregabalin, barbiturates, benzodiazepines, bromides, carbamates, carboxamides, fatty acids, fructose derivatives, hydantoins, oxazolidinediones, propionates, pyrimidinediones, pyrrolidines, succinimides, sulphonamides, triazines, ureas and valproyamides; and B) at least one biologically active compound selected from the group consisting of neurosteroids and neuroactive steroids, wherein the at least one neurosteroids and neuroactive steroids are one or more compounds selected from the group consisting of progesterone, progesterone prodrugs, other progesterone compounds selected from 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, 21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone, 17-p-bromophenylcarbamoyloxypregn-4-ene-3,20-dione, 17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione, 6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone, nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone, 16,17-cyclopropanoprogesterone, caproxyprogesterone, 21-hydroxy-6,19-oxidoprogesterone, 17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798, 3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate, progesterone-11HS-horseradish peroxidase, 21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione, 21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone, 11,19-oxidoprogesterone, 6-fluoroprogesterone, 2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(0-carboxymethyl oxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serum albumin, pentarane B, pentarane A, progesterone 6-hemimaleate, progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone, progesterone 3-(O-carboxymethyl)oxime-bovine serum albumin, 18-ethynylprogesterone, 18-vinylprogesterone, 6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin, allylestriol, progesterone-3-ethanolimine, 3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic 18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone, 17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione, 17-hydroxy-6-dehydroprogesterone, 2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone, hydroxyprogesterone hemisuccinate bovine serum albumin tetramethylrhodamine isothiocyanate, 11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate, progesterone 12-succinyltyrosine methyl ester, progesterone 11-succinyltyrosine methyl ester, 11-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate, 2-hydroxymethyleneprogesterone, 2-cyanoprogesterone, 17-(phenylseleno)progesterone and 21-(phenylseleno)progesterone, neuroactive progestagens, 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), 3α,17β-dihydroxy-5α-androstane, 3α-hydroxy-5α-androstan-17-one, 3α-hydroxy-5β-androstan-17-one, androst-5-ene-3β,17β-diol, 3β,17α-dihydroxy-pregn-5-en-20-one (17α-hydroxy-pregnenolone), 3β-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA), testosterone, androst-4-ene-3,17-dione (androstenedione)), neuroactive estrogens, neuroactive glucocorticoids, allopregnanolone, allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone (DHEA), estradiol benzoate, methylprednisolone, alphaxalone, alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-and pregnan-20-one (allotetrahydro), and wherein the formulation is in a form and a dosage with respect to each of its components such that it is adapted and arranged for administration to a mammal in need thereof, such that the development, or the risk of development, of neuropathology incident to traumatic brain injury is reduced, lessened, attenuated or prevented. ### Claim 29 (depends on 28) The composition of claim 28, wherein the at least one anticonvulsants and antiepileptics is at least one benzodiazepine selected from the group consisting clozepam, clonazepam, chlorazepate, diazepam, midazolam and lorazepam. ### Claim 30 (depends on 28) The composition of claim 28, wherein the at least one anticonvulsants and antiepileptics is at least one carboxamide selected from carbamazepine, oxcarbazepeine and eslicarbazepine acetate. ### Claim 31 (depends on 28) The composition of claim 28, wherein the at least one anticonvulsants and antiepileptics is at least one fatty acid selected from valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide and sec-butyl-propylacetamide. ### Claim 32 (depends on 28) The composition of claim 28, wherein the at least one neurosteroids and neuroactive steroids is at least one neuroactive progestagen selected from pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, deoxycorticosterone, 11-deoxycortisol, allopregnanolone and allotetrahydroDOC. ### Claim 33 (depends on 28) The composition of claim 28, wherein the at least one neurosteroids and neuroactive steroids is the glucocorticoid prednisolone. ### Claim 34 (depends on 28) The composition of claim 28, comprising a single dosage unit. ### Claim 35 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is gabapentin provided in a dosage range of from about 5.0 mg to about 9,600 mg. ### Claim 36 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is pregabalin provided in a dosage range of from about 0.5 mg to about 2,400 mg. ### Claim 37 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is valproic acid provided in a dosage range of from about 25 mg to about 8,400 mg. ### Claim 38 (depends on 28) The composition of claim 28, wherein the neurosteroid or neuroactive steroid is progesterone and is provided in a dosage range of from about 0.05 mg to about 1,200 mg. ### Claim 39 (depends on 28) The composition of claim 28, wherein the neurosteroid or neuroactive steroid is methyl-prednisolone and is provided in a dosage range of from about 0.02 mg to about 500 mg. ### Claim 40 (depends on 28) The composition of claim 28, wherein the neurosteroid or neuroactive steroid is medroxy-progesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. ### Claim 41 (depends on 28) The composition of claim 28, 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. ### Claim 42 (depends on 28) The composition of claim 28, wherein one or more of the compounds are provided in a controlled release form. ### Claim 43 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is gabapentin, and is provided in a dosage range of from 5 to 9,600 mg; and the neurosteroid or neuroactive steroid is progesterone, and is provided in a dosage range of from about 0.05 to about 1,200 mg. ### Claim 44 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is pregabalin, and is provided in a dosage range of from 0.5 to 2,400 mg; and the neurosteroid or neuroactive steroid is progesterone, and is provided in a dosage range of from about 0.05 to 1,200 mg. ### Claim 45 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is valproic acid, and is provided in a dosage range of from about 25 to about 8,400 mg; and the neurosteroid or neuroactive steroid is progesterone, and is provided in a dosage range of from about 0.05 to about 1,200 mg. ### Claim 46 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is gabapentin, and is provided in a dosage range of from about 5 to about 9,600 mg; and the neurosteroid or neuroactive steroid is methylprednisolone, and is provided in a dosage range of from about 0.02 to about 500 mg. ### Claim 47 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is pregabalin, and is provided in a dosage range of from 0.5 to 2,400 mg; and the neurosteroid or neuroactive steroid is methylprednisolone, and is provided in a dosage range of from about 0.02 to about 500 mg. ### Claim 48 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is valproic acid, and is provided in a dosage range of from 25 to 8,400 mg; and the neurosteroid or neuroactive steroid is methylprednisolone, and is provided in a dosage range of from about 0.02 to about 500 mg. ### Claim 49 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is gabapentin, and is provided in a dosage range of from 5 to 9,600 mg; and the neurosteroid or neuroactive steroid is medroxyprogesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. ### Claim 50 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is pregabalin, and is provided in a dosage range of from about 0.5 to about 2,400 mg; and the neurosteroid or neuroactive steroid is medroxyprogesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. ### Claim 51 (depends on 28) The composition of claim 28, wherein the anticonvulsant or antiepileptic is valproic acid, and is provided in a dosage range of from about 25 to about 8,400 mg; and the neurosteroid or neuroactive steroid is medroxyprogesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. ### Claim 52 (depends on 28) A method for reducing the effects of, for treating, or for reducing the risk of development of, neuropathology incident to a trauma, the method comprising the step of A) providing an effective amount of the composition of claim 28 to a mammal in need thereof. ### Claim 53 (depends on 52) The method of claim 52, wherein the composition is formulated for use during one or more temporal periods, wherein the periods consist of i) before the onset of the trauma, ii) in anticipation of the trauma, iii) during the trauma, iv) during a period after the trauma, and v) during a period of recovery from the trauma. ### Claim 54 (depends on 52) The method of claim 52, wherein the composition is formulated for use within 24 hours of the trauma. ### Claim 55 (depends on 52) The method of claim 52, wherein the composition is formulated for use within one week of the trauma.