USOO842O114B2

(12) United States Patent (10) Patent No.: US 8.420,114 B2 Zanella et al. (45) Date of Patent: Apr. 16, 2013

(54) ALPHA AND BETA ADRENERGIC 6,326,020 B1 12/2001 Kohane et al. RECEPTORAGONSTS FORTREATMENT 6,331,311 B1 12/2001 Brodbeck et al. OF PAN AND F OR NFLAMMATION 6,417, 184 B1 7, 2002 Ockert 6,428,804 B1 8, 2002 Suzuki et al. 6,461,631 B1 10/2002 Dunn et al. (75) Inventors: John M. Zanella, Cordova, TN (US); 6,524,607 B1 2/2003 Goldenheim et al. Sara Waynick, Memphis, TN (US) 6,534,048 B1 3/2003 Borgman 6,534,081 B2 3/2003 Goldenheim et al. (73) Assignee: Warsaw Orthopedic, Inc., Warsaw, IN 6,589,549 B2 7/2003 Shih et al. (US) 6,630, 155 B1 10/2003 Chandrashekar et al. 6,632.457 B1 10/2003 Sawhney *) NotOt1Ce: Subjubject to anyy d1Sclaimer,disclai theh term off thithis 6,723,741 B2 4/2004 Jeon et al. 6,756,058 B2 6/2004 Brubaker et al. patent is extended or adjusted under 35 6,773,714 B2 8, 2004 Dunn et al. U.S.C. 154(b) by 397 days. 6,921,541 B2 7/2005 Chasin et al. 6,974.462 B2 12/2005 Sater (21) Appl. No.: 12/424,368 6,992, 110 B2 1/2006 Kranzler et al. 7,144,412 B2 12/2006 Wolfetal. (22) Filed: Apr. 15, 2009 7,166.570 B2 1/2007 Hunter et al. 7,220.281 B2 5/2007 Lambrecht et al. (65) Prior Publication Data 7,229,441 B2 6/2007 Trieu et al. 7,235,043 B2 6/2007 Gellman US 2009/0263.454 A1 Oct. 22, 2009 7,287,983 B2 10/2007 Han 7,318,840 B2 1/2008 McKay 7,329,259 B2 2/2008 Cragg Related U.S. Application Data (Continued) (60) Provisional application No. 61/046,201, filed on Apr. 18, 2008, provisional application No. 61/146,352. FOREIGN PATENT DOCUMENTS filed on Jan. 22, 2009. WO O3005961 A2 1, 2003 WO 2004.091540 A2 10, 2004 (51) Int. Cl. WO 2005034998 A2 4/2005 A6 IK 9/14 (2006.01) WO 2007OO5177 A1 1, 2007 A6 IK3I/545 (2006.01) A6 IK3I/37 (2006.01) OTHER PUBLICATIONS (52) U.S. Cl. Campiglia et al. (Pre-Emptive analgesia for postoperative pain con USPC ...... 424/433; 424/468; 424/486; 424/501; trol. A review, Clinical Drug Investigation 30 Suppl. 2: 15-26 514/225.8: 514/649 (2010).* (58) Field of Classification Search ...... None Daniel P. Moore, Helping your patients with spasticity reach maxi See application file for complete search history. malfunction, Moore Helping patients with spasticity, vol. 104. No. 2, Aug. 1998, Postgraduate Medicine, http://www.postgradmed.com/ (56) References Cited issues, 1998,0898, moore.htm. Pharmacological Approaches, Medline article located at http://www. U.S. PATENT DOCUMENTS medscape.com/viewarticle/552267 3. 3,190,802 A 6, 1965 Zeile et al. 3,020,660 A 8, 1965 Zeile et al. Riku Antra, MD, PhD, ALpha2-Agonists, Sedatives or Analgesics, 4,624,255 A 11, 1986 Schenck et al. Department of Anesthesiology and Intensive Care, University of 4,742,054 A 5, 1988 Naftchi Turku, Finland. 4,765.974 A 8, 1988 Tokuda et al. 4,863,457 A 9, 1989 Lee (Continued) 5,175,052 A 12/1992 Tokuda et al. 5.447,947 A 9/1995 Campbell 5,484.607 A 1/1996 Horacek Primary Examiner — Robert A Wax 5,522,844 A 6, 1996 Johnson 5,626,838 A 5/1997 Cavanaugh, Jr. Assistant Examiner — Sarah Park 5,635,204 A 6, 1997 Gewirtz et al. 5,759,583 A 6, 1998 Iwamoto et al. (74) Attorney, Agent, or Firm — Sorell, Lenna and Schmidt 5,801, 188 A 9/1998 Hassenbusch, III et al. LLP 5,868,789 A 2f1999 Huebner 5,869,100 A 2f1999 Horacek 5,942,241 A 8, 1999 Chasin et al. (57) ABSTRACT 5,942,503 A 8/1999 Jung et al. 5,942,530 A 8, 1999 Panetta et al. 5,945,416 A 8, 1999 Shannon et al. Effective treatments of pain and/or inflammation are pro 5,980,927 A * 1 1/1999 Nelson et al...... 424/425 vided. Through the administration of an effective amount of 6,030,642 A 2/2000 Horacek at least one alpha adrenergic agonist and at least one beta 6,069,129 A 5/2000 Sandberg et al. adrenergic agonist at or near a target site, one can reduce, 6,147,102 A 11/2000 Borgman 6,179,862 B1 1/2001 Sawhney prevent or treat pain and/or inflammation. 6,248.345 B1 6/2001 Goldenheim et al. 6,267.972 B1* 7/2001 Breton et al...... 424/401 6,287,588 B1 9, 2001 Shih et al. 14 Claims, 25 Drawing Sheets US 8.420,114 B2 Page 2

U.S. PATENT DOCUMENTS 2006/0173060 A1* 8/2006 Chang et al...... 514/389 2006, O183786 A1 8/2006 Wang 7,345,065 B2 3, 2008 Gil et al. 2006, O189944 A1 8/2006 Campbell et al. 7,361,168 B2 4, 2008 Makover et al. 2006/0210604 A1 9/2006 Dadey et al. 7,367,978 B2 5/2008 Drewry et al. 2006/0228391 A1 10/2006 Seyedin et al. 7,507,398 B2 3, 2009 Rabinowitz et al. 2007,0004790 A1 1/2007 Chow et al. 7,524,812 B2 4, 2009 Ellis et al. 2007. O156180 A1 7/2007 Jaax et al. 2002fOOO9454 A1 1, 2002 Boone et al. 2007/O185497 A1 8, 2007 Cauthen et al. 2002fOO58656 A1 5, 2002 Ockert 2007/0202074 A1 8/2007 Shalaby 2002/0090398 A1 T/2002 Dunn et al. 2007/0219185 A1* 9/2007 Kobayashi et al...... 514,225.8 2002fOO94998 A1 T/2002 Burke et al. 2007/0243225 A1 10/2007 McKay 2003/0022926 A1 1, 2003 Lavand’Homme 2007/0243228 A1 10/2007 McKay 2003.01.18692 A1 6, 2003 Wang et al...... 426.6 2007/0248639 A1 10/2007 Demopulos et al. 2003/O185873 A1 10, 2003 Chasin et al. 2007,0253994 A1 11/2007 Hildebrand 2003/0204.191 A1 10, 2003 Sater et al. 2008.0020076 A1 1/2008 Jhamandas et al. 2003,0224033 A1 12, 2003 Li et al. 2008, 0021074 A1 1/2008 Cartt 2004/0028726 A1 2, 2004 Fischer et al. 2008/0091207 A1 4/2008 Truckai et al. 2004/OO72799 A1 4, 2004 Li et al. 2008. O152709 A1 6/2008 Bortz 2004/0082540 A1 4, 2004 Hermida Ochoa 2008.0171075 A1 7/2008 Ozturk et al. 2004/0101582 A1 5, 2004 Wolicki 2004/O1098.99 A1 6, 2004 Albahri 2009/0076595 A1* 3/2009 Lindquist et al...... 623, 143 2004/O2O8917 A1 10, 2004 Fischer et al. OTHER PUBLICATIONS 2004/02098.50 A1 10, 2004 Babul ...... 514,165 2004/0214793 A1 10, 2004 Hermida Ochoa Elizabeth A Moberg-Wolff, MD, Spasticity, Article Dec. 21, 2007, 2004/0265364 A1 12, 2004 Ozturk et al. 2005/0058696 A1 3, 2005 Donello et al. pp. 1-15. 2005/0059744 A1 3, 2005 Donello et al. U.S. Appl. No. 12/056,511, filed Mar. 27, 2008. 2005, 00792O2 A1 4, 2005 Chen et al...... 424/426 U.S. Appl. No. 12/388,635, filed Feb. 19, 2009. 2005/OO95277 A1 5/2005 Ozturk et al. Seo, S.-A. et al., “A local delivery system for fentanyl based on 2005. O142163 A1 6, 2005 Hunter et al. biodegradable poly(L-lactide-co-glycolide) oligomer'. Int. J. 2005/O175709 A1 8, 2005 Baty, III et al. Pharm., 2002, vol. 239, pp. 93-101. See abstract; table 1: figures 2-5; 2005, 0186261 A1 8, 2005 Avelar et al. conclusion. 2005/O197293 A1 9, 2005 Mellis et al. 2005.0245905 A1 11/2005 Schmidt et al. International Search Report and Written Opinion for International 2006, OO74422 A1 4, 2006 Story et al. Application No. PCT/US2009/041016 mailed on Nov. 18, 2009. 2006/0106361 A1 5, 2006 Muni et al. 2006, O148903 A1 T/2006 Burch et al. * cited by examiner U.S. Patent Apr. 16, 2013 Sheet 1 of 25 US 8.420,114 B2

U.S. Patent Apr. 16, 2013 Sheet 2 of 25 US 8.420,114 B2

FIG 2

U.S. Patent Apr. 16, 2013 Sheet 4 of 25 US 8.420,114 B2

i . S. . s E. E. i

Sr s X X X X X X s s s S X X X X X X X XSX

NNNNNS XXXXXXX ZZZZZZZZYZZ

RNNNNNNNNNN P-XXXXXXXXXXXXXXXXX H7ZZZZ ZZ Z2 ZZZ ZZ ZZ ZZ i

D 2NNNNNNNNNNNN XXXXXXXXXXXXXXXXXXXXXXX ZZZZZZZZYZZZZZYZ

E. s NNNNNNN P-XXXXXXXSSXXXXXXXXXXX ZZZZZZZZZZZZZZZZZZZZZZZZZ i

PNNNNNNNNNNNNNNNNNNNN KXXXXXXXXXXXXXXXXXXXXXXXXX RYZZZZZZY ...... H

D NNNNNNN SSSSSSSSS MaaZ s

PTTI NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN RXXXXXXXXXXXXXXXXXXXXXXXXX Z424

C Cd I s s s 5 s NITESW9 WOLNO OOHSH TWONWHOW U.S. Patent Apr. 16, 2013 Sheet 5 Of 25 US 8.420,114 B2

INVITRO RELEASE OF CLONDINE FROM 3 PELLET DOSE

2 O

1 O as: Oss ------so-o-o-o-wis

TIME, DAYS --66DLSE60178-23)IRR.7% CL - - - IRR.7%66b; CLcott8-15) - - IRR.EODESEco17835) 5% CL -O-(00178-23)mGPERDAY -o-, -87.5mOPERDAY -o- (0178-35)mCPERDAY so as so TARGET DALY DOSE, 24 mcg FIG. 5

CALCULATED DAY RELEASE OF CLONDINE FROM 3 PELLET DOSE -o- IRRAD, 7 wt.% CLONDINE, 100DL7E (00178-15) - - O - IRRAD, 7 wt.% CLONIDINE, 100DL5E (00178-23) L - -o- IRRAD. 5 wt.% CLONDINE, 100DL5E (00178-35) -a-7 wt.% CLONIDINE, 100 DL7E (00178-15) - a-- 7 wt.% CLONIDINE, 100DL5E (00178-23) - -a-. 5 wt.% CLONDINE, 100 DL5E (178-35) TARGETDAILY DOSE, 2.4 mcg

O a. ser A. O 5 10 15 20 25 30 35 40 45 50 55 60 65 U.S. Patent Apr. 16, 2013 Sheet 6 of 25 US 8.420,114 B2

CLONDINEHC ANIMAL STUDY FORMULATIONS FIG. 7

0 5 10 15 20 25 30 35 40 45 50 55 60 ELAPSEDTIME, DAYS

-A-7 wt.% CLONDINE, 100 DL5E (00178-23) -o- IRRAD, 7 wt.% CLONDINE, 100 DL5E (00178-23) - a-- 7 wt.% CLONDINE, 100 DL7E (00178-15) - O - IRRAD, 7 wt.% CLONDINE, 100 DL7E (00178-15) - -a-. 5 wt.% CLONDINE, 100 DL5E (00178-35) --O-, IRRAD. 5 wt.% CLONDINE, 100 DL5E (00178-35)

CLONDINEHCALL FORMULATIONS

70------.27 ... 60------i? 7-f-it------5 O

O 5 10 15 20 25 30 35 40 45 50 55 60 65 ELAPSEDTIME, DAYS -o- 10 wi%CLONDINE, 100 DL7E (00178-16) -- SWCSNDINEOPLEGACIAL - O - 7 wt.% CLONDINE,8515DLG(00178-21) ESSENSE -, -o- 7 wt.% CLONDINE, 100 DL5E (00178-23) in N3 ENVIRONMENf(00178-45) --O-- 7 wt.% CLONDINE, 100 DL 7E (00178-15) -- 5W.99NDINE, 100DEN2 -O-5 W. CLONDINE, 100DL 5E 87. A ENEREO EoAc COA (00178-45) ---5W5 conIDINE, looD7E0017836( ) --A-SESSEER i5MEs U.S. Patent Apr. 16, 2013 Sheet 7 of 25 US 8.420,114 B2

CUMULATIVE INVITRO RELEASE PROFLE

0 5 10 15 20 25 30 35 40 45 50 55 60 ELAPSEDTIME, DAYS

-- 7 wt.% CLONDINE, 8515DLG (00178-21) --O-. E. SSNIRINE, 100 DL 5E, - a-- 7 wt.% CLONDINE, 100DL5E (00178-23) 5 wt.% CONDINE, 100 DL 7E --A-. 7 wt.% CLONDINE, 100DL7E (00178-15) "" EA COATING ...A. 10 wt.% CLONDINE, 100DL7E (00178-16) 5 wt % CLONDINE, 100 DL 7E, -o- 5 wt.% CLONDINE, 100 DL 5E GACIAHOACDISSOLUTION - O - 5 wt.% CLONDINE, 100 DL7E --- SWESQNPN 002, PREPARED IN N2 ENVIRONMENT FIG. 9

IRRADATED CLONDINEHC FORMULATIONS CUMULATIVE INVITRO RELEASE PROFILE

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 ELAPSEDTIME, DAYS

00178-72, 5wt%, 100DL 7E, -o-00178-74, 7wt%, 6535 DLG 7E, IRRAD, DOUBLE EXTRUSION, IRRAD, -o- - 00178-71, 5wt.%. 6535 DLG 7E, IRRAD,

99,7873,DOUBLE EXTRUSION, 19W690P5, IRRAD. --O---o- 500178-75.3W.66535DLG wt.% CLONDINE, 100 DL5E 7E, (00178-35) IRRAD, FIG. 10 U.S. Patent Apr. 16, 2013 Sheet 8 of 25 US 8.420,114 B2

CALCULATED DALY RELEASE OF CLONDINE FROM 2/3/4 PELLET DOSE

O essar Y w O 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 TIME, DAYS

se-e- 00178-72.5Wt:600D75, DOUBLE -o- 00178-74,7Wt%,6535DLG 7E, IRRAD, (3PELLETS) 5ESSEESALE -o-- 00178-71,5wt.%. 6535DLG7E, IRRAD. (3PELLETS) - a-- USONAE 2EElefs) -o- 00178-53W26535DGIERRAD(PELLETS) was a was TARGET DALYy DOSE, 2.4 mcg --O-- 5 wt.% CLONDINE, 100 DL5E (00178-35) FIG 11

CALCULATED DALY RELEASE OF CLONDINE FROM 3 PELLET DOSE -- 00178-76-R1, 7.76 w%, COAXAL 100D 7E, RR. -O-- 00178-76-R2, 6.92 wt %, COAXAL 100DL 7E, IRR, - a-- 00178-76-R3, 6.76 wt %, COAXIAL, 10ODL 7E, IRR, --o-- 00178-76-R4, 8.0 wt.%, COAXAL 100DL 7E, RR. -a-00178-72, 5 wt.%, 10ODL 7E, DOUBLE EXTRUSION, IRR. (4 PELLETS) - A - 00178-73, 10 wit%, 10ODL 7E, DOUBLE EXTRUSION, IRR. (2 PELLETS) -o-00178-74, 7 wt.%, 6535 DLG 7E, RR. (3 PELLETS) -o-- 00178-71, 5 wt.%, 6535 DLG 7E, IRR. (3 PELLETS) -, -o- 00178-75, 3 wt.%, 6535DLG 7E, IRR. (4 PELLETS) 8 w w TARGET DALLY DOSE, 24 SS ...o. 5 wt.% CLONIDINE, 100 DL5E (00178-35) U.S. Patent Apr. 16, 2013 Sheet 9 Of 25 US 8.420,114 B2

CALCULATED DALY RELEASE OF CLONDINE FROM 2/3 PELLET DOSE - COAXAL FORMULATIONS 30 -- 00178-76-R1, 7.76 wt.%, CLONDINE, 1 OODL 7E IRRAD, BASE COATING - 0--00178-76-R2, 6.92 wit%, CLONDINE, 10ODL7E IRRAD, THICKER COATING 25- - a-- 00178-76-R3, 6.76 wt.%, CLONDINE, 1 OODL 7E IRRAD, THICKEST COATING --O-- 00178-76-R4, 8,0wt%, CLONDINE, 10ODL 7E, IRRAD, THINNEST COATING -0-00178-79-R1, 15% CORE, THIN COAT, 10ODL5E CORE AND SHEATH 2 O - - - 00178-79-R2, 15% CORE, THICKER COAT, 10ODL5E CORE AND SHEATH --O-- 00178-80-R1, 7.54% CLON. 100 DL5E CORE, 100DL5E SHEATH ----00178-80-R3, 8.90% CLON, 100 DL5E CORE AND SHEATH, THINNER COAT --O-- 00178-80-R5, 9.39% CLON. 100 DL5E CORE AND SHEATH, THIN COAT "O" 5 wt.% CLONDINE, 100 DL5E (00178-35) 8 8 U TARGETDAILY DOSE, 24 mcg 10

O 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 TIME, DAYS FIG. 13

IRRADIATED CLONDINE FORMULATIONS FOR VIVC STUDY CUMULATIVE INVITRORELEASE PROFILE 1 O O 90---00178-81.- 0--00178-77, 5wt%Two CLONDINE,CONDINE, 100D100 DL 5E 1.0mm 80E-...-- 00178-78,5wt.% CLONDINE, 100DL5E 0.8mm 70---0-7 wt.% CLONDINE, 100DL5E (00178-23) ------60----o-- 5 wt.% CLONDINE, 100DL 5E (00178-35) ------5O

O 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 ELAPSED TIME, DAYS FIG. 14 U.S. Patent Apr. 16, 2013 Sheet 10 of 25 US 8.420,114 B2

O CALCULATEDDAILY RELEASE OF CLONDINE FROM 3 PELLET DOSE-IVIVCSAMPLES -o-00178-81, 7wt.% CLONDINE, 100 DL5E - O - 00178-77, 5wt% CLONDINE, 100 DL5E ---. 00178-78, 5wt% CLONDINE, 100 DL 5E -o-- 7 wt.% CLONDINE, 100DL5E (00178-23) --O-- 5 wt.% CLONDINE, 100DL5E (00178-35) i-r TARGETDAILY DOSE, 24 mcg

O A Ca as al O O 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 TIME, DAYS FIG. 15

MICROGRAMS OF CONDINE RELEASED FROM 3 PELLET DOSE

TIME, DAYS -a-7 wt.% CLONIDINE,8515DLG (00178-21) - O - 5 wt.% CLONIDINE, 100 DL5E (00178-35) - a-- 7 wt.% CLONIDINE, 100 DL5E (00178-23) -, -o- 5 wt.% CLONIDINE, 100DL7E (00178-36) --a-a - 10wt wt.% %CONDINE, CLONIDINE, 199D7E 100 DL7E (091815), (00178-16) 5HoACDISSOLUTION wt.%C9NDINE,109DLIEGLACIAL (00178-44) TARGETDAILYDOSE, 24 mcg ---. 5 WCONRINE,00PZEPREPARED - a-- EtOAC COATING (00178-23) INN2 ENVIRONMENT (00178-45) - -a-. POLYMER SOIN COATING (00178-23) FIG. 16 U.S. Patent Apr. 16, 2013 Sheet 11 of 25 US 8.420,114 B2

-0- 13335-60-1 s -ms-Her L 13335-60-2 -A-me - 13335-60-3 -a- 1. 13335-60-4 d small-Has ar s 13335-60-5 d d O

------13335-65-1 ------13335-65-2 - - - A - - - - 13335-65-3 13335-65-4 re-OH 13335-65-5 -Anal 13335-65-6

80 100 120 TIME (DAYS) U.S. Patent Apr. 16, 2013 Sheet 12 of 25 US 8.420,114 B2

-(- 13335-97-1

s MO C LU -0- - L 13699-1-1 Y 2

5o s O CD

80 TIME (DAYS) U.S. Patent Apr. 16, 2013 Sheet 13 Of 25 US 8.420,114 B2

1 -- 13699-16-1 -ms--n- 13699-16-2 -a-A- 13699-16-3 sea-me 13699-16-4 sm-- 13699-16-5

60 80 TIME (DAYS)

-0- 13699-20-1 -e-H 13699-20-4 -A- 13699-20-5 wa-e- 13699-20-6 s-a- 13699-20-7 13699-20-8

60 80 TIME (DAYS) U.S. Patent Apr. 16, 2013 Sheet 14 of 25 US 8.420,114 B2

1 -O- 13699-28-1 -- 13699-28-2 -A- 13699-28-3

s 40 60 80 100 120 TIME (DAYS) FIG. 23

--- 12702-80-7 12702-80-8 U.S. Patent Apr. 16, 2013 Sheet 15 of 25 US 8.420,114 B2

2. C wraw 0s - H 13395-3-1 O - a - - - - - L 13395-3-2 2 sus was a 13395-3-3 5d d O C SS

13395-20-2 -A- 13395-20-3 -O- 13395-20-1 U.S. Patent Apr. 16, 2013 Sheet 16 of 25 US 8.420,114 B2

-2

FIG. 27

FIG. 28 U.S. Patent Apr. 16, 2013 Sheet 17 of 25 US 8.420,114 B2

-0- 13395-27-1 -A- 1 13395-27-3 13395-27-4 -- 6 O 13395-27-5

TIME (DAYS) FIG. 29

CLONIDINEHCIELUTION FROMD,L-PLA (10% DRUGLOAD)

a-0- 13395-34-2 13395-34-3 -A- 13395-34-4 U.S. Patent Apr. 16, 2013 Sheet 18 of 25 US 8.420,114 B2

2. O -O- le 13395-42-1 D - LU 2

5O e O O SS

13335-73-1 all 13335-73-2 - Ar-r 13335-73-3 13335-73-4 U.S. Patent US 8.420,114 B2

(%)ESWETENHALLWITTWOO

FIG. 34 U.S. Patent Apr. 16, 2013 Sheet 20 of 25 US 8.420,114 B2

e?uÁpolIwIeo?ue?oew ?u??ºseggo36e?ueouedseuMous 99"OICH

OfOz

euese uo Uebe pouse eoueuoeW.

U.S. Patent Apr. 16, 2013 Sheet 22 of 25 US 8.420,114 B2

e?sefileued?HIeuue?L ºu??ºseggoafie?ueouedseunaous Z$(91H.

euese uoy Aouee eMepuM Meeue U.S. Patent Apr. 16, 2013 Sheet 23 Of 25 US 8.420,114 B2

e?uÁpollyleo?ue?oew eu]]?seggoe6e?ueouedseuMous

euese uo Uealed pouse League Loew U.S. Patent Apr. 16, 2013 Sheet 24 of 25 US 8.420,114 B2

e?se6?ejed?HIeuue?L au??ºseggoe6e?ueouedseunaous Quauu?eoul 69ADIAH

euese uoyueous Aouee ewepuM me jeueu U.S. Patent Apr. 16, 2013 Sheet 25 Of 25 US 8.420,114 B2

e?uÁpolivleoque?oew ?ullºseago36equeouedseuwaous 0ý(SOIAI

-0°06

euese uoyuese pouseu eu eaew US 8,420,114 B2 1. 2 ALPHIA AND BETAADRENERGIC ments for pulmonary diseases such as asthma and chronic RECEPTORAGONSTS FOR TREATMENT obstructive pulmonary disease (including chronic bronchitis OF PAN AND F OR NFLAMMATION and emphysema), premature labor and cardiac disorders. However, to date alpha and beta adrenergic receptor ago This application claims the benefit of the filing date of nists have not been widely appreciated as effective localized Provisional Application No. 61/046,201, filed Apr. 18, 2008, treatments for pain and/or inflammation. Thus, there is a need entitled “Clonidine Formulations. In A Biodegradable Poly to develop alpha and beta adrenergic receptor agonists to mer Carrier' and the benefit of the filing date of Provisional prevent, treat or reduce pain and/or inflammation. Application No. 61/146,352, filed Jan. 22, 2009, entitled “Alpha And Beta Adrenergic Receptor Agonists For Treat 10 SUMMARY ment Of Pain And/Or Inflammation.” These entire disclosures are hereby incorporated by reference into the present disclo Novel compositions and methods are provided for effec SUC. tively reducing, preventing, or treating unwanted pain and/or inflammation. The pain and/or inflammation may be reduced BACKGROUND 15 for extended periods of time. In one embodiment, an implantable drug depot is provided Pain is typically experienced when the free nerve endings useful for reducing, preventing or treating pain and/or inflam of pain receptors are Subject to mechanical, thermal, chemical mation in a patient in need of such treatment, the implantable or other noxious stimuli. These pain receptors can transmit drug depot comprising a therapeutically effective amount of signals along afferent neurons to the central nervous system an alpha adrenergic receptor agonist and a beta adrenergic and then to the brain. When a person feels pain, any one or receptoragonist, the depot being implantable at a site beneath more of a number of problems can be associated with this the skin to reduce, prevent or treat pain and inflammation, sensation, including but not limited to reduced function, wherein the drug depot is capable of releasing an effective reduced mobility, complication of sleep patterns, and amount of the alpha adrenergic receptoragonist and the beta decreased quality of life. 25 adrenergic receptor agonist over a period of at least one day. The causes of pain include but are not limited to inflam In another embodiment, a method of treating or preventing mation, injury, disease, muscle stress, the onset of a neuro pain and/or inflammation in a patient in need of Such treat pathic event or syndrome, and damage that can result from ment is provided, the method comprising administering one Surgery or an adverse physical, chemical or thermal event or or more biodegradable drug depots comprising a therapeuti from infection by a biologic agent. When a tissue is damaged, 30 cally effective amount of an alpha adrenergic receptoragonist a host of endogenous pain inducing Substances, for example, and a beta adrenergic receptor agonist to a target tissue site bradykinin and histamine can be released from the injured beneath the skin, wherein the drug depot releases an effective tissue. The pain inducing Substances can bind to receptors on amount of the alpha adrenergic receptoragonist and the beta the sensory nerve terminals and thereby initiate afferent pain adrenergic receptor agonist over a period of at least 1 day. signals. After activation of the primary sensory afferent neu 35 In one exemplary embodiment, a method of reducing pain rons, the projection neurons may be activated. These neurons and/or inflammation in a patient in need of such treatment is carry the signal via the spinothalamic tract to higher parts of provided, the method comprising delivering one or more the central nervous system. biodegradable drug depots comprising a therapeutically One known class of pharmaceuticals to treat pain is the effective amount of an alpha-2 adrenergic receptor agonist opioids. This class of compounds is well-recognized as being 40 and a beta-2 adrenergic receptoragonist to a target tissue site among the most effective type of drugs for controlling pain, beneath the skin of the patient, wherein the drug depot Such as post-operative pain. Unfortunately, because opioids releases an effective amount of the alpha-2-adrenergic recep are administered systemically, the associated side effects toragonist and the beta-2 adrenergic receptor agonist over a raise significant concerns, including disabling the patient, period of at least 1 day. depressing the respiratory system, constipation, and psycho 45 In another exemplary embodiment, an implantable drug active effects such as sedation and euphoria, thereby institut depot useful for reducing, preventing or treating pain and ing a hurdle to recovery and regained mobility. Consequently, inflammation (e.g., from Sciatica, spondilothesis, Stenosis, physicians typically limit the administration of opioids to etc.) in a patient is provided, the implantable drug depot within the first twenty-four hours post-surgery. Thus, it would comprising a therapeutically effective amount of an alpha be preferable to use non-narcotic drugs that deliver direct, 50 adrenergic receptor agonist and a beta adrenergic receptor localized pain control at a Surgical site. agonist, and a polymer, wherein the drug depotis implantable One drug class that is known to the medical profession is at a site beneath the skin to reduce, prevent or treat pain and/or the alpha adrenergic receptor agonists. In general, the alpha inflammation, and the depot is capable of releasing (i) about adrenergic receptors mediate excitatory and inhibitory func 5% to about 20% of the alpha adrenergic and beta adrenergic tions: alpha-1 adrenergic receptors are typically excitatory 55 receptoragonist relative to a total amount of the alpha adren post-synaptic receptors which generally mediate responses in ergic and beta adrenergic receptoragonist loaded in the drug the effector organ, while alpha-2 adrenergic receptors are depot over a first period of up to 48 hours and (ii) about 21% located postsynaptically as well as presynaptically, where to about 99% of the alpha adrenergic and beta adrenergic they inhibit release of neurotransmitters. receptoragonist relative to a total amount of the alpha adren Examples of alpha adrenergic receptoragonists used clini 60 ergic receptor agonist loaded in the drug depot over a Subse cally to treat different condition include clonidine, phenoxy quent period of up to 3 to 90 days or 6 months. benzamine and prazosin (for treatment of hypertension and The compositions and methods provided may be used to opioid withdrawal), naphazoline (for nasal decongestion), reduce, prevent, or treat inflammation and/or pain, including UK-14.304 and p-aminoclonidine (for -glaucoma). but not limited to inflammation and/or pain that follows sur Another drug class that is known to the medical profession 65 gery, chronic inflammatory diseases, chronic inflammatory is the beta adrenergic receptor agonists. Beta adrenergic bowel disease, osteoarthritis, osteolysis, tendonitis, Sciatica, receptor agonists are widely recognized as effective treat herniated discs, Stenosis, myopathy, spondilothesis, lower US 8,420,114 B2 3 4 back pain, facet pain, carpal tunnel syndrome, tarsal tunnel which a drug depot containing an alpha adrenergic receptor syndrome, failed back pain or the like. agonist and a beta adrenergic receptor agonist can locally be The pharmaceutical composition may for example, be part administered thereto. of a drug depot. The drug depot may: (i) consist of the alpha FIG. 2 illustrates a schematic dorsal view of the spine and adrenergic and/or beta adrenergic receptor agonist and the sites at which a drug depot containing an alpha adrenergic biodegradable polymer(s); or (ii) consist essentially of the receptor agonist and a beta adrenergic receptor agonist can alpha adrenergic receptor agonist and/or beta adrenergic locally be administered thereto. receptoragonist; or (iii) comprise the alpha adrenergic recep FIG.3 is a graphic representation of the thermal paw with toragonist and/or beta adrenergic receptoragonist and one or drawal latency as a percentage from baseline for the following more other active ingredients, Surfactants, excipients or other 10 administrations using an alpha-2 adrenergic receptoragonist: ingredients or combinations thereof. When there are other clonidine 0.02 mg/kg/day subcutaneously, 100 DL 7E Con active ingredients, Surfactants, excipients or other ingredients trol, 5% CL-HCL, CL 5%, CL 8%, 1 CL 7%, POE Control or combinations thereof in the formulation, in some embodi and POECL-Base, at 7 days, 14 days, 21 days, 28 days, 35 ments these other compounds or combinations thereof com 15 days, 42 days, 49 days, 56 days and 63 days. CL-HCL refers prise less than 20 wt.%, less than 19 wt.%, less than 18 wt. to clonidine hydrochloride. “POE' refers to poly(orthoester). %, less than 17 wt.%, less than 16 wt.%, less than 15 wt.%, “CL-Base' refers to clonidine in its base form. less than 14 wt.%, less than 13 wt.%, less than 12 wt.%, less FIG. 4 is a graphic representation of the mechanical thresh than 11 wt.%, less than 10 wt.%, less than 9 wt.%, less than old as a percentage from baseline for the following adminis 8wt.%, less than 7 wt.%, less than 6 wt.%, less than 5 wt.%, trations: clonidine 0.02 mg/kg/day subcutaneously, 100 DL less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 7E Control, 5% CL-HCL, CL 5%, CL 8%, CL 7%, POE 1 wt.% or less than 0.5 wt.%. Control and POE CL-Base, at 8 days, 15 days, 22 days, 29 In some embodiments, the drug depot comprises at least days, 36 days, 43 days, 50 days, 57 days and 64 days. one biodegradable polymer in a wt % of about 99.5%, 99%, FIG. 5 is a graphic representation of an in vitro release of 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 25 clonidine from three pellet doses as measured by percentage 88%, 87%. 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, release and micrograms released. 78%, 74%, 73%, 72%, 71%, 70%. 65%, 60%, 55%, 50%, FIG. 6 is a graphic representation of the calculated daily 45%, 35%, 25%, 20%, 15%, 10%, or 5% based on the total release of clonidine from three pellet doses as measured by weight of the depot and the remainder is active and/or inactive micrograms released. pharmaceutical ingredients. 30 FIG. 7 is a graphic representation of clonidine HCl animal In some embodiments, there is a pharmaceutical formula study formulations as measured by the cumulative clonidine tion comprising: both an alpha adrenergic receptor agonist released percentage. and a beta adrenergic receptoragonist, wherein both the alpha FIG. 8 is a graphic representation of clonidine HCl release adrenergic receptor agonist and the beta adrenergic receptor for various formulations as measured by the cumulative 35 clonidine released percentage. agonist comprise from about 0.1 wt.% to about 40 wt.% of FIG.9 is a graphic representation of the cumulative in vitro the formulation, and at least one biodegradable polymer. In release profile for certain clonidine formulations. Some embodiments, the alpha adrenergic receptoragonistand FIG. 10 is a graphic representation of the cumulative the beta adrenergic receptoragonist comprise from about 0.5 release profiles for certain irradiated clonidine HCl formula wt.% to about 20 wt.%, about 3 wt.% to about 18 wt.%, 40 tions. about 5 wt.% to about 15 wt.% or about 7.5 wt.% to about FIG. 11 is a graphic representation of certain calculated 12.5 wt.% of the formulation. daily release measurements of clonidine from 2/3/4 pellets In Some embodiments, the drug depot provides a therapeu doses. tically effective dosage amount (e.g., alpha agonist and beta FIG. 12 is a graphic representation of the calculated daily agonist) and the release rate profile are Sufficient to reduce 45 release of clonidine from certain three pellet doses. inflammation and/or pain for a period of at least one day, for FIG. 13 is a graphic representation of the calculated daily example, 1-90 days, 1-10 days, 1-3 days, 3-7 days, 3-12 days: release of clonidine from certain 2/3 pellet dose coaxial for 3-14 days, 7-10 days, 7-14 days, 7-21 days, 7-30 days, 7-50 mulations. days, 7-90 days, 7-140 days, 14-140 days, 3 days to 135 days, FIG. 14 is a graphic representation of the cumulative in 3 days to 180 days, or 3 days to 6 months or 1 year or longer. 50 vitro release profile for certain irradiated clonidine formula Additional features and advantages of various embodi tions. ments will be set forth in part in the description that follows, FIG. 15 is a graphic representation of the calculated daily and in part will be apparent from the description, or may be release of clonidine for certain three pellet dose formulations. learned by practice of various embodiments. The objectives FIG. 16 is a graphic representation of the micrograms of and other advantages of various embodiments will be realized 55 clonidine released for certain three pellet dose formulations. and attained by means of the elements and combinations FIG. 17 is a graphic representation of the cumulative particularly pointed out in the description and appended release percentage of clonidine for certain formulations. claims. FIG. 18 is a graphic representation of the cumulative release percentage of clonidine for certain formulations. BRIEF DESCRIPTION OF THE DRAWINGS 60 FIG. 19 is a graphic representation of the cumulative release percentage of clonidine for certain formulations. In part, other aspects, features, benefits and advantages of FIG. 20 is a graphic representation of the cumulative the embodiments will be apparent with regard to the follow release percentage of clonidine for one formulation. ing description, appended claims and accompanying draw FIG. 21 is a graphic representation of the cumulative ings where: 65 release percentage of clonidine for certain formulations. FIG. 1 illustrates a number of common locations within a FIG. 22 is a graphic representation of the cumulative patient that may be sites at which pain occurs and locations at release percentage of clonidine for certain formulations. US 8,420,114 B2 5 6 FIG. 23 is a graphic representation of the cumulative the structure of each object shown, and thus, some features release percentage of clonidine for certain formulations. may be exaggerated in order to illustrate a specific feature of FIG. 24 is a graphic representation of the cumulative elu a Structure. tion percentage of clonidine for certain formulations. FIG. 25 is a graphic representation of the cumulative elu DETAILED DESCRIPTION tion percentage of clonidine for certain formulations. FIG. 26 is a graphic representation of the cumulative elu For the purposes of this specification and appended claims, tion percentage of clonidine for certain formulations. unless otherwise indicated, all numbers expressing quantities FIG. 27 is a graphic representation of the cumulative elu of ingredients, percentages or proportions of materials, reac tion percentage of clonidine for one formulation. 10 tion conditions, and other numerical values used in the speci FIG. 28 is a graphic representation of the cumulative fication and claims, are to be understood as being modified in release percentage of clonidine for one formulation. all instances by the term “about.” Accordingly, unless indi FIG. 29 is a graphic representation of the cumulative elu cated to the contrary, the numerical parameters set forth in the tion percentage of clonidine for certain formulations. following specification and attached claims are approxima FIG. 30 is a graphic representation of the cumulative elu 15 tions that may vary depending upon the desired properties tion percentage of clonidine for certain formulations. sought to be obtained by the present invention. At the very FIG. 31 is a graphic representation of the cumulative elu least, and not as an attempt to limit the application of the tion percentage of clonidine for one formulation. doctrine of equivalents to the scope of the claims, each FIG. 32 is a graphic representation of the cumulative numerical parameter should at least be construed in light of release percentage of clonidine for certain formulations. the number of reported significant digits and by applying FIG. 33 is a graphic representation of the cumulative ordinary rounding techniques. release percentage of clonidine for one formulation. Notwithstanding the numerical ranges and parameters set FIG. 34 is a graphic representation of the cumulative forth herein, the broad scope of the invention are approxima release percentage of clonidine for one formulation. tions, the numerical values set forth in the specific examples FIG. 35 is a graphic representation of the mechanical 25 are reported as precisely as possible. Any numerical value, threshold as a percentage from baseline in rats given treat however, inherently contains certain errors necessarily result ments of clonidine 0.02 mg/kg, tizanidine 100 micrograms/ ing from the standard deviation found in their respective kg, tizanidine 50 micrograms/kg, medetomidine 200 micro testing measurements. Moreover, all ranges disclosed herein grams/kg, medetomidine 100 micrograms/kg, guanfacine 5 are to be understood to encompass any and all Subranges mg/kg, guanfacine 1 mg/kg Subcutaneous every day for 15 30 subsumed therein. For example, a range of “1 to 10” includes days and tested for mechanical allodynia on days 8 and 15. any and all Subranges between (and including) the minimum FIG. 36 is a graphic representation of the thermal paw value of 1 and the maximum value of 10, that is, any and all withdrawal latency as a percentage from baseline in rats given Subranges having a minimum value of equal to or greater than clonidine 0.02 mg/kg, tizanidine 100 micrograms/kg, tizani 1 and a maximum value of equal to or less than 10, e.g., 5.5 to dine 50 micrograms/kg, medetomidine 200 micrograms/kg, 35 10. medetomidine 100 micrograms/kg, guanfacine 5 mg/kg, Reference will now be made in detail to certain embodi guanfacine 1 mg/kg Subcutaneous every day for 15 days. ments of the invention, examples of which are illustrated in FIG. 37 is a graphic representation of the thermal paw the accompanying drawings. While the invention will be withdrawal latency as a percentage from baseline in rats given described in conjunction with the illustrated embodiments, it clonidine 0.02 mg/kg, guanabenz 5 mg/kg, guanabenZ 1 40 will be understood that they are not intended to limit the mg/kg. oxymetazoline 0.3 mg/kg, oxymetazoline 0.1 mg/kg, invention to those embodiments. On the contrary, the inven phenylephrine 10 mg/kg, and phenylephrine 2 mg/kg Subcu tion is intended to cover all alternatives, modifications, and taneous every day for 15 days. equivalents that may be included within the invention as FIG. 38 is a graphic representation of the mechanical defined by the appended claims. threshold as a percentage from baseline in rats given cloni 45 The headings below are not meant to limit the disclosure in dine 0.02 mg/kg, guanabenz 5 mg/kg, guanabenz, 1 mg/kg. any way; embodiments under any one heading may be used in oxymetazoline 0.3 mg/kg, oxymetazoline 0.1 mg/kg, phe conjunction with embodiments under any other heading. nylephrine 10 mg/kg, and phenylephrine 2 mg/kg Subcutane It is noted that, as used in this specification and the ous every day for 15 days and mechanical allodynia tested at appended claims, the singular forms “a,” “an and “the days 8 and 15. 50 include plural referents unless expressly and unequivocally FIG. 39 is a graphic representation of the thermal paw limited to one referent. Thus, for example, reference to “a withdrawal latency as a percentage from baseline in rats given drug depot includes one, two, three or more drug depots. clonidine 0.02 mg/kg, ritodrine 5 mg/kg, ritodrine 2 mg/kg, The abbreviation “DLG' refers to poly(DL-lactide-co-gly salbutamol 10 mg/kg, salbutamol 5 mg/kg, terbutaline 0.5 collide). mg/kg, terbutaline 0.1 mg/kg, and Saline Subcutaneously 55 The abbreviation “DL refers to poly(DL-lactide). every day for 15 days. The abbreviation “LG' refers to poly(L-lactide-co-gly FIG. 40 is a graphic representation of the mechanical collide). threshold as a percentage from baseline in rats given cloni The abbreviation “CL” refers to polycaprolactone. dine 0.02 mg/kg, ritodrine 5 mg/kg, ritodrine 2 mg/kg, salb The abbreviation “DLCL refers to poly(DL-lactide-co utamol 10 mg/kg, Salbutamol 5 mg/kg, terbutaline 0.5 mg/kg, 60 caprolactone). terbutaline 0.1 mg/kg, and Saline Subcutaneously every day The abbreviation “LCL refers to poly(L-lactide-co-capro for 15 days. The rats were tested for mechanical allodynia at lactone). days 8 and 15. The abbreviation “G” refers to polyglycolide. It is to be understood that the figures are not drawn to scale. The abbreviation “PEG' refers to poly(ethylene glycol). Further, the relation between objects in a figure may not be to 65 The abbreviation “PLGA refers to poly(lactide-co-gly scale, and may in fact have a reverse relationship as to size. collide) also known as poly(lactic-co-glycolic acid), which are The figures are intended to bring understanding and clarity to used interchangeably. US 8,420,114 B2 7 8 The abbreviation “PLA” refers to polylactide. The term “alpha adrenergic agonist’ as used herein, refers The abbreviation “POE' refers to poly(orthoester). to any compound that binds to and/or activates and/or ago Alpha-adrenergic Agonists nizes at least one or more alpha-adrenergic receptor or its The methods and compositions of the present application Subtypes to any degree and/or stabilizes at least one or more utilize an alpha adrenergic agonist alone or in combination alpha-adrenergic receptor or its Subtypes in an active or inac with a beta adrenergic receptor agonist. Human adrenergic tive conformation. Thus, by the term alpha-adrenergic recep receptors are integral membrane proteins, which have been tor agonist it is meant to include partial agonists, inverse classified into two broad classes, the alpha and the beta adr agonists, as well as complete agonists of one or more alpha energic receptors. adrenergic receptors or its subtypes. Both types mediate the action of the peripheral sympa 10 The terms “alpha adrenergic receptor agonist’ “alpha adr thetic nervous system upon binding of catecholamines, nore energic agonist' and “alpha agonist’ as used herein, are syn pinephrine and epinephrine. Norepinephrine is produced by onymous. An alpha adrenergic agonist may be a selective adrenergic nerve endings, while epinephrine is produced by alpha-1 adrenergic agonist, a selective alpha-2 adrenergic the adrenal medulla. The binding affinity of adrenergic recep agonist, or a mixed alpha-1/alpha-2 adrenergic agonist. The tors for these compounds forms one basis of the classifica 15 term “mixed alpha-1/alpha-2 agonist as used herein, refers tion: alpha receptors tend to bind norepinephrine more to a drug that activates both the alpha-1 receptor and the strongly than epinephrine and much more strongly than the alpha-2 receptor including one or more of its subtypes. It may synthetic compound isoproterenol. The preferred binding also be referred to as a non-selective alpha agonist. affinity of these hormones is reversed for the beta receptors. In It will be understood by those of ordinary skill in the art that many tissues, the functional responses, such as Smooth selective alpha-2 agonists may weakly activate the alpha-1 muscle contraction, induced by alpha receptor activation are receptor and the alpha-1 agonist may weakly activate the opposed to responses induced by beta receptor binding. alpha-2 receptor but this weak activation will not be to any Subsequently, the functional distinction between alpha and significant amount and thus the compound is still classified as beta receptors was further highlighted and refined by the a selective alpha-1 or alpha-2 agonist. pharmacological characterization of these receptors from 25 The term “activate” or grammatical variants thereof, as various animal and tissue sources. As a result, alpha and beta used herein, refers to binding to a receptor and causing the adrenergic receptors were further subdivided into alpha-1, receptor to produce a cellular or physiological change. Ago alpha-2, alpha-1/alpha-2 Subtypes. Functional differences nist activation can be characterized using any of a variety of between alpha-1 and alpha-2 receptors have been recognized, routine assays, including, for example, Receptor Selection and compounds, which exhibit selective binding between 30 and Amplification Technology (RSAT) assays (Messier et al., these two subtypes have been developed. Thus, in published Pharmacol. Toxicol. 76:308-11 (1995); cyclic AMP assays international patent application WO92/0073, the selective (Shimizu et al., J. Neurochem. 16:1609-1619 (1969)); and ability of the R(+) enantiomer of terazosin to selectively bind cytosensor microphysiometry assays (Neve et al., J. Biol. to adrenergic receptors of the alpha-1 Subtype was reported. Chem. 267:25748-25753 (1992)). For example, such assays The alpha-1/alpha-2 selectivity of this compound was dis 35 generally are performed using cells that naturally express closed as being significant because agonist stimulation of the only a single alpha adrenergic receptor Subtype, or using alpha-2 receptors was said to inhibit secretion of epinephrine transfected cells expressing a single recombinant alpha-adr and norepinephrine, while antagonism of the alpha-2 receptor energic receptor Subtype. The adrenergic receptor can be a was said to increase secretion of these hormones. For a further human receptor or homolog of a human receptor having a general background on the alpha-adrenergic receptors, the 40 similar pharmacology. The RSAT assay measures receptor reader's attention is directed to text known in the art such as mediated loss of contact inhibition resulting in selective pro for example Robert R. Ruffolo, Jr., alpha-Adrenoreceptors: liferation of receptor-containing cells in a mixed population Molecular Biology, Biochemistry and Pharmacology, of confluent cells. The increase in cell number is assessed (Progress in Basic and Clinical Pharmacology series, Karger, with an appropriate detectable marker gene Such as beta 1991). The cloning, sequencing and expression of alpha 45 galactosidase, if desired, in a high throughput or ultra high receptor Subtypes from animal tissues has led to the Subclas throughput assay format. Receptors that activate the G pro sification of the alpha-1 adrenergic receptors into alpha-1A, tein, Gq, elicit the proliferative response. Alpha-adrenergic alpha-1B, and alpha-1D. Similarly, the alpha-2 adrenergic receptors, which normally couple to Gi, activate the RSAT receptors have also been classified alpha-2A, alpha-2B, and response when coexpressed with a hybrid Gq protein contain alpha-2C receptors based on their pharmacological and 50 inga Gireceptor recognition domain, designated Gq/i5 (Con molecular characterization: alpha-2A/D (alpha-2A in human klin et al., Nature 363:274-6 (1993)). and alpha-2D in rat); alpha-2B: and alpha-2C (Bylund et al., In some embodiments, the alpha adrenergic receptor ago Pharmacol. Rev. 46:121-136 (1994); and Hein and Kobilka, nist comprises an alpha-1 adrenergic receptoragonist, which Neuropharmacol. 357-366 (1995)). The alpha-2A and alpha acts as an analgesic and/or anti-inflammatory agent. Alpha 2B Subtypes can regulate arterial contraction in Some vascular 55 1-adrenergic receptors are members of the G protein-coupled beds, and the alpha-2A and alpha-2C subtypes mediate feed receptor Superfamily. Upon activation, a heterotrimeric G back inhibition of norepinephrine release from sympathetic protein, Gq, activates phospholipase C (PLC), which of nerve endings. The alpha-2A Subtype also mediates many of alpha-1 adrenergic receptor agonists include, but are in no the central effects of alpha-2 adrenergic agonists (Calzada way limited to methoxamine, methylnorepinephrine, and Artinano, Pharmacol. Res. 44: 195-208 (2001); Heinet 60 oxymetazoline, phenylephrine, 2-(anilinomethyl)imidazo al., Ann. NY Acad. Science 881:265-271 (1999). Each lines or a combination thereof. alpha-2 receptor Subtype appears to exhibit its own pharma In some embodiments, the alpha adrenergic receptor ago cological and tissue specificities. Compounds having a nist comprises an alpha-2 adrenergic receptoragonist, which degree of specificity for one or more of these Subtypes may be acts as an analgesic and/or anti-inflammatory agent. more specific therapeutic agents for a given indication than, 65 Examples of alpha-2 adrenergic receptor agonists useful in for example, an alpha-2 receptor pan-agonist (Such as the the present application include, but are in no way limited to drug clonidine). L-norepinephrine, clonidine, dexmetdetomidine, apracloni US 8,420,114 B2 10 dine, methyldopa, tizanidine, brimonidine, Xylometazoline, mixed beta-1/beta-2 agonists or non selective beta agonists, tetrahydrozoline, oxymetazoline, guanfacine, guanabenz, selective beta-1 agonists, or selective beta-2 agonists. guanoxabenz, guanethidine, Xylazine, moXonidine, mivaZ The term “beta adrenergicagonist’ as used herein, refers to erol, rillmenidine, UK 14,304, B-HT 933, B-HT 920, octo a drug that activates a beta adrenergic receptor. The terms pamine or a combination thereof. "beta adrenergic receptor agonist’ “beta adrenergic agonist' Other alpha adrenergicagonists include, but are not limited and “beta agonist’ as used herein, are synonymous. A beta to, amidephrine, amitraz, anisodamine, apraclonidine, cira adrenergic agonist may be a selective beta-1 adrenergicago Zoline, detomidine, epinephrine, ergotamine, etillefrine, nist, a selective beta-2 adrenergic agonist, or a mixed beta-1/ indanidine, lofexidine, medetomidine, mephentermine, met beta-2 adrenergic agonist. The term “mixed beta-1/beta-2 araminol, methoxamine, midodrine, naphazoline, norepi 10 agonist as used herein, refers to a drug that activates both the nephrine, norfenefrine, octopamine, oxymetazoline, phenyl beta-1 receptor and a beta-2 receptor. It may also be referred propanolamine, rillmenidine, romifidine, Synephrine, to as a non-selective beta agonist. talipexole, tizanidine, or a combination thereof. It will be understood by those of ordinary skill in the art that In one embodiment, the alpha adrenergic agonist can be selective beta-2 agonists may weakly activate the beta-1 used as a racemic mixture. In yet another embodiment, the 15 receptor and the beta-1 agonists may weakly activate the alpha adrenergic agonist is used as a single stereoisomer. In beta-2 receptor but this weak activation will not be to any another embodiment, the alpha adrenergic agonist is used as significant amount and thus the compound is still classified as a mixture of stereo isomers containing equal (1:1) or unequal a selective beta 1 or beta 2 agonist. amounts of stereoisomers. For example, in Some embodi The term “activate” or grammatical variants thereof, as ments, the alpha adrenergic agonist may comprise mixtures used herein, refers to binding to a receptor and causing the of (+)R and (-) enantiomers of the agonist. In various receptor to produce a cellular or physiological change. For embodiments, the alpha adrenergic agonist may comprise a example, in one embodiment, a drug that activates a beta 1:1 racemic mixture of the agonist. adrenergic receptor will cause an increase in the intracellular The target tissue site chosen for alpha-agonist delivery level of cyclic adenosine monophosphate (cAMP). depends on, among other things, upon the condition being 25 Determinationifa compound is a beta adrenergicagonist is treated, desired therapeutic concentration of the drug to be within the ability of one of ordinary skill in the art. For achieved in the patient and the duration of drug concentration example, one may utilize the assay as described in U.S. Pat. that must be maintained. No. 4,894.219 (the entire disclosure is herein incorporated by In some embodiments, local administration of the drug reference) to determine if the compound is a beta adrenergic depotator near the target tissue site allows for a lower dose of 30 receptor agonist. the alpha adrenergic agonist to be used than the usual oral, Suitable beta adrenergic agonists include, but are not lim intravenous, or intramuscular dose. For example, local ited to, albuterol, bambuterol, bitolterol, broxaterol, car administration of the drug depot containing the alpha adren buterol, cimaterol, clenbuterol, clorprenaline, colterol, deno ergic agonist and/or beta adrenergic agonist can be accom pamine, dioxethedrine, dopexamine, dopamine, dobutamine, plished with daily doses that are 20%, 15%, 10%, 5%, 1%, 35 ephedrine, epinephrine, norepinephrine, etafedrine, ethyl 0.5%, 0.1%, 0.01% of the usual oral, intravenous or intramus norepinephrine, fenoterol, formoterol, hexoprenaline, ibo cular dose. In turn, Systemic side effects. Such as for example, pamine, ibuterol, isoetharine, isoproterenol, isoxSuprine, lev liver transaminase elevations, hepatitis, liver failure, myopa abuterol, mabuterol, metaproterenol, methoxyphenamine, thy, constipation, etc. may be reduced or eliminated. oxyfedrine, orciprenaline, picumeterol, pirbuterol, prenal The concentration of alpha adrenergic receptor agonist 40 terol, procaterol, protokylol, ractopamine, reproterol, rimit (e.g., alpha-1, alpha-2, apha-1 and alpha-2) included in the erol, ritodrine, Soterenol, Salbutamol, Salmeterol, terbutaline, drug depot and used in the methodologies described herein is tretoquinol, tulobuterol. Xamoterol, Xinfoate, Zinterol, or a a concentration effective to produce a therapeutic effect of combination thereof. preventing, treating or reducing pain and/or inflammation. Other Suitable beta adrenergic agonists are those com Dosages of alpha adrenergic receptoragonist, e.g., clonidine 45 pounds disclosed in U.S. Pat. No. 4,600,710, the entire dis for producing an analgesic effect in human patients upon closure is herein incorporated by reference. local administration can typically range in Some embodi In some embodiments, the beta adrenergic agonist is a ments from between about 150 micrograms to 800 micro selective beta-1 adrenergic agonist, a selective beta-2 adren grams per day or from 3-12 micrograms/hour by local infu ergic agonist, or a mixed beta-1/beta-2 adrenergic agonist or Sion. 50 a combination thereof. However, as will be understood by the skilled artisan upon Examples of selective beta-2 adrenergic receptor agonists reading this disclosure, the effective concentration will vary include, but are not limited to, metaproterenol, terbutaline, depending upon the alpha adrenergic receptor agonist albuterol, isoetharine, pirbuterol, bitolterol, fenoterol, for selected, the route of administration, the frequency of admin moterol, procaterol, salmeterol, ritodrine, or a combination istration, the formulation administered, and the condition 55 thereof. being treated. Examples of selective beta-1 adrenergic receptor agonists In one embodiment, the alpha adrenergic agonist is admin include, but are not limited to, dobutamine, noradrenaline, istered in an amount of about 0.0001 mg/kg/day to about 40 isoprenaline, or a combination thereof. Examples of mixed mg/kg/day. In another embodiment, the alpha adrenergicago beta-1/beta-2 agonists include, but are not limited to, isopro nist is administered in an amount of about 0.001 mg/kg/day to 60 teronol, epinephrine, norepinephrine, or combinations about 4 mg/kg/day. In one embodiment, the alpha adrenergic thereof. agonist is administered in an amount of about 0.01 mg/kg/day In one embodiment, the beta adrenergic agonist used com to about 0.4 mg/kg/day. prises albuterol, Salmeterol, terbutaline, fenoterol, or a com Beta-Adrenergic Agonists bination thereof. In another embodiment, the beta adrenergic The methods and compositions of the present application 65 agonist can be used as a racemic mixture. In yet another utilize a beta adrenergic agonist alone or in combination with embodiment, the beta adrenergic agonist is used as a single an alpha adrenergicagonist. Betaadrenergic agonists include Stereoisomer. In another embodiment, the beta adrenergic US 8,420,114 B2 11 12 agonist is used as a mixture of stereo isomers containing equal adrenergic agonist is released in the first two days and less (1:1) or unequal amounts of stereoisomers. For example, in than 25 percent of the alpha adrenergic agonist is released in Some embodiments, the beta adrenergic agonist may com that time period. In some embodiments, more than 40 percent prise mixtures of (+)R and (-) enantiomers of the agonist. In of the beta adrenergic agonist is released in the first two days various embodiments, the beta adrenergic agonist may com and less than 35 percent of the alpha adrenergic agonist is prise a 1:1 racemic mixture of the agonist. released in that time period. In some embodiments, more than The beta-2 adrenergic agonist may be a short acting ago 50 percent of the beta adrenergic agonist is released in the first nist, such as for example, salbutamol, biltolterol, pirbuterol two days and less than 45 percent of the alpha adrenergic and terbutaline. In some embodiments, the beta-2 adrenergic agonist is released in that time period. agonist may be longer acting. Such as for example, salmeterol 10 In one embodiment, the one or more alpha and beta adren or formoterol. ergic agonists can be administered in a drug depot, which also The target tissue site chosen for beta-agonist delivery may contain another anti-inflammatory and/or an analgesic. depends on, among other things, the condition being treated, By including one or more alpha and beta adrenergic agonists desired therapeutic concentration of the drug to be achieved in the drug depot, this can enhance the effect of the analgesic in the patient and the duration of drug concentration that must 15 and/or anti-inflammatory. In one embodiment, "enhanced be maintained. effect” means that, when co-administered with an alpha adr In various embodiments, because the beta adrenergic energic agonist and a beta adrenergic agonist, lower doses of receptor agonist and/or alpha adrenergic agonist is locally the selected analgesic and/orant-inflammatory agent may be administered, therapeutically effective doses may be less than required to achieve the same analgesic effect as when the doses administered by other routes (oral, topical, etc.). In analgesic and/or anti-inflammatory is administered alone or turn, systemic side effects, such as for example, liver tran greater analgesic or anti-inflammatory effect is achieved saminase elevations, hepatitis, liver failure, myopathy, con when usual doses of the selected analgesic and/or anti-in stipation, etc. may be reduced or eliminated. flammatory is administered with an alpha adrenergic agonist In one embodiment, the beta adrenergic agonist is admin and a beta adrenergic agonist. istered in an amount of about 0.0001 mg/kg/day to about 40 25 Analgesic refers to an agent or compound that can reduce, mg/kg/day. In another embodiment, the beta adrenergicago relieve or eliminate pain. In addition to the alpha adrenergic nist is administered in an amount of about 0.001 mg/kg/day to agonist and/or beta agonist, examples of analgesic agents about 4 mg/kg/day. In one embodiment, the beta adrenergic include but are not limited to acetaminophen, a local anes agonist is administered in an amount of about 0.01 mg/kg/day thetic. Such as for example, lidocaine, bupivicaine, ropiv to about 0.4 mg/kg/day. 30 acaine, opioid analgesics such as buprenorphine, butorpha In various embodiments, it may be advantageous for there nol, dextromoramide, dezocine, dextropropoxyphene, to be a greater release of the alpha adrenergic receptor ago diamorphine, fentanyl, alfentanil, Sufentanil, hydrocodone, nist, i.e., a burst effect for the alpha adrenergic receptor ago hydromorphone, ketobemidone, levomethadyl, levorphanol, nist and either no burst effect for the beta adrenergic receptor mepiridine, methadone, morphine, nalbuphine, opium, oxy agonist or a relatively smaller burst effect for the beta adren 35 codone, papaveretum, pentazocine, pethidine, phenoperi ergic receptoragonist relative to the alpha adrenergic receptor dine, piritramide, dextropropoxyphene, remifentanil, Sufen agonist. Thus, in Some embodiments, there may be a release tanil, tilidine, tramadol, codeine, dihydrocodeine, profile of the alpha adrenergic agonist that releases a first meptazinol, dezocine, eptazocine, flupirtine or a combination percentage of the alpha adrenergic agonist relative to the total thereof. amount of alpha adrenergic agonist over the first two days and 40 The phrase “anti-inflammatory agent” refers to an agent or a release profile of the beta adrenergic agonist agent that compound that has anti-inflammatory effects. These agents releases a first percentage of the beta adrenergic agonist that may remedy pain by reducing inflammation. In addition to the is less than the alpha adrenergic agonist over the first two alpha adrenergic agonist and/or beta adrenergic agonist, days. In some embodiments, more than 30 percent of the examples of anti-inflammatory agents include, but are not alpha adrenergic agonist is released in the first two days and 45 limited to, a statin, Sulindac, SulfaSalazine, guanidinoethyld less than 25 percent of the beta adrenergic agonist is released isulfide, naroxyn, diclofenac, indomethacin, ibuprofen, flur in that time period. In some embodiments, more than 40 biprofen, ketoprofen, aclofenac, aloxiprin, aproxen, aspirin, percent of the alpha adrenergic agonist is released in the first diflunisal, fenoprofen, mefenamic acid, naproxen, phenylb two days and less than 35 percent of the beta adrenergic utaZone, piroxicam, meloxicam, Salicylamide, Salicylic acid, agonist is released in that time period. In some embodiments, 50 desoxysulindac, tenoxicam, ketoralac, flufenisal, Salsalate, more than 50 percent of the alpha adrenergic agonist is triethanolamine salicylate, aminopyrine, antipyrine, released in the first two days and less than 45 percent of the oxyphenbutaZone, apaZone, cintaZone, flufenamic acid, beta adrenergic agonist is released in that time period. clonixeril, clonixin, meclofenamic acid, flunixin, colchicine, In various embodiments, it may be advantageous for there demecolcine, allopurinol, oxypurinol, benzydamine hydro to be a greater release of the beta adrenergic receptoragonist, 55 chloride, dimefadane, indoxole, intrazole, mimbane hydro i.e., a burst effect for the beta adrenergic receptoragonist and chloride, paranylene hydrochloride, tetrydamine, benzin either no burst effect for the alpha adrenergic receptoragonist dopyrine hydrochloride, fluprofen, ibufenac, naproXol. or a relatively smaller burst effect for the alpha adrenergic fenbufen, cinchophen, diflumidone sodium, fenamole, flu receptor agonist relative to the beta adrenergic receptor ago tiazin, metaZamide, letimide hydrochloride, nexeridine nist. Thus, in Some embodiments, there may be a release 60 hydrochloride, octaZamide, molinazole, neocinchophen, profile of the beta adrenergic agonist that releases a first nimazole, proxazole citrate, tesicam, tesimide, tolmetin, tri percentage of the beta adrenergic agonist relative to the total flumidate, fenamates (mefenamic acid, meclofenamic acid), amount of beta adrenergic agonist over the first two days and nabumetone, celecoxib, etodolac, nimeSulide, apaZone, gold, a release profile of the alpha adrenergic agonist agent that tepoxalin; dithiocarbamate, or a combination thereof. Anti releases a first percentage of the alpha adrenergic agonist that 65 inflammatory agents also include other compounds Such as is less than the beta adrenergic agonist over the first two days. steroids, such as for example, fluocinolone, cortisol, corti In some embodiments, more than 30 percent of the beta Sone, hydrocortisone, fludrocortisone, prednisone, predniso US 8,420,114 B2 13 14 lone, methylprednisolone, triamcinolone, betamethasone, It is believed that the alpha adrenergic and beta adrenergic dexamethasone, beclomethasone, fluocinolone, fluticaSone agonists modulate the sympathetic nervous system, which interleukin-1 receptor antagonists, thalidomide (a TNF-C. modulates and regulates the differentiation and function of release inhibitor), thalidomide analogues (which reduce cells involved in host immune response (see, for example, Jim TNF-C. production by macrophages), bone morphogenetic Wong, et al. “Beta-adrenergic receptors (par): role in modu protein (BMP) type 2 or BMP-4 (inhibitors of caspase 8, a lating the host immune response'. Seminars in Anesthesia, TNF-C. activator), quinapril (an inhibitor of angiotensin II, Perioperative Medicine and Pain, Vol. 26, Pages. 10-16 which upregulates TNF-C.), interferons such as IL-11 (which (2007); Rainer Amann, et al. “Beta adrenergic inhibition of modulate TNF-C. receptor expression), and aurin-tricarboxy capsaicin-induced, NK1 receptor-mediated nerve growth fac 10 tor biosynthesis in rat skin’. Pain, Vol. 112, Pages 76-82 lic acid (which inhibits TNF-C.), guanidinoethyldisulfide, or a (2004); Han-Ting Zhang, et al. “Interaction between the anti combination thereof. depressant-like behavioral effects of beta adrenergic agonists Exemplary anti-inflammatory agents include, for example, and the cyclic AMPPDE inhibitor rolipram in rats'. Psychop naproxen; diclofenac; celecoxib; Sulindac; diflunisal; piroxi harmacology, Vol. 182, Pages 104-115 (2005). cam; indomethacin: etodolac, meloxicam, ibuprofen, keto 15 Unless otherwise specified or apparent from context, profen; r-flurbiprofen, mefenamic: nabumetone; Sulfasala where this specification and the set of claims that follows Zine, Sulindac, tolmetin, and sodium salts of each of the refer to an alpha adrenergic receptor agonist or alpha agonist foregoing: ketorolac bromethamine; ketorolac (e.g., alpha-2 agonist, alpha-2 selective agonist, alpha-1 tromethamine; ketorolac acid; choline magnesium trisalicy selective agonist, alpha-1/alpha-2 mixed or non-selective late; rofecoxib; Valdecoxib; lumiracoxib: etoricoxib; aspirin; agonist, etc.) or a beta adrenergic agonist (e.g., beta-1 selec salicylic acid and its sodium salt; Salicylate esters of alpha, tive agonist, beta-2 selective agonist or non-selective beta beta, gamma-tocopherols and tocotrienols (and all their d. 1, agonist), the inventor is also referring to a pharmaceutically and racemic isomers); methyl, ethyl, propyl, isopropyl. n-bu acceptable salt of thereof including stereoisomers. Pharma tyl, sec-butyl, t-butyl, esters of acetylsalicylic acid; tenoxi ceutically acceptable salts include those salt-forming acids cam; aceclofenac; nimeSulide; nepafenac; amfenac; bro 25 and bases that do not substantially increase the toxicity of the mfenac; flufenamate; phenylbutaZone, or a combination compound. Some examples of potentially suitable salts thereof. include Salts of alkali metals such as magnesium, calcium, Exemplary steroids include, for example, 21-acetoxypreg Sodium, potassium and ammonium, salts of mineral acids nenolone, alclometasone, algestone, amcinonide, beclom Such as hydrochloric, hydriodic, hydrobromic, phosphoric, ethasone, betamethasone, budesonide, chloroprednisone, 30 metaphosphoric, nitric and Sulfuric acids, as well as salts of clobetasol, clobetaSone, clocortolone, cloprednol, corticos organic acids such as tartaric, acetic, citric, malic, benzoic, terone, cortisone, cortivaZol, deflazacort, desonide, des glycollic, gluconic, gulonic. Succinic, arylsulfonic, e.g., Oximetasone, dexamethasone, dexamethasone 21-acetate, p-toluenesulfonic acids, or the like. dexamethasone 21-phosphate di-Na salt, diflorasone, diflu A "drug depot’ is the composition in which at least one cortolone, difluprednate, enoXolone, fluazacort, flucloronide, 35 alpha adrenergic receptoragonist and at least one beta adren flumethasone, flunisolide, fluocinolone acetonide, fluocino ergic agonist is administered to the body. Thus, a drug depot nide, fluocortin butyl, fluocortolone, fluorometholone, flu may comprise a physical structure to facilitate implantation perolone acetate, fluprednidene acetate, fluprednisolone, flu and retention in a desired site (e.g., a disc space, a spinal randrenolide, fluticasone propionate, formocortal, canal, a tissue of the patient, particularly at or near a site of halcinonide, halobetasol propionate, halometasone, halopre 40 Surgery, or other site of inflammation, etc.). The drug depot done acetate, hydrocortamate, hydrocortisone, loteprednol also comprises the drug itself. The term “drug as used herein etabonate, maZipredone, medrysone, meprednisone, methyl is generally meant to refer to any Substance that alters the prednisolone, mometasone furoate, paramethasone, predni physiology of a patient. The term “drug may be used inter carbate, prednisolone, prednisolone 25-diethylamino-ac changeably herein with the terms “therapeutic agent,” “thera etate, prednisolone sodium phosphate, prednisone, prednival, 45 peutically effective amount, and “active pharmaceutical prednylidene, rimexolone, tiXocortol, triamcinolone, triamci ingredient’ or API. It will be understood that unless other nolone acetonide, triamcinolone benetonide, triamcinolone wise specified a "drug formulation may include more than hexacetonide or a combination thereof. one therapeutic agent, wherein exemplary combinations of Examples of a useful statin for treatment of pain and/or therapeutic agents include a combination of two or more inflammation include, but are not limited to, atorvastatin, 50 drugs. The drug provides a concentration gradient of the simvastatin, pravastatin, cerivastatin, mevastatin (see U.S. therapeutic agent for delivery to the site. In various embodi Pat. No. 3,883,140, the entire disclosure is herein incorpo ments, the drug depot provides an optimal drug concentration rated by reference), Velostatin (also called synvinolin; see gradient of the therapeutic agent at a distance of up to about U.S. Pat. Nos. 4,448,784 and 4,450,171 these entire disclo 0.1 mm to about 5 cm from the implant site, and comprises at Sures are herein incorporated by reference), fluvastatin, lov 55 least one alpha adrenergic receptoragonist or its pharmaceu astatin, rosuvastatin and fluindostatin (Sandoz XU-62-320), tically acceptable salt. dalvastain (EP Applin. Publin. No. 738510 A2, the entire dis A “depot' includes but is not limited to capsules, micro closure is herein incorporated by reference), eptastatin, pitav spheres, microparticles, microcapsules, microfibers particles, astatin, orpharmaceutically acceptable salts thereofora com nanospheres, nanoparticles, coating, matrices, wafers, pills, bination thereof. In various embodiments, the statin may 60 pellets, emulsions, liposomes, micelles, gels, fiber, strip, comprise mixtures of (+)R and (-)-S enantiomers of the sta sheet or other pharmaceutical delivery compositions or a tin. In various embodiments, the statin may comprise a 1:1 combination thereof. The drug depot may comprise a pump racemic mixture of the statin. that holds and administers the pharmaceutical. In some Anti-inflammatory agents also include those with anti embodiments, the drug depot has pores that allow release of inflammatory properties, such as, for example, amitriptyline, 65 the drug from the depot. The drug depot will allow fluid in the carbamazepine, gabapentin, pregabalin, clonidine, or a com depot to displace the drug. However, cell infiltration into the bination thereof. depot will be prevented by the size of the pores of the depot. US 8,420,114 B2 15 16 In this way, in some embodiments, the depot should not formulation comprises one or more immediate release Sur function as a tissue scaffold and allow tissue growth. Rather, faces and one or more Sustain release Surfaces. the drug depot will solely be utilized for drug delivery. In The phrases “sustained release' or “sustain release' (also Some embodiments, the pores in the drug depot will be less referred to as extended release or controlled release) are used than 250 to 500 microns. This pore size will prevent cells from herein to refer to one or more therapeutic agent(s) that is infiltrating the drug depot and laying down scaffolding cells. introduced into the body of a human or other mammal and Thus, in this embodiment, drug will elute from the drug depot continuously or continually releases a stream of one or more as fluid enters the drug depot, but cells will be prevented from therapeutic agents over a predetermined time period and at a entering. In some embodiments, where there are little or no therapeutic level sufficient to achieve a desired therapeutic 10 effect throughout the predetermined time period. Reference pores, the drug will elute out from the drug depot by the action to a continuous or continual release stream is intended to of enzymes, by hydrolytic action and/or by other similar encompass release that occurs as the result of biodegradation mechanisms in the human body. in vivo of the drug depot, or a matrix or component thereof, or Suitable materials for the depot are ideally pharmaceuti as the result of metabolic transformation or dissolution of the cally acceptable biodegradable and/or any bioabsorbable 15 therapeutic agent(s) or conjugates of therapeutic agent(s). As materials that are preferably FDA approved or GRAS mate persons of ordinary skill are aware, Sustained release formu rials. These materials can be polymeric or non-polymeric, as lations may, by way of example, be created as films, slabs, well as synthetic or naturally occurring, or a combination sheets, pellets, microparticles, microspheres, microcapsules, thereof. In various embodiments, the drug depot may not be spheroids, shaped derivatives or paste. The formulations may biodegradable or comprise material that is not biodegradable. be in a form that is Suitable for Suspension in isotonic saline, Non-biodegradable polymers include, but are not limited to, physiological buffer or other solution acceptable for injection various cellulose derivatives (carboxymethyl cellulose, cel into a patient. Further, the formulations may be used in con lulose acetate, cellulose acetate propionate, ethyl cellulose, junction with any implantable, insertable or injectable system hydroxypropyl methyl cellulose, hydroxyalkyl methyl cellu that a person of ordinary skill would appreciate as useful in loses, and alkyl celluloses), silicon and silicon-based poly 25 connection with embodiments herein including but not lim mers (such as polydimethylsiloxane), polyethylene-co-(vinyl ited to parenteral formulations, microspheres, microcapsules, acetate), poloxamer, polyvinylpyrrolidone, poloxamine, gels, pastes, implantable rods, pellets, plates or fibers, etc. polypropylene, polyamide, polyacetal, polyester, polyethyl The phrase “immediate release' is used herein to refer to ene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE one or more therapeutic agent(s) that is introduced into the or “TeflonTM), styrene butadiene rubber, polyethylene, 30 body and that is allowed to dissolve in or become absorbed at polypropylene, polyphenylene oxide-polystyrene, poly-C.- the location to which it is administered, with no intention of chloro-p-xylene, polymethylpentene, polysulfone, non-de delaying or prolonging the dissolution or absorption of the gradable ethylene-vinyl acetate (e.g., ethylene vinyl acetate drug. Immediate release refers to the release of drug within a disks and poly(ethylene-co-vinyl acetate)), and other related short time period following administration, e.g., generally biostable polymers or combinations thereof. 35 within a few minutes to about 1 hour. The drug depot may comprise non-resorbable polymers as The term “mammal’ refers to organisms from the tax well. These non-resorbable polymers can include, but are not onomy class “mammalian, including but not limited to limited to, delrin, polyurethane, copolymers of silicone and humans, other primates such as chimpanzees, apes, orangu polyurethane, polyolefins (such as polyisobutylene and poly tans and monkeys, rats, mice, cats, dogs, cows, horses, etc. In isoprene), acrylamides (such as polyacrylic acid and poly 40 various embodiments, the mammal is a human patient. (acrylonitrile-acrylic acid)), neoprene, nitrile, acrylates (such The phrase “release rate profile' refers to the percentage of as polyacrylates, poly(2-hydroxyethyl methacrylate), methyl active ingredient that is released over fixed units of time, e.g., methacrylate, 2-hydroxyethyl methacrylate, and copolymers mcg/hr, mcg/day, mg/hr, mg/day, 10% per day for ten days, of acrylates with N-vinyl pyrrolidone), N-vinyl lactams, etc. As persons of ordinary skill know, a release rate profile polyacrylonitrile, glucomannan gel, Vulcanized rubber and 45 may be but need not be linear. By way of a non-limiting combinations thereof. Examples of polyurethanes include example, the drug depot may be a pellet that releases at least thermoplastic polyurethanes, aliphatic polyurethanes, seg one alpha agonistand at least one beta agonist over a period of mented polyurethanes, hydrophilic polyurethanes, polyether time. urethane, polycarbonate-urethane and silicone polyether-ure Treating or treatment of a disease or condition refers to thane. Typically, the non-degradable drug depots may need to 50 executing a protocol, which may include administering one or be removed. more drugs to a patient (human, normal or otherwise, or other A “therapeutically effective amount’ or “effective mammal), in an effort to alleviate signs or symptoms of the amount' is such that when administered, the drug (e.g., alpha disease. Alleviation can occur prior to signs or symptoms of adrenergic agonist and/or beta adrenergic agonist) results in the disease or condition appearing, as well as after their alteration of the biological activity, Such as, for example, 55 appearance. Thus, “treating or “treatment” includes “pre inhibition of inflammation, reduction or alleviation of pain, venting or “prevention of disease or undesirable condition. improvement in the condition through muscle relaxation, etc. In addition, “treating or “treatment” does not require com The dosage administered to a patient can unless otherwise plete alleviation of signs or symptoms, does not require a specified or apparent from context be as single or multiple cure, and specifically includes protocols that have only a doses depending upon a variety of factors, including the 60 marginal effect on the patient. "Reducing pain and/or inflam drug's administered pharmacokinetic properties, the route of mation' includes a decrease in pain and/or inflammation and administration, patient conditions and characteristics (sex, does not require complete alleviation of pain and/or inflam age, body weight, health, size, etc.), extent of symptoms, mation signs or symptoms, and does not require a cure. In concurrent treatments, frequency of treatment and the effect various embodiments, reducing pain and/or inflammation desired. In some embodiments the formulation is designed for 65 includes even a marginal decrease in pain and/or inflamma immediate release. In other embodiments the formulation is tion. By way of example, the administration of the effective designed for Sustained release. In other embodiments, the dosage of the alpha adrenergic receptor agonist and beta US 8,420,114 B2 17 18 adrenergic receptor agonist may be used to prevent, treat or release of therapeutic agent from the depot during the first 24 relieve the symptoms of pain and/or inflammation for differ hours, 2 days, 3 days, 4 days, or 5 days after the depot comes ent diseases or conditions. These disease/conditions may in contact with an aqueous fluid (e.g., synovial fluid, cerebral comprise chronic inflammatory diseases, including, but not spinal fluid, etc.). This burst effect is particularly beneficial limited to autoimmune diseases, such as multiple Sclerosis, for the analgesic, while in various embodiments, for the anti rheumatoid arthritis, osteoarthritis, insulin dependent diabe inflammatory agent a more linear release of a longer duration tes (type I diabetes), systemic lupus erythrematosis and pso may be desired. The “burst effect” is believed to be due to the riasis, immune pathologies induced by infectious agents, increased release of therapeutic agent from the depot. In Such as helminthic (e.g., leishmaniasis) and certain viral alternative embodiments, the depot (e.g., gel, pellet, wafer, infections, including HIV, and bacterial infections, including 10 etc.) is designed to avoid this initial burst effect. Lyme disease, tuberculosis and lepromatous leprosy, tissue The drug depot comprising at least one alpha adrenergic transplant rejection, graft versus host disease and atopic con agonist and beta adrenergic agonist or its pharmaceutically ditions, such as asthma and allergy, including allergic rhinitis, acceptable salt may be co-administered with a muscle relax gastrointestinal allergies, including food allergies, eosino ant. Co-administration may involve administering at the same philia, conjunctivitis or glomerular nephritis. 15 time in separate drug depots or formulating together in the One chronic condition is Sciatica. In general, Sciatica is an same drug depot. example of pain that can transition from acute to neuropathic Exemplary muscle relaxants include by way of example pain. Sciatica refers to pain associated with the Sciatic nerve and not limitation, alcuronium chloride, atracurium bescy which runs from the lower part of the spinal cord (the lumbar late, baclofen, carbolonium, carisoprodol, chlorphenesin car region), down the back of the leg and to the foot. Sciatica bamate, chlorZoxazone, cyclobenzaprine, dantrolene, deca generally begins with a herniated disc. The herniated disc methonium bromide, fazadinium, gallamine triethiodide, itself leads to local immune system activation. The herniated hexafluorenium, meladrazine, mephensin, metaxalone, disc also may damage the nerve root by pinching or com methocarbamol, metocurine iodide, pancuronium, pridinol pressing it, leading to additional immune system activation in mesylate, styramate, suxamethonium, SuXethonium, thio the area. In various embodiments, the alpha adrenergicago 25 colchicoside, tizanidine, tolperisone, tubocuarine, vecuro nist and beta adrenergic agonist may be used to reduce, treat, nium, or combinations thereof. or prevent Sciatic pain and/or inflammation by locally admin The drug depot may also comprise other therapeutic agents istering the alpha adrenergic agonist and the beta adrenergic or active ingredients in addition to the at least one alpha agonist at one or more target tissue sites (e.g., nerve root, adrenergic agonist and beta adrenergic agonist or its pharma dorsal root ganglion, focal sites of pain, at or near the spinal 30 ceutically acceptable salt. Suitable additional therapeutic column, etc.). agents include, but are not limited to, integrin antagonists, “Localized” delivery includes delivery where one or more alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, drugs are deposited within a tissue, for example, a nerve root interferon gamma antagonists, CTLA4-Ig agonists/antago of the nervous system or a region of the brain, or in close nists (BMS-188667), CD40 ligand antagonists, Humanized proximity (within about 10 cm, or within about 5 cm, or 35 anti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1 mAb within 0.1 cm for example) thereto. A “targeted delivery (Critical Therapeutics Inc.), anti-IL2R antibodies (dacli system’ provides delivery of one or more drugs depots, gels Zumab, basilicimab), ABX (anti IL-8 antibodies), recombi or depot dispersed in the gel having a quantity of therapeutic nant human IL-10, or HuMax IL-15 (anti-IL 15 antibodies). agent that can be deposited at or near the target site as needed Other Suitable therapeutic agents that may be co-adminis for treatment of pain, inflammation or other disease or con 40 tered with the alpha adrenergic agonist include IL-1 inhibi dition. tors, such Kineret(R) (anakinra) which is a recombinant, non The term “biodegradable' includes that all or parts of the glycosylated form of the human inerleukin-1 receptor drug depot will degrade over time by the action of enzymes, antagonist (IL-1Ra), or AMG 108, which is a monoclonal by hydrolytic action and/or by other similar mechanisms in antibody that blocks the action of IL-1. Therapeutic agents the human body. In various embodiments, “biodegradable' 45 also include excitatory amino acids such as glutamate and includes that the depot (e.g., microparticle, microsphere, etc.) aspartate, antagonists or inhibitors of glutamate binding to can break down or degrade within the body to non-toxic NMDA receptors, AMPA receptors, and/or kainate receptors. components after or while a therapeutic agent has been or is It is contemplated that where desirable a pegylated form of being released. By “bioerodible' it is meant that the depot the above may be used. Examples of other therapeutic agents will erode or degrade over time due, at least in part, to contact 50 include NF kappa B inhibitors such as glucocorticoids, and with Substances found in the Surrounding tissue, fluids or by antioxidants, such as dilhiocarbamate. cellular action. By “bioabsorbable' it is meant that the depot Specific examples of additional therapeutic agents Suitable will be broken down and absorbed within the human body, for for use include, but are not limited to, an anabolic growth example, by a cell or tissue. “Biocompatible” means that the factor or anti-catabolic growth factor, or an osteoinductive depot will not cause Substantial tissue irritation or necrosis at 55 growth factor or a combination thereof. the target tissue site. Suitable anabolic growth or anti-catabolic growth factors The phrase "pain management medication' includes one or include, but are not limited to, a bone morphogenetic protein, more therapeutic agents that are administered to prevent, a growth differentiation factor, a LIM mineralization protein, alleviate or remove pain entirely. These include one or more CDMP or progenitor cells or a combination thereof. alpha adrenergic agonists and one or more beta adrenergic 60 In addition to the alpha agonist and the beta agonist, Suit agonists alone or in combination with an anti-inflammatory able analgesic agents include, but are not limited to, acetami agent, muscle relaxant, analgesic, anesthetic, narcotic, or so nophen, bupivacaine, tramadol, opioid analgesics such as forth, or combinations thereof. amitriptyline, carbamazepine, gabapentin, pregabalin, opioid In various embodiments, the depot can be designed to analgesics or a combination thereof. Opioid analgesics cause an initial burst dose of therapeutic agent within the first 65 include, alfentanil, allylprodine, alphaprodine, anileridine, 24 hours, 2 days, 3 days, 4 days, or 5 days after implantation. benzylmorphine, bezitramide, buprenorphine, butorphanol, “Initial burst’ or “burst effect or “bolus dose” refer to the clonitaZene, codeine, desomorphine, dextromoramide, dezo US 8,420,114 B2 19 20 cine, diampromide, diamorphone, dihydrocodeine, dihydro form, but may be in the base form (e.g., free base). The dosage morphine, dimenoxadol, dimepheptanol, dimethylthiam may be from approximately 0.0005 to approximately 15,000 butene, dioxaphetyl butyrate, dipipanone, eptazocine, ug/day. Additional dosages of medetomidine, dexmedetomi ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto dine, tizanidine, or romifidine include from approximately nitaZene, fentanyl, heroin, hydrocodone, hydromorphone, 0.0005 to approximately 900 ug/day; approximately 0.0005 hydroxypethidine, isomethadone, ketobemidone, levorpha to approximately 500 g/day; approximately 0.0005 to nol, levophenacylmorphan, lofentanil, meperidine, meptazi approximately 250 ug/day; approximately 0.0005 to approxi nol, metazocine, methadone, metopon, morphine, myro mately 100 ug/day; approximately 0.0005 to approximately phine, narceline, nicomorphine, norlevorphanol, 75ug/day; approximately 0.001 to approximately 70 ug/day: normethadone, nalorphine, nalbuphene, normorphine, norpi 10 approximately 0.001 to approximately 65 ug/day; approxi panone, opium, oxycodone, oxymorphone, papaveretum, mately 0.001 to approximately 60 ug/day; approximately pentazocine, phenadoxone, phenomorphan, phenazocine, 0.001 to approximately 55 ug/day; approximately 0.001 to phenoperidine, piminodine, piritramide, propheptazine, approximately 50 ug/day; approximately 0.001 to approxi promedol, properidine, propoxyphene, Sufentanil, tilidine, mately 45 lug/day; approximately 0.001 to approximately 40 tramadol or a combination thereof. 15 ug/day; approximately 0.001 to approximately 35 ug/day; For each alpha adrenergic agonist and beta adrenergicago approximately 0.0025 to approximately 30 g/day; approxi nist, in Some embodiments, the release of each compound mately 0.0025 to approximately 25 ug/day; approximately may be for at least one, at least two, at least three, at least four, 0.0025 to approximately 20 g/day; approximately 0.0025 to at least five, at least six, at least seven, at least eight, at least approximately 15 g/day; approximately 0.0025 to approxi nine, at least ten, at least eleven, at least twelve, at least mately 10 ug/day; approximately 0.0025 to approximately 5 thirteen, at least fourteen, or at least fifteen days, or longer. ug/day; and approximately 0.0025 to approximately 2.5 The therapeutic agent (e.g., alpha agonist, beta agonist, ug/day. In another embodiment, the dosage of medetomidine, muscle relaxant, steroid, etc.) also includes its pharmaceuti dexmedetomidine, tizanidine, or romifidine may be from cally acceptable salt. As used herein, "pharmaceutically approximately 0.005 to approximately 15ug/day. In another acceptable salts' refer to derivatives of the disclosed com 25 embodiment, the dosage of medetomidine, dexmedetomi pounds (e.g., esters oramines) wherein the parent compound dine, tizanidine, or romifidine may be from approximately may be modified by making acidic or basic salts thereof. 0.005 to approximately 10 ug/day. In another embodiment, Examples of pharmaceutically acceptable salts include, but the dosage of medetomidine, dexmedetomidine, tizanidine, are not limited to, mineral or organic acid salts of basic or romifidine may be from approximately 0.005 to approxi residues such as amines; alkali or organic salts of acidic 30 mately 5 g/day. In another embodiment, the dosage of residues such as carboxylic acids. The pharmaceutically medetomidine, dexmedetomidine, tizanidine, or romifidine is acceptable salts include the conventional non-toxic salts or from approximately 0.005 to 2.5 Lig/day. In some embodi the quaternary ammonium salts of the parent compound ments, the amount of medetomidine, dexmedetomidine, tiza formed, for example, from non-toxic inorganic or organic nidine, or romifidine is between 40 and 600 g/day. In some acids. For example, Such conventional non-toxic salts include 35 embodiments, the amount of medetomidine, dexmedetomi those derived from inorganic acids such as hydrochloric, dine, tizanidine, or romifidine is between 200 and 400 ug/day. hydrobromic, Sulfuric, Sulfamic, phosphoric, or nitric acids; Xylazine/Guanfacine/Guanabenz or the salts prepared from organic acids Such as acetic, fuoric, In some embodiments, the drug depot comprises the alpha propionic, Succinic, glycolic, Stearic, lactic, malic, tartaric, agonist xylazine, guanfacine, guanabenZ, or combinations citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylace 40 thereof. When referring to these compounds, unless other tic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxybenzoic, wise specified or apparent from context it is understood that fumaric, tolunesulfonic, methanesulfonic, ethane disulfonic, the inventor is also referring to pharmaceutically acceptable oxalic, isethionic acid. Pharmaceutically acceptable also salts, racemates, enantiomers, amides, or esters thereof. includes the racemic mixtures ((+)-R and (-)-S enantiomers) Examples of potentially pharmaceutically acceptable salts or each of the dextro and levo isomers of the therapeutic agent 45 include those salt-forming acids and bases that do not Sub individually. The therapeutic agent may be in the free acid or stantially increase the toxicity of a compound, such as, salts of base form or be pegylated for long acting activity. alkali metals such as magnesium, potassium and ammonium, Particular Drugs salts of mineral acids such as hydriodic, hydrochloric, hydro Medetomidine/Dexmedetomidine/Tizanidine/Romifidine bromic, phosphoric, metaphosphoric, nitric and Sulfuric In some embodiments, the drug depot comprises the alpha 50 acids, as well as salts of organic acids such as tartaric, acetic, agonist medetomidine, dexmedetomidine, tizanidine, romifi citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, dine or combinations thereof. When referring to these com arylsulfonic, e.g., p-toluenesulfonic acids, or the like. pounds, unless otherwise specified or apparent from context it The dosage of the Xylazine, guanfacine, or guanabenz may is understood that the inventor is also referring to pharmaceu be from 0.0001 mg to 5000 mg per day. For example, the tically acceptable salts, racemates, enantiomers, amides, or 55 dosage of Xylazine, guanfacine, or guanabenZ may include esters thereof. Examples of potentially pharmaceutically from approximately 0.05 to approximately 900 ug/day: acceptable salts include those salt-forming acids and bases approximately 0.05 to approximately 500 ug/day; approxi that do not Substantially increase the toxicity of a compound, mately 0.05 to approximately 250 ug/day; approximately Such as, salts of alkali metals such as magnesium, potassium 0.05 to approximately 100 g/day; approximately 0.05 to and ammonium, Salts of mineral acids such as hydriodic, 60 approximately 75 ug/day; approximately 0.1 to approxi hydrochloric, hydrobromic, phosphoric, metaphosphoric, mately 70 ug/day; approximately 0.1 to approximately 65 nitric and Sulfuric acids, as well as salts of organic acids Such ug/day; approximately 0.1 to approximately 60 ug/day; as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, approximately 0.1 to approximately 55 Lig/day; approxi gulonic, Succinic, arylsulfonic, e.g., p-toluenesulfonic acids, mately 0.1 to approximately 50 ug/day; approximately 0.1 to or the like. 65 approximately 45 lug/day; approximately 0.1 to approxi In some embodiments, the medetomidine, dexmedetomi mately 40 ug/day; approximately 0.1 to approximately 35 dine, tizanidine, or romifidine may not only be in the salt ug/day; approximately 0.0025 to approximately 30 ug/day; US 8,420,114 B2 21 22 approximately 0.0025 to approximately 25 g/day; approxi Ritodrine mately 0.0025 to approximately 20 ug/day; approximately In some embodiments, the drug depot comprises the beta 0.0025 to approximately 15ug/day; approximately 0.0025 to agonist ritodrine. When referring to ritodrine, unless other approximately 10 ug/day; approximately 0.0025 to approxi wise specified or apparent from context it is understood that mately 5 g/day; and approximately 0.25 to approximately the inventor is also referring to pharmaceutically acceptable 2.5 Lig/day. In some embodiments, the dosage of Xylazine, salts, racemates, enantiomers, amides, or esters thereof. guanfacine, or guanabenz may be for example, 0.1 mg to 2 Examples of potentially pharmaceutically acceptable salts mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg. 30 mg, 35 mg, 40 mg. include those salt-forming acids and bases that do not Sub 45 mg, 50 mg, 55 mg, 60 mg. 65 mg, 70 mg, 75 mg, 75 mg, 80 stantially increase the toxicity of a compound, such as, salts of mg, 85 mg, 90 mg, 95 mg, 100 mg, 120 mg, 130 mg, 140 mg. 10 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg. alkali metals such as magnesium, potassium and ammonium, 300 mg, 350 mg, 400 mg. 450 mg. or 500 mg of xylazine, salts of mineral acids such as hydriodic, hydrochloric, hydro guanfacine, or guanabenz per day. bromic, phosphoric, metaphosphoric, nitric and Sulfuric Oxymetazoline acids, as well as salts of organic acids such as tartaric, acetic, In some embodiments, the drug depot comprises the alpha 15 citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, 1 agonist oxymetazoline. When referring to oxymetazoline, arylsulfonic, e.g., p-toluenesulfonic acids, or the like. unless otherwise specified or apparent from context it is In some embodiments, the ritodrine may not only be in the understood that the inventor is also referring to pharmaceuti salt form, but may be in the base form (e.g., free base). The cally acceptable salts, racemates, enantiomers, amides, or dosage of ritodrine may be from approximately 0.0002 to esters thereof. Examples of potentially pharmaceutically approximately 15,000 ug/day. In some embodiments, the acceptable salts include those salt-forming acids and bases dosages of ritodrine include from approximately 0.0005 to that do not Substantially increase the toxicity of a compound, approximately 900 ug/day; approximately 0.0005 to approxi Such as, salts of alkali metals such as magnesium, potassium mately 500 lug/day; approximately 0.0005 to approximately and ammonium, Salts of mineral acids such as hydriodic, 250 lug/day; approximately 0.0005 to approximately 100 hydrochloric, hydrobromic, phosphoric, metaphosphoric, 25 ug/day; approximately 0.0005 to approximately 75 ug/day; nitric and Sulfuric acids, as well as salts of organic acids Such approximately 0.001 to approximately 70 ug/day; approxi as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, mately 0.001 to approximately 65 ug/day; approximately gulonic, Succinic, arylsulfonic, e.g., p-toluenesulfonic acids, 0.001 to approximately 60 ug/day; approximately 0.001 to or the like. approximately 55 ug/day; approximately 0.001 to approxi In some embodiments, the oxymetazoline may not only be 30 mately 50 ug/day; approximately 0.001 to approximately 45 in the salt form, but may be in the base form (e.g., free base). ug/day; approximately 0.001 to approximately 40 ug/day; The dosage may be from approximately 0.0005 to approxi approximately 0.001 to approximately 35 ug/day; approxi mately 15,000 g/day. Additional dosages of may be from 0.1 mately 0.0025 to approximately 30 ug/day; approximately mg to 5000 mg per day. For example, the dosage of oxymeta 0.0025 to approximately 25ug/day; approximately 0.0025 to Zoline may be for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 35 approximately 20 g/day; approximately 0.0025 to approxi mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mately 15ug/day; approximately 0.0025 to approximately 10 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg. 85 mg, 90 ug/day; approximately 0.0025 to approximately 5 ug/day; mg, 95 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 and approximately 0.0025 to approximately 2.5 Lig/day. In mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg. 300 mg, 350 another embodiment, the dosage of ritodrine is from approxi mg, 400 mg. 450 mg. or 500 mg of oxymetazoline per day. 40 mately 0.005 to approximately 15 g/day. In another embodi Phenylephrine ment, the dosage of ritodrine is from approximately 0.005 to In some embodiments, the drug depot comprises the alpha approximately 10 g/day. In another embodiment, the dosage 1 agonist phenylephrine. When referring to phenylephrine, of ritodrine is from approximately 0.005 to approximately 5 unless otherwise specified or apparent from context it is ug/day. In another embodiment, the dosage of ritodrine is understood that the inventor is also referring to pharmaceuti 45 from approximately 0.005 to 2.5 g/day. cally acceptable salts, racemates, enantiomers, amides, or Additional dosages of may be from 0.1 mg to 5000 mg per esters thereof. Examples of potentially pharmaceutically day. For example, the dosage of ritodrine may be for example, acceptable salts include those salt-forming acids and bases 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg. that do not Substantially increase the toxicity of a compound, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70 mg, 75 Such as, salts of alkali metals such as magnesium, potassium 50 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 120 mg, 130 and ammonium, Salts of mineral acids such as hydriodic, mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 hydrochloric, hydrobromic, phosphoric, metaphosphoric, mg, 250 mg. 300 mg. 350 mg, 400 mg. 450 mg, or 500 mg of nitric and Sulfuric acids, as well as salts of organic acids Such ritodrine per day. In some embodiments, the ritodrine may be as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, in the form of ritodrine hydrochloride. gulonic, Succinic, arylsulfonic, e.g., p-toluenesulfonic acids, 55 Salbutamol or the like. In some embodiments, the drug depot comprises the beta In some embodiments, the phenylephrine may not only be agonist salbutamol. When referring to salbutamol, unless oth in the salt form, but may be in the base form (e.g., free base). erwise specified or apparent from context it is understood that The dosage may be from approximately 0.0005 to approxi the inventor is also referring to pharmaceutically acceptable mately 15,000 g/day. Additional dosages of may be from 0.1 60 salts, racemates, enantiomers, amides, or esters thereof. mg to 5000 mg per day. For example, the dosage of phenyle Examples of potentially pharmaceutically acceptable salts phrine may be for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 include those salt-forming acids and bases that do not Sub mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 stantially increase the toxicity of a compound, such as, salts of mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg. 85 mg, 90 alkali metals such as magnesium, potassium and ammonium, mg, 95 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 65 salts of mineral acids such as hydriodic, hydrochloric, hydro mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg. 300 mg, 350 bromic, phosphoric, metaphosphoric, nitric and Sulfuric mg, 400 mg. 450 mg. or 500 mg of phenylephrine per day. acids, as well as salts of organic acids such as tartaric, acetic, US 8,420,114 B2 23 24 citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, clonidine base formulation. By contrast, when formulating arylsulfonic, e.g., p-toluenesulfonic acids, or the like. clonidine with PLGA, it may be desirable to use the HCl salt In some embodiments, the salbutamol may not only be in form. the salt form, but may be in the base form (e.g., free base). The In one embodiment, the alpha adrenergic agonist is an dosage of salbutamol may be from approximately 0.0005 to alpha-2 adrenergic agonist and comprises clonidine, also approximately 15,000 ug/day. Additional dosages of may be referred to as 2,6-dichloro-N-2-imidazolidinyldenebenze from 0.1 mg to 5000 mg per day. For example, the dosage of namine. Clonidine or a pharmaceutically acceptable salt salbutamol may be for example, 0.1 mg to 2 mg, 5 mg, 10 mg. thereof is available from various pharmaceutical manufac 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 tures. 10 The dosage of clonidine may be from approximately mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg. 85 mg, 90 0.0005 to approximately 960 ug/day. Additional dosages of mg, 95 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 clonidine include from approximately 0.0005 to approxi mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg. 300 mg, 350 mately 900 ug/day; approximately 0.0005 to approximately mg, 400 mg. 450 mg. or 500 mg of salbutamol per day. In 500 ug/day; approximately 0.0005 to approximately 250 some embodiments, the salbutamol may be in the form of 15 ug/day; approximately 0.0005 to approximately 100 ug/day: salbutamol sulfate. approximately 0.0005 to approximately 75 g/day; approxi Terbutaline mately 0.001 to approximately 70 ug/day; approximately In some embodiments, the drug depot comprises the beta 0.001 to approximately 65 lug/day; approximately 0.001 to agonist terbutaline. When referring to terbutaline, unless oth approximately 60 ug/day; approximately 0.001 to approxi erwise specified or apparent from context it is understood that mately 55 ug/day; approximately 0.001 to approximately 50 the inventor is also referring to pharmaceutically acceptable ug/day; approximately 0.001 to approximately 45 ug/day; salts, racemates, enantiomers, amides, or esters thereof. approximately 0.001 to approximately 40 ug/day; approxi Examples of potentially pharmaceutically acceptable salts mately 0.001 to approximately 35 ug/day; approximately include those salt-forming acids and bases that do not Sub 0.0025 to approximately 30 ug/day; approximately 0.0025 to stantially increase the toxicity of a compound. Such as, salts of 25 approximately 25 g/day; approximately 0.0025 to approxi alkali metals such as magnesium, potassium and ammonium, mately 201g/day; approximately 0.0025 to approximately 15 salts of mineral acids such as hydriodic, hydrochloric, hydro ug/day; approximately 0.0025 to approximately 10 ug/day; bromic, phosphoric, metaphosphoric, nitric and Sulfuric approximately 0.0025 to approximately 5 lug/day; and acids, as well as salts of organic acids such as tartaric, acetic, approximately 0.0025 to approximately 2.5 g/day. In citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, 30 another embodiment, the dosage of clonidine is from approxi arylsulfonic, e.g., p-toluenesulfonic acids, or the like. mately 0.005 to approximately 15 g/day. In another embodi In some embodiments, the terbutaline may not only be in ment, the dosage of clonidine is from approximately 0.005 to the salt form, but may be in the base form (e.g., free base). The approximately 10 g/day. In another embodiment, the dosage dosage of terbutaline may be from approximately 0.0005 to of clonidine is from approximately 0.005 to approximately 5 approximately 15,000 ug/day. Additional dosages of may be 35 ug/day. In another embodiment, the dosage of clonidine is from 0.1 mg to 5000 mg per day. For example, the dosage of from approximately 0.005 to 2.5 ug/day. In some embodi terbutaline may be for example, 0.1 mg to 2 mg, 5 mg, 10 mg. ments, the amount of clonidine is between 40 and 600 ug/day. 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 In some embodiments, the amount of clonidine is between mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg. 85 mg, 90 200 and 400 lug/day. mg, 95 mg, 100 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 40 In various embodiments, there is a pharmaceutical formu mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg. 300 mg, 350 lation comprising: clonidine, wherein the clonidine com mg, 400 mg. 450 mg. or 500 mg of terbutaline per day. In prises from about 1 wt.% to about 30 wt.% of the formula some embodiments, the terbutaline may be in the form of tion, and at least one biodegradable polymer. In some terbutaline sulfate. embodiments, the pharmaceutical the clonidine comprises Clonidine 45 from about 3 wt.% to about 20 wt.%, about 3 wt.% to about When referring to clonidine, unless otherwise specified or 18 wt.%, about 5 wt.% to about 15 wt.% or about 7.5 wt.% apparent from context it is understood that the inventor is also to about 12.5 wt.% of the formulation. By way of example, referring to pharmaceutically acceptable salts. One well when using a 5%-15% clonidine composition, the mole ratio known commercially available salt for clonidine is its hydro of clonidine to polymer would be from approximately 16-52 chloride salt. Some other examples of potentially pharmaceu 50 when using an approximately 80 kDalton polymer that has a tically acceptable salts include those salt-forming acids and 267 grams/mole ratio. bases that do not substantially increase the toxicity of a com In some embodiments, the at least one biodegradable poly pound, such as, salts of alkali metals such as magnesium, mer used in the depot containing the alpha adrenergic recep potassium and ammonium, salts of mineral acids such as toragonist and/or beta adrenergic receptoragonist comprises hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric 55 poly(lactic-co-glycolide) (PLGA) or poly(orthoester) (POE) and Sulfuric acids, as well as salts of organic acids such as or a combination thereof. The poly(lactic-co-glycolide) may tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, comprise a mixture of polyglycolide (PGA) and polylactide gulonic, Succinic, arylsulfonic, e.g., p-toluenesulfonic acids, and in Some embodiments, in the mixture, there is more and the like. polylactide than polyglycolide. In various embodiments there Further, when referring to clonidine the active ingredient 60 is 100% polylactide and 0% polyglycolide: 95% polylactide may not only be in the salt form, but also in the base form and 5% polyglycolide; 90% polylactide and 10% polygly (e.g., free base). In various embodiments, if it is in the base collide; 85% polylactide and 15% polyglycolide; 80% poly form, it may be combined with polymers under conditions in lactide and 20% polyglycolide; 75% polylactide and 25% which there is not severe polymer degradation, as may be seen polyglycolide; 70% polylactide and 30% polyglycolide: 65% upon heat or solvent processing that may occur with PLGA or 65 polylactide and 35% polyglycolide; 60% polylactide and PLA. By way of a non limiting example, when formulating 40% polyglycolide: 55% polylactide and 45% polyglycolide; clonidine with poly(orthoesters) it may be desirable to use the 50% polylactide and 50% polyglycolide; 45% polylactide US 8,420,114 B2 25 26 and 55% polyglycolide; 40% polylactide and 60% polygly %, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least collide: 35% polylactide and 65% polyglycolide; 30% poly 80 wt.%, or at least 90 wt.%. lactide and 70% polyglycolide; 25% polylactide and 75% In some embodiments, the drug depot contains excipients polyglycolide; 20% polylactide and 80% polyglycolide; 15% along with the alpha and/or beta agonist. Exemplary excipi polylactide and 85% polyglycolide; 10% polylactide and 5 ents that may be formulated with alpha and/or beta agonis in 90% polyglycolide; 5% polylactide and 95% polyglycolide; addition to the biodegradable polymer include but are not and 0% polylactide and 100% polyglycolide. limited to MgO (e.g., 1 wt.%), 5050 DLG 6E, 5050 DLG 1A, In various embodiments that comprise both polylactide mPEG, TBO-Ac, mPEG, Span-65, Span-85, pluronic F127, and polyglycolide; there is at least 95% polylactide; at least TBO-Ac, sorbital, cyclodextrin, maltodextrin, pluronic F68, 10 CaCl, 50507A and combinations thereof. In some embodi 90% polylactide; at least 85% polylactide; at least 80% poly ments, the excipients comprise from about 0.001 wt.% to lactide; at least 75% polylactide; at least 70% polylactide; at about 50 wt.% of the formulation. In some embodiments, the least 65% polylactide; at least 60% polylactide; at least 55%; excipients comprise from about 0.001 wt.% to about 40 wt.% at least 50% polylactide; at least 45% polylactide; at least of the formulation. In some embodiments, the excipients 40% polylactide; at least 35% polylactide; at least 30% poly 15 comprise from about 0.001 wt.% to about 30 wt.% of the lactide; at least 25% polylactide; at least 20% polylactide; at formulation. In some embodiments, the excipients comprise least 15% polylactide; at least 10% polylactide; or at least 5% from about 0.001 wt.% to about 20 wt.% of the formulation. polylactide; and the remainder of the biopolymer is polygly In some embodiments, the excipients comprise from about collide. 0.001 wt.% to about 10 wt.% of the formulation. In some In various embodiments, the drug particle size (e.g., alpha embodiments, the excipients comprise from about 0.001 wt. and beta agonist) is from about 5 to 30 micrometers, however, % to about 50 wt.% of the formulation. In some embodi in various embodiments the drug particle size ranges from ments, the excipients comprise from about 0.001 wt.% to about 1 micron to 250 microns. In some embodiments, the about 2 wt.% of the formulation. biodegradable polymer comprises at least 50 wt.%, at least 60 A strategy of triangulation may be effective when admin wt.%, at least 70 wt.%, at least 80 wt.% of the formulation, 25 istering these pharmaceutical formulations. Thus, a plurality at least 85 wt.% of the formulation, at least 90 wt.% of the (at least two, at least three, at least four, at least five, at least formulation, at least 95 wt.% of the formulation or at least 97 six, at least seven, etc.) drug depots comprising the pharma wt.% of the formulation. ceutical formulations may be placed around the target tissue In some embodiments, at least 75% of the drug particles site (also known as the pain generator or pain generation site) have a size from about 10 micrometer to about 200 microme 30 Such that the targettissue site falls withina region that is either ters. In some embodiments, at least 85% of the drug particles between the formulations when there are two, or within an have a size from about 10 micrometer to about 200 microme area whose perimeter is defined by a set of plurality of for ters. In some embodiments, at least 95% of the drug particles mulations. have a size from about 10 micrometer to about 200 microme In some embodiments, the formulations are slightly rigid ters. In some embodiments, all of the drug particles have a 35 with varying length, widths, diameters, etc. For example, size from about 10 micrometer to about 200 micrometers. certain formulations may have a diameter of 0.50 mm and a In some embodiments, at least 75% of the drug particles length of 4 mm. It should be noted that particle size may be have a size from about 20 micrometer to about 180 microme altered by techniques such as using a mortar and pestle, ters. In some embodiments, at least 85% of the drug particles jet-drying or jet milling. have a size from about 20 micrometers to about 180 microme 40 In some embodiments, the alpha agonist (e.g., clonidine) is ters. In some embodiments, at least 95% of the drug particles released at a rate of 2-3 jug per day for a period of at least three have a size from about 20 micrometer to about 180 microme days. In some embodiments, this release rate continues for, at ters. In some embodiments, all of the drug particles have a least ten days, at least fifteen days, at least twenty-five days, size from about 20 micrometer to about 180 micrometers. at least fifty days, at least ninety days, at least one hundred In some embodiments, there is a pharmaceutical formula 45 days, at least one-hundred and thirty-five days, at least one tion comprising: clonidine and a beta agonist, wherein the hundred and fifty days, or at least one hundred and eighty clonidine is in the form of a hydrochloride salt, and comprises days. For some embodiments, 300-425 micrograms of cloni from about 1 wt.% to about 20 wt.% of the formulation, and dine as formulated with a biopolymer are implanted into a at least one biodegradable polymer, wherein the at least one person at or near a target tissue site. If clonidine is implanted biodegradable polymer comprises poly(lactide-co-glycolide) 50 at multiple sites that triangulate the target site then in some (or poly(lactic-co-glycolic acid)) or poly(orthoester) or a embodiments, the total amount of clonidine at each site is a combination thereof, and said at least one biodegradable fraction of the total 300-425 micrograms. For example, one polymer comprises at least 80 wt.% of said formulation. may implant a single does of 324 micrograms at one site, or In Some embodiments, there are methods for treating acute two separate doses of 162 micrograms at two sites, or three pain. These methods comprise: administering a pharmaceu 55 separate dose of 108 micrograms at three sites that triangulate tical composition to an organism, wherein said pharmaceuti the tissue site. It is important to limit the total dosage to an cal composition comprises from about 1 wt.% to about 20 wt. amount less than that which would be harmful to the organ % of the formulation, and at least one biodegradable polymer. ism. However, in some embodiments, although when there In some embodiments, the loading is from about 5 wt.% to are a plurality of sites each site may containless than the total about 10 wt.%. In some embodiments, the loading is from 60 dose that might have been administered in a single applica about 10 wt.% to about 20 wt.%. tion, it is important to remember that each site will indepen In some embodiments, there is a higher loading of cloni dent have a release profile, and the biopolymers concentra dine, e.g., at least 20 wt.%, at least 30 wt.%, at least 40 wt.%. tion and Substance should be adjusted accordingly to ensure at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least that the Sustain release occurs over Sufficient time. 80 wt.%, or at least 90 wt.%. 65 In some embodiments, there is a drug depot comprising In some embodiments, there is a higher loading of the beta clonidine or clonidine hydrochloride, a beta agonist and a agonist, e.g., at least 20 wt.%, at least 30 wt.%, at least 40 wt. polymer, wherein the polymeris one more of various embodi US 8,420,114 B2 27 28 ments, the drug depot comprises poly(lactide-co-glycolide) 8S,9R, 10S,11S,13S, 14S,16R,17R)-9-Fluoro-11,17-dihy (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, droxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11, D.L-lactide, L-lactide, D.L-lactide-co-e-caprolactone, D.L- 12, 14.15.16 octahydrocyclopentaa-phenanthren-3-one), or lactide-co-glycolide-co-e-caprolactone or a combination a pharmaceutically acceptable salt thereof, which is available thereof. from various manufacturers. In one exemplary dosing regimen, a rat may be provided In various embodiments, dexamethasone may be released with sufficient clonidine in a biodegradable polymer to pro from the depot at a dose of about 10pg to about 80 mg/day, vide sustain release of 0.240 ug/day for 135 days. The total about 2.4 ng/day to about 50 mg/day, about 50 ng/day to about amount of clonidine that is administered over this time period 2.5 mg/day, about 250 ng/day to about 250 ug/day, about 250 would be approximately 32.4 ug. In another exemplary dos 10 ing regimen, a human is provided with Sufficient clonidine in ng/day to about 50 ug/day, about 250 ng/day to about 25 a biodegradable polymer to provide Sustain release of 2.4 ug/day, about 250 ng/day to about 1 lug/day, about 300 ng/day ug/day for 135 days. The total amount of clonidine that is to about 750 ng/day or about 0.50 ug/day. In various embodi administered over this time period would be approximately ments, the dose may be about 0.01 to about 10 ug/day or about 324 ug. 15 1 ng to about 120 ug/day. When using a plurality of pellets, the pellet number is In one exemplary embodiment, the dexamethasone is dex based on the amount of drug loading into a pellet of appro amethasone sodium phosphate. priate size (i.e., 0.5 mm diameterx4 mm length) and how GED much drug is needed (e.g., approximately 325 ug clonidine (3 In one embodiment, in addition to the alpha agonistand the pellets)). In some embodiments there is a polymer that beta agonist, the therapeutic agent is GED (guanidinoethyld releases a bolus amount of compound over the first few (-5) isulfide), which is an inducible nitric oxide synthase inhibitor days before it settles down and releases 2.5 mg/day for 135 having anti-inflammatory properties. GED may be in its days. An exemplary formulation is 5% wt. clonidine, 100 DL hydrogen carbonate salt form. 5E. The dosage of GED may be from approximately 0.0005 In some embodiments, the polymer depots of present appli 25 ug/day to approximately 100 mg/day. Additional dosages of cation enable one to provide efficacy of the active ingredient GED include from approximately 0.0005 g/day to approxi that is equivalent to Subcutaneous injections that delivers mately 50 mg/day; approximately 0.0005ug/day to approxi more than 2.5 times as much drug. mately 10 mg/day; approximately 0.0005ug/day to approxi Fluocinoline mately 1 mg/day; approximately 0.0005 to approximately In one embodiment, in addition to the alpha agonist and the 30 800 ug/day; approximately 0.0005 to approximately 50 beta agonist, an anti-inflammatory agent is added to the drug g/day; approximately 0.001 to approximately 45 g/day: depot and comprises fluocinolone or a pharmaceutically approximately 0.001 to approximately 40 ug/day; approxi acceptable salt thereof such as the acetonide salt. Fluocino lone is available from various pharmaceutical manufacturers. mately 0.001 to approximately 35 ug/day; approximately The dosage of fluocinolone may be from approximately 35 0.0025 to approximately 30 ug/day; approximately 0.0025 to 0.0005 to approximately 100 g/day. Additional dosages of approximately 25 g/day; approximately 0.0025 to approxi fluocinolone include from approximately 0.0005 to approxi mately 20 ug/day; and approximately 0.0025 to approxi mately 50 ug/day; approximately 0.0005 to approximately 25 mately 15ug/day. In another embodiment, the dosage of GED ug/day; approximately 0.0005 to approximately 10 ug/day; is from approximately 0.005 to approximately 15 lug/day. In approximately 0.0005 to approximately 5 g/day; approxi 40 another embodiment, the dosage of GED is from approxi mately 0.0005 to approximately 1 ug/day; approximately mately 0.005 to approximately 10 g/day. In another embodi 0.0005 to approximately 0.75ug/day; approximately 0.0005 ment, the dosage of GED is from approximately 0.005 to to approximately 0.5 lug/day; approximately 0.0005 to approximately 5ug/day. In another embodiment, the dosage approximately 0.25 ug/day; approximately 0.0005 to of GED is from approximately 0.005 to 2.5 g/day. In some approximately 0.1 ug/day; approximately 0.0005 to approxi 45 embodiments, the amount of GED is between 40 and 600 mately 0.075ug/day; approximately 0.0005 to approximately ug/day. In some embodiments, the amount of GED is between 0.05 g/day; approximately 0.001 to approximately 0.025 200 and 400 lug/day. ug/day; approximately 0.001 to approximately 0.01 ug/day; In one exemplary embodiment the dosage of GED is approximately 0.001 to approximately 0.0075 ug/day: between 0.5 and 4 mg/day. In another exemplary embodiment approximately 0.001 to approximately 0.005 ug/day: 50 the dosage of GED is between 0.75 and 3.5 mg/day. approximately 0.001 to approximately 0.025 ug/day; and Lovastatin approximately 0.002 ug/day. In another embodiment, the In one exemplary embodiment, in addition to the alpha dosage of fluocinolone is from approximately 0.001 to agonist and the beta agonist, an anti-inflammatory agent is approximately 15ug/day. In another embodiment, the dosage added to the drug depot and comprises lovastatin. Lovastatin of fluocinolone is from approximately 0.001 to approxi 55 is a statin that may be obtained from various manufacturers in mately 10 g/day. In another embodiment, the dosage of various forms (e.g., injection, powder, etc.). For example, fluocinolone is from approximately 0.001 to approximately 5 lovastatin may be obtained from Merck as Mevacor R (see ug/day. In another embodiment, the dosage of fluocinolone is U.S. Pat. No. 4,231,938, the entire disclosure is herein incor from approximately 0.001 to 2.5 ug/day. In some embodi porated by reference). Suitable pharmaceutically acceptable ments, the amount of fluocinolone is between 40 and 600 60 salts of lovastatin include one or more compounds derived ug/day. In some embodiments, the amount of fluocinolone is from bases such as sodium hydroxide, potassium hydroxide, between 200 and 400 ug/day. lithium hydroxide, calcium hydroxide, 1-deoxy-2-(methy Dexamethasone lamino)-D-glucitol, magnesium hydroxide, Zinc hydroxide, In one embodiment of the present invention, in addition to aluminum hydroxide, ferrous or ferric hydroxide, ammonium the alpha agonist and the beta agonist, an anti-inflammatory 65 hydroxide or organic amines Such as N-methylglucamine, agent is added to the drug depot and comprises dexametha choline, arginine or the like or combinations thereof. Suitable Sone free base or dexamethasone acetate, also referred to as pharmaceutically acceptable salts of lovastatin include US 8,420,114 B2 29 30 lithium, calcium, hemicalcium, Sodium, potassium, magne In some embodiments, the depot material may have a melt sium, aluminum, ferrous or ferric salts thereof or a combina ing point or glass transition temperature close to or higher tion thereof. than body temperature, but lower than the decomposition or In various embodiments, the therapeutically effective degradation temperature of the therapeutic agent. However, amount of lovastatin comprises from about 0.1 pg to about the pre-determined erosion of the depot material can also be 2000 mg, for example, 0.1 ng to 1000 mg, 500 mg, 100 mg, 50 used to provide for slow release of the loaded therapeutic mg, 25 mg, 10 mg, 1 mg, 50 ug. 25ug. 101g, 1 Jug, 500ng, 250 agent(s). ng, 100 ng, 75 ng, 50 ng, 25 ng, 15 ng, 10 ng, 5 ng, or 1 ng of In various embodiments, the drug depot may not be biode lovastatin per day. In various embodiments, the dosage may gradable. For example, the drug depot may comprise poly be, for example from about 3 ng/day to 0.3 ug/day. 10 urethane, polyurea, polyether(amide), PEBA, thermoplastic Morphine elastomeric olefin, copolyester, and styrenic thermoplastic In one embodiment of the present invention, in addition to the alpha agonist and the beta agonist, an analgesic agent is elastomer, Steel, aluminum, stainless steel, titanium, metal added to the drug depot and comprises morphine. Morphine is alloys with high non-ferrous metal content and a low relative also referred to as (5a,6a)-7,8-didehydro-4,5-epoxy-17-me 15 proportion of iron, carbon fiber, glass fiber, plastics, ceramics thylmorphinan-3,6-diol and has the chemical formula or combinations thereof. Typically, these types of drug depots CHNO. Morphine and a pharmaceutically acceptable may need to be removed. salt thereof is available from various manufacturers. In one In some instances, it may be desirable to avoid having to exemplary embodiment, the morphine comprises morphine remove the drug depot after use. In those instances, the depot sulfate or hydrochloride. may comprise a biodegradable material. There are numerous The dosage of the morphine may be from 0.1 mg to 1000 materials available for this purpose and having the character mg per day. For example, the dosage of morphine may be for istic of being able to breakdown or disintegrate over a pro example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg. longed period of time when positioned at or near the target 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70 tissue. As a function of the chemistry of the biodegradable mg, 75 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 120 25 material, the mechanism of the degradation process can be mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 hydrolytical or enzymatical in nature, or both. In various mg, 200 mg of morphine per day. embodiments, the degradation can occur either at the Surface Tramadol (heterogeneous or Surface erosion) or uniformly throughout In one embodiment, in addition to the alpha agonist and the the drug delivery system depot (homogeneous or bulk ero beta agonist, an analgesic is added to the drug depot and 30 sion). comprises tramadol. Tramadol is also referred to as (t)cis-2- In various embodiments, the depot may comprise a bioab (dimethylamino)methyl-1-(3-methoxyphenyl) cyclohex sorbable, and/or a biodegradable biopolymer that may pro anol hydrochloride and has the chemical formula vide immediate release, or Sustained release of the at least one CHNO. Tramadol or a pharmaceutically acceptable salt analgesic agent and at least one anti-inflammatory agent. thereof is available from various manufacturers. In various 35 Examples of suitable sustained release biopolymers include embodiments, tramadol HCL was used. but are not limited to poly (alpha-hydroxy acids), poly (lac The dosage of the tramadol may be from 0.01 mg to 500 mg tide-co-glycolide) (PLGA or PLG), polylactide (PLA), per day. For example, the dosage of tramadol may be for polyglycolide (PG), polyethylene glycol (PEG) conjugates of example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg. poly (alpha-hydroxy acids), polyorthoesters, polyaspirins, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70 40 polyphosphagenes, collagen, starch, pre-gelatinized starch, mg, 75 mg, 75 mg, 80 mg. 85 mg, 90 mg.95 mg, 100 mg, 120 hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 Vitamin E analogs, such as alpha tocopheryl acetate, d-alpha mg, 200 mg, or 500 mg of tramadol per day. tocopheryl Succinate, D.L-lactide, or L-lactide, caprolactone, In one embodiment, the drug depot contains Sufficient tra dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA). PVA-g- madol to release between 2.5 and 30 mg/kg/day. In another 45 PLGA, PEGT-PBT copolymer (polyactive), methacrylates, embodiment the drug depot contains Sufficient tramadol to poly (N-isopropylacrylamide). PEO-PPO-PEO (pluronics), release between 3 and 27.5 mg/kg/day. PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG tri Other Embodiments block copolymers, SAIB (sucrose acetate isobutyrate) or 50 combinations thereof. As persons of ordinary skill are aware, The alpha adrenergic agonist and beta adrenergic agonist mPEG may be used as a plasticizer for PLGA, but other may also be administered with non-active ingredients. These polymers/excipients may be used to achieve the same effect. non-active ingredients may have multi-functional purposes mPEG imparts malleability to the resulting formulations. including the carrying, stabilizing and controlling the release In some embodiments, these biopolymers may also be of the therapeutic agent(s). The Sustained release process, for 55 coated on the drug depot to provide the desired release profile. example, may be by a solution-diffusion mechanism or it may In some embodiments, the coating thickness may be thin, for be governed by an erosion-sustained process. Typically, the example, from about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 depot will be a solid or semi-solid formulation comprised of microns to thicker coatings 60, 65,70, 75, 80, 85,90, 95, 100 a biocompatible material that can be biodegradable. The term microns to delay release of the drug from the depot. In some “solid is intended to mean a rigid material, while "semi 60 embodiments, the range of the coating on the drug depot Solid is intended to mean a material that has some degree of ranges from about 5 microns to about 250 microns or 5 flexibility, thereby allowing the depot to bend and conform to microns to about 200 microns to delay release from the drug the Surrounding tissue requirements. depot. In various embodiments, the non-active ingredients will be Where different combinations of polymers are used (bi, tri durable within the tissue site for a period of time equal to (for 65 (e.g., PLGA-PEO-PLGA) or terpolymers), they may be used biodegradable components) or greater than (for non-biode in different molar ratios, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, gradable components) the planned period of drug delivery. 9:1, or 10:1. In various embodiments, for the 130 day release, US 8,420,114 B2 31 32 the depot comprises 50:50 PLGA to 100 PLA and the alpha delivery. For example, one may use polymers with acid (e.g., and/or beta agonist. The molecular weight range is 0.45 to 0.8 carboxylic acid) and ester end groups (e.g., lauryl, methyl or dI/g. ethyl ester end groups). In various embodiments, the molecular weight of the poly Additionally, by varying the comonomer ratio of the vari mer can be a wide range of values. The average molecular 5 ous monomers that form a polymer (e.g., the L/G/CL or G/CL weight of the polymer can be from about 1000 to about ratio for a given polymer) used in the drug depot there will be 10,000,000; or about 1,000 to about 1,000,000; or about a resulting depot composition having a regulated burst index 5,000 to about 500,000; or about 10,000 to about 100,000; or and duration of delivery. For example, a depot composition about 20,000 to 50,000. having a polymer with a L/G ratio of 50:50 may have a short 10 duration of delivery ranging from about two days to about one In some embodiments, the at least one biodegradable poly month; a depot composition having a polymer with a L/G mer in the drug depot comprises poly(lactic-co-glycolic acid) ratio of 65:35 may have a duration of delivery of about two (PLA) or poly(orthoester) (POE) or a combination thereof. months; a depot composition having a polymer with a L/G The poly(lactic-co-glycolic acid) may comprise a mixture of ratio of 75:25 or L/CL ratio of 75:25 may have a duration of polyglycolide (PGA) and polylactide and in some embodi 15 delivery of about three months to about four months; a depot ments, in the mixture, there is more polylactide than polyg composition having a polymer ratio with a L/G ratio of 85:15 lycolide. In various other embodiments there is 100% poly may have a duration of delivery of about five months; a depot lactide and 0% polyglycolide: 95% polylactide and 5% composition having a polymer with a L/CL ratio of 25:75 or polyglycolide: 90% polylactide and 10% polyglycolide: 85% PLA may have a duration of delivery greater than or equal to polylactide and 15% polyglycolide; 80% polylactide and six months; a depot composition having a terpolymer of 20% polyglycolide; 75% polylactide and 25% polyglycolide; CL/G/L (CL refers to caprolactone, G refers to glycolic acid 70% polylactide and 30% polyglycolide: 65% polylactide and L refers to lactic acid) with G greater than 50% and L and 35% polyglycolide; 60% polylactide and 40% polygly greater than 10% may have a duration of delivery of about one collide; 55% polylactide and 45% polyglycolide; 50% poly month and a depot composition having a terpolymer of lactide and 50% polyglycolide; 45% polylactide and 55% 25 CL/G/L with Gless than 50% and L. less than 10% may have polyglycolide; 40% polylactide and 60% polyglycolide: 35% a duration months up to six months. In general, increasing the polylactide and 65% polyglycolide; 30% polylactide and G content relative to the CL content shortens the duration of 70% polyglycolide; 25% polylactide and 75% polyglycolide; delivery whereas increasing the CL content relative to the G 20% polylactide and 80% polyglycolide; 15% polylactide content lengthens the duration of delivery. and 85% polyglycolide; 10% polylactide and 90% polygly 30 In some embodiments, the biodegradable polymer com collide; 5% polylactide and 95% polyglycolide; and 0% poly prises at least 10 wt %, at least 50 wt.%, at least 60 wt.%, at lactide and 100% polyglycolide. least 70 wt.%, at least 80 wt.%, at least 85 wt.%, at least 90 In various embodiments that comprise both polylactide wt.%, at least 95 wt.%, or at least 99 wt.% of the formulation. and polyglycolide; there is at least 95% polylactide; at least In some embodiments, the at least one biodegradable polymer 90% polylactide; at least 85% polylactide; at least 80% poly 35 and the at least one alpha agonist and beta agonist are the only lactide; at least 75% polylactide; at least 70% polylactide; at components of the pharmaceutical formulation. least 65% polylactide; at least 60% polylactide; at least 55%; In some embodiments, there is a pharmaceutical formula at least 50% polylactide; at least 45% polylactide; at least tion comprising clonidine and a beta agonist, wherein the 40% polylactide; at least 35% polylactide; at least 30% poly clonidine is in a mixture of clonidine hydrochloride and lactide; at least 25% polylactide; at least 20% polylactide; at 40 clonidine base and the mixture comprises from about 0.1 wt. least 15% polylactide; at least 10% polylactide; or at least 5% % to about 30 wt.% of the formulation and a polymer com polylactide; and the remainder of the biopolymer being prises at least 70% of the formulation. In some embodiments, polyglycolide. the polymer in this formulation is polyorthoester. In various embodiments, the drug depot comprises poly In some embodiments, at least 75% of the particles used in (lactide-co-glycolide) (PLGA), polylactide (PLA), polygly 45 the drug depot have a size from about 1 micrometer to about collide (PGA), D-lactide, D.L-lactide, L-lactide, D.L-lactide 200 micrometers. In some embodiments, at least 85% of the co-e-caprolactone, D.L-lactide-co-glycolide-co-e- particles used in the drug depot have a size from about 1 caprolactone, glycolide-caprolactone or a combination micrometer to about 100 micrometers. In some embodiments, thereof. at least 95% of the particles have a size from about 5 In various embodiments, the depot may comprise of a 50 micrometer to about 30 micrometers. In some embodiments, biodegradable polyorthoester. The mechanism of the degra all of the particles of the drug depot have a size from about 10 dation process of the polyorthoester can be hydrolytical or micrometer to about 30 micrometers. enzymatical in nature, or both. In various embodiments, the In some embodiments, at least 75% of the particles have a degradation can occur either at the Surface (heterogeneous or size from about 5 micrometer to about 20 micrometers. In Surface erosion) or uniformly throughout the drug delivery 55 some embodiments, at least 85% of the particles have a size system depot (homogeneous or bulk erosion). Polyorthoester from about 5 micrometers to about 20 micrometers. In some can be obtained from A.P. Pharma, Inc. (Redwood City, embodiments, at least 95% of the particles have a size from Calif.) or through the reaction of a bis(ketene acetal) such as about 5 micrometer to about 50 micrometers. In some 3,9-diethylidene-2,4,8,10-tetraoxospiro5.5undecane embodiments, all of the particles have a size from about 5 (DETOSU) with suitable combinations of diol(s) and/or 60 micrometer to about 50 micrometers. polyol(s) such as 1,4-trans-cyclohexanedimethanol and 1.6- The depot may optionally contain inactive materials such hexanediol or by any other chemical reaction that produces a as buffering agents and pH adjusting agents such as potas polymer comprising orthoester moieties. sium bicarbonate, potassium carbonate, potassium hydrox As persons of ordinary skill in the art are aware, implant ide, Sodium acetate, Sodium borate, sodium bicarbonate, able elastomeric depot compositions having a blend of poly 65 Sodium carbonate, Sodium hydroxide or sodium phosphate: mers with different end groups are used the resulting formu degradation/release modifiers; drug release adjusting agents; lation will have a lowerburst index and a regulated duration of emulsifiers; preservatives such as benzalkonium chloride, US 8,420,114 B2 33 34 chlorobutanol, phenylmercuric acetate and phenylmercuric contact with the targeted tissue or after deployment from a nitrate, sodium bisulfite, sodium bisulfate, sodium thiosul targeted delivery system. The targeted delivery system may fate, thimerosal, methylparaben, polyvinyl alcohol and phe be, for example, a Syringe, a catheter, needle or cannula or any nylethyl alcohol; solubility adjusting agents; stabilizers; and/ other suitable device. The targeted delivery system may inject or cohesion modifiers. Typically, any such inactive materials the gel into or on the targeted tissue site. Thetherapeutic agent will be present within the range of 0-75 wt %, and more may be mixed into the gel prior to the gel being deployed at typically within the range of 0-30 wt.%. If the depot is to be the targeted tissue site. In various embodiments, the gel may placed in the spinal area, in various embodiments, the depot be part of a two-component delivery system and when the two may comprise sterile preservative free material. components are mixed, a chemical process is activated to The depot can be different sizes, shapes and configura 10 form the gel and cause it to Stick or to adhere to the target tions. There are several factors that can be taken into consid tissue. eration in determining the size, shape and configuration of the In various embodiments, a gel is provided that hardens or drug depot. For example, both the size and shape may allow stiffens after delivery. Typically, hardening gel formulations for ease in positioning the drug depot at the target tissue site may have a pre-dosed modulus of elasticity in the range of that is selected as the implantation or injection site. In addi 15 about 1x10° to about 3x10 dynes/cm, or 2x10 to about tion, the shape and size of the system should be selected so as 2x10 dynes/cm, or 5x10" to about 1x10 dynes/cm. The to minimize or prevent the drug depot from moving after post-dosed hardening gels (after delivery) may have a rubbery implantation or injection. In various embodiments, the drug consistency and have a modulus of elasticity in the range of depot can be shaped like a pellet, a sphere, a cylinder Such as about 1x10" to about 2x10° dynes/cm, or 1x10 to about a rod or fiber, a flat surface such as a disc, film or sheet or the 7x10dynes/cm, or 2x10 to about 5x10 dynes/cm. like. Flexibility may be a consideration so as to facilitate In various embodiments, for those gel formulations that placement of the drug depot. In various embodiments, the contain a polymer, the polymer concentration may affect the drug depot can be different sizes, for example, the drug depot rate at which the gel hardens (e.g., a gel with a higher con may be a length of from about 0.5 mm to 5 mm and have a centration of polymer may coagulate more quickly than gels diameter of from about 0.01 to about 2 mm, or 4 mm. In 25 having a lower concentration of polymer). In various embodi various embodiments, the drug depot may have a layer thick ments, when the gel hardens, the resulting matrix is solid but ness of from about 0.005 to 1.0 mm, such as, for example, is also able to conform to the irregular surface of the tissue from 0.05 to 0.75 mm. (e.g., recesses and/or projections in bone). In various embodiments, when the drug depot comprises a The percentage of polymer present in the gel may also pellet, it may be placed at the incision site before the site is 30 affect the viscosity of the polymeric composition. For closed. The pellet may for example be made of thermoplastic example, a composition having a higher percentage by weight materials. Additionally, specific materials that may be advan of polymer is typically thicker and more viscous than a com tageous for use in the pellet include but are not limited to the position having a lower percentage by weight of polymer. A compounds identified above as Sustained release biopoly more viscous composition tends to flow more slowly. There mers. The drug depot may be formed by mixing the at least 35 fore, a composition having a lower viscosity may be preferred one alpha adrenergic agonist and/or beta adrenergic agonist in some instances. with the polymer. In various embodiments, the molecular weight of the gel Radiographic markers can be included on the drug depot to can be varied by any one of the many methods known in the permit the user to position the depot accurately into the target art. The choice of method to vary molecular weight is typi site of the patient. These radiographic markers will also per 40 cally determined by the composition of the gel (e.g., polymer mit the user to track movement and degradation of the depot Versus non-polymer). For example in various embodiments, at the site over time. In this embodiment, the user may accu when the gel comprises one or more polymers, the degree of rately position the depot in the site using any of the numerous polymerization can be controlled by varying the amount of diagnostic imaging procedures. Such diagnostic imaging pro polymer initiators (e.g. benzoyl peroxide), organic solvents cedures include, for example, X-ray imaging or fluoroscopy. 45 or activator (e.g. DMPT), crosslinking agents, polymeriza Examples of Such radiographic markers include, but are not tion agent, incorporation of chain transfer or chain capping limited to, barium, bismuth, tantalum, tungsten, iodine, cal agents and/or reaction time. cium phosphate, and/or metal beads or particles. In various Suitable gel polymers may be soluble in an organic solvent. embodiments, the radiographic marker could be a spherical The solubility of a polymer in a solvent varies depending on shape or a ring around the depot. 50 the crystallinity, hydrophobicity, hydrogen-bonding and Gel molecular weight of the polymer. Lower molecular weight In various embodiments, the drug depot is a gel that has a polymers will normally dissolve more readily in an organic pre-dosed viscosity in the range of about 1 to about 2000 Solvent than high-molecular weight polymers. A polymeric centipoise (cps), about 1 to about 500 cps, 1 to about 200 cps, gel, which includes a high molecular weight polymer, tends to or 1 to about 100 cps. After the gel is administered to the target 55 coagulate or Solidify more quickly than a polymeric compo site, the viscosity of the gel will increase and the gel will have sition, which includes a low-molecular weight polymer. Poly a modulus of elasticity (Young's modulus) in the range of meric gel formulations, which include high molecular weight about 1x10° to about 6x10 dynes/cm, or 2x10 to about polymers, also tend to have a higher Solution viscosity than a 5x10 dynes/cm, or 5x10 to about 5x10dynes/cm. polymeric gel, which include a low-molecular weight poly In one embodiment, a depot is provided that contains an 60 C. adherent gel comprising at least one alpha adrenergic agonist When the gel is designed to be a flowable gel, it can vary and beta adrenergic agonist that is evenly distributed through from low viscosity, similar to that of water, to a high Viscosity, out the gel. The gel may be of any suitable type, as previously similar to that of a paste, depending on the molecular weight indicated, and should be sufficiently viscous so as to prevent and concentration of the polymer used in the gel. The Viscos the gel from migrating from the targeted delivery site once 65 ity of the gel can be varied such that the polymeric composi deployed; the gel should, in effect, “stick” or adhere to the tion can be applied to a patient's tissues by any convenient targeted tissue site. The gel may, for example, Solidify upon technique, for example, by brushing, spraying, dripping, US 8,420,114 B2 35 36 injecting, or painting. Different viscosities of the gel will and/or alpha agonist. In one embodiment, the microspheres depend on the technique used to apply the composition. provide for a Sustained release of the at least one beta agonist In various embodiments, the gel has an inherent viscosity and/or alpha agonist. In yet another embodiment, the gel. (abbreviated as “I.V. and units are in deciliters/gram), which which is biodegradable, prevents the microspheres from is a measure of the gel's molecular weight and degradation 5 releasing the at least one beta agonistand/or alpha agonist; the time (e.g., a gel with a high inherent viscosity has a higher microspheres thus do not release the at least one beta agonist molecular weight and longer degradation time). Typically, a and/or alpha agonist until it has been released from the gel. gel with a high molecular weight provides a stronger matrix For example, a gel may be deployed around a target tissue site and the matrix takes more time to degrade. In contrast, a gel (e.g., a nerve root). Dispersed within the gel are a plurality of with a low molecular weight degrades more quickly and 10 microspheres that encapsulate the desired therapeutic agent. provides a softer matrix. In various embodiments, the gel has Certain of these microspheres degrade once released from the a molecular weight, as shown by the inherent Viscosity, from gel, thus releasing the at least one beta agonist and/or alpha about 0.10 dL/g to about 1.2dL/g or from about 0.10 dL/g to agonist. The beta agonist and/or alpha agonist may be placed about 0.40 dL/g. into separate microspheres and then the microspheres com In various embodiments, the gel can have a viscosity of 15 bined, or the active ingredients can first be combined and then about 300 to about 5,000 centipoise (cp). In other embodi placed into the microspheres together. ments, the gel can have a viscosity of from about 5 to about Microspheres, much like a fluid, may disperse relatively 300 cps, from about 10 cps to about 50 cps, from about 15 cps quickly, depending upon the Surrounding tissue type, and to about 75 cps at room temperature. The gel may optionally hence disperse the at least one beta agonist and/or alpha have a viscosity enhancing agent such as, for example, agonist. In some embodiments, the diameter of the micro hydroxypropyl cellulose, hydroxypropyl methylcellulose, spheres range from about 10 microns in diameter to about 200 hydroxyethyl methylcellulose, carboxymethylcellulose and microns in diameter. In some embodiments they range from salts thereof, Carbopol, poly-(hydroxyethylmethacrylate), about 20 to 120 microns in diameters. Methods for making poly-(methoxyethylmethacrylate), poly(methoxyethoxy microspheres include but are not limited to solvent evapora ethyl methacrylate), polymethylmethacrylate (PMMA), 25 tion, phase separation and fluidized bed coating. In some methylmethacrylate (MMA), gelatin, polyvinyl alcohols, situations, this may be desirable; in others, it may be more propylene glycol, PEG 200, PEG 300, PEG 400, PEG 500, desirable to keep the at least one beta agonist and/or alpha PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG agonist tightly constrained to a well-defined target site. 1450, PEG 3350, PEG 4500, PEG 8000 or combinations The present invention also contemplates the use of adher thereof. 30 ent gels to so constrain dispersal of the therapeutic agent (e.g., In various embodiments, when a polymer is employed in beta agonist and/or alpha agonist). These gels may be the gel, the polymeric composition includes about 10 wt % to deployed, for example, in a disc space, in a spinal canal, or in about 90 wt % or about 30 wt % to about 60 wt % of the Surrounding tissue. polymer. Cannulas and Needles In various embodiments, the gel is a hydrogel made of high 35 It will be appreciated by those with skill in the art that the molecular weight biocompatible elastomeric polymers of depot (containing the alpha and/or beta agonist) can be synthetic or natural origin. A desirable property for the hydro administered to the target site using a “cannula” or “needle’ gel to have is the ability to respond rapidly to mechanical that can be a part of a drug delivery device e.g., a Syringe, a stresses, particularly shears and loads, in the human body. gun drug delivery device, or any medical device Suitable for Hydrogels obtained from natural Sources are particularly 40 the application of a drug to a targeted organ or anatomic appealing because they are more likely to be biodegradable region. The cannula or needle of the drug depot device is and biocompatible for in vivo applications. Suitable hydro designed to cause minimal physical and psychological gels include natural hydrogels, such as, for example, gelatin, trauma to the patient. collagen, silk, elastin, fibrin and polysaccharide-derived Cannulas or needles include tubes that may be made from polymers like agarose, and chitosan, glucomannangel, hyalu 45 materials, such as for example, polyurethane, polyurea, poly ronic acid, polysaccharides, such as cross-linked carboxyl ether(amide), PEBA, thermoplastic elastomeric olefin, containing polysaccharides, or a combination thereof. Syn copolyester, and styrenic thermoplastic elastomer, steel, alu thetic hydrogels include, but are not limited to those formed minum, stainless steel, titanium, metal alloys with high non from polyvinyl alcohol, acrylamides Such as polyacrylic acid ferrous metal content and a low relative proportion of iron, and poly (acrylonitrile-acrylic acid), polyurethanes, polyeth 50 carbon fiber, glass fiber, plastics, ceramics or combinations ylene glycol (e.g., PEG 3350, PEG 4500, PEG 8000), sili thereof. The cannula or needle may optionally include one or cone, polyolefins such as polyisobutylene and polyisoprene, more tapered regions. In various embodiments, the cannula or copolymers of silicone and polyurethane, neoprene, nitrile, needle may be beveled. The cannula or needle may also have Vulcanized rubber, poly(N-vinyl-2-pyrrolidone), acrylates a tip style vital for accurate treatment of the patient depending Such as poly(2-hydroxyethyl methacrylate) and copolymers 55 on the site for implantation. Examples of tip styles include, of acrylates with N-vinyl pyrolidone, N-vinyl lactams, poly for example, Trephine, Coumand, Veress, Huber, Seldinger, acrylonitrile or combinations thereof. The hydrogel materials Chiba, Francine, Bias, Crawford, deflected tips, Hustead, may further be cross-linked to provide further strength as Lancet, or Tuohey. In various embodiments, the cannula or needed. Examples of different types of polyurethanes include needle may also be non-coring and have a sheath covering it thermoplastic or thermoset polyurethanes, aliphatic or aro 60 to avoid unwanted needle Sticks. matic polyurethanes, polyetherurethane, polycarbonate-ure The dimensions of the hollow cannula or needle, among thane or silicone polyether-urethane, or a combination other things, will depend on the site for implantation. For thereof. example, the width of the epidural space is only about 3-5 mm In various embodiments, rather than directly admixing the for the thoracic region and about 5-7 mm for the lumbar therapeutic agents (e.g., beta agonist and/or alpha agonist) 65 region. Thus, the needle or cannula, in various embodiments, into the gel, microspheres may be dispersed within the gel, the can be designed for these specific areas. In various embodi microspheres being loaded with at least one beta agonist ments, the cannula or needle may be inserted using a trans US 8,420,114 B2 37 38 foraminal approach in the spinal foramen space, for example, the acceleration and conversion of electricity. E-beam steril along an inflammed nerve root and the drug depot implanted ization may be used, for example, when the drug depot is at this site for treating the condition. Typically, the transfo included in a gel. raminal approach involves approaching the intervertebral Other methods may also be used to sterilize the depot space through the intervertebral foramina. and/or one or more components of the device, including, but Some examples of lengths of the cannula or needle may not limited to, gas sterilization, such as, for example, with include, but are not limited to, from about 50 to 150 mm in ethylene oxide or steam sterilization. length, for example, about 65 mm for epidural pediatric use, Kits about 85 mm for a standard adult and about 110 mm for an In various embodiments, a kit is provided that may include 10 additional parts along with the drug depot and/or medical obese adult patient. The thickness of the cannula or needle device combined together to be used to implant the drug depot will also depend on the site of implantation. In various (e.g., pellet). The kit may include the drug depot device in a embodiments, the thickness includes, but is not limited to, first compartment. The second compartment may include a from about 0.05 to about 1.655. The gauge of the cannula or canister holding the drug depot and any other instruments needle may be the widest or smallest diameter or a diameter in 15 needed for the localized drug delivery. A third compartment between for insertion into a human or animal body. The may include gloves, drapes, wound dressings and other pro widest diameter is typically about 14 gauge, while the Small cedural Supplies for maintaining sterility of the implanting est diameter is about 25 gauge. In various embodiments the process, as well as an instruction booklet. A fourth compart gauge of the needle or cannula is about 18 to about 22 gauge. ment may include additional cannulas and/or needles. A fifth In various embodiments, like the drug depot and/or gel, the compartment may include the agent for radiographic imag cannula or needle includes dose radiographic markers that ing. Each tool may be separately packaged in a plastic pouch indicate locationator near the site beneath the skin, so that the that is radiation sterilized. A cover of the kit may include user may accurately position the depotator near the site using illustrations of the implanting procedure and a clear plastic any of the numerous diagnostic imaging procedures. Such cover may be placed over the compartments to maintain Ste diagnostic imaging procedures include, for example, X-ray 25 rility. imaging or fluoroscopy. Examples of Such radiographic Administration markers include, but are not limited to, barium, bismuth, In various embodiments, the alpha adrenergic agonist and/ tantalum, tungsten, iodine, calcium phosphate, and/or metal or beta adrenergic agonist may be parenterally administered. beads or particles. The term “parenteral as used herein refers to modes of In various embodiments, the needle or cannula may 30 administration, which bypass the gastrointestinal tract, and include a transparent or translucent portion that can be visu include for example, localized intravenous, intramuscular, alizable by ultrasound, fluoroscopy, X-ray, or other imaging continuous or intermittent infusion, intraperitoneal, intraste techniques. In Such embodiments, the transparent or translu mal. Subcutaneous, intra-operatively, intrathecally, intradis cent portion may include a radiopaque material or ultrasound cally, peridiscally, epidurally, perispinally, intraarticular responsive topography that increases the contrast of the 35 injection or combinations thereof. needle or cannula relative to the absence of the material or Parenteral administration may additionally include, for topography. example, an infusion pump that locally administers a phar Sterilization maceutical composition (e.g., alpha and beta adrenergicago The drug depot, and/or medical device to administer the nist) through a catheter near the spine or one or more inflamed drug may be sterilizable. In various embodiments, one or 40 joints, an implantable mini-pump that can be inserted at or more components of the drug depot, and/or medical device to near the target site, an implantable controlled release device administer the drug are sterilized by radiation in a terminal or Sustained release delivery system that can release a certain sterilization step in the final packaging. Terminal sterilization amount of the composition continuously per hour or in inter of a product provides greater assurance of sterility than from mittent bolus doses. One example of a suitable pump for use processes such as an aseptic process, which require individual 45 is the SynchroMed R (Medtronic, Minneapolis, Minn.) pump. product components to be sterilized separately and the final This pump has three sealed chambers. One contains an elec package assembled in a sterile environment. tronic module and battery. The second contains a peristaltic Typically, in various embodiments, gamma radiation is pump and drug reservoir. The third contains an inert gas, used in the terminal sterilization step, which involves utiliz which provides the pressure needed to force the pharmaceu ing ionizing energy from gamma rays that penetrates deeply 50 tical composition into the peristaltic pump. To fill the pump, in the device. Gamma rays are highly effective in killing the pharmaceutical composition is injected through the res microorganisms, they leave no residues nor have sufficient ervoir fill port to the expandable reservoir. The inert gas energy to impart radioactivity to the device. Gamma rays can creates pressure on the reservoir, and the pressure forces the be employed when the device is in the package and gamma pharmaceutical composition through a filter and into the sterilization does not require high pressures or vacuum con 55 pump chamber. The pharmaceutical composition is then ditions, thus, package seals and other components are not pumped out of the device from the pump chamber and into the stressed. In addition, gamma radiation eliminates the need for catheter, which will direct it for deposit at the target site. The permeable packaging materials. rate of delivery of pharmaceutical composition is controlled In various embodiments, electronbeam (e-beam) radiation by a microprocessor. This allows the pump to be used to may be used to sterilize one or more components of the 60 deliver similar or different amounts of pharmaceutical com device. E-beam radiation comprises a form of ionizing position continuously, at specific times, or at set intervals energy, which is generally characterized by low penetration between deliveries. and high-dose rates. E-beam irradiation is similar to gamma Potential drug delivery devices suitable for adaptation for processing in that it alters various chemical and molecular the methods described herein include but are not limited to bonds on contact, including the reproductive cells of micro 65 those described, for example, in U.S. Pat. No. 6,551,290 organisms. Beams produced for e-beam sterilization are con (assigned to Medtronic, the entire disclosure is herein incor centrated, highly-charged streams of electrons generated by porated by reference), which describes a medical catheter for US 8,420,114 B2 39 40 target specific drug delivery; U.S. Pat. No. 6,571,125 (as avoids the need to Suture the drug depot to the target site signed to Medtronic, the entire disclosure is herein incorpo reducing physical and psychological trauma to the patient. rated by reference), which describes an implantable medical In various embodiments, when the target site comprises a device for controllably releasing a biologically active agent; spinal region, a portion of fluid (e.g., spinal fluid, etc.) can be U.S. Pat. No. 6,594,880 (assigned to Medtronic, the entire withdrawn from the target site through the cannula or needle disclosure is herein incorporated by reference), which first and then the depot administered (e.g., placed, dripped, describes an intraparenchymal infusion catheter system for injected, or implanted, etc.). The target site will re-hydrate delivering therapeutic agents to selected sites in an organism; (e.g., replenishment of fluid) and this aqueous environment and U.S. Pat. No. 5,752.930 (assigned to Medtronic, the will cause the drug to be released from the depot. 10 FIG. 1 illustrates a number of common locations within a entire disclosure is herein incorporated by reference), which patient that may be sites at which inflammation and/or pain describes an implantable catheter for infusing equal Volumes may occur. It will be recognized that the locations illustrated of agents to spaced sites. In various embodiments, pumps in FIG. 1 are merely exemplary of the many different loca may be adapted with a pre-programmable implantable appa tions within a patient that may be the sites of inflammation ratus with a feedback regulated delivery, a micro-reservoir 15 and/or pain. For example, inflammation and/or pain may osmotic release system for controlled release of chemicals, occur at a patient’s knees 21, hips 22, fingers 23, thumbs 24. Small, light-weight devices for delivering liquid medication, neck 25, and spine 26. implantable microminiature infusion devices, implantable One exemplary embodiment where the depot is suitable for ceramic valve pump assemblies, or implantable infusion use in pain management due to inflammation is illustrated in pumps with a collapsible fluid chamber. Alzet(R) osmotic FIG. 2. Schematically shown in FIG. 2 is a dorsal view of the pumps (Durect Corporation, Cupertino, Calif.) are also avail spine and sites where the drug depot may be inserted using a able in a variety of sizes, pumping rates, and durations Suit cannula or needle beneath the skin 34 to a spinal site 32 (e.g., able for use in the described methods. In various embodi spinal disc space, spinal canal, Soft tissue Surrounding the ments, a method for delivering a therapeutic agent into a spine, nerve root, etc.) and one or more drug depots 28 and 32 Surgery site of a patient is provided. For example, the implant 25 are delivered to various sites along the spine. In this way, able Alzet(R) osmotic pump delivers the alpha agonist and/or when several drug depots are to be implanted, they are beta agonist locally to the target tissue site on a continuous implanted in a manner that optimizes location, accurate spac basis (e.g., the Alzet(R) osmotic pump allows a continuous ing, and drug distribution. infusion in microgram/hr delivery of the alpha agonist and/or Although the spinal site is shown, as described above, the beta agonist intrathecally near the Sciatic nerve). 30 drug depot can be delivered to any site beneath the skin, The method of the present application comprises inserting including, but not limited to, at least one muscle, ligament, a cannula at or near a target tissue site and implanting the drug tendon, cartilage, spinal disc, spinal foraminal space, near the depot at the target site beneath the skin of the patient and spinal nerve root, or spinal canal. brushing, dripping, spraying, injecting, or painting the gel in The at least one alpha adrenergic agonist and/or beta adr the target site to hold or have the drug depot adhere to the 35 energic agonist formulation may be used to form different target site. In this way unwanted migration of the drug depot pharmaceutical preparations (e.g., drug depots, injectable away from the target site is reduced or eliminated. formulations, etc.). The pharmaceutical preparations may be In various embodiments, because the alpha adrenergicago formed in and administered with a suitable pharmaceutical nist and/or beta adrenergic agonist is locally administered, carrier that may be solid or liquid, and placed in the appro therapeutically effective doses may be less than doses admin 40 priate form for parenteral or other administration as desired. istered by other routes (oral, topical, etc.). For example, the As persons of ordinary skill are aware, known carriers include drug dose delivered from the drug depot may be, for example, but are not limited to water, gelatin, lactose, starches, Stearic 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, acid, magnesium Stearate, Sicaryl alcohol, talc, vegetable oils, 99%, or 99.9% less than the oral dosage or injectable dose. In benzyl alcohols, gums, waxes, propylene glycol, polyalky turn, systemic side effects, such as for example, liver tran 45 lene glycols and other known carriers. saminase elevations, hepatitis, liver failure, myopathy, con Another embodiment provides a method for treating a stipation, etc. may be reduced or eliminated. mammal Suffering from pain and/or inflammation, said In various embodiments, to administer the gel having the method comprising administering a therapeutically effective drug depot dispersed therein to the desired site, first the can amount of at least one alpha adrenergic agonist and/or beta nula or needle can be inserted through the skin and Soft tissue 50 adrenergic agonist at a target site beneath the skin at or near down to the target tissue site and the gel administered (e.g., the target site. Theat least one alpha adrenergic agonistand/or brushed, dripped, injected, or painted, etc.) at or near the beta adrenergic agonist may for example be administered target site. In those embodiments where the drug depot is locally to the target tissue site as a drug depot. separate from the gel, first the cannula or needle can be In some embodiments, the therapeutically effective dosage inserted through the skin and soft tissue down to the site of 55 amount (e.g., alpha adrenergic agonist and/or beta adrenergic injection and one or more base layer(s) of gel can be admin agonist dose) and the release rate profile are Sufficient to istered to the target site. Following administration of the one reduce inflammation and/or pain for a period of at least one or more base layer(s), the drug depot can be implanted on or day, for example, 1-90 days, 1-10 days, 1-3 days, 3-7 days, in the base layer(s) so that the gel can hold the depot in place 3-12 days; 3-14 days, 7-10 days, 7-14 days, 7-21 days, 7-30 or reduce migration. If required a Subsequent layer or layers 60 days, 7-50 days, 7-90 days, 7-140 days, 14-140 days, 3 days of gel can be applied on the drug depot to Surround the depot to 135 days, 3 days to 150 days, or 3 days to 6 months. and further hold it in place. Alternatively, the drug depot may In some embodiments, the at least one alpha adrenergic be implanted first and then the gel placed (e.g., brushed, agonist and/or beta adrenergic agonist or a portion of the at dripped, injected, or painted, etc.) around the drug depot to least one alpha adrenergic agonist and/or beta adrenergic hold it in place. By using the gel, accurate and precise implan 65 agonist is administered as a bolus dose at the target tissue to tation of a drug depot can be accomplished with minimal provide an immediate release of the alpha adrenergic agonist physical and psychological trauma to the patient. The gel also and/or beta adrenergic agonist. US 8,420,114 B2 41 42 In some embodiments, there is a composition useful for the inflammation may be associated with orthopedic or spine treatment of inflammation comprising an effective amount of Surgery or a combination thereof. By way of further example, at least one alpha adrenergic agonist and/or beta adrenergic the Surgery may be arthroscopic Surgery, an excision of a agonist that is capable of being locally administered to a mass, hernia repair, spinal fusion, thoracic, cervical, or lum target tissue site. By way of example, they may be adminis bar Surgery, pelvic Surgery or a combination thereof. In some tered locally to the foraminal spine, the epidural space or the embodiments, the active ingredient may provide longer dura intrathecal space of a spinal cord. Exemplary administration tion of pain and/or inflammation relief for chronic diseases/ routes include but are not limited to catheter drug pumps, one conditions as discussed above with release of one or more or more local injections, polymer releases and combinations drugs up to 6 months or 1 year (e.g., 90, 100, 150, 180 days or thereof. 10 longer). In some embodiments, the at least one alpha adrenergic In some embodiments, the at least one alpha adrenergic agonist and/or beta adrenergic agonist is administered agonist and/or beta adrenergic agonist or pharmaceutically parenterally, e.g., by epidural injection. In some embodi acceptable salt thereof is encapsulated in a plurality of depots ments, the injection is intrathecal, which refers to an injection comprising microparticles, microspheres, microcapsules, into the spinal canal (intrathecal space Surrounding the spinal 15 and/or microfibers Suspended in a gel. cord). An injection may also be into a muscle or other tissue. In some embodiments, a method is provided of inhibiting In other embodiments, the alpha adrenergic agonist and/or pain and/or inflammation in a patient in need of Such treat beta adrenergic agonist is administered by placement into an ment, the method comprising delivering one or more biode open patient cavity during Surgery. gradable drug depots comprising a therapeutically effective In some embodiments, the formulation is implantable into amount of at least one alpha adrenergic agonist and/or beta a Surgical site at the time of Surgery. The active ingredients adrenergic agonist or pharmaceutically acceptable salt may then be released from the depot via diffusion in a sus thereof to a targettissue site beneath the skin before, during or tained fashion over a period of time, e.g., 3-15 days, 5-10 days after Surgery, wherein the drug depot releases an effective or 7-10 days post Surgery in order to address pain and/or amount of at least one alpha adrenergic agonist and/or beta inflammation. In some embodiments, the active ingredient 25 adrenergic agonist or pharmaceutically acceptable salt may provide longer duration of pain and/or inflammation thereof over a period of 3 days to 6 months. relief for chronic diseases/conditions as discussed above with In some embodiments, an implantable drug depot useful release of one or more drugs up to 6 months or 1 year (e.g.,90, for preventing or treating pain and/or inflammation in a 100, 150, 180 days or longer). patient in need of such treatment is provided, the implantable In some embodiments, the drug depot may release 5%, 30 drug depot comprising a therapeutically effective amount of 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, at least one alpha adrenergic agonist and/or beta adrenergic 90%. 95%, or 99% of the at least one alpha adrenergicagonist agonist or pharmaceutically acceptable salt thereof, the depot and/or beta adrenergic agonist or pharmaceutically accept being implantable at a site beneath the skin to prevent or treat able salt thereof relative to a total amount of at least one alpha inflammation, wherein the drug depot releases an effective adrenergic agonist loaded in the drug depot over a period of 3 35 amount of at least one alpha adrenergic agonist and/or beta to 12 days, 5 to 10 days or 7 to 10 days after the drug depot is adrenergic agonist or pharmaceutically acceptable salt administered to the target tissue site. In some embodiments, thereof over a period of 33 days to 6 months. the active ingredient may provide longer duration of pain In some embodiments, an implantable drug depot is pro and/or inflammation relief for chronic diseases/conditions as vided, wherein the drug depot (i) comprises one or more discussed above with release of one or more drugs up to 6 40 immediate release layer(s) that releases a bolus dose of at months or 1 year (e.g., 90, 100, 150, 180 days or longer). least one alpha adrenergic agonist and/or beta adrenergic In various embodiments, an implantable drug depot useful agonist or pharmaceutically acceptable salt thereof at a site for reducing, preventing or treating pain and/or inflammation beneath the skin and (ii) one or more Sustain release layer(s) is provided in a patient in need of such treatment, the implant that releases an effective amount of at least one alpha adren able drug depot comprising a therapeutically effective 45 ergic agonist and/or beta adrenergic agonist or pharmaceuti amount of a alpha adrenergic agonist and/or beta adrenergic cally acceptable salt thereof over a period of 3 to 12 days or 5 agonist or pharmaceutically acceptable salts thereof, the to 10 days or 7 to 10 days or 3 days to 6 months. By way of depot being implantable at a site beneath the skin to reduce, example, in the drug depot, the one or more immediate release prevent or treat pain and/or inflammation, wherein the drug layer(s) may comprise poly (lactide-co-glycolide) (PLGA) depot (i) comprises one or more immediate release layer(s) 50 and the one or more Sustain release layer(s) may comprise that is capable of releasing about 5% to about 20% of the polylactide (PLA). alpha adrenergic agonist and/or beta adrenergic agonist or Method of Making pharmaceutically acceptable salts thereof relative to a total In various embodiments, the drug depot comprising the amount of the alpha adrenergicagonistand/or betaadrenergic active ingredients (e.g., alpha agonistand/or beta agonist) can agonist or pharmaceutically acceptable salt thereofloaded in 55 be made by combining a biocompatible polymer and a thera the drug depot over a first period of up to 48 hours and (ii) one peutically effective amount of the active ingredients or phar or more Sustain release layer(s) that is capable of releasing maceutically acceptable salts thereof and forming the about 21% to about 99% of the alpha adrenergic agonist implantable drug depot from the combination. and/or beta adrenergic agonist or pharmaceutically accept Various techniques are available for forming at least a able salt thereof relative to a total amount of the alpha adren 60 portion of a drug depot from the biocompatible polymer(s), ergic agonist and/or beta adrenergic agonist or pharmaceuti therapeutic agent(s), and optional materials, including solu cally acceptable salt thereof loaded in the drug depot over a tion processing techniques and/or thermoplastic processing Subsequent period of up to 3 days to 6 months. techniques. Where solution processing techniques are used, a By way of a non-limiting example, the target tissue site Solvent system is typically selected that contains one or more may comprise at least one muscle, ligament, tendon, carti 65 Solvent species. The solvent system is generally a good sol lage, spinal disc, spinal foraminal space near the spinal nerve vent for at least one component of interest, for example, root, facet or spinal canal. Also by way of example, the biocompatible polymer and/or therapeutic agent. The par US 8,420,114 B2 43 44 ticular solvent species that make up the solvent system can agent(s), inactive ingredients, etc.) to form a mixture. A com also be selected based on other characteristics, including dry mon way of doing so is to apply mechanical shear to a mixture ing rate and Surface tension. of the biocompatible polymer(s) and additive(s). Devices in Solution processing techniques include solvent casting which the biocompatible polymer(s) and additive(s) may be techniques, spin coating techniques, web coating techniques, mixed in this fashion include devices such as single screw Solvent spraying techniques, dipping techniques, techniques extruders, twin screw extruders, banbury mixers, high-speed involving coating via mechanical Suspension, including air mixers, ross kettles and so forth. Suspension (e.g., fluidized coating), inkjet techniques and Any of the biocompatible polymer(s) and various additives electrostatic techniques. Where appropriate, techniques such may be premixed prior to a final thermoplastic mixing and as those listed above can be repeated or combined to buildup 10 shaping process, if desired (e.g., to prevent Substantial deg the depot to obtain the desired release rate and desired thick radation of the therapeutic agent among other reasons). CSS. For example, in various embodiments, a biocompatible In various embodiments, a solution containing solvent and polymer is precompounded with a radiographic agent (e.g., biocompatible polymer are combined and placed in a mold of radio-opacifying agent) under conditions oftemperature and the desired size and shape. In this way, polymeric regions, 15 mechanical shear that would result in Substantial degradation including barrier layers, lubricious layers, and so forth can be of the therapeutic agent, if it were present. This precom formed. If desired, the solution can further comprise, one or pounded material is then mixed with therapeutic agent (e.g., more of the following: other therapeutic agent(s) and other alpha agonist and/or beta agonist) under conditions of lower optional additives such as radiographic agent(s), etc. in dis temperature and mechanical shear, and the resulting mixture solved or dispersed form. This results in a polymeric matrix is shaped into the active ingredient containing drug depot. region containing these species after solvent removal. In other Conversely, in another embodiment, the biocompatible poly embodiments, a Solution containing solvent with dissolved or mer can be precompounded with the therapeutic agent under dispersed therapeutic agent is applied to a pre-existing poly conditions of reduced temperature and mechanical shear. meric region, which can be formed using a variety of tech This precompounded material is then mixed with, for niques including Solution processing and thermoplastic pro 25 example, a radio-opacifying agent, also under conditions of cessing techniques, whereupon the therapeutic agent is reduced temperature and mechanical shear, and the resulting imbibed into the polymeric region. mixture is shaped into the drug depot. Thermoplastic processing techniques for forming the The conditions used to achieve a mixture of the biocom depot or portions thereof include molding techniques (for patible polymerand therapeutic agent and other additives will example, injection molding, rotational molding, and so 30 depend on a number of factors including, for example, the forth), extrusion techniques (for example, extrusion, co-ex specific biocompatible polymer(s) and additive(s) used, as trusion, multi-layer extrusion, and so forth) and casting. well as the type of mixing device used. Thermoplastic processing in accordance with various As an example, different biocompatible polymers will embodiments comprises mixing or compounding, in one or typically soften to facilitate mixing at different temperatures. more stages, the biocompatible polymer(s) and one or more 35 For instance, where a depot is formed comprising PLGA or of the following: the active ingredients (e.g., alpha agonist), PLA polymer, a radio-opacifying agent (e.g., bismuth Sub optional additional therapeutic agent(s), radiographic carbonate), and a therapeutic agent prone to degradation by agent(s), and so forth. The resulting mixture is then shaped heat and/or mechanical shear (e.g., clonidine), in various into an implantable drug depot. The mixing and shaping embodiments, the PGLA or PLA can be premixed with the operations may be performed using any of the conventional 40 radio-opacifying agent attemperatures of about, for example, devices known in the art for Such purposes. 150° C. to 170° C. The therapeutic agent is then combined During thermoplastic processing, there exists the potential with the premixed composition and subjected to further ther for the therapeutic agent(s) to degrade, for example, due to moplastic processing at conditions of temperature and elevated temperatures and/or mechanical shear that are asso mechanical shear that are substantially lower than is typical ciated with Such processing. For example, certain therapeutic 45 for PGLA or PLA compositions. For example, where extrud agents may undergo Substantial degradation under ordinary ers are used, barrel temperature, Volumetric output are typi thermoplastic processing conditions. Hence, processing is cally controlled to limit the shear and therefore to prevent preferably performed under modified conditions, which pre Substantial degradation of the therapeutic agent(s). For vent the Substantial degradation of the therapeutic agent(s). instance, the therapeutic agent and premixed composition can Although it is understood that some degradation may be 50 be mixed/compounded using a twin screw extruder at Sub unavoidable during thermoplastic processing, degradation is stantially lower temperatures (e.g., 100-105°C.), and using generally limited to 10% or less. Among the processing con substantially reduced volumetric output (e.g., less than 30% ditions that may be controlled during processing to avoid of full capacity, which generally corresponds to a Volumetric Substantial degradation of the therapeutic agent(s) are tem output of less than 200 cc/min). It is noted that this processing perature, applied shear rate, applied shear stress, residence 55 temperature is well below the melting points of certain active time of the mixture containing the therapeutic agent, and the ingredients, such as alpha agonist and beta agonist because technique by which the polymeric material and the therapeu processing at or above these temperatures will result in Sub tic agent(s) are mixed. stantial therapeutic agent degradation. It is further noted that Mixing or compounding biocompatible polymer with in certain embodiments, the processing temperature will be therapeutic agent(s) (e.g., alpha agonist and beta agonist) and 60 below the melting point of all bioactive compounds within the any additional additives to form a substantially homogenous composition, including the therapeutic agent. After com mixture thereof may be performed with any device known in pounding, the resulting depot is shaped into the desired form, the art and conventionally used for mixing polymeric mate also under conditions of reduced temperature and shear. rials with additives. In other embodiments, biodegradable polymer(s) and one Where thermoplastic materials are employed, a polymer 65 or more therapeutic agents are premixed using non-thermo melt may be formed by heating the biocompatible polymer, plastic techniques. For example, the biocompatible polymer which can be mixed with various additives (e.g., therapeutic can be dissolved in a solvent system containing one or more US 8,420,114 B2 45 46 Solvent species. Any desired agents (for example, a radio agonist orpharmaceutically acceptable salt thereof and form opacifying agent, a therapeutic agent, or both radio-opacify ing the implantable drug depot from the combination. ing agent and therapeutic agent) can also be dissolved or Having now generally described the invention, the same dispersed in the solvents system. Solvent is then removed may be more readily understood through the following refer from the resulting solution/dispersion, forming a solid mate ence to the following examples, which are provided by way of rial. The resulting Solid material can then be granulated for illustration and are not intended to limit the present invention further thermoplastic processing (for example, extrusion) if unless specified. desired. EXAMPLES As another example, the therapeutic agent can be dissolved or dispersed in a solvent system, which is then applied to a 10 The examples below show certain particularly advanta pre-existing drug depot (the pre-existing drug depot can be geous results wherein the initial burst is not too large (i.e., not formed using a variety of techniques including solution and more than 7% of the load drug in the first five days) and the thermoplastic processing techniques, and it can comprise a daily does is approximately 2.4 ug/day-t().5 ug/day for 135 variety of additives including a radio-opacifying agent and/or days. See e.g., FIGS. 10 and 11; 14; and 19. The figures 15 further demonstrate that drug loadings 5 wt.% to 8 wt.% Viscosity enhancing agent), whereupon the therapeutic agent provide advantageous results. is imbibed on or in the drug depot. As above, the resulting A 2-month chronic constriction injury (CCI) model of Solid material can then be granulated for further processing, if neuropathic pain was used to evaluate different formulations desired. of clonidine, encapsulated in bioerodable polymers com Typically, an extrusion processes may be used to form the pared to clonidine given subcutaneously (SC). Different for drug depot comprising a biocompatible polymer(s), thera mulations as provided in Table 5 below were evaluated for peutic agent(s) and radio-opacifying agent(s). Co-extrusion reducing pain-associated behaviors: Thermal paw with may also be employed, which is a shaping process that can be drawal latency was evaluated at baseline 7, 14, 21, 28, 35, 42, used to produce a drug depot comprising the same or different 49, 56 and 63 days post-operatively, while mechanical thresh layers or regions (for example, a structure comprising one or 25 old was evaluated at 8, 15, 22, 29, 36, 43, 50, 57 and 64 days more polymeric matrix layers or regions that have permeabil post-operatively. Bar graphs depicting the results of these ity to fluids to allow immediate and/or Sustained drug tests are shown in FIGS. 3-4. release). Multi-region depots can also be formed by other The In-Vitro Elution Studies were carried out at 37° C. in processing and shaping techniques such as co-injection or phosphate-buffered saline (PBS, pH 7.4). Briefly, the rods sequential injection molding technology. 30 (n-3) were weighed prior to immersion in 5 mL of PBS. At In various embodiments, the depot that may emerge from regular time intervals, the PBS was removed for analysis and the thermoplastic processing (e.g., pellet, Strip, etc.) is cooled. replaced with 5 mL offresh PBS. The PBS-elution buffer was Examples of cooling processes include air cooling and/or analyzed for clonidine content using UV-Vis spectrometry. immersion in a cooling bath. In some embodiments, a water bath is used to cool the extruded depot. However, where a 35 Example 1 water-soluble therapeutic agent such as an active ingredient is used, the immersion time should be held to a minimum to Formulation Testing avoid unnecessary loss of therapeutic agent into the bath. In various embodiments, immediate removal of water or The inventors prepared a number of clonidine formulations moisture by use of ambient or warm air jets after exiting the 40 in which they varied the polymer type, drug load, excipient bath will also prevent re-crystallization of the drug on the (including some formulations in which there was no excipi depot Surface, thus controlling or minimizing a high drug ent), pellet size and processing. These formulations are dose “initial burst' or “bolus dose upon implantation or described below in Table 1, Table 2 and Table 3. A number of insertion if this is release profile is not desired. tests were performed on these formulations, including in vitro In various embodiments, the drug depot can be prepared by 45 release tests in which the number of micrograms released was mixing or spraying the drug with the polymer and then mold measured, as well as the cumulative percentage release of ing the depot to the desired shape. In various embodiments, clonidine. The results of these tests appear in FIGS. 7-36. active ingredients are used and mixed or sprayed with the The In-Vitro Elution Studies were carried out at 37° C. in PLGA or PEG550 polymer, and the resulting depot may be phosphate-buffered saline (PBS, pH 7.4). The rods (n=3) formed by extrusion and dried. 50 were weighed prior to immersion in 5 mL of PBS. At regular The drug depot may also be made by combining a biocom time intervals, the PBS was removed for analysis and patible polymer and a therapeutically effective amount of at replaced with 5 mL of fresh PBS. The PBS-elution buffer was least one alpha adrenergic agonist and/or beta adrenergic analyzed for clonidine content using UV-Vis spectrometry. TABLE 1 Drug Pellet Size (LX Load Dia; mm) or Notebook ID Polymer Type (Wt 9%) Excipient Description Processing 13335-60-1 8515 DLG 7E 10 NFA 0.75 x 0.75 Melt extrusion, co-spray dried drug polymer 13335-60-2 8515 DLG 7E 10 NFA 0.75 x 0.75 Melt extrusion, spray dried drug 13335-60-3 8515 DLG 7E 10 NFA 0.75 x 0.75 Melt extrusion, hand ground drug 13335-60-4 8515 DLG 7E 10 NFA 0.75 x 0.75 Melt extrusion, hand ground drug, spray dried polymer 13335-60-5 8515 DLG 7E 10 NFA 0.75 x 0.75 Melt extrusion w recycle loop, hand ground drug 13335-65-1 8515 DLG 7E S NA 3.0 x 0.75 Melt extrusion, spray dried drug US 8,420,114 B2 47 48 TABLE 1-continued Drug Pellet Size (LX Load Dia; mm) or Notebook ID Polymer Type (Wt 9%) Excipient Description Processing 333S-6S-2 8515 DLG 7E 10 NA 1.5 x 0.75 Melt extrusion, spray dried drug 333S-6S-3 8515 DLG 7E 2O NA 0.75 x 0.75 Melt extrusion, spray dried drug 333S-65-4 1OODL 7E 5 NA 3.0 x 0.75 Melt extrusion, spray dried drug 333S-65-S 1OODL 7E 10 NA 1.5 x 0.75 Melt extrusion, spray dried drug 333S-65-6 1OODL 7E 2O NA 0.75 x 0.75 Melt extrusion, spray dried drug 333S-97-1 8515 DLG 7E 7.5 NAA 3.0 x 0.75 Melt extrusion, spray dried drug 333S-97-2 1OODL 7E 5 NA 3.0 x 0.75 Melt extrusion, spray dried drug 333S-97-3 8515 DLG 7E 5 10% PEG 3.0 x 0.75 Melt extrusion, spray dried drug 333S-97-4 1OODL 7E 5 10% PEG 3.0 x 0.75 Melt extrusion, spray dried drug 3699-1-1 1OODL 7E 5 NA 3.0 x 0.75 Melt extrusion, spray dried drug 3699-16-1 8515 DLG 7E 10 NA 1.5 x 0.75 Melt extrusion, spray dried drug 3699-16-2 901O DLG 7E 10 NA 1.5 x 0.75 Melt extrusion, spray dried drug 3699-16-3 901O DLG 7E 5 NA 3.0 x 0.75 Melt extrusion, spray dried drug 3699-16-4 8515 DLG 7E 5 5% PEG 3.0 x 0.75 Melt extrusion, spray dried drug 3699-16-5 8515 DLG 7E 5 2.5% 3.0 x 0.75 Melt extrusion, spray dried drug PEG 3699-20-1 8515 DLG 7E 5 1% MgO 3.0 x 0.75 Melt extrusion, spray dried drug 3699-20-4 8515 DLG 7E 5 NA 3.0 x 0.75 Melt extrusion, spray dried drug 3699-20-S 1OODL 7E 5 10% SOSO 3.0 x 0.75 Melt extrusion, spray dried drug DLG 6E 3699-20-6 1OODL 7E 5 10% SOSO 3.0 x 0.75 Melt extrusion, spray dried drug DLG 1A 3699-20-7 8515 DLG 10 NA 1.5 x 0.75 Melt extrusion, spray dried drug Purac 3699-20-8 8515 DLG 7E 5 NA 3.0 x 0.75 Melt extrusion 2X, spray dried drug 3699-28-1 8515 DLG 7.5 NAA 3.0 x 0.75 Melt extrusion, spray dried drug Purac 3699-28-2 8516 DLG 2.S. N.A 2.0 x 0.75 Melt extrusion, spray dried drug Purac 3699-28-3 1OODL 7E 5 NA 3.0 x 0.75 Melt extrusion, spray dried drug 3699-31-1 8515 DLG 7E O NA NA heat press, spray dried drug 3699-31-2 8515 DLG 7E O NA NA heat press, spray dried drug 3699-31-3 8515 DLG 7E O NA NA heat press, spray dried drug 3699-31-4 8515 DLG 7E O NA NA Melt extrusion, spray dried drug 2702-13-4-a 16- O NA 3 x 3 Melt extrusion Hexanediolf tCHDM 2702-13-4-b 7S,2SPLGA O NA 3 x 3 Melt extrusion 27O2-68-12 75.25 PLGA 5 PEG 1 x 1 Melt extrusion 27O2-68-13 75.25 PLGA 5 TBO-Ac 1 x 1 Melt extrusion 27O2-72-1 75.25 PLGA 5 PEG 1 x 1 Melt extrusion 27O2-8O-7 75.25 PLGA O PEG 0.75 x 0.75 Melt extrusion 27O2-80-8 75.25 PLGA 5 PEG 0.75 x 0.75 Melt extrusion 3395-3-1 85.15 PLGA O PEG 0.75 x 0.75 Melt extrusion 3395-3-2 85.15 PLGA 5 PEG 0.75 x 0.75 Melt extrusion 3395-3-3 85.15 PLGA 5 PEG 0.75 x 0.75 Melt extrusion 3395-15 85.15 PLGA 5 PEG 0.75 x 0.75 Melt extrusion 3395-20-1 85.15 PLGA 5 Span-85 0.75 x 0.75 Melt extrusion 3395-20-2 85.15 PLGA 5 Pluronic- 0.75 x 0.75 Melt extrusion F127 3395-20-3 85.15 PLGA 5 NA 0.75 x 0.75 Melt extrusion 3395-21-1 DL-PLA 5 PEG 0.75 x 0.75 Melt extrusion 3395-21-2 85.15 PLGA 5 TBO-Ac 0.75 x 0.75 Melt extrusion 3.395-24-1 85.15 PLGA 5 Span-65 0.75 x 0.75 Melt extrusion 3395-27-1 85.15 PLGA 10 NA 0.75 x 0.75 Melt extrusion 3395-27-2 85.15 PLGA 15 NA 0.75 x 0.75 Melt extrusion 3395-27-3 85.15 PLGA 10 Span-65 0.75 x 0.75 Melt extrusion 3395-27-4 85.15 PLGA 10 TBO-Ac 0.75 x 0.75 Melt extrusion 3395-27-5 85.15 PLGA 10 Pluronic 0.75 x 0.75 Melt extrusion F127 3395-34-2 DL-PLA 10 NA 0.75 x 0.75 Melt extrusion 3395-34-3 DL-PLA 10 TBO-Ac 0.75 x 0.75 Melt extrusion 3.395-34-4 DL-PLA 10 PEG 0.75 x 0.75 Melt extrusion 3.395-42-1 DL-PLAPCL 10 NA 0.75 x 0.75 Melt extrusion 3395-42-2 DL-PLAPCL 15 NA 0.75 x 0.75 Melt extrusion

TABLE 2 Drug Load Pellet Size (Lx Dia; Notebook ID Polymer Type (Wt%) Excipient mm) or Description Processing 13335-73-1. POE58 10 NA 1.5 x 0.75 Melt extrusion 13335-73-2 POE58 2O NA O.75 x 0.75 Melt extrusion US 8,420,114 B2 49 50 TABLE 2-continued Drug Load Pellet Size (Lx Dia; Notebook ID Polymer Type (Wt%) Excipient mm) or Description Processing

333S-73-3 POE 60 10 NA 1.5 x 0.75 Melt extrusion 333S-73-4 POE 60 2O NA O.75 x 0.75 Melt extrusion 3699-1-2 POE 58 10 NA 4-1.5 x 0.75 Melt extrusion 3699-1-3 POE 58 2O NA 1-0.75 x 0.75 Melt extrusion 2702-23 tCHDM (100) 25 NA Microspheres Double emulsion 2702-26 tCHDMADET 42 NA Microspheres Double emulsion (70/30) 27O2-54 75.25 PLGA 2O NA Microspheres Double emulsion 27O2-68-9 7S,2S PLGA 5 PEG 3 x 3 Melt extrusion 27O2-68-10 7S,2S PLGA 5 TBO-Ac 3 x 3 Melt extrusion 2702-87 75.25 PLGA 15 PEG Mixer-Molder 27O2-90 85.15 PLGA 17 NA Mixer-Molder 2702-78-1 Polyketal 7 NA 2 x 3 Melt extrusion (12833-14-1) 3395-14 SOSOPLGA 10 PEG NA Melt extrusion (2A) 3395-17-1 POE (13166- 5 NA 1.5 x 1.5 Melt extrusion 75) 3395-17-2 POE (13166- 5 NA 1.5 x 1.5 Melt extrusion 77) 3395-47-1 DL-PCL 10 NA 1.3 x 1.3 Melt extrusion 3395-50 DL-PCL 10 NA 1.3 x 1.3 Melt extrusion; w/ solvent prep 3395-51 DL-PLA 10 PEG NA Melt extrusion

TABLE 3 Drug Load Notebook ID Polymer Type (Wt%) Processing OO178-23 OODLSE 8.1 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-15 OO DL 7E 7.2 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-3S OODLSE 5 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-16 OO DL 7E 10.2 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-21 8515 DL 7E 7.3 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-36 OO DL 7E 5 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-44 OO DL 7E S.1 Dissolved in glacial acetic acid and freeze dried OO178-45 OO DL 7E 4.5 Drug and polymer blended by mortaripestile, finely mixed, under N2 OO178-63 OO DL 7E 9.4 Drug and polymer blended by mortaripestle, finely mixed OO178-08 OO DL 7E 21.4 Blend with spatula, no reduction in drug particle size OO178-11 OO DL 7E 7.9 Blend with spatula, no reduction in drug particle size OO178-12 OO DL 7E 11.7 Blend with spatula, no reduction in drug particle size OO178-22 8515 DL 7E 83.3 Grind drug with mortaripestile, blend with spatula, coarsely mixed OO178-24 OODLSE 10.1 Grind drug with mortaripestile, blend with spatula, coarsely mixed tab 11 OOD 5 tab 11 OOD 5 tab 11 OOD 5 EtOAc coating tab 11 OOD 5 EtOAc coating tab 11 OOD 5 Glacial HoAc dissolution tab 11 OOD 5 prepared in N2 environment OO178-72 OOD 4.5 Double Extrusion (20% diluted to 5%) OO178-73 OOD 8.7 Double Extrusion (20% diluted to 10%) OO178-74 OOD 7.3 API mixed with polymer using mortaripestle OO178-71 6535 DLG 7E 5.3 API mixed with polymer using mortaripestle OO178-75 6535 DLG 7E 5.3 API mixed with polymer using mortaripestle 00178-76-R1 100 DL 7E core with 7.76 coaxial extrusion, 4 different coating thicknesses OODL coating OO178-76-R2 101 DL 7E core 6.92 coaxial extrusion, 4 different coating thicknesses with 100DL coating OO178-76-R3 102 DL 7E core 6.76 coaxial extrusion, 4 different coating thicknesses with 100DL coating US 8,420,114 B2 51 52 TABLE 3-continued Drug Load Notebook ID Polymer Type (Wt%) Processing OO178-76-R4 103 DL 7E core 8 coaxial extrusion, 4 different coating thicknesses with 100DL coating 00178-79-R1 100 DLSE core with 15 coaxial extrusion, thin coat OODL 5E coating 00178-79-R2 100 DLSE core with 15 coaxial extrusion, thick coat OODL 5E coating 00178-80-R1 100 DLSE core with 7.54 coaxial extrusion, different coating thicknesses OODL 5E coating 00178-80-R2 100 DLSE core with 8.9 coaxial extrusion, different coating thicknesses OODL 5E coating 00178-80-R3 100 DLSE core with 9.39 coaxial extrusion, different coating thicknesses OODL 5E coating OO178-77 OODLSE 5 repeat of 178-35 (0.8 MM & 1.0 mm diam) OO178-78 OODLSE 5 repeat of 178-35 (0.8 MM & 1.0 mm diam) OO178-81 OODLSE 7.2 repeat of 178-23 OO178-23B EtOAc coating OO178-23C Polymer Soln coating

2O The codes within the table for the polymer are explained as TABLE 5 follows. The first number or numbers refer to monomer mole percentage ratio of DL-lactide (e.g., polylactide) to glycolide Group (e.g., poly-glycolide). The letter code that follows the first Number Treatment Dose Comments number refers to the polymer(s) and is the polymer identifier. 25 1 Clonidine 0.02 mg/kg SC Clonidine control The second number, which follows the letter code for the 2 1OODL 7E O% 4 pellets (3 mm x 0.7 mm) polymer, is the target IV designator and is 10 times the mid- 3 1OODL 7E S90 sists reles point of a range in dl/g. The meanings of certain IV designa- 4 1OODLSE S90 Spellets (3 mm x 0.7 mm) tors are reflected in Table 4. 5 1OODLSE 7% 3 pellets (3 mm x 0.7 mm) 30 6 1OODL 7E 7% 3 pellets (3 mm x 0.7 mm) 7 POE O% 5 pellets TABLE 4 (1.5 mm x 0.7 mm) IV Target Designator IV Range 8 POE 10 and 20% legitiple 1 O.OS-0.15 4.10% (a) 1.5 mm x 0.7 mm) 1.5 O.10-0.2O 35 i. 5 9. 2.85 The inventors have conducted the present study for a period 3 O.25-0.35 of 64 days and have employed the following two tests: (1) the 3.5 O.30-0.40 Hargreaves test; and (2) the von Frey test. The Hargreaves 4 O.35-0.45 Tests of Thermal Hyperalgesia were conducted on days 7, 14, s 9. 0 21, 28, 35, 42,49, 56 and 63. The von Frey monofilament test 6 6007 of mechanical allodynia (performed the day following Ther 7 0.60-080 mal testing) were conducted on days-8, 15, 22, 29, 36, 43, 50. 8 O.7O-O.90 57 and 64. The results of these tests are summarized in FIGS. 9 O.80-1.O 3 and 4 and show the efficacy of clonidine of the recited time 45 periods. These results are summarized in FIGS. 3 and 4. The final letter within- 0 the code of the polymer is the end Theep pain behavioral responsep (measured( as a perpercentage 9. of designator. F les “E” refers t t d baseline) for thermal hyperalgesia (FIG. 3) indicates that group S.ay R p es d d CS O a SU clonidine delivered Subcutaneously at 0.02 mg/kg/day con group, Wn1le CIS UO all ac1 en group. sistently reduced the behavioral response when compared to By way of example, 1OO DL 7E is a polymer that has an 50 either unloaded polymer depots (100DL 7W Controlor POE inherent viscosity of 0.60-080 dLig. It contains 100% poly Control) (58% vs. 45%). All five clonidine-loaded polymer (DL-lactide) that has ester end groups. It is available from depots were able to reduce pain behavioral responses when Lakeshore Biomaterials, Birmingham, Ala. compared to unloaded depot; although, each formulation experienced a drop in efficacy at Some point after the initial Example 2 55 burst of drug at implantation. The pain behavioral response (measured as a percentage of baseline) for mechanical allo dynia indicates that clonidine delivered subcutaneously at di s year, style the city R Matt Cloni- 0.02 mg/kg/day reduced the behavioral response when com ine/Polymer Drug Depot in the Rat On1C COnStrict1On pared to either unloaded polymer depots (100 DL 7W Control Injury Model. The animal model was the Bennett Model (Wistar rat). The purpose: To determine whether a five month 60 or POE Control). polymer clonidine-eluting depot can improve pain associated Example 3 behavioral responses in a rat model of neuropathic pain. Experimental Design: Four loose chromic gut ligatures, 1 Clonidine Drug Depot Release Profiles mm apart, were tied around the common Sciatic nerve at 65 mid-thigh. Each animal received treatment of test or control FIG. 5 is a graphic representation of an in vitro release of article—according to the dosing described in Table 5. clonidine from three pellet doses as measured by percentage US 8,420,114 B2 53 54 release and micrograms released (Table 2). Some formula duced as indicated in Table 1. The formulation containing 20 tions released 80% of the clonidine for 45 days. The two, wt % clonidine drug load and the polymer 8515 DLG 7E had three, or four pellet doses mimics the doses that would be about 90 cumulative release % of drug released from the implanted in a human. All the formulations had an initial burst depotas long as 140 days, which is suitable for many chronic effect within the first two days, where the drug depot had a conditions of pain and/or inflammation. 10% to 80% cumulative release. In general, formulations with FIG. 19 is a graphic representation of the cumulative the higher drug loads had a faster release profile. release percentage of clonidine for certain formulations FIG. 6 is a graphic representation of the calculated daily (Table 1). Some formulations released about 95% of the release of clonidine from three pellet doses as measured by clonidine over 110 days. micrograms released (Table 3). Some formulations released 10 FIG. 20 is a graphic representation of the cumulative the clonidine over 60 days. The target daily dose was 2.4 release percentage of clonidine for one formulation (Table 1) mg/day. All the formulations had an initial burst effect within over 60 days. The release was relatively continuous. the first two days, where the drug depot released a bolus dose FIG. 21 is a graphic representation of the cumulative of about 35 to 65 mcg. In general, formulations with the release percentage of clonidine for certain formulations higher drug loads had a faster release profile. 15 (Table 1) over about 40 days. FIG. 7 is a graphic representation of clonidine HCl animal FIG. 22 is a graphic representation of the cumulative study formulations as measured by the cumulative clonidine release percentage of clonidine for certain formulations released percentage (Table 3). Some formulations released at (Table 1) over about 20 days. least 60% of the clonidine for 60 days. In general, formula FIG. 23 is a graphic representation of the cumulative tions with the higher drug loads had a longer release profile release percentage of clonidine (Table 1) for certain formu over 45 to 60 days. lations over 3-5 days. FIG. 8 is a graphic representation of clonidine HCl release FIG. 24 is a graphic representation of the cumulative elu for various formulations (Table 3) as measured by the cumu tion percentage of clonidine for certain formulations pro lative clonidine released percentage. Some formulations duced as indicated in Table 1. All formulations had about 90 released at least 70% of the clonidine for 60 days. In general, 25 cumulative release % of drug released from the depot for 7 formulations with the higher drug loads had a longer release days. The formulations here had smaller size (0.75mmx0.75 profile over 60 days. mm), which increases Surface area for release as compared to FIG.9 is a graphic representation of the cumulative in vitro depots with larger diameters. release profile for certain clonidine formulations (Table 3). FIG. 25 is a graphic representation of the cumulative elu Some formulations released at least 60% of the clonidine for 30 tion percentage of clonidine for certain formulations pro 60 days. duced as indicated in Table 1. All formulations had over 100 FIG. 10 is a graphic representation of the cumulative cumulative release % of drug released from the depot for over release profiles for certain irradiated clonidine HCl formula 30 days. tions (Table 3). Some formulations released at least 50% of FIG. 26 is a graphic representation of the cumulative elu the clonidine for over 80 days. 35 tion percentage of clonidine for certain formulations pro FIG. 11 is a graphic representation of certain calculated duced as indicated in Table 1. Span 85 is a plasticizer for one daily release measurements of clonidine from 2/3/4 pellets formulation. All formulations had about 30 to 50 cumulative doses (these approximate human doses). Some formulations release % of drug released from the depot for over 50 days. (Table 3) released clonidine for 85 days. FIG. 27 is a graphic representation of the cumulative FIG. 12 is a graphic representation of the calculated daily 40 release percentage of clonidine for one formulation produced release of clonidine from certain three pellet doses (Table 3). as indicated in Table 1. The formulation containing 5 wt % Some formulations released clonidine for over 65 days. clonidine drug load and the polymer 85.15 PLGA had about FIG. 13 is a graphic representation of the calculated daily 100 cumulative release % of drug released from the depot as release of clonidine from certain 2/3 pellet dose coaxial for long as over 75 days, which is suitable for many chronic mulations (Table 3). Some formulations released clonidine 45 conditions of pain and/or inflammation. for over 85 days. FIG. 28 is a graphic representation of the cumulative FIG. 14 is a graphic representation of the cumulative in release percentage of clonidine for one formulation produced vitro release profile for certain irradiated clonidine formula as indicated in Table 1. The formulation containing 5 wt % tions (Table 3). Some formulations released about 50% of the clonidine drug load and the polymer 85.15 PLGA and Span 65 clonidine for over 85 days. 50 as a plasticizer had about 65 cumulative release % of drug FIG. 15 is a graphic representation of the calculated daily released from the depot as long as 70 days, which is suitable release of clonidine for certain three pellet dose formulations for many chronic conditions of pain and/or inflammation. (Table 3). Some formulations released clonidine for over 85 FIG. 29 is a graphic representation of the cumulative elu days. tion percentage of clonidine for certain formulations pro FIG. 16 is a graphic representation of the micrograms of 55 duced as indicated in Table 1. All formulations had about 90 clonidine released for certain three pellet dose formulations to 110 cumulative release % of drug released from the depot (Table 3). Some formulations had an initial burst effect for for over 100 days, except one, which had about 90 cumulative about 2 days, then a continuous daily release for over 60 days. release % of drug released from the depot for about 20 days. FIG. 17 is a graphic representation of the cumulative FIG. 30 is a graphic representation of the cumulative elu release percentage of clonidine for certain formulations pro 60 tion percentage of clonidine for certain formulations pro duced as indicated in Table 1. The formulation containing 10 duced as indicated in Table 1. All formulations had about 55 wt % clonidine drug load and the polymer 8515 DLG 7E had to 85 cumulative release % of drug released from the depot for about 90 cumulative release % of drug released from the over 28 days. depot as long as 120 days, which is suitable for many chronic FIG. 31 is a graphic representation of the cumulative conditions of pain and/or inflammation. 65 release percentage of clonidine for one formulation produced FIG. 18 is a graphic representation of the cumulative as indicated in Table 1. The formulation containing 10 wt % release percentage of clonidine for certain formulations pro clonidine drug load and the polymer DL-PLA had about 45 US 8,420,114 B2 55 56 cumulative release % of drug released from the depot for saline in the rat Chronic Constriction Injury model (i.e., Ben about 18 days, which may be suitable for acute conditions of nett Model) using Wistar rats. The purpose: To determine pain and/or inflammation. whether an alpha-2-receptor agonist can improve pain asso FIG. 32 is a graphic representation of the cumulative elu ciated behavioral responses in a rat model of neuropathic tion percentage of clonidine for certain formulations pro 5 pain. The doses given would mimic those achievable by a duced as indicated in Table 2. All formulations had POE and continuous release drug depot containing a biodegradable 10% or 20% clonidine drug load. All formulations had about polymer (7 rats in each group). 80 to 90 cumulative release % of drug released from the depot for over 120 days, except one formulation, which released drug within about 35 days. 10 FIG. 33 is a graphic representation of the cumulative GRP Drug (alpha-2-agonist) Dose Route release percentage of clonidine for one formulation produced 1 clonidine 0.02 mg/kg SC as indicated in Table 2. The formulation containing 10 wt % 2 tizanidine 100 mcg/kg SC clonidine drug load and the polymer POE had about 60% 3 tizanidine 50 mcg/kg SC cumulative release % of drug released from the depot for 15 4 medletomidine 200 mcg/kg SC 5 medletomidine 100 mcg/kg SC about 60 days, which may be suitable for chronic conditions 6 guanfacine 5 mg/kg SC of pain and/or inflammation. 7 guanfacine 1 mg/kg SC FIG. 34 is a graphic representation of the cumulative 8 Saline control O.5 mL. SC release percentage of clonidine for one formulation produced as indicated in Table 2. The formulation had about 35% cumulative release % of clonidine released from the depot for Experimental Design: Four loose chromic gut ligatures, 1 about 23 days. mm apart, were tied around the common Sciatic nerve at The examples show different drug depot formulations use mid-thigh. Each group received the treatment indicated above ful for reducing, preventing or treating pain and/or inflamma for total of 15 days and subjected to the following two tests: tion including but not limited to inflammation and/or pain that 25 (1) the Hargreaves test on days 7 and 14; and (2) the von Frey follows Surgery, acute pain and/or inflammation, chronic test on days 8 and 15. inflammatory diseases, chronic inflammatory bowel disease, FIG. 35 is a graphic representation of the mechanical osteoarthritis, osteolysis, tendonitis, Sciatica, herniated discs, threshold as a percentage from baseline in rats given treat Stenosis, myopathy, spondilothesis, lower back pain, facet ments of clonidine 0.02 mg/kg, tizanidine 100 micrograms/ pain, carpal tunnel syndrome, tarsal tunnel syndrome, failed 30 kg, tizanidine 50 micrograms/kg, medetomidine 200 micro back pain or the like. grams/kg, medetomidine 100 micrograms/kg, guanfacine 5 mg/kg, and guanfacine 1 mg/kg Subcutaneous every day for Example 4 15 days and tested for mechanical allodynia on days 8 and 15. Shown in FIG.35, the pain behavioral response (measured The inventors evaluated the efficacy of a various alpha-2- 35 as a percentage of baseline) for mechanical allodynia indi adrenergic receptor agonists and compared them against cates that clonidine 0.02 mg/kg, tizanidine 100 micrograms/ saline in the rat Chronic Constriction Injury model (i.e., Ben kg, medetomidine 200 micrograms/kg, and guanfacine 5 nett Model) using Wistar rats. The purpose: To determine mg/kg given subcutaneous every day for 15 days had statis whether an alpha-2-receptor agonist can improve pain asso tically significant results of decreasing pain responses at day ciated behavioral responses in a rat model of neuropathic 40 pain. The doses given would mimic those achievable by a 15 (indicated by the # or *) when compared against saline. continuous release drug depot containing a biodegradable FIG. 36 is a graphic representation of the thermal paw polymer (7 rats in each group). withdrawal latency as a percentage from baseline in rats given clonidine 0.02 mg/kg, tizanidine 100 micrograms/kg, tizani 45 dine 50 micrograms/kg, medetomidine 200 micrograms/kg, medetomidine 100 micrograms/kg, guanfacine 5 mg/kg, and GRP Drug (alpha-2-agonist) Dose Route guanfacine 1 mg/kg Subcutaneous every day for 15 days. 1 clonidine 0.02 mg/kg SC In FIG. 36, the pain behavioral response (measured as a 2 xylazine 8.0 mg/kg SC percentage of baseline) for thermal hyperalgesia indicates 3 xylazine 3.0 mg/kg SC 50 4 romifidine 200 mcg/kg SC that clonidine 0.02 mg/kg, tizanidine 100 micrograms/kg, 5 romifidine 20 mcg/kg SC medetomidine 100 micrograms/kg, guanfacine 5 mg/kg 6 dexmedetomidine 100 mcg/kg IP given Subcutaneous every day for 15 days had statistically 7 dexmedetomidine 50 mcg/kg IP significant result of decreasing pain responses at days 7 and 8 Saline control O.5 mL. SC 14 (indicated by the it or *) and at day 14 for medetomidine 55 200 micrograms/kg. These results show that the alpha-2 ago Experimental Design: Four loose chromic gut ligatures, 1 nists clonidine, tizanidine, medetomidine, and guanfacine mm apart, were tied around the common Sciatic nerve at may be useful in reducing, preventing, and/or treating pain mid-thigh. Each group received the treatment indicated above and/or inflammation. for total of 15 days and subjected to the following two tests: (1) the Hargreaves test on days 7 and 14; and (2) the von Frey 60 Example 6 test on days 8 and 15. The results did not show any statistically significance. Results from another rat chronic constriction injury model study silimar to that discussed in Example 5, except some Example 5 drug compositions having predominantly alpha 1 agonist 65 activity and some drug compositions having predominantly The inventors evaluated the efficacy of a various alpha-2- alpha 2 agonist activity were given as indicated in the table adrenergic receptor agonists and compared them against below. The doses given would mimic those achievable by a US 8,420,114 B2 57 58 continuous release drug depot containing a biodegradable were given as indicated in the table below. The doses given polymer (7 rats in each group). would mimic those achievable by a continuous release drug depot containing a biodegradable polymer (7 rats in each group).

GRP Drug Dose Route 1 clonidine (alpha-2-agonist) 0.02 mg/kg SC 2 guanabenz (alpha-2-agonist) 5 mg/kg SC GRP Drug Dose Route 3 guanabenz (alpha-2-agonist) 1 mg/kg SC 1 clonidine (alpha-2-agonist) 0.02 mg/kg SC 4 oxymetazoline (alpha-1-agonist) 0.3 mg/kg SC 10 2 ritodrine (beta-2-agonist) 5 mg/kg SC 5 oxymetazoline (alpha-1-agonist) 0.1 mg/kg SC 3 ritodrine (beta-2-agonist) 2 mg/kg SC 6 phenylepherine (alpha-1-agonist) 10 mg/kg SC 4 salbutamol (albuterol) (beta-2- 10 mg/kg SC 7 phenylepherine (alpha-1-agonist) 2 mg/kg SC agonist) 8 Saline control O.5 mL. SC 5 salbutamol (albuterol) (beta-2- 5 mg/kg SC agonist) 6 terbutaline (beta-2-agonist) 0.5 mg/kg SC Each group received the treatment indicated above for total 7 terbutaline (beta-2-agonist) 0.1 mg/kg SC of 14 days and the following two tests: (1) the Hargreaves test 8 Saline control O.5 mL. SC on days 7 and 14; and (2) the von Frey test on days 8 and 15. FIG. 37 is a graphic representation of the thermal paw Each group received the treatment indicated above for total withdrawal latency as a percentage from baseline in rats given 2O of 15 days and the following two tests: (1) the Hargreaves test clonidine 0.02 mg/kg, guanabenz 5 mg/kg, guanabenZ 1 on days 7 and 14; and (2) the von Frey test on days 8 and 15. mg/kg. oxymetazoline 0.3 mg/kg, oxymetazoline 0.1 mg/kg, FIG. 39 is a graphic representation of the thermal paw phenylephrine 10 mg/kg, and phenylephrine 2 mg/kg Subcu withdrawal latency as a percentage from baseline in rats given taneous every day for 15 days. In FIG.37, the pain behavioral clonidine 0.02 mg/kg, ritodrine 5 mg/kg, ritodrine 2 mg/kg, response (measured as a percentage of baseline) for thermal as salbutamol 10 mg/kg, salbutamol 5 mg/kg, terbutaline 0.5 hyperalgesia indicates that clonidine 0.02 mg/kg, oxymeta mg/kg, terbutaline 0.1 mg/kg, and Saline Subcutaneously Zoline 0.3 mg/kg, and phenylephrine 10 mg/kg given Subcu every day for 15 days. In FIG. 39, the pain behavioral taneous every day for 15 days had statistically significant response (measured as a percentage of baseline) for thermal result of decreasing pain responses at days 7 and 14 (indicated hyperalgesia indicates that salbutamol 10 mg/kg, Salbutamol by the # or *) and at day 7 for guanabenZ, 1 mg/kg, oxymeta- 30 5 mg/kg, terbutaline 0.5 mg/kg, and terbutaline 0.1 mg/kg Zoline 0.1 mg/kg, and phenylephrine 2 mg/kg. These results given Subcutaneous every day for 15 days had statistically show that the alpha-1 and alpha-2 agonists may be useful in significant result of decreasing pain responses at days 7 and reducing, preventing, and/or treating pain and/or inflamma 14 (indicated by the # or *), day 7 for ritodrine 2 mg/kg and at tion. day 14 for clonidine 0.02 mg/kg and ritodrine 5 mg/kg when FIG. 38 is a graphic representation of the mechanical 35 compared with the Saline group. threshold as a percentage from baseline in rats given cloni FIG. 40 is a graphic representation of the mechanical dine 0.02 mg/kg, guanabenz 5 mg/kg, guanabenz, 1 mg/kg. threshold as a percentage from baseline in rats given cloni oxymetazoline 0.3 mg/kg, oxymetazoline 0.1 mg/kg, phe dine 0.02 mg/kg, ritodrine 5 mg/kg, ritodrine 2 mg/kg, salb nylephrine 10 mg/kg, and phenylephrine 2 mg/kg Subcutane utamol 10 mg/kg, salbutamol 5 mg/kg, terbutaline 0.5 mg/kg, ous every day for 15 days and mechanical allodynia tested at 40 terbutaline 0.1 mg/kg, and saline Subcutaneously every day days 8 and 15. for 15 days. The rats were tested for mechanical allodynia at The pain behavioral response (measured as a percentage of days 8 and 15. baseline) for mechanical allodynia indicates that oxymetazo In FIG. 40, the pain behavioral response (measured as a line 0.3 mg/kg and oxymetazoline 0.1 mg/kg Subcutaneous percentage of baseline) for mechanical allodynia indicates every day for 15 days resulted in decreasing pain responses at 45 that salbutamol 10 mg/kg given Subcutaneous every day for day 8 and 15 when compared to the saline group. Guanabenz 15 days had statistically significant result of decreasing pain 1 mg/kg and phenylephrine 10 mg/kg decreased mechanical responses at days 8 and 15 (indicated by the it or *) and at day allodynia on day 8 when compared to Saline, and Guanabenz 14 for ritodrine 5 mg/kg, salbutamol 5 mg/kg and terbutaline 5 mg/kg decreased mechanical allodynia on day 15 when 0.5 mg/kg when compared with the saline group. compared to saline. These results show that guanabenz, 50 These results show that clonidine (an alpha-2 agonist) and oxymetazoline and phenylephrine may be useful in reducing, the beta-2 agonists ritodrine, salbutamol, and terbutaline, preventing, and/or treating pain and/or inflammation. alone or in combination with the alpha agonist may be useful in reducing, preventing, and/or treating pain and/or inflam Example 7 mation. 55 It will be apparent to those skilled in the art that various The inventors evaluated the efficacy of a various beta-2- modifications and variations can be made to various embodi adrenergic receptoragonists and compared them to clonidine ments described herein without departing from the spirit or (an alpha-2-agonist) and Saline in the rat Chronic Constric Scope of the teachings herein. Thus, it is intended that various tion Injury model (i.e., Bennett Model) using Wistar rats. The embodiments cover other modifications and variations of purpose: To determine whether the beta-2-adrenergic recep- 60 various embodiments within the scope of the present teach tor agonists can improve pain associated behavioral ings. responses in a rat model of neuropathic pain. What is claimed is: Hargreaves tests were conducted on days 7 and 14; and Von 1. A composition comprising one or more implantable drug Frey tests were performed on days 8 and 15, where some drug depots useful for reducing or treating pain and/or inflamma compositions having predominantly beta-2 agonist activity 65 tion in a patient in need of Such treatment, the implantable were compared to clonidine a drug composition that has drug depot comprising an alpha adrenergic agonist compris predominantly alpha-2 agonist activity and Saline. The drugs ing clonidine hydrochloride and a beta adrenergic receptor US 8,420,114 B2 59 60 agonist comprising ritodrine, salbutamol, or terbutaline, the 8. A composition comprising one or more implantable drug drug depot being implantable at a site beneath the skin to depots useful for reducing or treating pain and/or inflamma reduce or treat pain and/or inflammation, wherein the one or tion in a patient in need of such treatment, the implantable more drug depots contain sufficient amounts to release about drug depot comprising an alpha adrenergic-2 agonist com 0.01 to about 0.4 mg/kg/day of clonidine hydrochloride, and 5 prising clonidine hydrochloride and a beta-2 adrenergic 160 to 500 mg/day of ritodrine, 20 to 500 mg/day of salbuta receptoragonist comprising ritodrine, salbutamol, or terbuta mol, or 20 to 500 mg/day of terbutaline, over a period of 3 line, and a polymer; wherein the drug depot is implantable at days to 6 months, and wherein the drug depot contains no a site beneath the skin to reduce or treat pain and/or inflam Water and comprises at least one biodegradable polymer.com mation, and the one or more depots contain sufficient prising one or more of poly(lactide-co-glycolide) (PLGA), 10 amounts to release about 0.01 to about 0.4 mg/kg/day of polylactide (PLA), polyglycolide (PGA), D-lactide, D.L-lac clonidine hydrochloride, and 160 to 500 mg/day of ritodrine, tide, L-lactide, poly(D.L-lactide), poly(D.L-lactide-co-ca 20 to 500 mg/day of salbutamol, or 20 to 500 mg/day of prolactone) or poly(L-lactide-co-caprolactone) or a combina terbutaline, over a period up to 6 months, and are capable of tion thereof and the polymer has an average molecular weight releasing (i) about 5% to about 20% of the alpha-2 adrenergic of from about 5,000 to about 500,000 daltons and the drug 15 agonist and beta-2 adrenergic agonist relative to a total depot has a diameter of about 0.01 mm to about 2 mm wherein amount of the alpha-2 adrenergic agonist and beta-2 adren the drug depot further comprises methoxypolyethylene gly ergic agonist loaded in the drug depot over a first period of up col (mPEG). to 72 hours and (ii) about 21% to about 99% of the alpha-2 2. An implantable drug depot according to claim 1, wherein adrenergic agonist and beta-2 adrenergic agonist relative to a the alpha-2 adrenergic agonist further comprises L-norepi total amount of the alpha-2 adrenergic agonist and beta-2 nephrine, dexmetdetomidine, apraclonidine, tizanidine, bri adrenergic agonist loaded in the drug depot over a subsequent monidine, Xylometazoline, tetrahydrozoline, oxymetazoline, period of up to 6 months, wherein the drug depot contains no guanfacine, guanabenz. Xylazine, moxonidine, rillmenidine, water and comprises at least one biodegradable polymer.com UK 14.304, B-HT 933, B-HT 920, mivazerol, octopamine, prising one or more of poly(lactide-co-glycolide) (PLGA), tizanidine, or a combination thereof and the beta-2 adrenergic 25 polylactide (PLA), polyglycolide (PGA), D-lactide, D.L-lac agonist further comprises metaproterenol, albuterol, isoet tide, L-lactide, poly(D.L-lactide), poly(D.L-lactide-co-ca harine, pirbuterol, bitolterol, fenoterol, formoterol, pro prolactone), or poly(L-lactide-co-caprolactone) or a combi caterol, or a combination thereof. nation thereof and the polymer has an average molecular 3. An implantable drug depot according to claim 1, wherein weight of from about 5,000 to about 500,000 daltons and the the polymer comprises about 60% to 99% of the total weight 30 drug depot has a length of about 0.5 mm to about 5 mm and a % of the drug depot. diameter of from about 0.01 mm to about 2 mm wherein the 4. An implantable drug depot according to claim 1, wherein drug depot further comprises methoxypolyethylene glycol the drug depot releases (i) abolus dose of the alpha adrenergic (mPEG) and an excipient comprising sorbitan tristearate agonist and the beta adrenergic agonist at a site beneath the (Span-65). skin over a period of up to 3 days and (ii) an effective amount 35 9. An implantable drug depot according to claim8, wherein of the alpha adrenergic agonist and the beta adrenergicago the alpha-2 and beta-2 adrenergic agonists have a particle size nist over a period of up to 6 months. of about 5 micrometers to about 30 micrometers. 5. An implantable drug depot according to claim 1, wherein 10. An implantable drug depot according to claim 8. the drug depot releases about 20% to about 99% of the alpha wherein the alpha-2 and beta-2 adrenergic agonists have a adrenergic agonist and the beta adrenergic agonist relative to 40 particle size of about 1 micrometer to about 250 micrometers. a total amount of the alpha adrenergic agonist and the beta 11. An implantable drug depot according to claim 8. adrenergic agonist loaded in the drug depot over a period of 3 wherein the polymer has an average molecular weight of days to 6 months after the drug depot is administered to a about 20,000 to about 50,000. target tissue site. 12. An implantable drug depot according to claim 8. 6. An implantable drug depot according to claim 1, wherein 45 wherein the polymer has an average molecular weight of the drug depot comprises from about 5 wt.% to about 15 wt. about 10,000 to about 100,000. % of clonidine hydrochloride and at least 80 wt.% of a 13. An implantable drug depot according to claim 8. biodegradable polymer based on the total weight of the drug wherein the drug depot has a modulus of elasticity of 2x10 to depot and the drug depot is adapted to release an effective about 5x10 dynes/cm. amount of the clonidine over a period of at least 135 days. 50 14. An implantable drug depot according to claim 8. 7. An implantable drug depot according to claim 1, wherein wherein the drug depot has a length of about 5 mm the drug depot is in the form of a pellet.