(12) Patent Application Publication (10) Pub. No.: US 2009/011 1844 A1 Sadee Et Al

US 200901 11844A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/011 1844 A1 Sadee et al. (43) Pub. Date: Apr. 30, 2009

(54) COMBINATION ANALGESC EMPLOYING Related U.S. Application Data OPOD AND NEUTRAL ANTAGONST (60) Provisional application No. 60/981,034, filed on Oct. (75) Inventors: Wolfgang Sadee, Upper Arlington, 18, 2007. OH (US); Edward Bilsky, Publication Classification Biddeford, ME (US); Janet Yancey-Wrona, Freeport, ME (US) (51) Int. Cl. A63L/485 (2006.01) Correspondence Address: (52) U.S. Cl...... S14/282 BROMIBERG & SUNSTEIN LLP (57) ABSTRACT 125 SUMMER STREET BOSTON, MA 02110-1618 (US) A non-addictive analgesic co-formulation comprising an opioid agonist in an amount Sufficient to confer analgesia in a (73) Assignee: AIKO Biotechnology, Portland, mammalian Subject and a neutral opioid antagonist in an ME (US) amount sufficient to inhibit peripheral effects, and insufficient to block substantial central effects, of the opioid agonist in the (21) Appl. No.: 12/288,347 Subject. Such formulations, and methods of using same, may also deter diversion, inhibit peripheral effects, and reduce (22) Filed: Oct. 17, 2008 addiction liability. Patent Application Publication Apr. 30, 2009 Sheet 1 of 31 US 2009/011 1844 A1

: 75 5 vo

HC 10 20 60 90 120 18O 6 hrs Control Time of Pre-treatment (min) (63-naltrexol 0.56 mg/kg, i.v.)

FIG 1A Patent Application Publication Apr. 30, 2009 Sheet 2 of 31 US 2009/011 1844 A1

100

: 75 5 Yo

HC 15 30 60 90 120 180 6 hrs 12 hrs 24 hrs Control Time of Pre-treatment (min) (63-naltrexol 5.6 mg/kg, p.o.)

FIG 1B Patent Application Publication Apr. 30, 2009 Sheet 3 of 31 US 2009/011 1844 A1

100 1N s CMJ 75 O w O g 50 O op w S. < SNC 25

HC 0.10 0.18 0.32 0.56 Control Dose of 63-naltrexol (mg/kg, i.v.)

FIG 2A Patent Application Publication Apr. 30, 2009 Sheet 4 of 31 US 2009/011 1844 A1

100

HC 1.0 1.8 3.2 5.6 Control -- Dose of 63-naltrexol (mg/kg, p.o.)

FIG 2B Patent Application Publication Apr. 30, 2009 Sheet 5 of 31 US 2009/011 1844 A1

100 Co-Administration (p.0.) Y W -O-Hydrocodone Control -9-6b-naltrexol (3.2 mg/kg) C W W -H-- 6b-naltrexol (32(10 mg/kg) : 80 NN a-O-Saline Control 5 r) 60

N K

M) EN F ; 21. In py. No O 30 60 90 120 150 180 Time (min) FIG 3 Patent Application Publication Apr. 30, 2009 Sheet 6 of 31 US 2009/011 1844 A1

100

Saline HC 0.010 0.032 0.10 0.32 Control Control -- Dose of AIKO-150 (mg/kg, i.v.)

FIG 4A Patent Application Publication Apr. 30, 2009 Sheet 7 of 31 US 2009/011 1844 A1

100

s 75 CM) JB

CD & S 25 S.

Saline HC 0.10 0.32 1.0 Control Control -- Dose of 6B-naltrexol (mg/kg, p.o.)

FIG 4B Patent Application Publication Apr. 30, 2009 Sheet 8 of 31 US 2009/011 1844 A1

100

Saline HC 0.32 1.0 3.2 Control Control -- Dose of 63rnaltrexol (mg/kg, p.o.)

FIG 5 Patent Application Publication Apr. 30, 2009 Sheet 9 of 31 US 2009/011 1844 A1

O Hydrocodone (A90 i.v.) GI Transit -O-Hydrocodone (A90 i.v.) Antinociception 100

0.001 0.01 0.1 1 10 100 Dose of 63-maltrexol (mg/kg, i.v.) FIG 6A Patent Application Publication Apr. 30, 2009 Sheet 10 of 31 US 2009/011 1844 A1

-O-Hydrocodone (A90 i.v.) GI Transit -O-Hydrocodone (A90 i.v.) Antinociception 100

0.001 0.01 0.1 l 10 100 Dose of 6B-naltrexol (mg/kg, p.o.) FIG 6B Patent Application Publication Apr. 30, 2009 Sheet 11 of 31 US 2009/011 1844 A1

-O Hydrocodone (A90 p.o.) GI Transit 1. i-O- Hydrocodone (A90 p.o.) Antinociception > 100 s M SH 80 N

d 60 > s 40 O C O 2 20 PC

SNe O

0.001 0.01 0.1 1 10 100 Dose of 6B-naltrexol (mg/kg, p.o.) FIG 6C Patent Application Publication Apr. 30, 2009 Sheet 12 of 31 US 2009/011 1844 A1

100 1. s CM)SH 75 O o w) O Od 50 O

op w

SNC 25 S. CN:

HC 20 60 90 120 180 Control - Time of Pre-treatment (min) (6 f-naltrexamide 10 mg/kg, i.v.)

FIG 7A Patent Application Publication Apr. 30, 2009 Sheet 13 of 31 US 2009/011 1844 A1

100

75 5 w

50 ; 25 HC 30 60 120 18O 6 hrs. Control -- Time of Pre-treatment (min) (6 B-naltrexamide 56 mg/kg, p.o.)

FIG 7B Patent Application Publication Apr. 30, 2009 Sheet 14 of 31 US 2009/011 1844 A1

100 1. s dM 75

opO ro O GD 50 O opS. v < SNe 25 S S.

HC 1.0 3.2 10 Control -- Dose of 6B-naltrexamide (mg/kg, i.v.)

FIG 8A Patent Application Publication Apr. 30, 2009 Sheet 15 of 31 US 2009/011 1844 A1

100

50 ; 25 HC 10 18 32 56 Control t Dose of 6p–naltrexamide (mg/kg, p.o.)

FIG 8B Patent Application Publication Apr. 30, 2009 Sheet 16 of 31 US 2009/011 1844 A1

100 Co-Administration (p.o.) -O-Hydrocodone Control -G-6b-maltrexamide (100 mg/kg) -H 6b-naltrexamide (180 mg/kg) Saline Control 80

60 ; 40 O 30 60 90 120 150 180 Time (min) FG 9 Patent Application Publication Apr. 30, 2009 Sheet 17 of 31 US 2009/011 1844 A1

100

Saline HC 0.032 0.10 0.32 Control Control -- Dose of 63-maltrexamide (mg/kg, i.v.)

FIG 10A Patent Application Publication Apr. 30, 2009 Sheet 18 of 31 US 2009/011 1844 A1

100

Saline HC 1.0 1.8 3.2 Control Control -- Dose of 63-naltrexamide(mg/kg, p.o.)

FIG 10B - Patent Application Publication Apr. 30, 2009 Sheet 19 of 31 US 2009/011 1844 A1

-O-Hydrocodone (A90 i.v.) GI Transit O Hydrocodone (A90 i.v.) Antinociception 100

0.001 0.01 0.1 1. 10 100 Dose of 6f-naltrexamide (mg/kg, i.v.) FIG 11A Patent Application Publication Apr. 30, 2009 Sheet 20 of 31 US 2009/011 1844 A1

-O-Hydrocodone (A90 i.v.) GI Transit 1. O-Hydrocodone (A90 i.v.) Antinociception > OO s CM) 80

Y CD 60 > A: 40 O PC O 2 20 PC

&C O 0.001 0.01 0.1 1 10 OO Dose of 6B-naltrexamide (mg/kg, p.o.) FIG 11B Patent Application Publication Apr. 30, 2009 Sheet 21 of 31 US 2009/011 1844 A1

100

: 75 5 wo

50 5 25

HC 10 20 30 60 90 Control - Time of Pre-treatment (min) (Naltrexone 0. 10 mg/kg, i.v.)

FIG 12A Patent Application Publication Apr. 30, 2009 Sheet 22 of 31 US 2009/011 1844 A1

100 1. s SHMD 75 O s wo O Gld 50 O op w < SNe 25 S. S

HC 15 30 45 60 120 Control -- Time of Pre-treatment (min) (Naltrexone 0.56 mg/kg, p.o.)

FIG 12B Patent Application Publication Apr. 30, 2009 Sheet 23 of 31 US 2009/011 1844 A1

100

HC 0.010 0.032 0.10 Control -- Dose of Naltrexone (mg/kg, i.v.)

FIG 13A Patent Application Publication Apr. 30, 2009 Sheet 24 of 31 US 2009/011 1844 A1

100

50 ; 25 HC 0.32 0.56 v 1.0 Control Dose of Naltrexone (mg/kg, p.o.)

FIG 13B Patent Application Publication Apr. 30, 2009 Sheet 25 of 31 US 2009/011 1844 A1

OO Co-Administration (p.o.) 1. -O-Hydrocodone Control > -e-Naltrexone (0.32 mg/kg) -H Naltrexone (1.0 mg/kg) ?a -- Naltrexone (3.2 mg/kg) w 80 arO- Saline Control SH

.S.ro 60

op9 9 e NM 40 w) MS

C SN 20 N

e s N

O 30 60 90 120 150 18O Time (min) FG 14 Patent Application Publication Apr. 30, 2009 Sheet 26 of 31 US 2009/011 1844 A1

100

Saline HC O.032 0.10 0.32 Control Control -- Dose of Naltrexone (mg/kg, i.v.)

FG 15A Patent Application Publication Apr. 30, 2009 Sheet 27 of 31 US 2009/011 1844 A1

100

Saline HC 0.10 0.18 0.32 Control Control -- Dose of Naltrexone (mg/kg, p.o.)

FG 15B Patent Application Publication Apr. 30, 2009 Sheet 28 of 31 US 2009/011 1844 A1

100

Saline HC 0.32 1.0 3.2 Control Control -- Dose of Naltrexone (mg/kg, p.o.)

FG 16 Patent Application Publication Apr. 30, 2009 Sheet 29 of 31 US 2009/011 1844 A1

On Hydrocodone (A90 i.v.) GI Transit 1. O Hydrocodone (A90 i.v.) Antinociception > 100 s CV) SH 80 CS 2 9 60 > A: 40 O IC O 2 20 C

SNC O

0.001 0.01 0.1 l 10 100 Dose of Naltrexone (mg/kg, i.v.) FIG 17A Patent Application Publication Apr. 30, 2009 Sheet 30 of 31 US 2009/011 1844 A1

-O-Hydrocodone (A90 i.v.) GI Transit -O- Hydrocodone (A90 i.v.) Antinociception 100

0.001 0.01 O.1 11 10 100 Dose of Naltrexone (mg/kg, p.o.) FIG 17B Patent Application Publication Apr. 30, 2009 Sheet 31 of 31 US 2009/011 1844 A1

-O Hydrocodone (A90 p.o.) GI Transit 1. -O-Hydrocodone (A90 p.o.) Antinociception

> 100 s M SH 80 p CS Y G9 60 > s G9 40 O C O 2 20 C

O SNC

0.001 0.01 0.1 l 10 100 Dose of Naltrexone (mg/kg, p.O.) FIG 17C US 2009/011 1844 A1 Apr. 30, 2009

COMBINATION ANALGESCEMPLOYING 15 mg hydrocodone. These ratios of naltrexol to opioid range OPOD AND NEUTRAL ANTAGONST from 0.03:1 (i.e. 15.5-fold less naltrexol than opioid) to nearly a 1:1 ratio of naltrexol to opioid. Given the complete lack of CROSS REFERENCE TO RELATED Supporting data, these suggested dosages are uninformative APPLICATIONS and effectively meaningless, representing mere guesses. Fur 0001. This application claims priority from U.S. Provi ther, Kaiko teaches the use of antagonists that have aversive sional Application Ser. No. 60/981,034, filed in the United effects in humans and precipitate severe withdrawal Symp States Patent and Trademark Office on Oct. 18, 2007, which toms. Simon extrapolates to propose a dosage chart in para is hereby incorporated by reference herein. graph 0156 for other kinds of opioid agonists. TECHNICAL FIELD SUMMARY OF THE INVENTION 0002 The present invention relates to co-formulations of 0006. The present invention teaches the use of an opioid/ opioid agonists and opioid antagonists, and in particular to opioid antagonist co-formulation, co-administration of the Such co-formulations using neutral antagonists. agonist with the antagonist, or separate but overlapping administration of the agonist with the neutral antagonist, BACKGROUND ART wherein such co-formulation, co-administration or separate 0003 Opioidagonists, while creating analgesia in humans administration is uniquely designed to address both addiction and other mammalian Subjects, typically are addictive and liability of the opioid and peripheral side effects, such as also typically have serious adverse side effects, including constipation. constipation and nausea. To address the addictive qualities of 0007. In a first embodiment of the invention there is pro opioid agonists, the prior art teaches the use of co-formula vided a unit dosage of an analgesic composition comprising tions that include both opioid agonists and opioidantagonists. an opioid agonist in an amount Sufficient to confer analgesia Most prior art co-formulations utilize opioidantagonists Such in a mammalian Subject and a neutral opioid antagonist in an as naltrexone or naloxone, which themselves have aversive amount sufficient to inhibit peripheral effects, and insufficient effects in human and mammalian Subjects. In fact, these to block substantial central effects, of the opioid agonist in the compounds can trigger severe, and sometimes life-threaten Subject. ing, withdrawal symptoms. Such opioid antagonists are 0008. In a related embodiment of the invention the anal referred to in the present application as “aversive.” U.S. Pat. gesic composition comprises an opioid agonist, which is No. 6,627,635 to Palermo et al. and U.S. Pat. Nos. 6,696,066, selected from the group consisting of alfentanil, allylprodine, 6,475,494 and 6,375,957 to Kaiko et al. provide examples of alphaprodine, anilleridine, benzylmorphine, bezitramide, co-formulations that employ aversive opioid antagonists. buprenorphine, butorphanol, clonitaZene, codeine, desomor Recent research by Marczak et al. emphasizes the aversive phine, dextromoramide, dezocine, diampromide, diamor effects of both naltrexone and naloxone in opioid-dependent phone, dihydrocodeine, dihydromorphine, dimenoxadol, subjects. Marczak E., Jinsmaa Y., Li T., Bryant S. D., Tsuda dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, Y., Okaday. Lazaraus L. H. (Jul 12, 2007)“N-Allyl-Dmt1 dipipanone, eptazocine, ethoheptazine, ethylmethylthiam endomorphins are u-opioid receptor antagonists lacking butene, ethylmorphine, etonitaZene, fentanyl, heroin, hydro inverse agonist properties. J. Pharmacol. Exp. Ther. Fast codone, hydromorphone, hydroxypethidine, isomethadone, Forward. ketobemidone, levorphanol, levophenacylmorphan, lofenta 0004 U.S. Pat. No. 6,713,488 B2 to Wolfgang Sadée et al., nil, meperidine, meptazinol, metazocine, methadone, meto which is hereby incorporated herein by reference and is here pon, morphine, myrophine, narceline, nicomorphine, nor inafter referred to as “Sadée teaches the use of “neutral levorphanol, normethadone, noroxycodone, nalorphine, opioidantagonists, which do not have aversive effects, to treat nalbuphene, normorphine, norpipanone, opium, oxycodone, opioid agonist addiction. Sadée identifies as neutral antago oxymorphone, papaveretum, pentazocine, phenadoxone, nists certain naltrexone and naloxone analogs, including phenomorphan, phenazocine, phenoperidine, piminodine, 6.3-maltrexol and 6B-maltrexamide. Sadée also teaches that piritramide, propheptazine, promedol, properidine, pro neutral antagonists can be used to treat other side-effects of poxyphene, Sufentanil, tilidine and tramadol, in an amount opioid agonists, including constipation and respiratory Sufficient to confer analgesia in a mammalian Subject. In depression. addition, the neutral opioid antagonist may be a naloxone or 0005 Building on Sadée's research, United States Patent maltrexone analog showing neutral nonaversive properties. Application 2004/0024006 A1 to David Lew Simon, herein 0009 Naltrexone analogs may be represented by formula after referred to as “Simon proposes non-addictive opioid IC, or IB, including pharmaceutically acceptable salts thereof: agonist/antagonist co-formulations that include neutral (IC) opioidantagonists such as 6B-maltrexol. Simon's disclosure is R12 prophetic in nature, however, and lacks Supporting, experi mental data. For example, paragraphs 01 07 and 108 of Simon discuss a known effective dosage of morphine (0.15) mg/kg body weight) and then Suggest a completely unknown and untested range of possible doses for 6.f3-maltrexol from 0.00026-0.0015 mg/kg is body weight, providing no data for such a formulation ever being effective. Similarly, in para graph O155 of Simon's application, Simon uses data pro vided by Kaiko in the U.S. Pat. No. 6,475,494 patent to propose that 0.5 to 12 mg of 6f-naltrexol be administered per US 2009/011 1844 A1 Apr. 30, 2009

0019 Naloxone analogs may be represented by formula -continued IC, or IB, including pharmaceutically acceptable salts thereof:

(IC)

(IB)

wherein: s' IX2 0010) R' is cycloalkyl(alkyl), for example, C-C, (cy w cloalkyl)alkyl, for example, C-C (cycloalkyl)methyl Such R3C O XI as (cyclopropyl)methyl or Cs-C (cycloalkenyl)alkyl, 0011 R is H, OH or esters thereof, such as OAc(OC wherein: (alkyl)), for example O(C-C alkyl); I0020) R' is alkenyl, for example C-C alkenyl, such as allyl: 0012 R is H, alkyl for example, C-C alkyl, or (alkyl) (0021 R is H, OH or esters thereof, such as —OAc(OC C=O for example, ((C-C)alkyl)-C=O; (alkyl)), for example O(C-C alkyl); 0013 Rand Rare independently H, halogen (F, Cl, Br or I0022 R is H, alkyl for example, C-C alkyl, or (alkyl) I), alkyl, for example C-C alkyl, alkoxy, Such as C-C, C=O for example, ((C-C)alkyl)-C=O; (0023 R and Rare independently H, halogen (F, Cl, Br or alkoxy, nitro, amino, cyano, carboxyl or acyl which may be I), alkyl, for example C-C alkyl, alkoxy, Such as C-C, Substituted for one or more hydrogens on the ring; alkoxy, nitro, amino, cyano, carboxyl or acyl which may be 0014 X and X’ are the same or different, and may be H. Substituted for one or more hydrogens on the ring; C-C alkyl, -OR - NR7RR, NCOR', -NO, or I0024 X and X’ are the same or different, and may be H. SR'', alkyl, OR, NRRR, NCOR', NO, or - SR'', 0025 wherein, 0015 wherein, (0026 RandR'' are independently H, alkyl, for example I0016 RandR'' are independently H, alkyl, for example C-C alkyl, Substituted alkyl, cycloalkyl, for example C-C, C-C alkyl, Substituted alkyl, cycloalkyl, for example C-C, cycloalkyl, Substituted cycloalkyl, aryl, for example phenyl, cycloalkyl, Substituted cycloalkyl, aryl, for example phenyl, naphthyl, imidazole, quinoline, isoquinoline, oxazole, ben naphthyl, imidazole, quinoline, isoquinoline, oxazole, ben ZOxazole, thiazole, pyrimidyl, pyrazolyl, indole, Substituted ZOxazole, thiazole, pyrimidyl, pyrazolyl, indole, Substituted aryl, acyl, for example C-C, acyl Such as —C(O)—C-C, aryl, acyl, for example C-C, acyl Such as —C(O)C-C alkyl alkyl wherein n is typically 6-10 but may be 10-20 or greater, whereinn is typically 6-10 but may be 10-20 or greater, aroyl, aroyl, for example benzoyl, naphthoyl, imidazoyl, quinoli for example benzoyl, naphthoyl, imidazoyl, quinolinoyl, iso noyl, isoquinolinoyl, oxazoyl, benzoxazoyl, thiazoyl, indoyl, and pyrimidoyl, polyethyleneglycyl (PEGyl), or other similar quinolinoyl, oxazoyl, benzoxazoyl, thiazoyl, indoyl, and Substitutions such as polyether groups; pyrimidoyl, polyethyleneglycyl (PEGyl), or other similar (0027 R, R and R'' are independently hydrogen, alkyl, Substitutions such as polyether groups; for example C-C alkyl substituted alkyl, cycloalkyl for 0017 R, R and R'' are independently hydrogen, alkyl, example C-C, cycloalkyl, Substituted cycloalkyl, aryl, Sub for example C-C alkyl, substituted alkyl, cycloalkyl for stituted aryl; example C-C cycloalkyl, Substituted cycloalkyl, aryl, Sub 10028. RandR can be present or absent and are indepen stituted aryl; dently hydrogen, alkyl, for example C-C alkyl, Substituted alkyl cycloalkyl for example C-C, cycloalkyl, Substituted I0018. RandR can be present or absent and are indepen cycloalkyl, aryl, for example phenyl, naphthyl, imidazole, dently hydrogen, alkyl, for example C-C alkyl, Substituted quinoline, isoquinoline, oxazole, benzoxazole, thiazole, alkyl, cycloalkyl for example C-C-7 cycloalkyl, Substituted pyrimidyl, pyrazolyl, indole, Substituted aryl; cycloalkyl, aryl, for example phenyl, naphthyl, imidazole, and pharmaceutically acceptable salts thereof. quinoline, isoquinoline, oxazole, benzoxazole, thiazole, (0029. For generic formulae IC. and IB, when X" and X’ are pyrimidyl, pyrazolyl, indole, Substituted aryl; the same, the stereocenter at this position, marked by an and pharmaceutically acceptable salts thereof. asterisk, goes away. US 2009/011 1844 A1 Apr. 30, 2009

0030. In related embodiments, the naloxone or naltrexone mulation comprising an amount of opioid agonist Sufficient to analog may be, including 6B-maltrexol, 63-maltrexamide, induce a euphoric state or sufficient to relieve pain upon 6B-naloxol. 6C.-naltrexol. 6C.-naloxol. 6C.-naltrexamine, ingestion or administration, the opioid agonist having a blood 6-deoxynaltrexone, 6B-maltrexamine, and 6C.-naltrexamide, half-life, and an effective amount of a neutral opioid antago pharmaceutically acceptable physical isomorphs thereof, and nist with a ratio fixed relative to that of the opioid agonist, the pharmaceutically acceptable salts thereof. neutral antagonist having a blood half-life Substantially 0031. In a further related embodiment of the invention longer than the blood half-life of the opioid agonist, wherein described above, the mammalian Subject is a human. upon Successive administration, the blood concentration ratio 0032. In another related embodiment of the invention of neutral opioid antagonist to opioid agonist increases with described above, the analgesic composition is for oral or each Successive administration, as measured in mg per kg of intravenous administration and the neutral opioid antagonist body weight of the Subject, and Such that repeated adminis is 6B-maltrexol. Dosage ranges for the neutral antagonist rela tration of the formulation in a dosage regimen exceeding tive to the analgesic, in separate formulations for co-admin therapeutically recommended limits results in reduced istration, may range from a dosage of approximately 0.0008 euphoria and reduced pain relief in the Subject and so deters 0.08 mg of 6f-naltrexol per kg of body weight of the subject diversion. for i.v. administration of both the antagonist and agonist, and from a dosage range of approximately 0.008-0.24 mg 6B-nal 0041. Yet another embodiment provides a method for trexol per kg of body weight for oral administration of both inhibiting peripheral effects of an opioid agonist while still the antagonist and agonist, and from a dosage range of from permitting Substantial central effects of the opioid agonist in 0.008-0.08 mg of 6f-naltrexol per kg of body weight for oral a Subject in need thereof, the method comprising co-admin administration of the antagonistandi.V. administration of the istering to the Subject in need thereof the opioid agonist with agonist. These dosage ranges were calculated as “human an effective amount of a unit dosage of a neutral opioid equivalent dosages' from the effective dosages determined in antagonist, the effective amount Sufficient to inhibit periph rodent models; it is anticipated that some dosage adjustment eral effects and insufficient to block substantial central effects be made for other species, and specifically humans. The dos in the subject. age for the analgesic in separate formulations suitable for 0042. A more particular embodiment provides a method co-administration with the neutral antagonist, was an Ago of deterring addiction in a subject being administered an dosage, which means it confers 90% analgesic activity. opioid agonist, the method comprising co-administering to 0033. In another related embodiment of the invention the Subject the opioid agonist with an effective amount of a described above, the neutral opioidantagonist is 6B-maltrexol unit dosage of a neutral opioid antagonist, the effective in a dosage of approximately 0.0008-0.24 mg per kg of body amount Sufficient to reduce euphoria and reduce pain relief weight of the subject. upon Successive administrations beyond therapeutically rec 0034. In another related embodiment of the invention ommended limits, thereby deterring addiction. described above, the neutral opioidantagonist is 6B-maltrexa 0043. In related method embodiments, the unit dosage of mide in a dosage of approximately 0.0024-0.8 mg per kg of the opioid antagonist is selected from the group consisting of body weight of the subject. 6.3-maltrexol. 6(B-naltrexamide, 6 B-naloxol. 6C.-naltrexol, 0035. In another related embodiment of the invention 6C.-naloxol. 6O-maltrexamine, 6B-maltrexamine, 6-deoxynal described above, the analgesic composition is co-adminis trexone, and 6C.-naltrexamide, pharmaceutically acceptable tered orally with neutral opioid antagonist. In still further physical isomorphs thereof, and pharmaceutically acceptable related embodiments, the neutral opioid antagonist is 6B-nal salts thereof. trexamide in an oral administration with the agonist given by 0044. In other related method embodiments, the opioid i.V., wherein the neutral antagonist dosage is approximately agonist and unit dosage may be administered in a manner 0.024-0.8 mg per kg of body weight of the subject. Again, the selected from the group consisting of orally, perorally, intra analgesic is given at an Ago dose. gastrically, Sublingually, by Suppository, intravenously and a 0036 Similar ranges are determined, as indicated, for combination thereof, and wherein co-administration is over other neutral antagonists of the present invention. lapping Such that administration may be of a single co-for 0037 Another embodiment comprises a method for inhib mulation comprising agonistandantagonist, or may be simul iting peripheral effects of an opioidagonist while still permit taneous or sequential administration of separate agonist and ting Substantial central effects of the opioid agonist in a Sub antagonist formulations. ject, the method comprising co-administering the opioid 0045. In various related embodiments of this invention, agonist with an effective amount of a unit dosage of a neutral the opioid agonist of the analgesic composition is hydroc opioidantagonist formulated as described to a Subject in need odone. In other particular embodiments, the unit dosage, thereof. pharmaceutical composition, and any or all of the methods 0038 Still another embodiment provides a method of may further comprise a neutral opioid antagonist that is Suit deterring addiction in a Subject being administered an opioid able for formulation in a slow-release formulation, or is for agonist, the method comprising co-administering the opioid mulated in a slow-release formulation. agonist with an effective amount of a unit dosage of a neutral 0046. In a further related embodiment of the invention opioid antagonist formulated according to as described to a described above, the neutral opioid antagonist has a blood subject in need thereof. half-life substantially longer than the blood half-life of the 0039. In related embodiments, the opioid agonist and unit opioid agonist, so that repeated abusive administration of the dosage are administered orally, perorally, intragastrically, dosage causes a greater increase in blood concentration of the Sublingually, by Suppository, or intravenously. antagonist than of the agonist, so as to deter diversion, dis 0040. Other embodiments provide a pharmaceutical for courage abuse and/or reduce addiction liability to the agonist mulation that deters diversion of an opioid agonist, the for resulting from Such administration. US 2009/011 1844 A1 Apr. 30, 2009

0047. In a further related embodiment of the invention orally-administered 6B-maltrexol on an orally-co-adminis described above, the neutral antagonist has physicochemical tered, antinociceptive dose of hydrocodone. properties similar to that of the opioid agonist, so as to deter 0056 FIG. 4A is a dose response curve reflecting the diversion of the agonist by extraction or other means. potency of intravenously-administered 63-maltrexol to 0.048. In various embodiments, whether the embodiments reverse hydrocodone-induced GI transit slowing, where the are methods for inhibiting peripheral effects, deterring diver two compounds are not co-administered. sion or addiction, or reducing addiction liability, among other 0057 FIG. 4B is a dose response curve reflecting the methods, are whether the embodiments are for a unit dosage potency of orally-administered 6 B-maltrexol to reverse hydro or a pharmaceutical composition, the neutral antagonist may codone-induced GI transit slowing, where the two com be formulated alone or together with the opioid agonist in a pounds are not co-administered. slow-release co-formulation. In Such co-formulations, the 0.058 FIG. 5 is a dose response curve reflecting the neutral antagonist may be provided with an opioid agonist potency of 6f-naltrexol to reverse hydrocodone-induced GI wherein only the neutral antagonist is provided in a slow transit slowing when the two compounds are orally co-ad release form. Other embodiments provide a neutral antago ministered. nist with an opioid agonist in a co-formulation, wherein only 0059 FIG. 6A shows the summarized potency data for the opioid agonist is provided in the co-formulation in a inhibition of hydrocodone activity by 6.f3-maltrexol in GI tran slow-release form. Still other embodiments provide a neutral sit studies (peripheral effects) and antinociception studies antagonist with the opioid agonist in a co-formulation, (central effects), where both 6f-naltrexol and hydrocodone wherein both the neutral antagonist and the opioid agonist are were administered intravenously. formulated as slow-release agents. 0060 FIG. 6B shows the summarized potency data for 0049. To deter diversion the neutral antagonist of the inhibition of hydrocodone activity by 6.f3-maltrexol in GI tran present invention is relatively lipophilic, similar to the ago sit studies (peripheral effects) and antinociception studies nists; moreover, greatest protection against diversion is (central effects), where 6f-naltrexol was administered orally achieved by making the two components in a co-formulation and hydrocodone was administered intravenously. not easily separable. Further, the neutral antagonist is potent 0061 FIG. 6C shows the summarized potency data for and is at least partially excluded from the brain, not primarily inhibition of hydrocodone activity by 6.f3-maltrexol in the GI by means of high polarity, which also tends to reduce receptor transit studies (peripheral effects) and antinociception studies potency (such as occurs with methylmaltrexone (MNTX)), (central effects) where both 6.3-maltrexol and hydrocodone but by other means, including but not limited to, the action of were orally co-administered. an extrusion pump (e.g. —the multi-drug resistance pump 0062 FIG. 7A is a graph that shows data reflecting the MDR1, which also keeps loperamide (immodium) out of the duration of the inhibitive effects of intravenously-adminis brain). The combination of these features makes the com tered 6B-maltrexamide on an antinociceptive, intravenous pounds of the invention unique. Lastly, Such potent and rela dose of hydrocodone, and demonstrates the time of peak tively lipophilic antagonists have the tendency to show sig effect of antinociception inhibition. nificantly delayed central activity (for kinetic reasons) 0063 FIG. 7B is a graph that shows data reflecting the compared to peripheral effects. This is advantageous for short duration of the inhibitive effects of orally-administered term use, and it facilitates dosage schedules that prevent 6B-maltrexamide on an antinociceptive, intravenous dose of inappropriate dosage escalation. hydrocodone, and demonstrates the time of peak effect of antinociception inhibition. BRIEF DESCRIPTION OF THE DRAWINGS 0064 FIG. 8A is a dose response curve reflecting the 0050. The foregoing features of the invention will be more potency of the inhibitive effects of intravenously-adminis readily understood by reference to the following detailed tered 6B-maltrexamide on an antinociceptive, intravenous description, taken with reference to the accompanying draw dose of hydrocodone. ings, in which: 0065 FIG. 8B is a dose response curve reflecting the 0051 FIG. 1A is a graph that shows data reflecting the potency of the inhibitive effects of orally-administered duration of the inhibitory effects of intravenously-adminis 6B-maltrexamide on an antinociceptive, intravenous dose of tered 6B-maltrexol on an antinociceptive, intravenous dose of hydrocodone. hydrocodone, and demonstrates the time of peak effect of 0.066 FIG. 9 is a graph that shows data reflecting the antinociception inhibition. potency of the inhibitive effects of various concentrations of 0052 FIG. 1B is a graph that shows data reflecting the orally-administered 6B-maltrexamide on an orally-co-admin duration of the inhibitive effects of orally-administered istered, antinociceptive dose of hydrocodone. 6B-maltrexol on an antinociceptive, intravenous dose of 0067 FIG. 10A is a dose response curve reflecting the hydrocodone, and demonstrates the time of peak effect of potency of intravenously-administered 6B-maltrexamide to antinociception inhibition. reverse hydrocodone-induced GI transit slowing, where the 0053 FIG. 2A is a dose response curve reflecting the two compounds are not co-administered. potency of the inhibitive effects of intravenously-adminis 0068 FIG. 10B is a dose response curve reflecting the tered 6B-maltrexol on an antinociceptive, intravenous dose of potency of orally-administered 6f-naltrexamide to reverse hydrocodone. hydrocodone-induced GI transit slowing, where the two com 0054 FIG. 2B is a dose response curve reflecting the pounds are not co-administered. potency of the inhibitive effects of orally-administered 0069 FIG. 11A shows the summarized potency data for 6B-maltrexol on an antinociceptive, intravenous dose of inhibition of hydrocodone activity by 6 B-maltrexamide in GI hydrocodone. transit studies (peripheral effects) and antinociception studies 0055 FIG. 3 is a graph that shows data reflecting the (central effects), where both 6f-naltrexamide and hydroc potency of the inhibitive effects of various concentrations of odone were administered intravenously at different times. US 2009/011 1844 A1 Apr. 30, 2009

0070 FIG. 11B shows the summarized potency data for I0083 6?-naltrexol is a naltrexone analog with the follow inhibition of hydrocodone activity by 6.3-maltrexamide in the ing structure: GI transit studies (peripheral effects) and antinociception studies (central effects), where 6f-naltrexamide was admin istered orally and hydrocodone was administered intrave nously at different times. 0071 FIG. 12A is a graph that shows data reflecting the duration of the inhibitive effects of intravenously-adminis tered naltrexone on an antinociceptive, intravenous dose of hydrocodone, and demonstrates the time of peak effect of antinociception inhibition. 0072 FIG. 12B is a graph that shows data reflecting the duration of the inhibitive effects of orally-administered nal trexone on an antinociceptive, intravenous dose of hydroc 6B-Naltrexol odone, and demonstrates the time of peak effect of antinoci I0084 6f-naltrexamide is a naltrexone analog with the fol ception inhibition. lowing structure: 0073 FIG. 13A is a dose response curve reflecting the potency of the inhibitive effects of intravenously-adminis tered naltrexone on an antinociceptive, intravenous dose of hydrocodone. 0074 FIG. 13B is a dose response curve reflecting the potency of the inhibitive effects of orally-administered naltr exone on an antinociceptive, intravenous dose of hydroc odone. 0075 FIG. 14 is a graph that shows data reflecting the potency of the antinociception-inhibitive effects of various concentrations of orally-administered naltrexone on an HO NHCOCH orally-co-administered, antinociceptive dose of hydroc 6B-Naltrexamide odone. 0076 FIG. 15A is a dose response curve reflecting the I0085 Compounds 6,3-Naltrexol and 6(3-Naltrexamide potency of intravenously-administered naltrexone to reverse may be represented by the generic formula If, where the hydrocodone-induced GI transit slowing. Stereocenter at position 6 is indicated by an asterisk. 0077 FIG. 15B is a dose response curve reflecting the potency of orally-administered naltrexone to reverse hydro codone-induced GI transit slowing. (IB) 0078 FIG. 16 is a dose response curve reflecting the potency of naltrexone to reverse hydrocodone-induced GI transit slowing when the two compounds are orally co-ad ministered. 0079 FIG. 17A shows the summarized potency data for inhibition of the effects of intravenously-administered hydro codone by intravenously-administered naltrexone in the GI transit studies (peripheral effects) and antinociception studies s' (central effects). Ow 0080 FIG. 17B shows the summarized potency data for inhibition of the effects of intravenously-administered hydro I0086. The alpha isomers of 6-Naltrexoland 6-Naltrexam codone by orally-administered naltrexone in the GI transit ide may be represented by the generic formula IC.: studies (peripheral effects) and antinociception studies (cen tral effects). 0081 FIG. 17C shows the summarized potency data for (IC) inhibition of the effects of hydrocodone by naltrexone in the GI transit studies (peripheral effects) and antinociception studies (central effects) where both compounds are orally co-administered.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS 0082 Definitions. As used in this description and the accompanying claims, the following terms shall have the meanings indicated, unless the context otherwise requires: US 2009/011 1844 A1 Apr. 30, 2009

I0087. For generic formulae IC. and IB, when X" and X’ are of the Lopioid receptor resulting in reducing adverse effects the same, the stereocenter at this position, marked by an associated with current pain management such as diarrhea asterisk, goes away. and constipation and without significantly inhibiting the cen I0088. “IDso value” refers to a dose which inhibits activity tral effects such as pain relief. by 50%. 0096. The neutral antagonist compositions of this inven I0089) “A blood half-life substantially longer than the tion can be administered in vivo, for example, a human, oran blood half-life of the opioid agonist as used herein means a animal. Alternatively, a neutral antagonist can also be admin blood half-life that is in the order of 2-fold greater, or more, as istered orally, transdermally, or parenterally Such as by injec measured at t=60 min than that for the opioid agonist. tion, implantation (e.g., Subcutaneously, intramuscularly, 0090 “A dose” refers to the dose, for example of an intraperitoneally, intracranially, and intradermally), adminis opioid agonist, which produces 90% analgesic activity. tration to mucosal membranes (e.g., intranasally, intravagi 0091 Pharmaceutically acceptable salts of the naltrexone nally, intrapulmonary, buccally or by means of a Supposi and naloxone analogs, which are neutral antagonists at the L tory), or in situ delivery (e.g., by enema or aerosol spray) to opioid receptor, include salts derived from an appropriate provide the desired dosage of naltrexone or naloxone analog base, such as an alkali metal (for example, sodium, potas to modulate undesirable effects of narcotic analgesic (Such sium), an alkaline earth metal (for example, calcium, magne constipation, nausea, vomiting) in the treatment of pain or sium), ammonium and NX." (wherein X is C-C alkyl). anesthesia, in an individual in need thereof. Pharmaceutically acceptable salts of an amino group include 0097. “Neutral antagonists’ as that term is used herein, salts of organic carboxylic acids such as acetic, lactic, tar refers to agents that block the effects of an agonist at the target taric, malic, lactobionic, fumaric, and Succinic acids; organic receptor, but do not significantly affect the level of spontane Sulfonic acids such as methanesulfonic, ethanesulfonic, ous activity present at the target receptor. “Neutral antagonist isethionic, benzenesulfonic and p-toluenesulfonic acids; and attheuopioid receptor as that term is used herein refers to an inorganic acids Such as hydrochloric, hydrobromic, Sulfuric, agent which can bind selectively to the resting, drug-sensitive phosphoric and Sulfamic acids. L opioid receptor state, to the constitutively active L opioid 0092. In enantiomeric forms, compounds of the invention receptor State, or to both, blocking the effects of an agonist at include individual enantiomers of the compounds in single the receptor, but not significantly effecting the level of spon species form Substantially free of the corresponding enanti taneous activity present at the receptor. omer, as well as in admixture (in mixtures of enantiomeric 0098. The naloxone and naltrexone analogs represented pairs and/or in mixtures of multiple enantiomer species). by the structures presented herein can be synthesized using 0093. Opiates are a class of centrally acting compounds standard synthetic procedures Such as those described in and are frequently used agents for pain control. Opiates are March J. Advanced Organic Chemistry, 3rd Ed. (1985), narcotic agonistic analgesics and are drugs derived from employing, for example, naltrexone or naloxone as the start opium, Such as morphine, codeine, and many synthetic con ing material. geners of morphine, with morphine being the most widely 0099 Many of the analogs of naltrexone and naloxone used derivative. Opioids are natural and synthetic drugs with which possess neutral antagonist activity at the L opioid morphine-like actions and include the opiates. Opioids are receptor, for example, the analogs wherein the 6-keto func narcotic agonistic analgesics which produce drug depen tionality has been reduced to an —OH functionality, are dence of the morphine type and are Subject to control under known compounds, and their syntheses have been described, federal narcotics law because of their addicting properties. for example, by Chatterjie et al., J. Med. Chem., 18, pp. 0094. The chemical classes of opioids with morphine-like 490-492 (1975) and Jiang et al., J. Med. Chem. 20, pp. activity are the purified alkaloids of opium consisting of 1100-1102 (1977), incorporated by reference herein. When phenanthrenes and benzylisoquinolines, semi-synthetic modification of the naltrexone or naloxone at the 6-keto posi derivatives of morphine, phenylpiperidine derivatives, mor tion results in an additional chiral carbon in the analog, the B phinan derivatives, benzomorphan derivatives, diphenyl-hep orientation at the newly formed chiral carbon is preferred tane derivatives, and propionanilide derivatives. The princi over the C. orientation, although the latter may be also appro pal phenanthrenes are morphine, codeine, and thebaine. The priate in certain applications. This preference is based upon principal benzoisoquinolines are papaverine, a Smooth the probably slower conversion of the B analogs back to muscle relaxant, and noscapine. Semi-synthetic derivatives naloxone or naltrexone. Further, if desired, conversion of the of morphine include diacetylmorphine (heroin), hydromor maltrexone or naloxone analog can be blocked by any Suitable phone, oxymorphone, hydrocodone, apomorphine, etorpine, inhibitory agent. For example, in the case of 6f or 6O.-naloxol and oxycodone. Phenylpiperidine derivatives include meperi or naltrexol, conversion of the –OH at the 6 position back to dine and its congeners diphenoxylate and loperamide, the keto functionality of the naloxone or naltrexone can be alphaprodine, anilleridine hydrochloride or phosphate, and inhibited with alcohol dehydrogenase inhibitors, such as piminodine esylate. Morphinan derivatives include levorpha 4-methylpyrazole (Plapp, B.V., “Control of Alcohol Metabo nol. The diphenyl-heptane derivatives include methadone and lism, pp. 311-322 in Towards a Molecular Basis of Alcohol its congeners, and propoxyphene. Propionanilide derivatives Use and Abuse, eds. Janssenet al., Birkhaeuser Verlag, 1994). include fentanyl citrate and its congeners Sufentanil citrate Further, the replacement of the 6-keto functionality with, for and alfenatil hydrochloride. example, an amine or amide resulting in 6C.- and 6B-maltrex 0095. As used herein, a “therapeutically effective amount amine and naltrexamide is likely to undergo much slower, if refers to the amount of the naltrexone or naloxone analog or any, conversion to naltrexone. Sustained release composition having the naltrexone or 0100 Other examples of potential neutral antagonists naloxone analog incorporated therein, needed to elicit the include the C-6-H reduced analogue of naltrexol (access to desired biological response following administration. The the CNS++), whose molecular formula is CHNO and desired biological response herein can be sufficient blockade whose IUPAC name is 17-(cyclopropylmethyl)4.5-epoxy-3, US 2009/011 1844 A1 Apr. 30, 2009

14-dihydroxymorphinan but for the purposes of this applica during which a therapeutically significant amount of the tion is referred to as 6-deoxynaltrexone. Still other possibili naloxone or naltrexone analog, or the opioid agonist, would ties for neutral antagonists, based on the naloxone or be available following direct administration of a solution of maltrexone core formulas, can be envisioned, or may be iden the analog. The period of Sustained release can be, for tified, and are considered to fall within the scope of the example, about one day, about two days, about seven days, invention and encompassed by the claims. For example, the about ten days to one month, or more, as needed to attain the C-6 position could be modified in other ways, whether by desired results. A Sustained release of a naltrexone or nalox replacement of the keto group with halogens, alkyl- and one analog of the invention from a Sustained release compo alkoxyl groups, alkylamine groups, vinyl groups, secondary sition, or of an opioid agonist in a co-formulation with a and tertiary amine groups, among others, or by modification neutral antagonist from a Sustained release composition, may at other sites, or in other ways, that retain the neutral antago be a continuous or a discontinuous release, with relatively nist activity at the LL receptor. constant or varying rates of release. The continuity of release 0101 This definition of neutral antagonist also encom and level of release can be affected by the type of polymer passes compounds that are not based on the naltrexone or composition used (e.g., monomer ratios, molecular weight, naloxone core formulas, but may represent a new type of and varying combinations of polymers), agent loading, and/ compound that still possesses the properties associated with a or selection of excipients to produce the desired effect. neutral antagonist of the LL receptor. 0107 The polymers of the sustained release compositions 0102 Thus, while the concept of neutral antagonist has described herein are biocompatible. Suitable biocompatible been particularly shown and described with references to polymers, can be either biodegradable or non-biodegradable preferred embodiments thereof, it will be understood by those polymers or blends or copolymers thereof, as described skilled in the art that various changes inform and details to the herein. neutral antagonist core formulas, or to the development of 0.108 Suitable biocompatible polymers, can be either bio completely unrelated core formulas for neutral antagonists, degradable or non-biodegradable polymers or blends or may be made therein without departing from the scope of the copolymers thereof, as described herein. A polymer is bio invention encompassed by the appended claims. compatible if the polymer and any degradation products of 0103) The term “sustained release composition” as the polymer are non-toxic to the recipient and also possess no defined herein, can comprise a biocompatible polymer having significant deleterious or untoward effects on the recipient's incorporated therein at least one naloxone or naltrexone ana body, such as an immunological reaction at the injection site. log which is a neutral antagonist at the L opioid receptor. 0109 “Biodegradable', as defined herein, means the com Suitable biocompatible polymers, can be either biodegrad position will degrade or erode in vivo to form smaller chemi able or non-biodegradable polymers or blends or copolymers cal species. Degradation can result, for example, by enzy thereof, as described herein. matic, chemical and physical processes. Suitable 0104. The sustained release compositions of the present biocompatible, biodegradable polymers include, for inventions may comprise a neutral antagonist formulated example, poly(lactides), poly(glycolides), poly(lactide-co alone or together with an opioid agonist in a slow-release glycolides), poly(lactic acid)S. poly(glycolic acid)S. polycar co-formulation. In such co-formulations, the neutral antago bonates, polyesteramides, polyanhydrides, poly(amino nist may be provided with an opioid agonist wherein only the acids), polyorthoesters, poly(dioxanone)S. poly(alkylene neutral antagonist is provided in a slow-release form. In other alkylate)S. copolymers or polyethylene glycol and poly co-formulations with a neutral antagonist and an opioid ago orthoester, biodegradable polyurethane, blends thereof, and nist, only the opioid agonist is provided in the co-formulation copolymers thereof. in a slow-release form. And in still other co-formulations with 0110 Suitable biocompatible, non-biodegradable poly a neutral antagonist and an opioid agonist, both the neutral mers include non-biodegradable polymers selected from the antagonist and the opioid agonist are formulated as slow group consisting of polyacrylates, polymers of ethylene-vi release agents. nyl acetates and other acyl Substituted cellulose acetates, 0105. The sustained release compositions of this invention non-degradable polyurethanes, polystyrenes, polyvinylchlo can beformed into many shapes such as a film, a pellet, a rod, ride, polyvinyl fluoride, poly(vinylimidazole), chlorosulpho a filament, a cylinder, a disc, a wafer or a microparticle. A nate polyolefin, polyethylene oxide, blends thereof, and microparticle is preferred. A “microparticle' as defined copolymers thereof. herein, comprises a polymer component having a diameter of 0111. Acceptable molecular weights for polymers used in less than about one millimeter and having a naltrexone or this invention can be determined by a person of ordinary skill naloxone analog which is a neutral antagonist at the L opioid in the art taking into consideration factors such as the desired receptor dispersed therein. A microparticle can have a spheri polymer degradation rate, physical properties such as cal, non-spherical or irregular shape. Typically, the micropar mechanical strength, and rate of dissolution of polymer in ticle will be of a size suitable for injection. A preferred size Solvent. Typically, an acceptable range of molecular weight is range for microparticles is from about one to about 180 of about 2,000 Daltons to about 2,000,000 Daltons. microns in diameter. 0112. In a particular embodiment, the polymer is biode 0106. As defined herein, a sustained release of a naltrex gradable polymer or copolymer. In a more preferred embodi one or naloxone analog of the present invention is a release of ment, the polymer is a poly(lactide-co-glycolide) (hereinafter the agent from a Sustained release composition. As explained “PLG'). The PLG can have a lactide:glycolide ratio, for above, a Sustained release of a neutral antagonist with an example, of about 10:90, 25:75, 50:50, 75:25 or 90:10 and a opioid agonist may be release of the antagonist, or release of molecular weight of about 5,000 Daltons to about 70,000 the agonist, or release of both the neutral antagonist and the Daltons. opioid agonist from a Sustained release composition. The 0113. It is understood that when the naltrexone or nalox release occurs over a period which is longer than that period one analog, which is a neutral antagonist at the L opioid US 2009/011 1844 A1 Apr. 30, 2009 receptor, or when the opioid agonist, separately or in a co 0119. In this method, a mixture comprising a biologically formulation with a neutral antagonist, is incorporated into a active agent, a biocompatible polymer and a polymer Solvent biocompatible polymer for Sustained release of the analog is processed to create droplets, wherein at least a significant and/or agonist, the Sustained release composition can include portion of the droplets contains polymer, polymer solvent and additional components which can stabilize the analog and/or the active. These droplets are then frozen by a suitable means. modify the release profile of the naltrexone or naloxone ana Examples of means for processing the mixture to form drop log from the Sustained release composition. That is, the nal lets include directing the dispersion through an ultrasonic trexone or naloxone analog, or opioid agonist, of the Sus nozzle, pressure nozzle, Rayleigh jet, or by other known tained release composition can be stabilized against loss of means for creating droplets from a solution. potency and/or loss of activity, all of which can occur during I0120 Means suitable for freezing droplets include direct formation of the Sustained release composition having the ing the droplets into or near a liquified gas, such as liquid maltrexone or naloxone analog and/or opioid agonist dis argon or liquid nitrogen to form frozen microdroplets which persed therein, and/or prior to and during in Vivo release of the are then separated from the liquid gas. The frozen microdrop analog and/or agonist. In addition, the period of release of the lets are then exposed to a liquid or Solid non-solvent, such as maltrexone or naloxone analog, and/or the opioid agonist, can ethanol, hexane, ethanol mixed with hexane, heptane, ethanol be prolonged. mixed with heptane, pentane or oil. 0114. A suitable excipient or a specific combination of I0121 The solvent in the frozen microdroplets is extracted excipients can be employed in the Sustained release compo as a solid and/or liquid into the non-solvent to form a poly sition. "Excipient’, as that term is used herein, is any agent mer/active agent matrix comprising a biocompatible polymer which binds or interacts in a covalent or non-covalent manner and a biologically active agent. Mixing ethanol with other or is included with the naloxone or naltrexone analog in the non-solvents. Such as hexane, heptane or pentane, can Sustained release composition. increase the rate of solvent extraction, above that achieved by 0115 Suitable excipients include, for example, carbohy ethanol alone, from certain polymers, such as poly(lactide drates, amino acids, fatty acids, Surfactants, and bulking co-glycolide) polymers. agents, and are known to those skilled in the art. An acidic or 0122. A wide range of sizes of Sustained release compo a basic excipient is also Suitable. The amount of excipient sitions can be made by varying the droplet size, for example, used is based on ratio to the naltrexone or naloxone analog, on by changing the ultrasonic nozzle diameter. If the Sustained a weight basis. For amino acids, fatty acids and carbohy release composition is in the form of microparticles, and very drates, such as Sucrose, trehalose, lactose, mannitol, dextran large microparticles are desired, the microparticles can be and heparin, the ratio of carbohydrate to analog, is typically extruded, for example, through a syringe directly into the cold between about 1:10 and about 20:1. For surfactants the ratio liquid. Increasing the Viscosity of the polymer Solution can of surfactant to analog is typically between about 1:1000 and also increase microparticle size. The size of the micropar about 2:1. Bulking agents typically comprise inert materials. ticles which can be produced by this process ranges, for Suitable bulking agents are known to those skilled in the art. example, from greater than about 1000 to about 1 microme 0116. The excipient can also be a metal cation component ters in diameter. which acts to modulate the release of the naltrexone or nalox I0123 Yet another method of forming a sustained release one analog. A metal cation component used in modulating composition, from a suspension comprising a biocompatible release typically comprises at least one type of multivalent polymerand a biologically active agent, includes film casting, metal cation. Examples of metal cation components suitable Such as in a mold, to form a film or a shape. For instance, after to modulate release include or contain, for example, Mg(OH) putting the Suspension into a mold, the polymer solvent is , MgCO (such as 4MgCO.Mg(OH).5H2O), MgSO, then removed by means known in the art, or the temperature Zn(OAc), Mg(OAc), ZnCO (such as 3Zn(OH)2.2ZnCO), of the polymer Suspension is reduced, until a film or shape, ZnSO, ZnCl2, MgCl, CaCO, Zn(CHO) and Mgs with a consistent dry weight, is obtained. (CHO). A suitable ratio of metal cation component to 0.124. A further example of a conventional microencapsu polymer is between about 1:99 to about 1:2 by weight. The lation process and microparticles produced thereby is dis optimum ratio depends upon the polymer and the metal cation closed in U.S. Pat. No. 3,737,337, incorporated by reference component utilized. A polymer matrix containing a dispersed herein in its entirety, wherein a solution of a wall or shell metal cation component to modulate the release of a an agent forming polymeric material in a solvent is prepared. The from the polymer matrix is further described in U.S. Pat. No. solvent is only partially miscible in water. A solid or core 5,656.297 to Bernstein et al. the teachings of which are incor material is dissolved or dispersed in the polymer-containing porated herein by reference in their entirety. mixture and, thereafter, the core material-containing mixture 0117. A number of methods are known by which sustained is dispersed in an aqueous liquid that is immiscible in the release compositions (polymer/active agent matrices) can be organic solvent in order to remove solvent from the micro formed. In many of these processes, the material to be encap particles. Sulated is dispersed in a solvent containing a wall forming 0.125. Another example of a process in which solvent is material. At a single stage of the process, Solvent is removed removed from microparticles containing a Substance is dis from the microparticles and thereafter the microparticle prod closed in U.S. Pat. No. 3,523,906, incorporated herein by uct is obtained. reference in its entirety. In this process a material to be encap 0118 Methods for forming a composition for the sus Sulated is emulsified in a solution of a polymeric material in a tained release of biologically active agent are described in solvent that is immiscible in water and then the emulsion is U.S. Pat. No. 5,019,400, issued to Gombotzet al., and issued emulsified in an aqueous solution containing a hydrophilic U.S. Pat. No. 5,922,253 issued to Herbert et al. the teachings colloid. Solvent removal from the microparticles is then of which are incorporated herein by reference in their entirety. accomplished by evaporation and the product is obtained. US 2009/011 1844 A1 Apr. 30, 2009

0126. In still another process as shown in U.S. Pat. No. X., Hruby V. J., Porreca F. (2000 April) “Antinociceptive 3.691,090, incorporated herein by reference in its entirety, activity of beta-methyl-2',6'-dimethyltyrosine(1)-substi organic solvent is evaporated from a dispersion of micropar tuted cyclic D-Pen (2), D-Pen(5) Enkephalin and D-Ala(2), ticles in an aqueous medium, preferably under reduced pres Asp(4) Deltorphin analogs.JPharmacol Exp. Ther; 293(1): SUC. 151-8; Raehal K. M., Lowery J. J., Bhamidipati C. M., 0127. Similarly, the disclosure of U.S. Pat. No. 3,891,570, Paolino R. M., Blair J. R., Wang D. Sadee W., Bilsky E. J. incorporated herein by reference in its entirety, shows a (2005 June: Epub 2005 Feb. 16) “In vivo characterization of method in which solvent from a dispersion of microparticles 6.beta-naltrexol, an opioid ligand with less inverse agonist in a polyhydric alcohol medium is evaporated from the micro activity compared with naltrexone and naloxone in opioid particles by the application of heator by Subjecting the micro dependent mice. J Pharmacol Exp Ther 313(3): 1150-62). particles to reduced pressure. Male ICR mice (UNE) or CD-1 mice (Charles River) 25-40 0128. Another example of a solvent removal process is grams were used in all procedures. Mice were weighed and shown in U.S. Pat. No. 3,960,757, incorporated herein by the tails marked with indelible ink, with an in size of 8-10 reference in its entirety. mice/group. The latency to the first sign of a rapid tail-flick 0129. Tice et al., in U.S. Pat. No. 4.389.330, describe the was used as the behavioral endpoint (Jannsen et al., 1963). preparation of microparticles containing an active agent by a Briefly, each mouse was tested for baseline latency by method comprising: (a) dissolving or dispersing an active immersing the distal third of its tail into the water bath and agent in a solvent and dissolving a wall forming material in recording the time until a vigorous tail-flick response to the that solvent; (b) dispersing the Solvent containing the active noxious stimulus. Latencies typically averaged between 1.5 agent and wall forming material in a continuous-phase pro and 2.5 S in drug naive subjects with any mice having a cessing medium; (c) evaporatingaportion of the solvent from baseline latency greater than 5 s eliminated from further the dispersion of step (b), thereby forming microparticles testing. Upon completion of baseline testing mice were containing the active agent in the Suspension; and (d) extract injected and retested for tail-flick latencies at various times ing the remainder of the solvent from the microparticles. after injection (typically 10, 20, 30, 45, 60,90, 120 and 180 0130. Further suitable methods of preparation are minutes or until the test latency approaches the baseline described in U.S. Pat. No. 6,194,006 to Lyons et al., U.S. Pat. latency, e.g., less than 20% MPE for the group.). A maximal Nos. 6,110,503, 5,916,598 and 5,792.477 to Rickey et al. and score was assigned to mice not responding within 10 S to 5,650,173 to Ramstacket al. the entire content of all of which avoid tissue damage. The percentage of antinociception was is hereby incorporated by reference. calculated as (test latency-baseline latency)/(10-baseline 0131 While this invention has been particularly shown latency)* 100. and described with references to preferred embodiments I0134) Antinociception Studies for Determining Time of thereof, it will be understood by those skilled in the art that Peak Effect of 6 B-maltrexol. various changes in form and details may be made therein 0.135 The duration of 6f-naltrexol effects was measured without departing from the scope of the invention encom by pretreating mice with 6B-maltrexol at various times prior to passed by the appended claims. an injection of an antinociceptive Aso dose of hydrocodone Effect of 6f-Naltrexol on Hydrocodone-Induced Antinocice (3.2 mg/kg, i.v. dose determined previously; data not shown). ption Mice were tested 10 min later at the time of peak effect for hydrocodone in the tail-flickassay. 6(3-maltrexol doses of 0.56 0132 Previous work confirms that 6B-maltrexol antago mg/kg fori.V. administration (FIG. 1A) and 5.6 mg/kg for p.o. nizes the central effects of opioids. For example, research by Wang D, Raehal K M, Bilsky E. J. Sadee W. (2001 June) administration (FIG. 1B) were used. “Inverse agonists and neutral antagonists at mu opioid recep 0.136 These time ranging experiments illustrated that tor (MOR): possible role of basal receptor signaling in nar 6.3-maltrexol was capable of reversing the centrally mediated cotic dependence. J Neurochem., 77(6):1590-600 showed antinociceptive effects of hydrocodone (FIGS. 1A and 1B). that 6B-maltrexol reverses morphine-induced antinociception with a time of peak effect at 90 min for i.v. administration and when administered intraperitoneally. Other experiments have 120 min when administered p.o. further shown that 6f-naltrexol prevents the stereotypic cir 0.137 Antinociception Studies for Determining Antago cling induced by morphine in non-dependent and chronically nist Potencies. dependent mice (Wang D. Raehal K. M., Lin E.T., Lowery J. 0.138. Both oral and i.v. potencies were determined by J., Kieffer B. L., Bilsky E.J., Sadee W. (2004 February Epub administering vehicle or various doses of 6B-maltrexol at 2003 Nov. 4) “Basal signaling activity of mu opioid receptor appropriate times prior to an Ago dose of hydrocodone (3.2 in mouse brain: role in narcotic dependence. J Pharmacol mg/kg, i.v.). The respective i.v. and p.o. pretreatment times Exp Ther; 308(2): 512-20; Raehal K. M., Lowery J. J., Bha were 90 min (FIG. 2A) and 120 min (FIG. 2B). Mice were midipati C.M., Paolino R. M., Blair J. R. Wang D., Sadee W. tested 10 min post hydrocodone injection (time of hydroc Bilsky E.J. (2005 June: Epub 2005 Feb. 16) “In vivo charac odone peak effect) in the 55° C. tail-flickassay. At least three terization of 6B-maltrexol, an opioid ligand with less inverse doses were tested to produce a dose-response curve. The agonist activity compared with naltrexone and naloxone in percent antinociception was then calculated for each dose and opioid-dependent mice. J Pharmacol Exp. Ther compared to hydrocodone controls. 313(3):1150-62). 0.139. These dose response curves were used to determine Experimental Data Demonstrates that 6f-Naltrexol Reverses IDso value for 6 B-maltrexol. The percentage of inhibition or Hydrocodone-Induced Antinociception. reversal of the hydrocodone-induced antinociception was cal culated as (test-hydrocodone control)/(Saline control-hydro Example 1 codone control)* 100. From this data an IDso value (and 95% 0.133 Tail-Flick Assay. Antinociception was assessed confidence interval) was calculated for each route using linear using a 55°C. warm-water tail-flickassay (Bilsky E. J., Qian regression (FlashCalc software; Dr. Michael Ossipov, Uni US 2009/011 1844 A1 Apr. 30, 2009

versity of Arizona, Tucson, Ariz.). IDso values for 6B-maltr constructed for the antagonist. At least three doses were used exol inhibition of hydrocodone-induced antinociception were for each route and the results were compared to Saline and determined to be 0.222 mg/kg (95% CI=0.194-0.253) for i.v. hydrocodone controls. administration, and 2.35 mg/kg (95% CI-2.11-2.63) for oral 0145 IDso values were calculated for 6.f3-maltrexol to administration, consistent with this compound's 14% bio determine potency to inhibit hydrocodone effects. 6(3-maltr availability in the rodent (previously determined data not exoland hydrocodone were administered at appropriate times shown). so that time of peak effect (as determined in the tail-flick 0140 Antinociception Studies for Oral Co-Administra assay) occurred during charcoal administration. 6B-maltrexol tion. The tail-flick assay was used to construct full dose- and dose-dependently reversed the inhibition of GI transit by time-response Summaries for 63-maltrexol in combination hydrocodone (Ago dose, i.v.), yielding IDso values of 0.0443 with hydrocodone. Vehicle or various doses of 6f-naltrexol mg/kg (95% CI=0.0275-0.0713) and 0.410 (95% CI=0.310 were orally co-administered with an Ago dose of hydrocodone 0.543) mg/kg for i.v. and p.o. (FIGS. 4A and 4B) administra (32 mg/kg, p.o.) determined previously (data not shown) at tion, respectively. t=0 min. Tail-flick latencies were determined at t=10, 20, 30, 0146 GI Transit Studies for Oral Co-Administration. 45, 60,90, 120 and 180 minutes post injection (or until 20% Vehicle (saline) or various doses of 6f-naltrexol were orally MPE was reached) and % antinociception was calculated for co-administered with an antinociceptive Ago dose of hydroc each mouse (FIG. 3). odone (32 mg/kg, p.o.) 60 min prior to charcoal administra tion (FIG. 5). This time was chosen so that the time of peak 0141. The antinociception experiments shown in FIG. 3 effect for the antagonist would occur during intestinal transit yield an IDs value of 12.3 mg/kg (95% CI=10.4-14.7) for of the charcoal meal. Vehicle (saline) controls were also 6.3-maltrexol co-administered with hydrocodone. assessed p.o. to compare the observed effects to opioid naive 0142. The experiments shown in FIGS. 1-3 demonstrate mice. The percentage of GI transit was calculated for each that 63-maltrexol blocks hydrocodone-induced antinocicep mouse and a dose-response curve was constructed. At least tion regardless of the route of administration. three doses were used and the results were compared to Saline and hydrocodone controls. 6B-maltrexol again dose-depen Effect of 6f-Naltrexol on Hydrocodone-Induced Gas dently reversed GI inhibition (FIG. 5) with an IDs of 1.290 trointestinal Tract Slowing mg/kg (95% CI=0.990-1.68). 0147 Statistical Analysis. The dose-response curves Example 2 shown in FIG. 2-5 were used to estimate and compare central (antinociception) to peripheral (GI transit) potencies of 0143 GI Transit Assay. Opioid-induced GI inhibition was 6.3-maltrexol. The percentage of inhibition or reversal of the measured using a standard protocol (Current Protocols in hydrocodone effect in either assay was determined for each Pharmacology, number 5.3). Male CD-1 mice (Charles mouse in the antagonist groups. The percent reversal was River) 25-40 grams are used in all procedures. Mice are calculated as (test-hydrocodone control)/(Saline control-hy weighed and the tails marked with indelible ink, with an in size drocodone control)*100. From this data an IDs value (and of 8-10 mice/group. Mice were deprived of food for approxi 95% confidence interval) was calculated for each routefan mately 18 hr prior to the start of the experiment. 6 B-maltrexol tagonist/assay using linear regression (FlashCalc software; or saline was injected at 1 ml/100 g bodyweight (route and Dr. Michael Ossipov, University of Arizona, Tucson, Ariz.). pretreatment time vary) prior to an oral delivery of a charcoal suspension (constant volume of 250 uL). At t=0 minutes, the Potency of 6f-Naltrexol for Slowing GI-Transit and for oral charcoal is delivered using an 18 gauge curved gavage Reversing Antinociception. needle (Popper & Sons) on a 1 cc syringe. The Suspension is made the day of use at 10% charcoal (100-400 mesh) with 0148 Comparison of the calculated potencies (IDs) for 2.5% arabic acid in distilled water and mixed thoroughly and 6.3-maltrexol to reverse either the central effects, antinocice repeatedly to minimize needle obstruction. Animals were ption, or peripheral effects, GI-transit slowing, induced by sacrificed 30 min after administration of the charcoal meal by hydrocodone, led to the Surprising discovery that 6B-maltr light ether anesthesia followed by cervical dislocation. The exol is 5-10-fold more potent peripherally than centrally. Small intestine (duodenum to cecum) was dissected out and FIGS. 6A-C demonstrate this potency difference showing carefully uncoiled. The distance covered by the charcoal was data derived from the dose response curves described above. measured and compared to the total length of the Small intes 0149 6?-naltrexol was found to have significant shifts in tine for each animal. The mean percent transit was then cal potency between the two assays for all administration param culated as (distance covered by the charcoal)/(total length of eters (FIGS. 6A-C). Both i.v. (FIG. 6A) and p.o. (FIG. 6B) the small intestine)*100. administration of 6f-naltrexol were approximately 5-times 0144 GI Transit Studies for Determining 6.f3-Naltrexol more potent at reversing GI effects of i.v. hydrocodone than Potency. The ability of 6f-naltrexol to block hydrocodone antinociceptive effects (Table 1). Furthermore, oral co-ad induced GI inhibition was assessed. Both i.v. (FIG. 4A) and ministration with hydrocodone resulted in a 9.53-fold shift in oral potencies (FIG. 4B) were determined by administering potency (FIG. 6C, Table 1). These data suggest that 6f-nal vehicle or various doses of 6f-naltrexol prior to an antinoci trexol is more potent at inhibiting peripheral effects than ceptive Ago dose of hydrocodone (3.2 mg/kg, i.v.). The pre central effects induced by opioids. treatment times corresponded with the time of peak effect for I0150 Calculations of IDso potencies from these data fur the antinociception studies. The charcoal meal was given 10 ther suggest that 6f-naltrexol is 9.5-fold more potent for min following the injection of hydrocodone. Vehicle (saline) slowing GI-transit than for reversing antinociception when controls were also assessed i.v. The percentage of GI transit both drugs are administered orally, as would be utilized for was calculated for each mouse and a dose-response curve was therapeutic use (Table 1). US 2009/011 1844 A1 Apr. 30, 2009

0151. These results indicate that there is a therapeutic E., Brine D. R, Perez-Reyes M. (1981) “Metabolism and window of effectiveness for 6 B-maltrexol where peripheral Disposition of Naltrexone in Man after Oral and Intravenous side effects of opioid use are reduced without inhibition of Administration, Drug Metabolism and Disposition Drug analgesia. In the case of orally co-administered 6B-maltrexol Metabolism and Disposition, 9(4):369-375; Verebey K. and hydrocodone, that therapeutic window occurs when (1980) “The Clinical Pharmacology of Naltrexone: Pharma 6.3-maltrexol is administered to a mouse from 0.1-3.0 mg/kg cology and Pharmacodynamics. Naltrexone: NIDA (FIG. 6C). Research Monograph, 28, RE Willette and G Barnett, eds. pp 147-158: Wall M. E., Brine D. R., Perez-Reyes M. (1980) TABLE 1. “The Metabolism of Naltrexone in Man, Naltrexone: NIDA Research Monograph, 28, RE Willette and G Barnett, eds. pp The fold-shift in peripheral vs. central potency was calculated from the data presented in FIG. 6A-C and is shown in Table 1 as 105-131; Perez-Reyes M. and Wall M. E. (1980) “A Com (antinociception IDso)/(GI transit IDso). (A fold-shift less than parative Study of the Oral, Intravenous, and Subcutaneous 1.0 indicates a greater central potency over peripheral potency. Administration f3 h-Naltrexone to normal male volunteers.” Naltrexone: NIDA Research Monograph 28, RE Willette and Antinociception Drug GI Transit IDso IDs (95% CI) Fold G Barnett, eds. pp. 93-101), meaning humans are exposed to Combination (95% CI) (mg/kg) (mg/kg) Shift 20 mg of 6f-naltrexol following such a dose. Given that human dosages are determined for a standard 70 kg person, 6B-maltrexol 0.0443 (0.0275-0.0713) 0.222 (0.194-0.253) S.O1 persons are routinely exposed to >0.3 mg 63-maltrexol/kg (i.v.). Hydrocodone body weight daily and often much higher dosages and blood (i.v.) levels are utilized. As such, there is evidence that this treat 6B-maltrexol 0.410 (0.310-0.543) 2.35 (2.11-2.63) 5.73 ment level is safe in humans (for examples, see: Dunbar J. L., (p.o.) Hydrocodone Turncliff R. Z., Dong Q. Silverman B. L. Ehrich E. W., (i.v.) Lasseter K. C. (2006) “Single- and Multiple-Dose Pharma 6B-maltrexol 1.290 (0.990-1.68) 12.3 (10.4-147) 9.53 cokinetics of Long-acting Injectable Naltrexone. Alcohol: (p.o.), Clin and Exper Res. 30(3):48.0-490; Jayaram-Lindstrom N., Hydrocodone Wennberg P. Beck O. Franck J. (2005) “An open clinical trial (p.o.) of naltrexone for amphetamine dependence: Compliance and tolerability.” Nord J Pschy 59(3):167-171; Brewer C. and 0152 This therapeutic window is surprising because it Wong V. S. (2004) “Case Report. Naltrexone: report of lack of diverges dramatically from the ratios postulated by Simon in hepatotoxicity in acute viral hepatitis, with a review of the United States Patent Application 2004/0024006A1. Our data literature.” Addict Bio 9, 81-87). also demonstrate that use of the dosages postulated by Simon Substantially Longer Retention of 6?-Naltrexol and 6 B-Nal (see United States Patent Application 2004/0024006 A1 at trexamide in Plasma and Brain Tissue after i.p Injection in paragraphs 107 and 155) would either have no effect (in Mice Compared to Naltrexone. the case of paragraph 107) or have the unwanted effect of reversing antinociception (in the case of paragraph 155). Example 3 0153. The mouse data can be extrapolated to provide for 0155 This study shows crude pharmacokinetics of effective formulation for humans. The 0.1-3.0 mg/kg mouse 6B-maltrexoland 6b-naltrexamide in mouse plasma and brain suggests a Human Equivalent Dose (HED) of 0.0081-0.243 (the naltrexol data were published in Wang et al. 2004; the mg/kg. This calculation is based on a body Surface area cal maltrexamide data were not published) compared with naltr culation published in FDA guidelines for Estimating the Safe exone. Mice were injected i.p. with 1 mg/kg naltrexone, 1 Starting Dose in Clinical Trials for Therapeutics in Adult mg/kg 63-maltrexol. 1 mg/kg 6B-maltrexamide, 10 mg/kg Healthy Volunteers, available on Aug. 16, 2007 at www.fda. 6.3-maltrexol or 10 mg/kg 6f-naltrexamide and sacrificed gov/cber/gdlins/dose.htm. If this dose is applied to a 70 kilo after 10 or 60 min. Blood samples and whole brain were human, the human subject would need between 0.567-17.0 collected. Samples were analyzed for the presence of the mg to have the desired effect of relieving GI transit slowing antagonists using mass spectrometry. without inhibiting analgesia. A person skilled in the art could 0156 Naltrexone, 6.3-maltrexol and 6.3-maltrexamide were predict and conduct clinical testing to confirm similar phar extracted from plasma or braintissue homogenates, measured macokinetics in humans and determine the absolute correct by liquid chromatography/mass spectrometry/mass spec dosage. trometry (LC/MS/MS), using APCI/positive ionization. Nal 0154 It should be noted that the concentrations required to buphine served as the internal standard. The method was reverse the antinociceptive effects of hydrocodone are con sensitive to ~1 ng/mL (g) (3-4 nM). 6(3-Naltrexol was detect sistent with the human blood levels of 6f-maltrexol obtained able in plasma but not brain tissue after the naltrexone dose after standard naltrexone treatment for alcohol or opioid (1.9 ng/mL and 1.7 ng/mL after 10 and 60 min, respectively). addiction maintenance where blocking the central effect is In contrast, no naltrexone was detectable after administration intended. Typically, a minimum dose of 50 mg naltrexone is of 6B-maltrexol. The concentrations of two compounds in administered daily to a human patient. The human must be each row of the table represent the injected parent drug only. opioid-free so there are no compounding effects on GI slow Mean+SD, n=3. ing or drug interactions altering pharmacokinetics or absorp 0157. As shown, similar brain levels were achieved with tion. The literature teaches that approximately 43% of naltr equipotent doses of naltrexone and 6B-maltrexol or 6B-maltr exone is converted to 6B-maltrexol (for examples, see: Cone, examide (1 mg/kg and 10 mg/kg, respectively). Surprisingly, E. J. Gorodetzky C. W. and Yea SY (1974) “The Urinary after 60 min, the levels of 6f-naltrexol and 6.3-maltrexamide Excretion Profile of Naltrexone and Metabolites in Man.” had not changed from those measured at 10 min, whereas the Drug Metab and Disp2(6): 506-512: ReViaTMLabel; Wall M. levels of naltrexone declined nearly 90% by 60 min. This US 2009/011 1844 A1 Apr. 30, 2009 indicates a Substantially longer retention in plasma and par ing higher than prescribed doses of the co-formulation pre ticularly in brain for 6.f3-maltrexol and 6.3-maltrexamide than vents addiction and deters abuse because at higher or multiple for naltrexone. These data can be extrapolated to suggest a doses, the neutral antagonist begins to accumulate and then substantially longer half-life for 6 B-maltrexol and 6.3-maltr competes with the effects of the opioid, lessoning the pain examide than that of opioid agonists such as naltrexone, in relief, or, if the formulation is taken for pleasure, the euphoria. general. In humans the half-life of naltrexone is 4 hours, while 0.161. In cases where the co-formulation is injected as a that of 6f-naltrexol is ~15 hours. Importantly, both 6f-naltr form of abuse, the higher bioavailability of the antagonist exoland 6.3-maltrexamide are much more effectively retained administered directly to the bloodstream will allow antago in the brain, Suggesting a much longer effective duration of nism of the central effects at lower doses. As with oral admin action compared to naltrexone in mice, while immediate istration, the effects will become more profound over time as access is considerably less. Opioid agonist half lives in levels of the antagonist continue to accumulate through humans are typically shorter, ~2-6 hours. repeated dosing due to the limited half-life of the opioid. Yet, because 63-maltrexol is a neutral antagonist, these effects will TABLE 2 manifest without, or with Substantially less, precipitating withdrawal, providing an effective means for preventing mis Concentrations of naltrexone, 63naltrexol and 63-maltrexamide use. See Sadee and Simon. in plasma and brain tissue after i.p. iniection in mice. Plasma concentration Brain concentration Effect of 6f-Naltrexamide on Hydrocodone-Induced Anti (ng/ml) (ng/g) nociception Time after injection Time after injection min min Example 4 Injection 10 60 10 60 0162 Tail Flick Assay. The tail-flick assay was used to Naltrexone, 1 mg/kg 54 - 16 4 + 1 69 - 20 9 - 1 measure antinociception as described above under Example 63-Naltrexol, 1 mg/kg 617 2428 7 6 9 - 1 1. 6B-Naltrexol, 10 mg/kg 857 - 122 7S 25 89 6 74 - 14 0163 Antinociception Studies for Determining Time of 63-Naltrexamide, 1 mg/kg 115 - 2 18 - 1 6 - 1 4 + 1 Peak Effect of 6?-Naltrexamide. The duration of 6f-maltrexa 6B-Naltrexamide, 10 mg/kg 933 + 221 166 it 77 27 6 24 1 mide effects were measured by pretreating mice with 6f-nal trexamide at various times prior to an injection of an antinoci ceptive Ao dose of hydrocodone (3.2 mg/kg, i.V., dose 6(3-Naltrexol--Opioid as a Co-Formulated Product determined previously; data not shown). Mice were then 0158. The results in Table 1 and Table 2 indicate that a tested 10 min later, at time of peak effect for hydrocodone, in co-formulated product containing a specified dose of hydro the tail-flickassay. 6.3-maltrexamide doses of 10 mg/kg (FIG. codone and 6.3-maltrexol can be created that will effectively 7A) and 56 mg/kg (FIG. 7B) were used for i.v. and p.o. treat moderate to severe pain with limited peripheral side administration, respectively. effects Such as, but not limited to, constipation, and may 0164. These time ranging experiments illustrated that possibly also reduce nausea and Vomiting. The pain relief 6B-maltrexamide was capable of reversing the centrally medi would be similar to treatment with hydrocodone alone while ated antinociceptive effects of hydrocodone (FIGS. 7A and the peripheral side effects would be much reduced. 7B), with a time of peak effect at 120 min for i.v. administra 0159 Moreover, this co-formulation will confer abuse tion and 120-180 min when administered p.o. resistance because the central effects of the opioid will be 0.165 Antinociception Studies for Determining Antago antagonized by the 63-maltrexol when doses exceeding those nist Potencies. Both oral and i.v. potencies were determined prescribed are taken by any route of administration, including by administering vehicle or various doses of 6B-maltrexamide if the tablet is manipulated, crushed and injected or snorted. In at appropriate times prior to an Ago dose of hydrocodone (3.2 the case where doses exceeding those prescribed are taken mg/kg, i.v.). The respective i.v. (FIG. 8A) and p.o. (FIG. 8B) orally, the substantially longer half-life of 6f-naltrexol com pretreatment times were 120 min. Mice were tested 10 min pared to opioid will cause 6B-maltrexol to accumulate to doses post hydrocodone injection (time of hydrocodone peak that will sufficiently penetrate the CNS to antagonize cen effect) in the 55°C. tail-flickassay. At least three doses were trally-mediated opioid effects such as pain relief and eupho tested to produce a dose-response curve. The percent anti ria. This will be beneficial in cases of both accidental and nociception was then calculated for each dose and compared intentional overdose. Due to the substantially longer half-life to hydrocodone controls. of 6f-naltrexol compared to opioid agonists, the effects will 0166 These dose response curves were used to determine become more profound as doses are increased, thus prevent IDso value for 6 B-maltrexamide. The percentage of inhibition, ing this co-formulated product from oral or other abuse as is or reversal of the hydrocodone-induced antinociception, was now common for opioids. calculated as (test-hydrocodone control)/(Saline control-hy 0160. In other words, the substantially longer half-life for drocodone control)*100. From this data an IDs value (and the neutral antagonists than of the opioid agonists means the 95% confidence interval) was calculated for each route using neutral antagonist will accumulate. Dosage will therefore be linear regression (FlashCalc software; Dr. Michael Ossipov, determined such that when steady-state is achieved, there will University of Arizona, Tucson, Ariz.). IDso values for 6B-nal be relief of the GI side effects (including possibly nausea and trexamide inhibition of hydrocodone-induced antinocicep Vomiting) without impacting pain relief. The co-formulation tion were determined to be 4.06 mg/kg (95% CI=3.27-5.04) will be made, factoring in a calculation for regular dosing of for i.v. administration, and 27.4 (22.6-33.2) for oral adminis the opioid, such that the patient or subject will receive the tration. appropriate level of neutral antagonist to relieve GI side 0.167 Antinociception Studies for Oral Co-Administra effects, yet still allow the opioid agonist to relieve pain. Tak tion. The tail-flickassay was used to construct full dose- and US 2009/011 1844 A1 Apr. 30, 2009

time-response Summaries for 6B-maltrexamide in combina tral (antinociception) to peripheral (GI transit) potencies of tion with hydrocodone. Vehicle or various doses of antagonist 6.3-maltrexamide. The percentage of inhibition or reversal of were orally co-administered with an Ago dose of hydrocodone the hydrocodone effect in either assay was determined for (32 mg/kg, p.o.) determined previously (data not shown). each mouse in the 63-maltrexamide groups. The percent Tail-flick latencies were determined at t=10, 20, 30, 45, 60, reversal was calculated as (test-hydrocodone control)/(Saline 90, 120 and 180 minutes post injection (or until 20% MPE control-hydrocodone control)* 100. From this data an IDso was reached) and % antinociception was calculated for each value (and 95% confidence interval) was calculated for each mouse (FIG. 9). routefantagonist/assay using linear regression (FlashCalc 0168 The experiments shown in FIG. 7-9 demonstrate software; Dr. Michael Ossipov, University of Arizona, Tuc that 63-maltrexamide blocks hydrocodone-induced antinoci son, Ariz.). ception regardless of the route of administration, with a Potency of 6f-Naltrexamide for Slowing GI-Transit and for potency approximately 10-fold lower than that of 6f-naltr Reversing Antinociception. exol. 0.175 Comparison of the calculated potencies (ID50) for 6.3-maltrexamide to reverse either the central effects, antinoci Effect of 6B-Naltrexamide on Hydrocodone-Induced Gas ception, or peripheral effects, GI-transit slowing, induced by trointestinal Tract Slowing hydrocodone, led to the Surprising discovery that 6B-maltr examide is 14-25-fold more potent peripherally than cen Example 5 trally. FIGS. 11A and B demonstrate this potency difference 0169 GI Transit Assay. Opioid-induced GI transit inhibi showing data derived from the dose response curves tion was measured using standard protocols as described described above. 6 B-maltrexamide was found to have signifi above under Example 2. cant shifts in potency between the two assays for all injection 0170 GI Transit Studies for Determining 6 B-maltrexamide parameters.I.V. (FIG. 11A, Table 3) administration of 6f-nal potency. The ability of 6f-naltrexamide to block hydroc trexamide was approximately 23-times more potent at revers odone induced GI inhibition was assessed. Both i.v. (FIG. ing GI effects of i.v. hydrocodone than antinociceptive effects 10A) and oral potencies (FIG. 10B) were determined by while orally administered 6 B-maltrexamide demonstrated administering vehicle or various doses of 6B-maltrexamide 14-fold more potency for reversing GI effects compared to prior to an antinociceptive Ago dose of hydrocodone (3.2 antinociceptive effects (FIG. 11B, Table 3). These data Sug mg/kg, i.v.). The pretreatment times corresponded with the gest that 63-maltrexamide is significantly more potent at time of peak effect for the antinociception studies. The char inhibiting the peripheral effects than the central effects coal meal was given 10 min following the injection of hydro induced by opioids. Furthermore, oral co-administration with codone. Vehicle (saline) controls were also assessed i.v. The hydrocodone is expected to show a 10-25-fold and potentially percentage of GI transit was calculated for each mouse and a up to a 50-fold shift in potency as well. dose-response curve was constructed for the antagonist. At 0176 Thus, it is anticipated that 6f-naltrexamide will be least three doses were used for each route and the results were 10-25-fold, and potentially 50-fold, more potent for slowing compared to Saline and hydrocodone controls. GI-transit than for reversing antinociception when both drugs (0171 IDs values were calculated for 6 B-maltrexamide to are administered orally, so could be utilized for therapeutic determine potency to inhibit hydrocodone effects. 6(3-maltr use. The 6B-maltrexamide exhibited a much larger potency examide and hydrocodone were administered at appropriate shift than predicted from its chemical structure, Suggesting times so that time of peak effect (as determined in the tail that 6f-naltrexamide may be actively prevented from enter flick assay) occurred during charcoal administration. When ing, or is transported out of the CNS compared to 6f-naltr given i.v. (FIG. 10A) and p.o. (FIG. 10B) 6.3-maltrexamide exol, and thus may provide a larger therapeutic window than dose-dependently reversed the inhibition of GI transit by 6.3-maltrexol. hydrocodone (Aso dose, i.v.), yielding IDs values of 0.173 (95% CI=0.131-0.230) and 1.92 (95% CI=1.03-3.56) for i.v. TABLE 3 and p.o. administration, respectively. The fold-shift in peripheral vs. central potency was calculated and 0172 GI Transit Studies for Oral Co-Administration. is shown as (antinociception IDso)f(GI transit IDso). A fold-shift Vehicle (saline) or various doses of 6f-naltrexamide are less than 1.0 indicates a greater central potency over peripheral orally co-administered with an antinociceptive Aso dose of potency. hydrocodone (32 mg/kg, p.o.) 60 min prior to charcoal Antinociception administration. This time is chosen so that the time of peak GI Transit IDso IDso (95% Fold effect for the antagonist will occur during the intestinal transit Drug Combination (95% CI) (mg/kg) CI) (mg/kg) Shift of the charcoal meal. Vehicle (saline) controls are also 6B-maltrexamide (i.v.), 0.173 (0.131-0.230) 4.06 (3.27-5.04) 23.5 assessed p.o. to compare the observed effects to opioid naive Hydrocodone (i.v.) 63-maltrexamide (p.o.), 1.92 (1.03-3.56). 27.4 (22.6-33.2) 14.3 mice. The percentage of GI transit is calculated for each Hydrocodone (i.v.) mouse and a dose-response curve is constructed. At least 63-maltrexamide (p.o.), 1-2 3-5 10-50 three doses are used for each antagonist and the results are Hydrocodone (p.o.)* compared to Saline and hydrocodone controls. 0173 When given i.v. and p.o. 6 B-maltrexamide is *Predicted expected to dose-dependently reverse the inhibition of GI transit by hydrocodone and other analgesics with an IDs in Effect of Naltrexone, a Well-Known and Characterized the range of 0.1 to 0.2 mg/kg and 1 to 2 mg/kg for i.v. and p.o. Antagonist, on Hydrocodone-Induced Antinociception. administration, respectively. 0177 Experiments with naltrexone illustrate the signifi 0.174 Statistical Analysis. The dose-response curves cant differences between the compounds taught by this appli shown in FIG. 7-10 were used to estimate and compare cen cation and known, characterized antagonists. US 2009/011 1844 A1 Apr. 30, 2009

Example 6 0185. The experiments shown in FIG. 12-14 demonstrate that naltrexone blocks hydrocodone-induced antinociception 0.178 Tail Flick Assay. The tail-flick assay was used to regardless of the route of administration, consistent with the measure antinociception as described above under Example many published reports on naltrexone and its clinical use for 1 the treatment of alcoholism and opioid addiction. 0179 Antinociception Studies for Determining Time of Effect of Naltrexone on Hydrocodone-Induced Gastrointes Peak Effect of Naltrexone. The duration of naltrexone effects tinal Tract Slowing were measured by pretreating mice with naltrexone at various times prior to an injection of an antinociceptive Ago dose of Example 7 hydrocodone (3.2 mg/kg, i.V., dose determined previously; 0186 GI Transit Assay. Opioid-induced GI transit inhibi data not shown). Mice were tested 10 min later at time of peak tion was measured using standard protocols as described effect for hydrocodone in the tail-flick assay. Naltrexone above under Example 2. doses of 0.10 mg/kg for i.v. (FIG. 12A) and 0.56 mg/kg for 0187 GI Transit Studies for Determining Naltrexone p.o. (FIG. 12B) were used. Potency. The ability of naltrexone to block hydrocodone 0180. These time ranging experiments illustrate that nal induced GI inhibition was assessed. Both i.v. (FIG. 15A) and trexone was capable of reversing the centrally mediated anti oral potencies (FIG. 15B) were determined by administering nociceptive effects of hydrocodone (FIGS. 13A and 13B), vehicle or various doses of naltrexone prior to an antinocice with a time of peak effect at 30 min for i.v. administration and ptive Ago dose of hydrocodone (3.2 mg/kg, i.v.). The pretreat 45 min when administered p.o. ment times corresponded with the time of peak effect for the 0181 Antinociception Studies for Determining Antago antinociception studies. The charcoal meal was given 10 min nist Potencies. Both oral and i.v. potencies were determined following the injection of hydrocodone. Vehicle (saline) con by administering vehicle or various doses of naltrexone at trols were also assessed i.v. The percentage of GI transit was appropriate times prior to an Ago dose of hydrocodone (3.2 calculated for each mouse and a dose-response curve was mg/kg, i.v.). The respective i.v. (FIG. 13A) and p.o. (FIG. constructed. At least three doses were used for each route and 13B) pretreatment times were 30 and 45 min. Mice were the results were compared to Saline and hydrocodone con tested 10 min post hydrocodone injection (time of hydroc trols. odone peak effect) in the 55° C. tail-flickassay. At least three 0188 IDso values were calculated for naltrexone to deter doses were tested to produce a dose-response curve. The mine potency to inhibit hydrocodone effects. Naltrexone and percent antinociception was then calculated for each dose and hydrocodone were administered at appropriate times so that compared to hydrocodone controls. time of peak effect (as determined in the tail-flick assay) 0182. These dose response curves were used to determine occurred during charcoal administration. When given by i.v. IDso value for naltrexone in these experiments for compari (FIG. 15a) and p.o. (FIG. 15b) naltrexone dose-dependently son purposes. The percentage of inhibition or reversal of the reversed the inhibition of GI transit by hydrocodone (Aso hydrocodone-induced antinociception was calculated as dose, i.v.), yielding IDs values of 0.0456 (95% CI=0.0275 (test-hydrocodone control)/(Saline control-hydrocodone 0.0757) for i.v. and 0.194 (95% CI=0.136-0.277) for p.o. control)* 100. From this data an IDso value (and 95% confi administration, respectively. dence interval) was calculated for each route using linear (0189 GI Transit Studies for Oral Co-Administration. regression (FlashCalc software; Dr. Michael Ossipov, Uni Vehicle (saline) or various doses of naltrexone was orally versity of Arizona, Tucson, Ariz.). IDs values for naltrexone co-administered with an antinociceptive Ago dose of hydroc inhibition of hydrocodone-induced antinociception were odone (32 mg/kg, p.o.) 15 min prior to charcoal administra tion (FIG. 16). This time was chosen so that the time of peak determined to be 0.0411 (0.0319-0.0529) for i.v. administra effect for the antagonist would occur during the GI transit of tion, and 0.534 (0.47 1-0.605) for oral administration. These the charcoal meal. Vehicle (saline) controls were also values are consistent with published values for the oral bio assessed p.o. to compare the observed effects to opioid naive availability of naltrexone and with the published observation mice. The percentage of GI transit was calculated for each that 6f-naltrexol is approximately 5-10-fold less potent than mouse and a dose-response curve was constructed. At least maltrexone for reversing morphine-induced antinociception three doses were used for each antagonist and the results were (Wang D. Raehal K. M., Lin E.T., Lowery J.J., Kieffer B. L., compared to Saline and hydrocodone controls. Bilsky E. J., Sadee W. (2004 February Epub 2003 Nov. 4) 0.190 Naltrexone orally co-administered with hydroc “Basal signaling activity of mu opioid receptor in mouse odone (Ago dose, p.o.) again dose-dependently reversed GI brain: role in narcotic dependence. J Pharmacol Exp Ther: inhibition (FIG. 16) with an IDs of 1.40 mg/kg (95% CI =1. 308(2):512-20; Raehal K. M., Lowery J. J., Bhamidipati C. 07-184). M., Paolino R. M., Blair J. R., Wang D., Sadee W., Bilsky E. 0191 Statistical Analysis. The dose-response curves J. (2005 June: Epub 2005 Feb. 16), depending on route of shown in FIG. 13-16 were used to estimate and compare administration. central (antinociception) to peripheral (GI transit) potencies 0183 Antinociception Studies for Oral Co-Administra for naltrexone. The percentage of inhibition or reversal of the tion. The tail-flick assay was used to construct full dose- and hydrocodone effect in either assay was determined for each time-response Summaries for naltrexone in combination with mouse in the naltrexone groups. The percent reversal was hydrocodone. Vehicle or various doses of antagonist were calculated as (test-hydrocodone control)/(Saline control-hy orally co-administered with an Aso dose of hydrocodone (32 drocodone control)*100. From this data an IDs value (and mg/kg, p.o.) determined previously (data not shown). Tail 95% confidence interval) was calculated for each routefan flick latencies were determined att=10, 20, 30, 45, 60,90, 120 tagonist/assay using linear regression (FlashCalc software; and 180 minutes post injection (or until 20% MPE was reached) and % antinociception was calculated for each Dr. Michael Ossipov, University of Arizona, Tucson, Ariz.). mouse (FIG. 15). Potency of Naltrexone for Slowing GI-Transit and for 0184 The antinociception experiments shown in FIG. 14 Reversing Antinociception. yield an IDs value of 0.914 mg/kg (95% CI=3.27-5.04) for (0192 Comparison of the calculated potencies (IDs) for maltrexone co-administered with hydrocodone. maltrexone to reverse either the central effects, antinocicep US 2009/011 1844 A1 Apr. 30, 2009 tion, or peripheral effects, GI-transit slowing, demonstrated hydromorphone, hydroxypethidine, isomethadone, ketobe that naltrexone was nearly equipotent peripherally and cen midone, levorphanol, levophenacylmorphan, lofentanil, trally. FIG. 17A-B illustrate the potency differences showing meperidine, meptazinol, metazocine, methadone, metopon, data derived from the dose response curves described above. morphine, myrophine, narceline, nicomorphine, norlevorpha 0193 Naltrexone was found to have small or negligible nol, normethadone, noroxycodone, nalorphine, nalbuphene, shifts in potency between the two assays for all injection normorphine, norpipanone, opium, oxycodone, oxymor parameters. I.V. (FIG. 17A, Table 4) administration of naltr phone, papaveretum, pentazocine, phenadoxone, phenomor exone was approximately equipotent at reversing GI effects phan, phenazocine, phenoperidine, piminodine, piritramide, of i.v. hydrocodone than antinociceptive effects while orally propheptazine, promedol, properidine, propoxyphene, Sufen administered naltrexone demonstrated only a 3-fold differ ence in potency for reversing GI effects compared to antinoci tanil, tilidine and tramadol. ceptive effects (FIG. 17B, Table 4). Furthermore, oral co 3. A unit dosage of an analgesic composition according to administration with hydrocodone resulted in a 0.6-fold shift claim 2, wherein the Subject is a human. in potency, actually exhibiting more central than peripheral 4. A unit dosage of an analgesic composition according to potency (FIG. 17C, Table 4). These data suggest that naltrex claim 3, Such composition being Suitable for oral, peroral, one is nearly equipotent for inhibiting peripheral effects and intragastric, Sublingual, Suppository, or intravenous adminis central effects induced by opioids, consistent with its medici tration. nal use as a treatment for alcoholism and opioid addiction. 5. A unit dosage of an analgesic composition according to claim 4. Such composition being Suitable for a plurality of TABLE 4 Successive administrations, wherein the neutral opioid antagonist is selected from the group consisting of 6B-maltr The fold-shift in peripheral vs. central potency was calculated and is shown in Table 4 as (antinociception IDso), (GI transit IDso). A exol, a pharmaceutically acceptable isomorph thereof, and a fold-shift less than 1.0 indicates a greater central potency over pharmaceutically acceptable salt thereof, and wherein the peripheral potency. unit dosage for each Successive administration is calculated to Antinociception deliver a Sustained and/or cumulative dosage of approxi Drug GI Transit IDso IDs (95% CI) Fold mately 0.0008-0.24 mg per kg of body weight of the subject. Combination (95% CI) (mg/kg) (mg/kg) Shift 6. A unit dosage of an analgesic composition according to claim 4. Such composition being Suitable for a plurality of Naltrexone 0.0456 (0.0275-0.0757) 0.0411 (0.0319-0.0529) O.901 (i.v.). Successive administrations, wherein the neutral opioid Hydro antagonist is selected from the group consisting of 63-maltr codone examide, a pharmaceutically acceptable isomorph thereof, (i.v.) and a pharmaceutically acceptable salt there, and wherein the Naltrexone 0.194 (0.136-0.277) 0.534 (0.47 1-0.605) 2.75 (p.o.), unit dosage for each Successive administration is calculated to Hydro deliver a Sustained and/or cumulative dosage of approxi codone mately 0.002-0.8 mg per kg of body weight of the subject. (i.v.) 7. A unit dosage of an analgesic composition according to Naltrexone 1.40 (1.07-1.84) 0.914 (0.628–1.33) O.653 (p.o.), claim 5 or 6 wherein the opioid agonist is hydrocodone. Hydro 8. A unit dosage according to claim 4, wherein the neutral codone opioid antagonist has a blood half-life Substantially longer (p.o.) than the blood half-life of the opioid agonist, so that repeated administration of the dosage or administration above a pre 0194 These data illustrate the difference in activity scribed dosage causes a greater increase in blood concentra between known, clinically used antagonists and the novel tion of the antagonist than of the agonist, so as to deter activities of the neutral antagonists taught in this application. diversion, discourage abuse and/or reduce addiction liability 0.195 Moreover, a strong induction of diarrhea was to the agonist resulting from Such administration. present with administration of naltrexone, but was absent 9. A method for inhibiting peripheral effects of an opioid with naltrexol and naltrexamide. agonist while still permitting substantial central effects of the What is claimed is: opioid agonist in a Subject, the method comprising: 1. A unit dosage of an analgesic composition comprising: co-administering the opioid agonist with an effective an opioid agonist in an amount Sufficient to confer analge amount of a unit dosage of a neutral opioid antagonist sia in a mammalian Subject; and formulated according to claim 4 to a Subject in need a neutral opioid antagonist in an amount Sufficient to thereof. inhibit peripheral effects, and insufficient to block sub 10. A method according to claim 9, wherein the opioid stantial central effects, of the opioid agonist in the Sub agonist is hydrocodone. ject. 11. A method of reducing addiction liability in a subject 2. A unit dosage of analgesic composition according to being administered an opioid agonist, the method compris claim 1, wherein the opioid agonist is selected from the group ing: consisting of alfentanil, allylprodine, alphaprodine, anilleri co-administering the opioid agonist with an effective dine, benzylmorphine, bezitramide, buprenorphine, butor amount of a unit dosage of a neutral opioid antagonist phanol, clonitaZene, codeine, desomorphine, dextromora formulated according to claim 8 to a Subject in need mide, dezocine, diampromide, diamorphone, thereof. dihydrocodeine, dihydromorphine, dimenoxadol, dimephep 12. A method according to claim 9 or 11, wherein the tanol, dimethylthiambutene, dioxaphetyl butyrate, dipi opioid agonist and unit dosage are administered orally, per panone, eptazocine, ethoheptazine, ethylmethylthiambutene, orally, intragastrically, Sublingually, by Suppository, or intra ethylmorphine, etonitaZene, fentanyl, heroin, hydrocodone, venously. US 2009/011 1844 A1 Apr. 30, 2009 16

13. A method according to claim 11, wherein the opioid or are formulated in a slow-release formulation or co-formu agonist is hydrocodone. lation, either separately or together. 14. A pharmaceutical formulation that deters diversion of 21. A pharmaceutical composition according to claim 14, an opioid agonist, the formulation comprising: wherein the neutral opioid antagonist and/or agonist are Suit an amount of opioid agonist Sufficient to induce a euphoric able for formulation in a slow-release formulation, slow release co-formulation, or are formulated in a slow-release state or Sufficient to relieve pain upon ingestion or formulation or co-formulation, either separately or together. administration, the opioid agonist having a blood half 22. A method according to any of claims 9, 11, 15, or 16, life; and wherein the neutral opioid antagonist and/or agonist are Suit an effective amount of a neutral opioid antagonist with a able for formulation in a slow-release formulation, slow ratio fixed relative to that of the opioid agonist, the release co-formulation, or are formulated in a slow-release neutral antagonist having a blood half-life Substantially formulation or co-formulation, either separately or together. longer than the blood half-life of the opioid agonist, 23. A unit dosage of an analgesic composition, wherein the wherein upon Successive administration, the blood con opioid agonist is hydrocodone, such composition being Suit centration ratio of neutral opioid antagonist to opioid able for a plurality of successive administrations, wherein the agonist increases with each Successive administration neutral opioid antagonist is selected from the group consist until a steady state is reached, as measured in mg per kg ing of 6B-maltrexamide, a pharmaceutically acceptable iso of body weight of the subject, and such that repeated morph thereof, and a pharmaceutically acceptable salt there, administration of the formulation exceeding therapeuti and wherein the unit dosage for each Successive administra cally recommended limits results in reduced euphoria tion is calculated to deliver a Sustained and/or cumulative and reduced pain relief in the Subject upon Successive dosage of approximately 0.002-0.8 mg per kg of body weight administrations beyond therapeutically recommended of the Subject, and wherein the neutral opioid antagonist limits and so deters diversion. and/or agonist are suitable for formulation in a slow-release 15. A method for inhibiting peripheral effects of an opioid formulation, slow-release co-formulation, or are formulated agonist while still permitting substantial central effects of the in a slow-release formulation or co-formulation, either sepa opioid agonist in a Subject in need thereof, the method com rately or together. prising: 24. A unit dosage of an analgesic composition, wherein the co-administering to the Subject in need thereof the opioid opioid agonist is hydrocodone, such composition being Suit agonist with an effective amount of a unit dosage of a able for a plurality of successive administrations, wherein the neutral opioidantagonist, the effective amount sufficient neutral opioid antagonist is selected from the group consist to inhibit peripheral effects and insufficient to block ing of 6B-maltrexol, a pharmaceutically acceptable isomorph substantial central effects in the subject. thereof, and a pharmaceutically acceptable salt thereof, and 16. A method of deterring addiction in a subject being wherein the unit dosage for each Successive administration is calculated to deliver a Sustained and/or cumulative dosage of administered an opioid agonist, the method comprising: approximately 0.0008-0.24 mg per kg of body weight of the co-administering to the Subject the opioid agonist with an Subject, and wherein the neutral opioid antagonist and/or effective amount of a unit dosage of a neutral opioid agonist are Suitable for formulation in a slow-release formu antagonist, the effective amount Sufficient to reduce lation, slow-release co-formulation, or are formulated in a euphoria and reduce pain relief upon Successive admin slow-release formulation or co-formulation, either separately istrations beyond recommended therapeutic limits, or together. thereby deterring diversion. 25. A method according to claim 12, wherein the neutral 17. A method according to claim 15 or 16, wherein the opioid antagonist and/or agonist are Suitable for formulation opioid agonist is hydrocodone. in a slow-release formulation, slow-release co-formulation, 18. A method according to claim 17, wherein the opioid or are formulated in a slow-release formulation or co-formu antagonist is selected from the group consisting of 6B-maltr lation, either separately or together. exol, 6B-maltrexamide, 6B-naloxol. 6C.-naltrexol. 6C.-naloxol. 26. A method according to claim 17, wherein the neutral 6.C.-maltrexamine, 6B-maltrexamine, 6-deoxynaltrexone, and opioid antagonist and/or agonist are Suitable for formulation 6.C.-maltrexamide, pharmaceutically acceptable physical iso in a slow-release formulation, slow-release co-formulation, morphs thereof, and pharmaceutically acceptable salts or are formulated in a slow-release formulation or co-formu thereof. lation, either separately or together. 19. A method according to claim 18, wherein the opioid 27. A method according to claim 18, wherein the neutral agonist and unit dosage may be administered in a manner opioid antagonist and/or agonist are Suitable for formulation selected from the group consisting of orally, perorally, intra in a slow-release formulation, slow-release co-formulation, gastrically, Sublingually, by Suppository, intravenously and a or are formulated in a slow-release formulation or co-formu combination thereof, and wherein co-administration is over lation, either separately or together. lapping Such that administration may be of a single co-for 28. A method according to claim 19, wherein the neutral mulation comprising agonistandantagonist, or may be simul opioid antagonist and/or agonist are Suitable for formulation taneous or sequential administration of separate agonist and in a slow-release formulation, slow-release co-formulation, antagonist formulations. or are formulated in a slow-release formulation or co-formu 20. A unit dosage according to claim 5, wherein the neutral lation, either separately or together. opioid antagonist and/or agonist are Suitable for formulation in a slow-release formulation, slow-release co-formulation, c c c c c