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(12) Patent Application Publication (10) Pub. No.: US 2016/0106690 A1 BUCKS Et Al US 201601 06690A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0106690 A1 BUCKS et al. (43) Pub. Date: Apr. 21, 2016 (54) PAIN RELIEF COMPOSITIONS, Publication Classification MANUFACTURE AND USES (51) Int. Cl. (71) Applicant: API GENESIS, LLC, Fairfax, VA (US) A613 L/65 (2006.01) A69/06 (2006.01) (72) Inventors: Daniel BUCKS, Millbrae, CA (US); A619/00 (2006.01) Philip J. BIRBARA, West Hartford, CT A63L/96 (2006.01) (US) A63L/25 (2006.01) A63L/045 (2006.01) A63L/05 (2006.01) (73) Assignee: API GENESIS, LLC, Fairfax, VA (US) A619/08 (2006.01) A613/618 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/482,930 CPC ................. A61 K31/165 (2013.01); A61 K9/08 (2013.01); A61 K9/06 (2013.01); A61 K9/0014 (22) Filed: Sep. 10, 2014 (2013.01); A61 K3I/618 (2013.01); A61 K 31/125 (2013.01); A61 K3I/045 (2013.01); A6 IK3I/05 (2013.01); A61 K31/196 (2013.01) Related U.S. Application Data - - - (57) ABSTRACT (62) Division of application No. 13/609,100, filed on Sep. The present invention relates to TRPV1 selective agonist 10, 2012, now Pat. No. 8,889,659. topical compositions including capsaicinoid- - - and analgesic (60) Provisional application No. 61/533,120, filed on Sep. agent compositions and methods of manufacture and meth 9, 2011, provisional application No. 61/642.942, filed ods of providing pain relief as well as treating a variety of on May 4, 2012. disorders with Such compositions. Patent Application Publication Apr. 21, 2016 Sheet 1 of 4 US 2016/0106690 A1 FIGURE 1 - API-CAPSTOLERABILITY COMPOSTE AP-CAPSTOERABLTY FOR RGH & LEFT KNEES ASA FUNCTION OF CAPSACN CONCENTRATIONS (Tolerability measurements taken after 1530, 45 & 60 minutes post dosage application for 4 visits) O%. Concentration 2% Concentration 5%. Concentration 10% Concentration 2% Concertraig i.e. are:nas were all. are:: . - i.e.,x* . seila area &: 0 1 2 3 4 5 789 10 0 1 2 3 4 5 s 7 g g g c 1 2 3 4 5 5. 7 is 9 to 2 3 4 5 G 8 g TOERABLITYSCALF. (0.10) TQLERA31LITYSCALE- (0-0) rol ERABLY SCALE - (0-10) foLERABILITYSCAE O-0) OLERAbi TYSCALE- (0-0) Patent Application Publication Apr. 21, 2016 Sheet 2 of 4 US 2016/0106690 A1 FIGURE 2 - API-CAPS BURNING & STINGING SCORES ASA FUNCTION OF PATIENT VISITS COMPOSTE BURNING & STNGING SCORES ASA FUNCTION OF PATIENT WISS (All 598 post-application assessment times combined) 2 s Assessments done 15 rain, 3G nin, 45 min, t-“"w.---. : and 60 rein post-application "-ox."ws.-- 1.5 ------ :- t 1 - so ----------...- ... ------. -- . y .3543x 2.8966, R 883 , WSury (All 598 post-application assessment times combined) Patent Application Publication Apr. 21, 2016 Sheet 3 of 4 US 2016/0106690 A1 FIGURE 3 - API-CAPS, 0.25% CAPSAICIN, EFFICACY IN OSTEOARTHRITIC PAIN MANAGEMENT i c. o has O E s SS O O vas Percent Painco-o-o-o-o-o-o-o-o-ed Reduction Patent Application Publication Apr. 21, 2016 Sheet 4 of 4 US 2016/0106690 A1 FIGURE 4 - API-CAPS, 0.25% CAPSAICIN, TOLERABILTY 1200 i? seemaa-axex-aesa----- -----COMPOSITE ----------------- LEFT & RIGHT SIDE TOLERABILITYRATING-------- FOR TREATED HANOS 8. KNEES 1 "(2666 hands & knees treated with the 0.25% formulation) g OOO 4. O O 200 0 1 2 3 4 5 6 7 8 9 10 TOLERABILITYRATING - (0-10 Scale) US 2016/0106690 A1 Apr. 21, 2016 PAIN RELIEF COMPOSITIONS, dropout rates during clinical trials have typically exceeded MANUFACTURE AND USES fifty percent. The most frequently encountered adverse effect with capsaicin is burning pain at the site of application, par 0001. This application claims priority from U.S. Prov. ticularly in the first week of application. This can make it Applin. 61/533,120, filed Sep. 9, 2011 and U.S. Prov. Appln. impossible to blind trials and can lead to dropout rates ranging 61/642.942, filed May 4, 2012, the entire contents of both of from 33 to 67% (Watson C P et al. “A randomized vehicle which are incorporated herein by reference. controlled trial of topical capsaicin in the treatment of pos FIELD OF THE INVENTION therpetic neuralgia.” Clinical Therapeutics. 15.3 (1993):510-26.) Another factor in compliance is the time 0002 The present invention relates to compositions of delay before therapeutic effect is observed. Daily topical transient receptor potential vanilloid 1 (TRPV1) selective applications for at least a week or two may be required. agonists such as capsaicin, and related compounds, methods 0007. Many individuals discontinue the prolonged treat of manufacture and methods of providing pain relief, as well ment of topical capsaicin prior to the anticipated analgesic as methods of treating a variety of medical conditions. effects of capsaicin due to the intense stinging and burning pain. It was reported that 26 out of 39 (66.7%) patients suf BACKGROUND OF THE INVENTION fering from post-herpetic neuralgia did not tolerate the treat 0003 ment of a 0.025% capsaicin preparation (Zostrix, Gen Derm, USA). 0008. With a 0.075% preparation (Zostrix-HP. Gen Derm, HO USA), 5 out of 16 (31.3%) and 45 out of 74 (60.8%) patients with post-herpetic neuralgia did not tolerate the long term topical treatment. (Peikert, A. et al., Topical 0.025% capsai No N cin in chronic post-herpetic neuralgia. efficacy, predictors of response and long-term course, J. Neural. 238:452-456, O 1991; Watanabe, A. etal, Eficacy of capsaicin ointment (Zos Capasaicin trix) in the treatment of herpetic pain and postherpetic neu ralgia, Pain Clinic 15:709–713, 1994; Bernstein J. E. et al., 0004 Capsaicin is the main capsaicinoid in capsicum Topical capsaicin treatment of chronic postherpetic neural plants including chili peppers. It is a pungent Substance that gia, J. Am. Acad. Dermatol 21:265-270, 1989; and Watson C. has long been used for the relief of pain because of its selec P. N. et al. A randomized vehicle-controlled trial of topical tive action on the small diameter afferent nerve fibers (C capsaicin in the treatment of postherpetic neuralgia, Clin. fibers and A-delta fibers) that are believed to signal pain. Ther. 15:510-526, 1993.) From Studies in animals, capsaicin appears to trigger C fiber 0009. The spontaneous burning pain and hyperalgesia are membrane depolarization by opening cation channels perme believed to be due to intense activation and temporary sensi able to calcium and sodium. tization of the peripheral nociceptors at the site of capsaicin 0005 Capsaicin has been reported to work by depleting a application. This activation and sensitization occurs prior to compound called Substance P, which is a neuropeptide that the desensitization phase and is a barrier to topical capsaicin functions as a neurotransmitter and promotes pain percep use because the burning pain produced compromises tion, from the nerve terminal fibers. However, capsaicin also patients tolerability of treatment. can elicit erythema and/or an intense burning or stinging 0010 Capsaicin is believed to relieve pain by causing a sensation upon application. The intense burning or stinging localized degradation of the C neuron endings. The activity of can be intolerable for some. Additionally, it may take more capsaicin results from its binding to, and activating, an ion thana day or two for effectuating actual pain relief, and for the channel called vanilloid receptor 1, or VR1. Under normal intense burning to stop. Following the initial period of intense circumstances, when the VR1 ion channel is activated, it burning pain that may be accompanied by erythema, topical opens for a short time, causing the C neurons to transmit a capsaicinapplication causes insensitivity to pain elicited by a pain signal toward the brain. When capsaicin binds to, and variety of noxious stimuli or disease states. In theory, neurons activates VR1, it causes a series of events within the cell that shut down after they’ve been stimulated by capsaicin, so the degrade the pain-sensing endings, or terminals of the C neu burning and other unrelated sensations—including pain— ron, thereby preventing the neuron from transmitting pain cease. The results from Studies testing the low concentrations signals. of capsaicin present in most over-the-counterproducts (0.075 (0011. In 1997, a research team led by David Julius of percent or less) haven’t been impressive. Many people are University of California, San Francisco showed that capsai bothered by the burning sensation, so they don’t stick with the cin selectively binds to a protein known as TRPV1 that treatment. Current over-the-counter capsaicin products are resides on the membranes of pain and heat sensing neurons not effective for many people. High-dose capsaicin patches TRPV1 is a heat activated calcium channel, which opens have been developed, but they require local or regional anes between 37 and 45° C. (98.6 and 113°F., respectively). When thesia and therefore are only appropriate for treatment for capsaicin binds to TRPV1, it causes the channel to open severe chronic pain under the Supervision of a physician. below 37° C. (normal human body temperature), which is 0006 Because of the ability of capsaicin to desensitize why capsaicin is linked to the sensation of heat. Prolonged nociceptors in peripheral tissues, their potential analgesic activation of these neurons by capsaicin depletes presynaptic effects have been assessed in various clinical trials. However, substance P, one of the body's neurotransmitters for pain and since the application of capsaicin itself frequently causes heat. Neurons that do not contain TRPV1 are unaffected. The burning pain and hyperalgesia apart from the neuropathic result appears to be that the chemical mimics a burning sen pain being treated, patient compliance has been poor and the sation; the nerves are overwhelmed by the influx, and are US 2016/0106690 A1 Apr.
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