US008512759B1 (12) United States Patent (10) Patent No.: US 8,512,759 B1 McMahen et al. (45) Date of Patent: Aug. 20, 2013 (54) METHODS OF FORMULATING AND 4,996,047 A 2f1991 Kelleher DESIGNING LIOUID DRUG SUSPENSIONS A E. E.Ca et al. CONTAINING ON EXCHANGE RESN 2003/OO99711 A1 5/2003 Meadows et al. PARTICLES 2004/0052849 A1 3, 2004 Ohare 2005/0013792 A1 1/2005 Hollenbeck et al. ......... 424/78.1 (75) Inventors: Russell McMahen, Flower Mound, TX 2006/0193877 A1 8/2006 Tengler et al. (US); Mark Tengler, Colleyville, TX 2007/0059.270 A1 3, 2007 Hall et al. s s 2007. O140983 A1 6/2007 Hall et al. (US); Michael Sloane, Forth Worth, TX 2007. O148239 A1 6, 2007 Hall et al. (US); Daniel Lockhart, Euless, TX (US) 2009 OO11027 A1 1/2009 Pathak et al. 2009,0176884 A1 7/2009 Dickerson et al. (73) Assignee: Neos Therapeutics, LP, Grand Prairie, TX (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Prabhu et al. (“Comparison of Dissolution Profiles for Sustained patent is extended or adjusted under 35 Release Resinates of BCS Class I Drugs Using USP Apparatus 2 and U.S.C. 154(b) by 0 days. shiel Note”, AAPS PharmSciTech, vol. 9, No. 3, Sep. (21) Appl. No.: 13/490,697 Hadzija et al. (Journal of Forensic Sciences 1996; 41(5):878-880).* Prabhu et al., “Comparison of Dissolution Profiles for Sustained (22) Filed: Jun. 7, 2012 Release Resinates of BCS Class 1 Drugs. Using USP Apparatus 2 and 9 4: A Technical Note”, AAPS PharmSciTech, vol. 9, No.3, Sep. 2008. Related U.S. Application Data FDA's "Guidance for industry” (Jun. 14, 2006, pp. 1-35). (62) Division of application No. 12/985,340, filed on Jan.5, * cited by examiner 2011. (60) Provisional application No. 61/292.420, filed on Jan. Primary Examiner — Aradhana Sasan 5, 2010. (74) Attorney, Agent, or Firm — Hunton & Williams LLP (51) Int. Cl. A 6LX 9/50 (2006.01) (57) ABSTRACT A6 IK 9/14 (2006.01) The invention relates to the formulation and quality control of A6 IK3I/74 (2006.01) liquid drug Suspensions. In particular, the invention relates to (52) U.S. Cl. methods of formulatinggl1C liquid Suspensionsp comprisingpr1S1ng drug USPC ........................... 424/501; 424/78.1; 424/486 containing resin particles. The invention also relates to meth (58) Field of Classification Search ods of confirming the acceptability of drug-containing resin USPC ......................................... 424/78.1, 486,501 particles for use in formulating liquid drug Suspensions. The See application file for complete search history. invention further relates to methods of formulating liquid Suspensions in which drug-containing resin particles, the liq (56) References Cited uid Suspension, or both are modified to achieve a desired in vitro dissolution profile. The invention also relates to a novel U.S. PATENT DOCUMENTS dissolution method and methods of predicting in vivo 2.990,332 A 6/1961 Keating bioeduivalence based on in vitro dissolution methods. 4,221,778 A 9/1980 Raghunathan 4,619,934 A 10, 1986 Sunshine et al. 4,762,709 A * 8/1988 Sheumaker ................ 424/78.11 18 Claims, 14 Drawing Sheets Brand Tussionex sea-a-a-a-row. so xxxxxxxxxxxxxx:xxxxxxxxxxx: ---4- ParticleSize (m) U.S. Patent Aug. 20, 2013 Sheet 1 of 14 US 8,512,759 B1 () \ ?onpoldIeul ?IJOueduol?n|OSSIC] U.S. Patent Aug. 20, 2013 Sheet 2 of 14 US 8,512,759 B1 ~——————~~~~ uo?eued?ja U.S. Patent Aug. 20, 2013 Sheet 3 of 14 US 8,512,759 B1 SÐÅ|OJHAUI….….…….……….….….……….……….…….……….….….……….…….….……….…….….….….….….………:() 9ER|[15)||-|| oN,· ******************************************************************************************************************************************e—eneuquinba.…….….……….………….………….….….……uo?ejed?ja?ae?…….….……….…|?onpolaeloquea (¿eqe?deope) |. (),K??oeds-øs. ?š??šišmiš|°||paleooºpepeoTleul-!-|}?ºlºE.Kessvuonnossid |-· O?uoiellSºulse!!! ubuens||No.ººººº,) 9^?10\/?u U.S. Patent Aug. 20, 2013 Sheet 4 of 14 US 8,512,759 B1 Effect of pH Release 1OO 90 8O 7O 6O 5O 40 3O - A - Chlorpheniramine (at 90 min) 2O -- Hydrocodone (at 90 min) 1O O 3.O 3.5 4.O 4.5 5. O 5.5 6.O 6.5 pH Figure 4 Dissolution Performed in 0.1N HCl (pH - 1.2) 100 90 80 70 60 50 40 - A - Chlorpheniramine 30 20 10O --A A A O 2 4 6 8 10 12 14 Time (Hours) Figure 5 U.S. Patent Aug. 20, 2013 Sheet 5 of 14 US 8,512,759 B1 Chlorpheniramine Plasma Level 1 2 1 O 8 6 4 O O 5 1 O 15 2O 25 Time (Hours) Figure 6 Hydrolone Dissolution Profile -- Low Coating Level -O- Medium Coating Level -3- High Coating Level Figure 7 U.S. Patent Aug. 20, 2013 Sheet 6 of 14 US 8,512,759 B1 Hvdrocodone In-Vitro Dissolution Profile 100 90 80 70 IC 60 : 50 SS 40 e 30 -0 Lower Coating Level 20 -O-Reference Listed Drug O - A Higher Coating Level O O 2 4. 6 8 O Time (hours) Figure 8 Hydrocodone Release Rates 120 80 t vs CD 60 --8=E, 5:S 40 -O-Test A -OH Test B 20 - A-TuSSionex Brand O O 2 4 6 8 10 Time (Hours) Figure 9 U.S. Patent Aug. 20, 2013 Sheet 7 of 14 US 8,512,759 B1 Chlorpheniramine Release Rates 100 80 60 -O-Test A 40 1. -H Test B SS 20 - A - TuSSionex Brand O O 2 4 6 8 10 -20 Time (Hours) Figure 10 7 - s s 3. X l m - TIME HOURS) ESA, "ESE REFERENCE Figure 11 U.S. Patent Aug. 20, 2013 Sheet 8 of 14 US 8,512,759 B1 9 8 a 6 5 4 " a. D == REFERENCE Figure 12 7O 60 y 3E-07e9187x 50 2 R = O.9877 40 1O O 8O 85 90 95 1OO 105 Amount Dissolved Figure 13 U.S. Patent Aug. 20, 2013 Sheet 9 of 14 US 8,512,759 B1 Calculated Hydrocodone Plasma profile in Test B 16 14 12 2 - A - Calculated Profile 3 10 -o-Clinical Data 8 S 6 4 2 O & O 5 10 15 20 25 Time (Hours) Figure 14 Hydrocodone Polistirex Resin High Coating Level - Lab Batch 450 400 350 3O.O | gld 25.0 t; 20.0 -o-Day 0 | 150 -K)- Day 7 | - A Day 14 10.0 -O-Day 30 50 O.O O 1 2 3 4 5 6 7 8 9 Time (Hours) Figure 15 U.S. Patent Aug. 20, 2013 Sheet 10 of 14 US 8,512,759 B1 Hydrocodone Polistirex Resin Low Coating Level - Lab Batch 95.0 90.0 850 80.0 75.0 70.0 265.0 Š600 55.0 500 450 40.0 O 1 2 3 4 5 6 7 8 9 Time (Hours) Figure 16 Hvdrocodone Release Profile - Pilot Batch 60 50 40 S. 30 A1 SS -A-Day 1 20 -O-Day 28 10 O O 2 4 6 8 10 12 14 Time (Hours) Figure 17 U.S. Patent Aug. 20, 2013 Sheet 11 of 14 US 8,512,759 B1 Hydrocodone Release Profile Final Mix at 50°C OOO 90.0 t 80.0 3. s 70.0 -(-DaVay O -O-Day 14 600 -x-Day 30 50.0 O 2 3 4 5 6 7 8 9 Time (Hours) Figure 18 Hydrocodone Release Profile Sample with pH of 3.78 80.0 70.0 ux-*-3– t 60.0 50.0 e 40.0 -H Initial A4 & 30.0 0-7 Day. -O- 14 Day 20.0 -X-21 Day 10.0 O.O O 2 3 4 5 6 7 8 9 Time (Hours) Figure 19 U.S. Patent Aug. 20, 2013 Sheet 12 of 14 US 8,512,759 B1 Hydrocodone Release Profile Sample without Chlorpheniramine Polistirex 7O.O 6O.O 50.0 s 40.0 -HDay 1 SY 30.0 1. -O-Day 7 2O.O - A - 4 Weeks -O-3 Months O.O O O 2 3 4 5 6 7 8 9 Time (Hours) Figure 20 Low Coated Hydrocodone Polistirex 1OO 90 8O 7O 5 6.O 3 50 - RaW Material 40 -o-Suspension - Day 1 or 30 2O O O 2 4 6 8 1O Time (Hours) Figure 21 U.S. Patent Aug. 20, 2013 Sheet 13 of 14 US 8,512,759 B1 High Coated Hydrocodone Polistirex 2 5 -- RaW Material -o-Suspension - Day 1 O O 2 4 6 8 1O Time (Hours) Figure 22 2 i : Brand Tussionex sea----------- ; : :*::::::::::: & xxxx:x:x:i:ii:3:::::::::::::::::::::::::::::::4- x: : . O , Particle Size Crn) Figure 23 U.S. Patent Aug. 20, 2013 Sheet 14 of 14 US 8,512,759 B1 arts: Sigis is gig ressessessex. O Particle Size (in -Greater than 18Oum - Average -15Dum to 173um - Average - DSurn to 24 um - Average -75um to 105um - Average -Pan Sample - Average -125um to 49 unn - kerage Figure 24 US 8,512,759 B1 1. 2 METHODS OF FORMULATING AND a carrier resin Such as an ion-exchange resin. However, while DESIGNING LIOUID DRUG SUSPENSIONS complexing drugs on ion-exchange resins has been effective CONTAINING ON EXCHANGE RESIN for taste-masking, such uncoated complexes provide only a PARTICLES relatively short delay of drug release and a poor control of drug release, because control of release rate is limited to CROSS-REFERENCE TO RELATED variation in particle size and cross-linkage of the Sulfonic APPLICATIONS acid-type resin used to prepare the adsorption compounds. Another approach to prepare liquid Suspensions having This application is a divisional application of U.S. appli Sustained-released capabilities is by coating drug resins with cation Ser.