(12) Patent Application Publication (10) Pub. No.: US 2012/0027693 A1 Bean Et Al
Total Page:16
File Type:pdf, Size:1020Kb
US 2012002 7693A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0027693 A1 Bean et al. (43) Pub. Date: Feb. 2, 2012 (54) METHODS AND COMPOSITIONS FOR Publication Classification PREVENTING AND RELIEVING MUSCLE (51) Int. Cl. CRAMPS AND FOR RECOVERY FROM A636/906 (2006.01) NEUROMUSCULAR RRTABILITY AND A6II 3/16 (2006.01) FATGUE FOLLOWING EXERCISE A6II 3/12 (2006.01) A6IP 2L/02 (2006.01) (76) Inventors: Bruce P. Bean, Waban, MA (US); A633/42 (2006.01) Donald MacKinnon, New York, A6II 3/94 (2006.01) NY (US); Roderick MacKinnon, A 6LX 3L/375 (2006.01) New York, NY (US) A69/68 (2006.01) A6II 3/19 (2006.01) (52) U.S. Cl. ........... 424/48; 424/739: 514/627: 514/678: (21) Appl. No.: 13/191,941 514/557; 424/601: 514/574: 514/474 (22) Filed: Jul. 27, 2011 (57) ABSTRACT The methods and compositions of the present invention are Related U.S. Application Data directed to the treatment or amelioration of muscle cramps using a composition that includes one or more TRPV1 chan (60) Provisional application No. 61/368,059, filed on Jul. nel activators, and/or one or more TRPA1 channel activators, 27, 2010. and/or one or more ASIC channel activators. Patent Application Publication Feb. 2, 2012 Sheet 1 of 8 US 2012/002 7693 A1 Figure 1 A : 1/800,000 Capsicum extract ...... .--------- B: 115,000 Cinnamon extract C: 1/12,000 Ginger extract lonomycin lonomycin A B C Patent Application Publication Feb. 2, 2012 Sheet 2 of 8 US 2012/002 7693 A1 Figure 2 Subject A Flexor hallucis brevis 8 Hz stim (5 Control #1 (12 min before TRP-Stim) 47 sec Cramp 2.g2 O Sec Control #2 (4 min before TRP-Stim) 46 sec cramp 11 min after TRP-Stim 4 Sec Cramp 2O min after TRP-Stim No cramp 2 1/2 hrs after TRP-Stim 1 sec Cramp Patent Application Publication Feb. 2, 2012 Sheet 3 of 8 US 2012/002 7693 A1 Figure 3 Subject B Flexor hallucis brevis CD Control 12-29 min after TRP-Stim ce 8 Hz gigof A 20 sec19Hz 10 Hz 12H2 12 Hz f 70 sec Cramp No cramp 14 Hz No cramp 2 hrs after TRP-Stim 4 hrs after TRP-Stim 10 Hz. D 10 Hz No cramp No cramp 12 Hz 12 Hz ? 4 sec Cramp N No Cramp 14 Hz 4 sec cramp No cramp Patent Application Publication Feb. 2, 2012 Sheet 4 of 8 US 2012/002 7693 A1 Figure 4 Subject C Flexor hallucis brevis 8. HZ 18 Hz Stil stim (D - (D 11 hrs after 1st TRP-Stim >i Control >i 52 sec cramp g 58 sec cramp op 5. 3. 20 Sec - o Shi 8 min after TRP-Stim 1 hrs 10 min after 1st TRP-Stim 54 sec cramp 27 sec cramp 15 min after TRP-Stim O min after 2nd TRP-Stim 8 sec Cramp No cramp 2O in after TRP-Stin 12 min after 2nd TRP-Stim No Cramp No cramp 2 hrs after TRP-Stim 22 min after 2nd TRP-Stim No Cramp No Cramp Patent Application Publication Feb. 2, 2012 Sheet 5 of 8 US 2012/002 7693 A1 Figure 5 Subject D (4 hrs after triathlon) Flexor hallucis brevis Control 13-30 min after 3hrs after TRP-Stim TRP-Stim S. 6 Hz 8 Hz 8 HZ 8 Hz 3. 172SeC Cram p No cramp No cramp 3. 50 sec 10 Hz O HZ 10 HZ 222 sec cramp No Cramp No cramp - - - 12 HZ 12 Hz No Cramp No cramp 4 hrs after 20 min after TRP-Stim 2nd TRP-Stim 10Hz 10Hz 58 sec Cramp No cramp 12 HZ 12 Hz 205 sec cramp No cramp -- - - - - a - 14 Hz No Cramp Patent Application Publication Feb. 2, 2012 Sheet 6 of 8 US 2012/002 7693 A1 Figure 6 Subject E Calf muscle Stimulation 28 Hz 20 Sec Control 59 sec cramp 3 min after TRP-Stim 3 Sec Cramp Patent Application Publication Feb. 2, 2012 Sheet 7 of 8 US 2012/002 7693 A1 Figure 7 Subject F Calf muscle 24 Hz Stimulation Control 96 sec cramp 4 min after TRP-Stim No cramp 40 min after TRP-Stim No Cramp Patent Application Publication Feb. 2, 2012 Sheet 8 of 8 US 2012/002 7693 A1 Figure 8 Subject G Spontaneous cramping of flexor hallucis brevis Voluntary toe flex Controit 8 sec Cramp Sec Control #2 5 sec Cramp O min after TRP-Stim No cramp Voluntary toe flex six 15 in after TRP-Stim No cramp US 2012/0027693 A1 Feb. 2, 2012 METHODS AND COMPOSITIONS FOR channel activators, TRPA1 channel activators, or ASIC chan PREVENTING AND RELEVING MUSCLE nel activators, or any combination thereof. CRAMIPS AND FOR RECOVERY FROM 0008. In still another aspect, the invention features a NEUROMUSCULAR RRTABILITY AND method for improving muscle recovery (e.g., muscle recovery FATGUE FOLLOWING EXERCISE following exercise) in a subject in need thereof, where the method includes administering to the Subject a composition CROSS-REFERENCE TO RELATED that includes an effective amount of one or more TRPV1 APPLICATIONS channel activators, TRPA1 channel activators, or ASIC chan nel activators, or any combination thereof. 0001. This application claims benefit of U.S. Provisional 0009. In any of the foregoing methods, the composition Application No. 61/368,059, filed on Jul. 27, 2010, which is can be, e.g., an oral formulation (e.g., a liquid, beverage, gel. hereby incorporated by reference in its entirety. semi-solid, frozen liquid, lozenge, hard candy, dissolving strip, or spray). BACKGROUND OF THE INVENTION 0010. In certain embodiments of any of the methods 0002. In general, the invention relates to methods and described herein, the composition is administered to the sub compositions for preventing, treating or ameliorating muscle ject prior to exercise, during exercise, or following exercise cramping and/or accelerating nerve-muscle recovery from (e.g., within 0-120 minutes prior to exercise, or within 0-360 exercise fatigue. minutes, 0-15 minutes, or 2-6 hours following exercise. 0003 Muscle cramps, the involuntary and forceful con 0011 Muscle cramps that can be treated or prevented traction of muscles, are often painful and can last for a pro using the methods and compositions described herein longed period of time. Muscle contractions and cramping can include, e.g., muscle cramps resulting from exercise, noctur be triggered by exercise and can also occur spontaneously nal cramps, and menstrual cramps. (e.g., nocturnal or night cramps). The underlying physiologi 0012. In particular embodiments of any of the methods cal mechanism of muscle cramping is unknown. Recent described herein, the composition includes an effective understanding has led to the hypothesis that cramping results amount of two or three different TRP channel activators inde from excessive electrical firing of the neurons (motor neu pendently selected from: rons) that project from the spinal cord and trigger contraction 0013 (a) capsacin or other capsaicinoids; of skeletal muscles (Schwellnus, Br J Sports Med. 43:401-8, 0014 (b) cinnamaldehyde or cinnamon oil; and 2009; Miller et al., MedSci Sports Exerc. 42:953-61, 2010). 0015 (c) gingerols. Recovery from strenuous exercise can be associated with 0016. In other embodiments of any of the methods neuromuscular irritability, associated with neuromuscular described herein, each channel activator, independently, fatigue, that may or may not be associated with the develop includes between 0.001% to 1% weight percent of a compo ment of frank cramps. Few treatments and therapeutic regi sition that is a solid, semi-solid, gel, or chewing gum, or 0.001 mens are available to alleviate this neuromuscular irritability. to 1% (v/v) of a composition that is a liquid, beverage, or 0004. There exists a need in the art for improved methods Spray. and compositions for preventing, treating, and ameliorating 0017. In still other embodiments of any of the methods muscle cramping and/or accelerating nerve-muscle recovery described herein, the composition is any of the compositions from exercise fatigue by reducing neuromuscular irritability. described herein. As shown herein, compositions that include activators of TRP 0018. The invention also features a composition formu and ASIC channels may be useful to prevent, treat, or ame lated for oral ingestion by a Subject. The composition liorate muscle cramping and/or accelerate nerve-muscle includes an effective amount of one or more channel activa recovery from, e.g., exercise fatigue. Further, these composi tors (e.g., one or more Substantially pure channel activators) tions can be useful in treating neuromuscular irritability that selected from TRPV1 channel activators, TRPA1 channel may or may not be associated with the development of frank activators, and ASIC channel activators. Desirably, the com Cramps. position is a liquid, beverage, gel, semi-solid, frozen liquid, lozenge, hard candy, dissolving Strip, or spray. SUMMARY OF THE INVENTION 0019 Desirably, the channel activator is capable of acti Vation of a channel in a gastroesophogeal neuron when 0005. The present invention is directed to the prevention, administered to a subject treatment or amelioration of muscle cramps and/or acceler 0020. The channel activators can be substantially pure or ating nerve-muscle recovery from exercise fatigue using a not substantially pure (e.g., part of a crude extract). composition with an activator of TRPV1 channels, an activa 0021. In certain embodiments, the channel activators are tor of TRPA1 channels, and/oran activator of ASIC channels. capable of activation of a channel in a gastroesophogeal neu 0006. In a first aspect, the invention features a method for ron when administered to a Subject.