US010512655B1 (12 ) United States Patent ( 10 ) Patent No.: US 10,512,655 B1 Brooks (45 ) Date of Patent : Dec. 24 , 2019 ( 54 ) METHODS AND COMPOSITIONS FOR THE Ghosh et al. , “ Methods of Enhancement of Transdermal Drug TOPICAL TREATMENT OF PERIPHERAL Delivery : Part IIB , Chemical Permeation Enhancers ” , Pharmaceu NEUROPATHY tical Technology, 17 ( 5 ) , 68-76 , May 1993 . Swinyard et al ., " Pharmaceutical Necessities ” , Remington's Phar ( 71) Applicant: Jeffrey S. Brooks, Inc., St. Louis , MO maceutical Sciences , 1985, 17th Edition , Chapter 68 , pp . 1278 1320 . (US ) Head , K. , “ Peripheral Neuropathy : Pathogenic Mechanisms and (72 ) Inventor: Jeffrey S. Brooks, St. Louis , MO (US ) Alternative Therapies ” , Alternative Medicine Review , 2006 , 11 ( 4 ) : 294-329 . ( 73 ) Assignee: Jeffrey S. Brooks, Inc., St. Louis , MO Balakumar , P. et al. , “ The multifaceted therapeutic potential of (US ) benfotiamine ” , Pharmacological Research , 2010 , 61 : 482-488 . Fraser , D.A. et al. , “ The effects of long - term oral benfotiamine ( * ) Notice : Subject to any disclaimer , the term of this supplementation on peripheral nerve function and inflammatory patent is extended or adjusted under 35 markers in patients with type 1 diabetes : a 24 -month , double- blind , randomized , placebo -controlled trial ” , Diabetes Care , 2012 , 35 ( 5 ) : 1095 U.S.C. 154 ( b ) by 296 days . 1097 . Fonseca et al. , “ Metanx in Type 2 Diabetes with Peripheral Neuropathy: ( 21) Appl. No .: 14 /202,161 A Randomized Trial” , A Med J , 2013 , 126 ( 2 ) : 141-149 . Filed : Bighley et al ., “ Salt Forms of Drugs and Absorption, ” in Encyclo ( 22 ) Mar. 10 , 2014 pedia of Pharmaceutical Technology , J. Swarbrick and J.C. Boylan , Eds. (Marcel Dekker , New York , 1996 ) , vol. 13 , pp . 453-499 . Related U.S. Application Data Hahn , John , “ The Naturopathic Management of Diabetic Peripheral (60 ) Provisional application No. 61/ 777,582 , filed on Mar. Neuropathy” , Townsend Letter, 2010 , Feb.- March , pp . 56-62 . Parminder et al. , " Current Therapeutic Strategies in Diabetic 12 , 2013 . Neuropathy ” , International Research Journal of Pharmacy , 2012 , 3 ( 3 ): 22-29 . (51 ) Int. Ci. Boulton et al. , “ Diabetic Peripheral Neuropathy : Diagnosis and A61K 31/675 ( 2006.01 ) Management” , Medscape Education, pp . 1-49, released Aug. 16 , A61K 45/06 ( 2006.01 ) 2011 . A61K 31/485 ( 2006.01 ) St. Onge et al. , “ Pain Associated with Diabetic Peripheral Neuropathy ” , A61K 31/519 ( 2006.01) P & T , Mar. 2008 , 33 ( 3 ) : 166-176 . ( 52 ) U.S. CI. Ang et al ., “ Vitamin B for treating peripheral neuropathy ( Review ) ” , CPC Cochrane Database System Review , 2008 , 16 ( 3 ) : 1-39 . A61K 31/675 ( 2013.01 ) ; A61K 31/485 Cheng et al. , “ Painful Diabetic Neuropathy ” , Neuropathic Pain : ( 2013.01) ; A61K 31/519 (2013.01 ) ; A61K Mechanisms, Diagnosis and Treatment, Chapter 11 , 2012 , pp . 45/06 (2013.01 ) 165-189 . (58 ) Field of Classification Search “ Topical Drugs” , Remington : The Science and Practice of Phar CPC A61K 31/675 ; A61K 31/51 macy , 20th edition , (Lippincott , Williams & Wilkins, 2003 ) , Chapter See application file for complete search history . 65, pp . 1200-1218 . Authia Cream , Commercial product description [online ], Westlake ( 56 ) References Cited Laboratories Inc. ( retrieved on Aug. 15 , 2014 ] . Retrieved from the Internet : < URL : www.westlake-labs.com/products/authia-cream > . U.S. PATENT DOCUMENTS Neuro- Immune Stabilizer Topical Cream , Commercial product descrip tion [online ], Neuro Biologix [ retrieved on Aug. 15 , 2014 ]. Retrieved 6,143,278 A 11/2000 Elkhoury from the Internet : < URL : www.neurobiologix.com/Neuro-Immune 7,235,249 B2 6/2007 Bissett 7,666,442 B2 2/2010 Morariu Stabilizer - B12-136 - Vitamin - D - Cream - p /46.htm > . 8,137,711 B2 3/2012 Wolicki Topical B Complex , Commercial product description [ online ], 2005/0019354 A1 1/2005 Perricone Sarati Labs (retrieved on Aug. 15 , 2014 ] , Retrieved from the 2006/0045896 A1 * 3/2006 Morariu A61K 8/4926 Internet : <URL : www.amazon.com/Topical-Complex-Sarati-Labs 424/401 Tube / dp /B00ONGM342 > . 2006/0084066 A1 4/2006 Sah et al . (Continued ) 2007/0190126 A1 * 8/2007 Stuart A61K 9/0014 424/449 Primary Examiner Rachael E Bredefeld 2008/0102137 Al 5/2008 Guffey 2009/0311167 A1 12/2009 Height et al. (74 ) Attorney, Agent, or Firm Stinson LLP 2010/02 10582 A1 8/2010 Stewart et al. 2010/0279984 Al 11/2010 Bonke et al. (57 ) ABSTRACT 2011/0263710 Al 10/2011 Moskowitz et al . Methods for the treatment of peripheral neuropathy are provided which include applying a topical composition to a OTHER PUBLICATIONS peripheral appendage of a subject in need of such treatment. Smith et al. , Percutaneous Penetration Enhancers , Chapter 1.1 and The topical composition includes a B1 vitamer , a B6 vita Chapter 1.2 , 1995 , pp . 1-20 . mer , and a B9 vitamer in a dermatologically acceptable Ghosh et al. , “ Methods of Enhancement of Transdermal Drug carrier . The methods are effective in preventing further Delivery : Part I, Physical and Biochemical approaches ” , Pharma degeneration and / or restoring epidermal nerve fiber density ceutical Technology , 17 ( 3 ) , 72-98 , Mar. 1993 . (ENFD ) in patients with peripheral neuropathy, and in Ghosh et al ., “ Methods of Enhancement of Transdermal Drug preventing or alleviating neuropathic pain . Delivery: Part IIA , Chemical Permeation Enhancers” , Pharmaceu tical Technology , 17 ( 4 ) , 62-90 , Apr. 1993 . 29 Claims, No Drawings US 10,512,655 B1 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Jayabalan , B., et al. , “ Vitamin B Supplementation for Diabetic Peripheral Neuropathy, ” Singapore Medical Journal, 2016 , pp . 55-59 , vol. 57 , No. 2 . * cited by examiner US 10,512,655 B1 1 2 METHODS AND COMPOSITIONS FOR THE because of issues associated with tolerance and addiction . TOPICAL TREATMENT OF PERIPHERAL Drug therapy for symptomatic relief in DPN includes the use NEUROPATHY of tricyclic antidepressants , serotonin and norepinephrine reuptake inhibitors, N -methyl - D -aspartate (NMDA ) antago CROSS - REFERENCE TO RELATED 5 nists , anticonvulsants , and opioids. Unfortunately , there is no evidence that any of these agents modifies the underlying APPLICATIONS pathophysiology of DPN . This application claims the benefit of U.S. Provisional To date , three oral medications have been approved by the Patent Application Ser. No. 61 / 777,582 , filed Mar. 12 , 2013 , U.S. Food and Drug Administration (FDA ) for treatment of the entirety of which is herein incorporated by reference . 10 DPN pain . Pregabalin (Lyrica , commercially available from Pfizer, New York , N.Y.) is an anticonvulsant agent that FIELD OF THE INVENTION binds with high affinity to the a2-8 subunit of calcium channels . This is thought to produce an analgesic effect by The present invention relates to methods and composi decreasing Ca + 2 influx into nerve terminals and decreases tions for the topical treatment of peripheral neuropathy. 15 neurotransmitter release . Side effects of pregabalin include More particularly , the present invention relates to methods dizziness , somnolence , dry mouth , edema, blurred vision , and topical compositions to decrease neuropathic pain and weight gain , and attention deficit . A further side effect increase epidermal nerve fiber density . associated with Lyrica® is an increased risk of suicidal thoughts and behavior. BACKGROUND OF THE INVENTION 20 Duloxetine (Cymbalta® , commercially available from Eli Lilly , Indianapolis , Ind . ) is an antidepressant that inhibits Peripheral neuropathy , characterized by slow nerve con serotonin and norepinephrine reuptake. Its mechanism of duction and by pain , numbness , and tingling in the extremi action involves an increased availability of 5 -hy ties , can be extremely debilitating . Pain is a serious symp droxytryptamine and noradrenaline, which suppress pain tom formany patients , and may be described as a dull aching 25 impulses . Side effects of duloxetine include headache, sensation , an intense burning sensation , or as intermittent, fatigue, nauseas , constipation , and increased blood pressure . stabbing pain . On occasion , patients notice that their skin is This drug cannot be used to treat patients with liver disease, hypersensitive to tactile sensation , such as from standing on renal failure , or glaucoma. their feet or from the touch of clothing or bedding . Some Tramadol (Nucynta® , commercially available from John patients note an exaggerated pain resulting from stimulus to 30 son & Johnson , New Brunswick , N.J.) is a u - opioid agonist the affected area , a form of pain termed allodynia . that also inhibits reuptake of serotonin . Adverse effects Peripheral neuropathy encompasses a wide spectrum of include respiratory depression , nausea , somnolence , vomit clinical disorders that affect sensory , motor , and autonomic ing, and headache. Patients receiving tramadol require care peripheral nerve fibers. Nerve fiber dysfunction can be the ful monitoring for signs of abuse and addiction . Risk for result of genetics , systemic or infectious disease, environ- 35 addiction occurs even under appropriate medical use , and is mental toxins , alcoholism , nutritional deficiencies , or the increased for patients with a family history of substance side effect of certain medications. Peripheral neuropathy can abuse ( including alcohol or drugs ) or mental illness ( e.g. also be caused by traumatic injury, surgery , radiation , and major depression ). chemotherapy