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(12) Patent Application Publication (10) Pub. No.: US 2010/0210732 A1 Babul (43) Pub US 2010O2.10732A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0210732 A1 Babul (43) Pub. Date: Aug. 19, 2010 (54) METHODS OF PREVENTING THE Publication Classification SEROTONINSYNDROME AND (51) Int. Cl COMPOSITIONS FOR USE THEREFOR A63L/35 (2006.01) (76) Inventor: Najib Babul, Blue Bell, PA (US) A6IP 25/00 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................................ 514/646 Najib Babul 146 Medinah Drive Blue Bell, PA 19422-3212 (US) (57) ABSTRACT (21) Appl. No.: 12/223,987 The present invention is directed to pharmaceutical compo sitions and the use thereof for preventing or minimizing the (22) PCT Filed: Nov. 2, 2006 intensity of the serotonin syndrome. The present invention is directed at a method of preventing or minimizing the intensity (86). PCT No.: PCT/US2O06/042962 of the serotonin syndrome in humans which comprises 371 1 administering proserotonergic agents and serotonin Surge S. ), Aug. 13, 2008 protectors, wherein said concurrent administration reduces or (2), (4) Date: lug. 15, prevents serotonin excess, which is the cause of the serotonin Related U.S. Application Data syndrome. The present invention is also directed to pharma ceutical compositions comprising proserotonergic agents and (60) Provisional application No. 60/732,121, filed on Nov. serotonin Surge protectors useful for carrying out the method 2, 2005. of the present invention. Patent Application Publication Aug. 19, 2010 Sheet 1 of 29 US 2010/0210732 A1 Figure 1. UV Spectrum of tramadol HC in water s g S s Figure 2. Formulation 052/014 dissolution profile Formula 1 O52014 Poloxaraer Ba/HPMCK10OMAerosi Patent Application Publication Aug. 19, 2010 Sheet 2 of 29 US 2010/0210732 A1 Figtre 3. Formulation 052/015 dissolution profile ForTula Cs2cts Getteresorpracters Figure 4. Formulation 0.52019 dissolution profile, Gelucire 50/02 with Methocet K 100M Formula 3 529 Gelucre soloapClarus Patent Application Publication Aug. 19, 2010 Sheet 3 of 29 US 2010/0210732 A1 Figures. Formulation 0527024 dissolution profile Tramadol to in Geluctre 5G/02, formulation 0527024 in BEF + pancreatin Figure 6, Formulation 052024 dissolution profile in SEF containing pancreatin Release profile of Tradio h.ch Gelucire 5Druz Raf Cs2O24 Patent Application Publication Aug. 19, 2010 Sheet 4 of 29 US 2010/0210732 A1 Figure 7. Dissolution profile of propranokol HCl in Gelucire 50/02 in SIF without pancreatin Propranolol HC in Golucre soro2 in SIF without prioratin, Roos2O62 Figure 8, Dissolution profile of propranolol HC in Gelucire 50/02 in SIF containing pancreatin Propranole HCI in Goluciro 6002. In SF Pancreatin, 6 caps Raf D.52054 Patent Application Publication Aug. 19, 2010 Sheet 5 of 29 US 2010/0210732 A1 Figure 9. Combined averaged dissolution profiles of propranolol HCl in Gelucire 50/02 in SF with and without pancreatin Averages of proprolol Cin Gelucra 5002bn SF with and without Pincreatl Ref$252s csiros Gelucing 5002 without pancreatin Figure 10, Combined dissolution profiles of 2ydol XL 50 and Dromadol SR lablets in SF Zydol XL SO & Domado SR dissolution a SF no pancreatin) Time his The two cut Figures at Nird radingaru due to DronadasR. The Monarfigures ore throws prising fron2dox so Patent Application Publication Aug. 19, 2010 Sheet 6 of 29 US 2010/0210732 A1 Figurell. Combined dissolution profiles of seven different excipient formulations in SIF hydrocota Mszois-d Release rate of rardo HC Barnpikas Refosaics Hydrokota APS to353 Beeswaterac sers 18 1s 20 22 24 as 2 30 32 3 Tigars Figure 12. Combined dissolution profiles of seven different excipient formulations, extended scale Release rate of Tranradoc Samples Ros2034 1 2 4 2 2s 2 3 a 34 4 4. rters Patent Application Publication Aug. 19, 2010 Sheet 7 of 29 US 2010/0210732 A1 Figure li. Combined dissolution profiles of five base excipients in HPMC modified formulations Tramadolic rolease profile with time, combinad formulations plot sterotr NP,254 PMC52040-4 - hydrokota 2, 15 HPMCOSACS Cayalcohol, 1GPMCOsos s e e Figure 14. Dissolution profiles of five capsule sample of cely alcohol formulation with 10% HPMC Dissolution of Tramadol Hocrom Golyalocholt hpMC Refos2O39-1) Patent Application Publication Aug. 19, 2010 Sheet 8 of 29 US 2010/0210732 A1 figure 15. Dissolution profiles of modified Sterottx NF formulation Tramadol HC in Storotax (with HPMCK 1.5M) in SF (nopancroatin Raf C52ross a. te O es ar Figure 16. Average dissolution profiles of modified Sterotex NF formulation Average tramadol HCl dissolution profile from Sterotox NF 082/OSB Patent Application Publication Aug. 19, 2010 Sheet 9 of 29 US 2010/0210732 A1 Figure d7. Dissolution profiles of further modificed Sterottx NF formulation Tramadol HC in Storetox (with HPAC & Aerosil) in SEF (no pancreatin) Refoszioso Figure 18, Average dissolution profiles of further modified Sterotex NF formulation Average plot of tramadol HCL try starotax with PMC K is as Aurosticok B4,052 loso Patent Application Publication Aug. 19, 2010 Sheet 10 of 29 US 2010/0210732 A1 Figure 19. Dissolution profiles of Hydrokole formulations containing Methocel K 100M or Methocel K. 15M Tramada HC in Hydrokota 112 (with KOOM & KSM HPMC - Aerosii) in SF D827O62-182 with Methodsk 1.5M. with Mehdcel KOOM e s c Figure20. Avcraged dissolution profiles of Hydrokote formulations containing Methocel K 100M or Methocel K. SM Tramadol HC bro Hydrokote 112 average plots for KOCA & KSMHPMC in SF C52,062-182 With Methocal KSM -e 21 Wehda Kl Patent Application Publication Aug. 19, 2010 Sheet 11 of 29 US 2010/0210732 A1 Figure 2. Dissolution profiles of 250 mg Tramadol HCl in a 550 mg Sterotex NF based formulation 250 rig Tramadol 4 Clin Storodox (ro HPMC) to 650 mg in Sir OS2Jose is Figure 22, Averaged dissolution profiles of 250 mg Tramadol HCl in a 550 mg Sterolex NF based formulation Avorage 250 mg Trumadol HC in storotex (no HPMC) to 60 mg in SIF O52066 Patent Application Publication Aug. 19, 2010 Sheet 12 of 29 US 2010/0210732 A1 Figure 23, Dissolution profiles of 75 mg Tramadol HCl in beeswax with 20% HPMC based formulation 75 mg tramadolic in theswax (20 PMcKSM-AeroslainsFOs2O58 Figure24. Averaged dissolution profiles of 75 mg Tramadol HC) in beeswax with 20% HPMC based formulation Average for 75 mg tramadol HC in beeswax (with 20% HPMCK 15M+Aerosi. COK 84.2%) in SIF s22s s Patent Application Publication Aug. 19, 2010 Sheet 13 of 29 US 2010/0210732 A1 Figure 2. Dissolution profiles of 75 mg Trumadol HCl in beeswax with 23% HPMC based formulation 75 g tranadocribeswat 23% HPMcKSMAeros. 26) in SFOS2070 Figure 26. Averaged dissolution profiles of 75 mg Tratadol HCl in beeswax with 23% HPMC based formulation Average for 75 m tamadol HC in teeswaxwith 23 PMCKSMt AerosiCOK 842 tn SIF Patent Application Publication Aug. 19, 2010 Sheet 14 of 29 US 2010/0210732 A1 figure27. Comparison of averaged dissolution profiles of Tramadol HCl in bceswax with 20% and 23% HPMC based formulation comprison of average tramadol HC in beeswax with 20 & 23%HPMCKBR Aroucox. 64.2%) in SF 520s solo Figure 28. Combined dissolution profiles of first three Tramadol HCl formulations 75 mg Tramadol HCl tribDoswax, Gelucio 50702 and estyl alcohol; 052,072-1,052,072-2,052/073-3 Patent Application Publication Aug. 19, 2010 Sheet 15 of 29 US 2010/0210732 A1 Figure 29. Tramadol HCL in beeswax dissolution profile normalised to HPLC assay data Tramadot HClinto Swax 0.52O72-1) absorbance data nomalised with HPlc assay dats E s 5 g e Figure 30, Tramadol HCl in Gelucire 5002 dissolution profile normalised to HPLC assay data frarnadol HC in Gluct solo OS21072-2) absorbance data normallsed with HPLC assay data Patent Application Publication Aug. 19, 2010 Sheet 16 of 29 US 2010/0210732 A1 figure 31, Tramadol HCl in Gelucire 50/02 repeat dissolution profile normalised to HPLC assay data Tramadol Cllr Golulro SOD2 (0.52F072-2) absorbanco data nomalised with HPLC data 4. n protect SNo 1 () -e-Gaurice sou No.2 Picate 1 r -o-HP data se Figure 32. Tramadol HCL in cetyl alcohol dissolution profile normalised to HPLC assay data Tramadol HCln Cotylistcohol (O52O73-3) absortance data nomalisiod with HPLC assay data Patent Application Publication Aug. 19, 2010 Sheet 17 of 29 US 2010/0210732 A1 Figure 33. Tramadol HCl in cetyl alcohol repeat dissolution profile normalised to HPLCassay data Tramadol HCln Coty alcohol (0.52.0733) absorbangs data normallsud with HPLC data V th --CayacchcNo 1 s -o-cyl sicching g o HPLC dists --RPC data e Figure 34. Combined dissolution profiles of second three Tramadol HCl formulations 75 ring Tramadol HCI in Sterotox NF, Clth roll GMS, Hydrokoto 112; O52PO734,052,073-5, 052 074-6 citro GMs: 52073-5 . 21 lista1 17 2-1 -21Sisterosex NF: osarov 2 ts21 21 Patent Application Publication Aug. 19, 2010 Sheet 18 of 29 US 2010/0210732 A1 Figure 35. Tramadol HCL in Sterotex NF dissolution profile normalised to HPLC assay data Tramadol HCl in Sterotox (062073-4) absorbanco data nomalised with HPLC data t s e s Go R Figure.j6. Tramadol HCL in Sterolex NF dissolution profile normalised to HPLC assay data with extended time scale Traradocin staroto 0.52-073-4 absortance data normalised with hPLC data Patent Application Publication Aug. 19, 2010 Sheet 19 of 29 US 2010/0210732 A1 Figure 37, Tramadol HCL in Cithrol GMS dissolution profile normalised to HPLC assay data Tremadol HC in Citrot GMs (0.52O3-5) absorbunto data nomalised with HPLC data o s s Figure 38. Tramadol HCL in Cithrol GMS dissolution profile normalised to HPLC assay data with extended time scale Tramadul HCI in Citrol GMS(062073-5) absorbance data nomalised with HPLC data Patent Application Publication Aug.
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