US 2012O157420A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0157420 A1 Schneider (43) Pub. Date: Jun. 21, 2012 (54) TREATMENT AND PREVENTION OF A 6LX 3L/505 (2006.01) SECONDARY INTURY AFTER TRAUMA OR A6IP 29/00 (2006.01) DAMAGE TO THE CENTRAL NERVOUS A6II 3/47 (2006.01) SYSTEM A6IP 25/00 (2006.01) A6IP3/06 (2006.01) (76) Inventor: Eric B Schneider, Glen Arm, MD A6IP 9/00 (2006.01) (US) A6IP 25/22 (2006.01) A6IP 25/24 (2006.01) (21) Appl. No.: 13/392,371 A63L/366 (2006.01) A6II 3/40 (2006.01) (22) PCT Filed: Aug. 31, 2010 (52) U.S. Cl. ......... 514/171; 514/460, 514/419:514/510; (86). PCT No.: PCT/US 10/472O6 514/277; 514/275: 514/423: 514/311 S371 (c)(1), (57) ABSTRACT (2), (4) Date: Feb. 24, 2012 A method of administering one or multiple medications to human patients with CNS injury through oral or parenteral Related U.S. Application Data (including transdermal, intravenous, Subcutaneous, intra (60) Provisional application No. 61/238,453, filed on Aug. muscular) routes. Inflammatory and immunological pro 31, 2009. cesses have been shown to cause secondary damage to CNS s tissues in individuals with acute CNS injury. The present O O invention administers one or more of the following medica Publication Classification tions, which have properties that mitigate the inflammatory (51) Int. Cl. and immunological processes that lead to secondary CNS A6 IK3I/56 (2006.01) damage, via trans-dermal absorption: a statin compound A6 IK 3/405 (2006.01) (e.g., a HMG-CoA reductase inhibitor), a progesterone com A6 IK 3L/25 (2006.01) pound, or a cholinesterase inhibiting compound, among oth A6 IK 3/448 (2006.01) ers, either alone or in combination with other compounds. Patent Application Publication Jun. 21, 2012 Sheet 1 of 8 US 2012/O15742.0 A1 Matrix systems - rig-irradhesive Matilayer Reserweis system Simple matrix system atix inpei vious layer ifug i? ailesive matrix Polynesis: matrix i Achesive Bayer Polymeric matrix 2 S. Rate-contfošing S Reservoir layer frters & FIG. 1. Patent Application Publication Jun. 21, 2012 Sheet 2 of 8 US 2012/O15742.0 A1 as is a writis trus Scietios Sai Solution ESS FRESSESSEE SEESSES FIG. 2. Patent Application Publication Jun. 21, 2012 Sheet 3 of 8 US 2012/O15742.0 A1 SSSSSS SS S s | ''''''''''''''''''''''''''''''| tsSS Sir S FIG. 3. Patent Application Publication Jun. 21, 2012 Sheet 4 of 8 US 2012/O15742.0 A1 itrasotis FIG. 4. Patent Application Publication Jun. 21, 2012 Sheet 5 of 8 US 2012/O15742.0 A1 FIG 5. Patent Application Publication Jun. 21, 2012 Sheet 6 of 8 US 2012/O15742.0 A1 - tri-sers FIG. 6. Patent Application Publication Jun. 21, 2012 Sheet 7 of 8 US 2012/O15742.0 A1 FIG. 7. Patent Application Publication Jun. 21, 2012 Sheet 8 of 8 US 2012/O15742.0 A1 & s'ss is as 8.8s is is & 88ss S8. 888 & FIG. 8. US 2012/O157420 A1 Jun. 21, 2012 TREATMENT AND PREVENTION OF 0006 Inflammation in the central nervous system is not SECONDARY INTURY AFTER TRAUMA OR limited to acute conditions but is also present in chronic DAMAGE TO THE CENTRAL NERVOUS progressive conditions leading to dementia. From the time of SYSTEM Alois Alzheimer, neuro-inflammation has also been impli cated as a factor in dementia. At this point, population-based FIELD studies are equivocal as to a potential moderating role for statins in late life dementia. It seems likely that the long-term 0001. This application describes methods of treatment or inflammatory processes associated with many chronic neu prevention of secondary injury to the human central nervous rological and neuropsychiatric illnesses may either com system after trauma or damage (both internal and external in mence as a result of neuro-immuno-biochemical process origin) and pharmaceutical preparations for use in Such meth associated with acute CNS insult or that these long term ods, as well as methods of manufacture of such preparations. inflammatory processes may be abetted by acute insults and the body's reaction to them. BACKGROUND 0007. At present, there are limited pharmacological inter ventions available to reduce the impact or delay the onset of 0002 Brain injury and dementia are significant public dementing conditions in either acute or chronic settings. health issues at present and are likely to grow in importance as Available agents, including Aricept, Namenda and Meman the population ages. Nearly 1.5 million individuals suffer a tine, may delay disability or slow deterioration to a small traumatic brain injury (TBI) each year and 5.3 million indi extent, but these agents do not preventor reverse the course of viduals are living with disabilities that were acquired through dementia. It is important to note that many of the studies on TBI. Among those who suffer brain trauma in the United the cost effectiveness of these medications were sponsored by States every year, more that 50,000 die as a result of their the pharmaceutical industry (see: Loveman, et al. 2006). injury. Further, 235,000 individuals with brain injury require Appropriately applied, the therapeutic interventions for acute hospitalization and approximately 1.1 million are treated in CNS injury described herein may play a role in reducing the emergency medical facilities and released. (Brain Injury long-term risk of chronic CNS illness and in lowering the Association B.I.A., 2006) burdens associated with these devastating diseases. WO 0003 Acute incidents that damage the central nervous 2006/002127, WO 2006/119598, WO 2009/080301, WO system (CNS) including the brain, such as but not limited to 2007/106862, WO 2003/086379 are all incorporated herein TBI, have been implicated as possible contributors to by reference in their entirety. increased risk of developing chronic neurological and neu ropsychiatric illness, including dementia and parkinsonism SUMMARY among others, across the lifespan. Looking at Alzheimer's 0008. The present invention provides methods for the disease (AD), which is just one of many chronic neuropsy treatment and prevention of acute CNS injury whereby sec chiatric illnesses, it is projected that there will be approxi ondary damage to the CNS is mitigated or eliminated. The mately 8,640,000 individuals in the U.S. alone living with a new methods described herein are especially useful in treat diagnosis of AD by the middle of this century. The economic, ing patients who are unconscious, intubated or who otherwise Social and family burdens associated with caring for this cannot accept medications via oral administration. The number of individuals are daunting. present invention provides a method of treating or preventing 0004 To date, no pharmacological therapy has been avail secondary injury in a patient with a brain injury where a statin able to treat acute trauma to the central nervous system (in is administered to a patient. It also provides a method of cluding the brain and spinal cord) at or very near the time of treating or preventing secondary injury in a patient currently injury with the aim of preventing secondary damage related to on lipid-lowering therapy by administering a statin to a naturally occurring internal inflammatory and immunologi patient. The invention provides a method of treating or pre cal responses in the CNS. Acute traumas to the CNS include venting secondary injury in a patient at risk for a brain injury traumatic brain injury, traumatic spinal cord injury, ischemic by prophylactically administering a statin to a patient. and hemorrhagic events (e.g., stroke), transient ischemic 0009. In one aspect, the present invention includes a attack, encephalopathies (including but not limited to viral method of administering one or multiple medications to encephalitis and acute disseminated encephalomyelitis), human patients with CNS injury through oral or parenteral cerebral anoxia, and any other event where the CNS is acutely (including transdermal, intravenous, Subcutaneous, intra damaged Such that inflammatory and immunological pro muscular) routes. Inflammatory and immunological pro cesses are activated. A continuing and unmet need exists for cesses have been shown to cause secondary damage to CNS new and innovative medical treatments for the prevention and tissues in individuals with acute CNS injury. It is another treatment of post-traumatic secondary injury to the CNS. aspect of the present invention to administer one or more of 0005 Statin use has been associated with reduced mortal statin-like medications, which have properties that mitigate ity and reduced damage to brain tissue in controlled trials of the inflammatory and immunological processes that lead to animals Subjected to traumatic brain injury or induced secondary CNS damage, via trans-dermal absorption: a statin ischemic stroke (Elkind, et al., 2005). While the underlying compound (e.g., a HMG-CoA reductase inhibitor), a proges mechanisms are not clearly understood, it is Suspected that terone compound, or a cholinesterase inhibiting compound, statins may function as “potent vascular anti-inflammatory among others, either alone or in combination with other com agents' (Laio, 2004). Better functional outcomes, as mea pounds. Sured using spatial learning tasks, have been reported in sta 0010. In humans, statin use is associated with decreased tin-treated rats subjected to brain infarction/brain trauma than rates of severe inflammatory reactions, such as sepsis, in in similarly injured rats not treated with Statins (Lu, et al., individuals with bacterial infections (Almog, et al. 2004). The 2004). systemic inflammatory cascade seen in sepsis bears some US 2012/O157420 A1 Jun. 21, 2012 resemblance to the inflammatory processes seen in patients said patient. The invention can be used with a patient that has with traumatic injuries. Statins may have significant anti a history or cardiovascular disease, where the patient could be inflammatory effects in humans beyond their antihyperlipi an athlete, military personnel, an emergency responder, or a demic qualities (see: Liappis, et al., 2001).