Multiple-component pharmaceutical formulations and methods for their use in treating neuropathology and neurodegeneration caused by traumatic injury

Abstract

Novel two-component formulations, procedures and methods for use in treating neuropathology and neurodegeneration 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 pregabalin. 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.

1 . A formulation comprising
 A. at least one biologically active compound selected from the group comprising anticonvulsants and antiepileptics; and   B. at least one biologically active compound selected from the group comprising neurosteroids and neuroactive steroids.   
     
     
         2 . The formulation of  claim 1 ,
 wherein the compound selected from the group comprising anticonvulsants and antiepileptics is at least one form of gabapentin or pregabalin; and   wherein the compound selected from the group comprising neurosteroids and neuroactive steroids is at least one form of progesterone or synthetic progestin.   
     
     
         3 . The formulation of  claim 1 , wherein the at least one anticonvulsant or antiepileptic is 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 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.   
     
     
         4 . The formulation of  claim 1 , 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, 21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone, 17-p-bromopheny-lcarbamoyloxypregn-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-(O-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, 21-(phenylseleno)progesterone and others known and unknown, and include other neurosteroids or neuroactive steroids such as, but not exclusive to neuroactive progestagens (including but not limited to pregnenolone (3beta-hydroxypregn-5-en-20-one), 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, deoxycorticosterone, 11-deoxycortisol, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC)), 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 (including but not limited to estradiol, 17β-estradiol (βE2), 17α-estradiol (αE2), estrone (E1) and estriol (E3), and phytoestrogens), neuroactive glucocorticoids (including but not limited to prednisolone), other neuroactive steroids metabolically downstream from these principal neuroactive steroids including but not limited to allopregnanolone, allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone (DHEA), additional neuroactive steroids including other derivatives such as estradiol benzoate, neurosteroids and neuroactive steroids including, but not limited to, prednisolone, methylprednisolone, alphaxalone, alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydro), as well as metabolites of neurosteroids and neuroactive steroids, and including any corticoid, glucocorticoid, estrogen, estrogen compound, androgen or androgen compound or any such compound acting on or through a progesterone, corticosteroid, glucocorticoid, estrogen, androgen or other neurosteroid or neuroactive steroid receptor or through any other mechanism upon which progesterone, a corticosteroid, a glucocorticoid, an estrogen or other neurosteroid or neuroactive steroid 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 or neuroactive steroid, as well as any related slow-release compound.   
     
     
         5 . The formulation of  claim 1 , 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, especially a human, in need thereof, such that the development, or the risk of development, of neuropathology is reduced, lessened, attenuated or prevented. 
     
     
         6 . The formulation of  claim 4 , 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, the at least one form of pregabalin is provided in a dosage range of from about 0.05 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 0.05 mg to about 1,200 mg. 
     
     
         7 . The formulation of  claim 1 , wherein the formulation comprises a single dosage unit adapted and arranged to be administered a plurality of times of one or more dosage units per day 
     
     
         8 . The formulation of  claim 1 , 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, analogs, homologs, 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. 
     
     
         9 . The formulation of  claim 1 , wherein
 A. the anticonvulsant or antiepileptic is at least one form of pregabalin; and   B. wherein the neurosteroid or neuroactive steroid is at least one form of progesterone.   
     
     
         10 . The formulation of  claim 1 , wherein
 A. the anticonvulsant or antiepileptic is at least one form of gabapentin; and   B. the neurosteroid or neuroactive steroid is at least one form of synthetic progestin.   
     
     
         11 . The formulation of  claim 1 , wherein
 A. the anticonvulsant or antiepileptic is at least one form of pregabalin; and   B. the neurosteroid or neuroactive steroid is at least one form of synthetic progestin.   
     
     
         12 . The formulation of  claim 1 , wherein
 A. the anticonvulsant or antiepileptic is at least one form of gabapentin; and   B. wherein the neurosteroid or neuroactive steroid is at least one form of progesterone.   
     
     
         13 . The formulation of  claim 1 , wherein the formulation is adapted and arranged to be administered with respect to time in relation to 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. 
     
     
         14 . A method for using the formulation of  claim 1  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 the formulation of  claim 1 , wherein the formulation is 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 pharmaceutically effective amount of:
 i. at least one biologically active compound from the group comprising anticonvulsants and antiepileptics; 
 ii. at least one biologically active compound from the group comprising neurosteroids and neuroactive steroids; 
 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 of  claim 1  to a mammal in need thereof. 
 
     
     
         15 . The method of  claim 14 , wherein Step B is effected with respect to time in relation to 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. 
     
     
         16 . The method of  claim 14 ,
 wherein the compound selected from the group comprising anticonvulsants and antiepileptics is at least one form of gabapentin or pregabalin; and   wherein the compound selected from the group comprising neurosteroids and neuroactive steroids is at least one form of progesterone or synthetic progestin.   
     
     
         17 . The method of  claim 14 , wherein the formulation is adapted and arranged to be first administered within two hours after the trauma. 
     
     
         18 . The method of  claim 14 , wherein the formulation is adapted and arranged to be first administered as a single dosage unit within 24 hours after the onset of the trauma. 
     
     
         19 . The method of  claim 14 , wherein the formulation is adapted and arranged to be first administered preventively or prophylactically within 6 hours before the expected onset of the trauma as a single dosage unit. 
     
     
         20 . The method of  claim 14 , wherein the formulation is adapted and arranged to be administered additionally one or a plurality of times after the formulation is first administered. 
     
     
         21 . A method for the treatment of preventing the development of neuropathology or neurodegeneration, and for the amelioration of the effects caused by trauma 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 the two biologically active compounds, for preventing, reducing the effects of, and reducing the risk of development of, neuropathology and neurodegeneration incident to trauma, the method comprising the steps and actions of
 A. providing a formulation adapted for the prevention of the development of neuropathology or neurodegeneration, 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 pharmaceutically effective amount of:
 i. at least one biologically active compound from the group comprising anticonvulsants and antiepileptic drugs; and 
 ii. at least one biologically active compound from the group comprising neurosteroids and neuroactive steroids;
 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, and such that the development, or the risk of development, of neuropathology or neurodegeneration is reduced, lessened, attenuated or prevented, and 
 
   B. administering the formulation to a mammal in need thereof.   
     
     
         22 . The method of  claim 21 , wherein the compound selected from the group of anticonvulsants and antiepileptics is at least one form of gabapentin or pregabalin, or at least one form of a pharmaceutically acceptable salt, ester or prodrug of gabapentin pregabalin. 
     
     
         23 . The method of  claim 21 , wherein the compound selected from the group of neurosteroids and neuroactive steroids is at least one form of progesterone or synthetic progestin or at least one form of a pharmaceutically acceptable salt, ester or prodrug thereof. 
     
     
         24 . The method of  claim 22 , wherein the gabapentin or the at least one form of the pharmaceutically acceptable salt, ester or prodrug thereof, is administered in a dosage range selected from the ranges of (i) from about 5.0 mg to about 9,600 mg, (ii) from about 50 mg to about 4,800 mg, (iii) from about 100 mg to about 2,400 mg, and (iv) from about 200 mg to about 600 mg. 
     
     
         25 . The method of  claim 22 , herein the pregabalin or the at least one form of the pharmaceutically acceptable salt, ester or prodrug thereof, is administered in a dosage range selected from the ranges of (1) from about 0.5 mg to about 2,400 mg, (ii) from about 15 mg to about 1,200 mg, (iii) from about 25 mg to about 600 mg, and (iv) from about 50 mg to about 150 mg. 
     
     
         26 . The method of  claim 23 , wherein the progesterone or synthetic progestin, or the at least one form of the pharmaceutically acceptable salt, ester or prodrug thereof, is administered in a dosage range selected from the ranges of (i) from about 0.05 mg to about 1,200 mg, (ii) from about 5 mg to about 600 mg, (iii) from about 50 mg to about 450 mg, and (iv) from about 100 mg to about 300 mg. 
     
     
         27 . The method of  claim 21 , wherein the neuropathology or neurodegeneration in a subject is selected from the group consisting of damage, injury, harm, loss, change in structure, change in phenotype, change in gene expression, change in function or survival of nerves, nerve cells, neural support cells or neural support tissue that occurs after a traumatic event and develops over the seconds, minutes, hours, days, weeks or months following such an event and results from biochemical cascades of cellular and metabolic processes that are activated or triggered by the trauma-induced direct tissue damage and wherein damage is considered to involve endogenous processes or biosynthetic pathways that govern, regulate or influence the structure, health, function, gene expression or survival of nerves or nerve cells, or cells or tissues upon which nerves or nerve cells depend to maintain health and function, such as neural support cells and neural support tissues and wherein neuropathology is selected from the group consisting of traumatic brain injury and ischemia, spinal cord neuropathology includes compression, vertebral collapse, cutting wounds, puncture wounds and ischemia, enteric nervous system neuropathology includes damage or injury to enteric nerve cells, progenitor cells, glial cells, interstitial cells of Cajal and cells and tissues upon which normal function and health are dependent, injury to the enteric nervous system includes that resulting from chemotherapy, radiation therapy, ischemia, chemical and inflammatory trauma, physical trauma such as puncture wounds, parasitic and amoeboid infection, burns to the body, among other types of trauma, and peripheral nervous system neuropathology includes damage or injury to nerve cells, nerve roots, ganglia, plexi, autonomic nerves or nerve cells, sensory nerves or nerve cells, motor nerves or nerve cells, and to neural support cells or neural support tissues upon which nerve cells depend for normal function and health. 
     
     
         28 . The method of  claim 21 , wherein the trauma to a subject consists of one or more of trauma selected from the group consisting of that induced by vehicle accidents, workplace accidents, sports accidents, falls, burns, radiation, battlefield injuries such as but not exclusive to concussive blast injuries and injuries from landmines or improvised explosive devices (IED's), and penetrating injuries. 
     
     
         29 . The method of  claim 21 , wherein the effects caused by trauma to a subject consists of one or more of processes and mechanisms selected from the group consisting of those that promote or interfere with at least one or more parts of processes that are activated, induced or enhanced by trauma and that are involved in maintaining or damaging nerves or nerve cells, or cells upon which the health or function of nerves, nerve cells, neural support cells or neural support tissues, or cells or tissues upon which neuron cell function depends. 
     
     
         30 . The method of  claim 21 , wherein the neuropathology or neurodegeneration in a subject is caused by trauma selected from the group consisting of one or more of a wound, injury or damage to a mammalian body or body part, or a condition resulting from such a wound or injury including physical, chemical, metabolic, medical or surgical injury or damage to any tissue nerve or nerve cell, whether in the central nervous system or in the periphery and wherein a chemical trauma is selected from the group consisting of medication or medication overdose, drug or drug overdose, drug abuse (such as methylenedioxyamphetamine, or MDMA, and the like), alcohol overdose, stimulant drugs such as pentylenetetrazol, carbon dioxide poisoning, heavy metals, acrylamide and related chemicals, overexposure to certain environmental chemicals such as copper or natural hazards such as scorpion venom toxin, herbicides, agricultural insecticides such as lindane, hazardous industrial chemicals, neurotoxin bioterrorism chemicals such as soman and sarin, radiation bioterrorism chemicals such as polonium and strontium, and wherein metabolic trauma is selected from the group consisting of hypoxia, central nervous system ischemia, peripheral ischemia, enteric nervous system ischemia, hypoperfusion of nerve tissue, multiple sclerosis, shingles (herpes zoster), diabetes, diabetic shock, stroke, epileptic or other seizure, post-polio syndrome, HIV/AIDS peripheral neuropathic pain, subacute posttraumatic myelopathy, and other effects, syndromes and conditions following some type of trauma to the body or its nervous system, and wherein metabolic trauma can also include but is not exclusive to hypoglycemia, hyperglycemia, ischemia, diabetic shock, epilepsy or other seizure, hypoperfusion of nerve tissue during cardiac arrest, hypoperfusion in newborns resulting from complications at delivery, and wherein the trauma induced by medical treatment and procedure is selected from the group consisting of one or more of injections, inoculation, implants, antibiotics, biologic drugs, antibodies, chemotherapy, radiation therapy, immunosuppressants, during a medical procedure that can reduce or impede the blood supply for any period of time, and whereas trauma from surgery includes laparoscopy, amputation, mastectomy, cesarean section, cardiac surgery, hernia repair, cholecystectomy, joint replacement, thoracotomy, reparative surgery, any case, condition and situation where there is detectable or undetectable cut, wound, injury or damage to nerves, nerve cells, neural support cells or neural support tissues, and where long-term outcome from surgery can include adverse health conditions and disability as with failed back syndrome. 
     
     
         31 . The method of  claim 27 , wherein the neural support cell is selected from the group consisting of cells that support and could be considered to support the health, normal function and survival of nerves and nerve cells, and include glial cells, microglia, myelin cells and satellite cells, astroglia, oligodendrocytes, satellite cells, Schwann cells, vascular endothelial cells, gastric epithelial cells, and interstitial cells of Cajal. 
     
     
         32 . The method of  claim 27 , wherein the neural support tissue is selected from the group consisting of tissue that supports the health, normal function, phenotype, gene expression or survival of nerves, nerve cells or support cells, the group also consisting of cells of the vasculature or microvasculature, particularly the endothelial cells that prevent blood from leaking into nerve tissue and that provide the selective blood-nerve and blood-brain barrier that allows the passage of certain supportive chemicals into nerve tissue as well as the passage of nerve tissue wastes out of nerve tissue, as well as epithelial cells and interstitial cells of Cajal of the gut. 
     
     
         33 . The method of  claim 21 , wherein the pharmaceutically effective amount is selected from the group of one or more chemical entities that will alter, modify or promote adaptive responses to trauma or interfere with, lessen or inhibit maladaptive processes, for example by binding to an enzyme, receptor, allosteric site or other step of an endogenous biochemical, metabolic or biosynthetic pathway to the extent that the effective functioning of such pathway is altered, enabled, allowed or facilitated, as in the case of adaptive processes, or would prevent, inhibit or lessen its effective functioning, as in the case of maladaptive processes. 
     
     
         34 . The method of  claim 21 , wherein the administration of the pharmaceutically effective amounts of the biologically active compounds or pharmaceutically acceptable salts, esters or prodrugs thereof to a subject in need thereof, is one or more selected from the group consisting of oral, buccal, mucosal, parenteral, rectal, sub-cutaneous, transdermal, topical, 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 and subcutaneous. 
     
     
         35 . The method of  claim 21 , wherein the form of the pharmaceutically effective amounts of biologically active compounds to be administered is one or more of pharmaceutically acceptable salts, esters or prodrugs thereof, excipients, penetration enhancers, stabilizers, absorption enhancers and carriers is selected from the group consisting of a pharmaceutically acceptable substance that assists or enhances the delivery or effectiveness of the compound or compounds of invention embodiments 
     
     
         36 . The method of  claim 21 , wherein the formulation is administered additionally one, or a plurality of, times after the formulation is first administered. 
     
     
         37 . The method of  claim 21 , wherein the formulation is administered one, or a plurality of times as a sustaining dose. 
     
     
         38 . The method of  claim 21 , wherein said method is commenced at a time selected from the group consisting of one or more of (i) one month after the trauma, (ii) one week after the trauma, (iii) one day after the trauma, (iv) less than one day after the trauma, (v) less than 18 hours after the trauma, (vi) less than twelve hours after the trauma, (vii) less than six hours after the trauma and (viii) less than one hour after the trauma. 
     
     
         39 . The method of  claim 21 , wherein the method is commenced as a prophylactic step at a time period before a possible trauma selected from the group consisting of one or more of (i) less than one hour before the possible trauma, (ii) less than six hours before the possible trauma and (iii) less than twenty-four hours before the possible trauma. 
     
     
         40 . The method of  claim 21 , wherein the method is commenced as a preventive step at a time selected from the group consisting of one or more of (i) less than one hour before the trauma, (ii) less than six hours before the trauma, and (iii) less than twenty-four hours before the trauma.