US 20140221277A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0221277 A1 Menzaghi et al. (43) Pub. Date: Aug. 7, 2014

(54) METHOD FOR ELEVATING PROLACTIN IN tion No. 12/300,595, filed on Apr. 22, 2009, now Pat. MAMMALS No. 8,217,000, filed as application No. PCT/US2007/ 012285 on May 22, 2007. (71)71) Applicants:Applicants MStFrederi Le.g.,M hi, RVe, S. SterNY E.(US) ); (60) Provisional application No. 60/808,677, filed on May (US); Derek T. Chalmers, Riverside, CT 26, 2006. (US) Publication Classification (72) Inventors: Frederique Menzaghi, Rye, NY (US); (51) Int. Cl. Michael E. Lewis, West Chester, PA A638/07 (2006.01) (US); Derek T. Chalmers, Riverside, CT A6II 45/06 (2006.01) (US) (52) U.S. Cl. CPC ...... A61 K38/07 (2013.01); A61K 45/06 (73) Assignee: CARATHERAPEUTICS, INC., (2013.01) SHELTON, CT (US) USPC ...... 514/4.7: 514/7.3; 514/11.5 (21) Appl. No.: 14/087,142 (57) ABSTRACT Methods for elevating and stabilizing prolactin levels in a (22) Filed: Nov. 22, 2013 mammal including methods of treating disorders and condi tions associated with reduced serum levels of prolactin are O O provided. Also provided are methods of using certain Syn Related U.S. Application Data thetic tetrapeptide amides which are peripherally selective (63) Continuation of application No. 13/543,128, filed on kappa receptor agonists to elevate or stabilize serum Jul. 6, 2012, now abandoned, Continuation of applica prolactin levels. Patent Application Publication Aug. 7, 2014 Sheet 1 of 7 US 2014/0221277 A1

Figure 1: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 1 hour IV Infusion in Male Subjects (Part A)

O 2 A. 6, B 10 2 Time post-dose (h) Placebo (1-hour infusion) o 0.015 mg/kg CR665 (1-hour infusion) 0.03 mg/kg CR665 (1-hour infusion) (0.06 mg/kg. CR665 (1-hour infusion) 0.12 mg/kg CR665 (3-hour infusion) o 0.24 mg/kg. CR665 (1-hour infusion) to.36 mg/kg CR665 (1-hour infusion) 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (1-hour infusion)

Figure 2: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 1 hour IV Infusion in Female Subjects (Part A).

O 2 A 6 8 - to 2 Time post-dose (h)

Placebo (1-hour infusion) O 0.24 mg/kg CR665 (1-hour infusion) Patent Application Publication Aug. 7, 2014 Sheet 2 of 7 US 2014/0221277 A1

Figure 3: Arithmetic Mean Changes from Baseline (Pre dose) in Serum Prolactin Concentrations Following a 5 minute IV Infusion in Male Subjects (Part B)

Time post-dose (h)

Placebo (5-minute infusion)(Male o 0.03 mg/kg CR665 (5-minute infusion),Male 0.06 mg/kg CR665 (5-minute infusion)(Malel do.09 mg/kg CR665 (5-minute infusion) Male) 0.06 mg/kg CR665 (5-minute infusion) (Femalel

Figure 4: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV Infusion in Male Subjects (Part A) (Linear Scale)

o 2 4. 6 8 10 2 Time post-dose (h) 0.015 mg/kg CFR665 (i-hour infusion) O 0.03 mg/kg CR665 (1-hour infusion) is 0.06 mg/kg CR665 1-hour infusion) 0.12 mg/kg CR665 (1-hour infusion) 0.24 mg/kg CR565 (i-hour infusion) o 0.36 mg/kg CR665 (1-hour infusion) * 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (t-hour intusion) - - - Lower limit of quantification (1.00 mg/mL) Patent Application Publication Aug. 7, 2014 Sheet 3 of 7 US 2014/0221277 A1

Figure 5: Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV . Infusion in Male Subjects (Part A) (Semi logarithmic Scale) 110OO OOO

Time post-dose (h) 0.015 mg/kg CR665 (1-hour infusion) O 0.03 mg/kg CR665 (1-hour infusion) 0.06 mg/kg CR665 (1-hour infusion) 0.12 mg/kg CR665 (1-hour infusion) 0.24 mg/kg CR665 (1-hour infusion) 8 O.36 mg/kg CR665 (1-hour infusion) 0.42 mg/kg CR665 (1-hour infusion) * 0.48 mg/kg CR665 (I-hour infusion) - - - Lower limit of quantification (1.00 ng/ml)

Figure 6: Geometric Mean AUCo. for CR665 Versus Dose Level. Following a 1 hour IV Infusion in Male Subjects (Part A)

logarithmic Scale OOOO

OOO

0.05 0.03 0.06 0,12 0.24 0.369.48 Dose of CR665 (mg/kg) O4 Patent Application Publication Aug. 7, 2014 Sheet 4 of 7 US 2014/0221277 A1

Figure 7: Geometric Meari Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg CR665 in Female Subjects (Part A) (Linear Scale)

s S.

8 S U cus S 8 scretire"r-s-s-p-...-s:-...--si-...------...--- - -w------4. 6 8 O 12 Time post-dose (h)

0.24 mg/kg. Ca565 i-hour infusion) --- Lower limit of quantification (1.00 nglml)

Figure 8: Geometric Mean Plasma Concentrations of CR665 Following a hour IV Infusion of 0.24 mg/kg CR665 in Female Subjects (Part A) (Semi logarithmic Scale)

1OOO iScy loo - , 5t 100 5 10 i 1. sI l N l 1 tic-casses, lesses essess------als - r Time post-dose (h)

0.24 mg/kg CR665 (1-hour infusion) - - - Lower limit of quantification (1.00 ng/mL) Patent Application Publication Aug. 7, 2014 Sheet 5 of 7 US 2014/0221277 A1

Figure 9: Arithmetic Mean (SD) Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg CR665 in Male and Female Subjects (Part A) (Linear Scale)

so . Nm

sh9

SC d d

s s S V S

10 Time post-dose (h 0.24 mg/kg gR665 (1-hour infusion)(Male o 0.24 mg/kg CR665 (1-hour infusion) Female)

Figure 10: Geometric Mean Plasma Concentrations of CR665 Following a 5-minute IV Infusion in Male and Female Subjects (Part B) (Linear Scale)

o 2 4. 6 8 10 2 Time post-dose (h) 0.03 mg/kg CR665 (5-minute infusion)(Male) o 0.06 mg/kg CR665 (5-minute infusion),Male 0.09 mg/kg CR665 (5-minute infusion) Mae E.O.05 mg/kg CR665 (5-minute infusion)(Female - - - Lower limit of quantification (1.00 mg/ml) Patent Application Publication Aug. 7, 2014 Sheet 6 of 7 US 2014/0221277 A1

Figure 11: Geometric Mean Plasma Concentrations of CR665 Following a 5-minute IV infusion in Male and Female Subjects (Part B) (Semi logarithmic Scale) -

- t r -r 6 8 O 12 Time post-dose (h) 0.03 mg/kg CR665 (5-minute infusion)Male C 0.06 mg/kg CR665 (5-minute infusion)(Male) 0.09 mg/kg. CR665 (5-minute infusion) Male) 0.06 mg/kg CR665 (5-minute infusion)(Female) - - - lower lirit of quantification (1.00 ng/ml)

Figure 12: Geometric Mean AUCo. for CR665 Versus Dose Level Following a 5 minute IV Infusion in Male Subjects (Part B)

Logarithmic scale 1000

0.06 Dose of CR665 (mg/kg) Patent Application Publication Aug. 7, 2014 Sheet 7 of 7 US 2014/0221277 A1

Figure 13: Relationship Between AUCo-2, of Changes from Baseline in Serum Prolactin and AUCo. of CR665 over the 0.015 to 0.36 mg/kg Dose Range in Male Subjects (Part A)

200 a

0 250 so 75o 1OOO AUC(O-int) (ng.html) OF CR665 Correlation coefficient=0.667; P-value=0.0004

Figure 14: Relationship Between Cmax of Changes from Baseline in Serum Prolactin and Cmax of CR665 over the 0.015 to 0.36 mg/kg Dose Range in Male Subjects (Part A) 80

60

40 O

--- O 20 e e d

0. | ------O 100. 2O) 300 400 500 600 FOO 800 900 Cmax (ng/mL) OF CR665 Correlation coefficient=0.565; P-value=0.0040 US 2014/022 1277 A1 Aug. 7, 2014

METHOD FOR ELEVATING PROLACTN IN most current version of their guidance on breastfeeding, MAMMALS “Extensive research using improved epidemiologic methods and modern laboratory techniques documents diverse and CROSS-REFERENCE TO RELATED compelling advantages for infants, mothers, families, and APPLICATIONS Society from breastfeeding and use of human milk for infant feeding. These advantages include health, nutritional, immu 0001. This application claims priority to and incorporates nologic, developmental, psychologic, social, economic, and by reference herein U.S. Provisional Application Ser. No. environmental benefits.” Because of the well documented 60/808,677 filed May 26, 2006 and entitled “METHOD FOR benefits of breastfeeding, insufficient lactation is now viewed ELEVATING PROLACTIN IN MAMMALS as an important medical problem. 0007. There are numerous risk factors for insufficient lac BACKGROUND OF THE INVENTION tation, including: 0002 1. Field of the Invention 0008 (i) restarting lactation after termination, e.g., to care 0003. The invention relates to the use of peripherally for a sick infant (Thompson N Relactation in a newborn selective kappa agonists to elevate serum intensive care setting.J. Hum. Lact. 12: 233-235, 1996) levels of prolactin for the benefit of a mammal in need of such 0009 (ii) physical abnormality of the breast (Neifert MR elevation. et al. Lactation failure due to insufficient glandular develop 0004 2. Background ment of the breast. Pediatrics 76:823-828, 1985) 0005 Prolactin is a 198 amino acid polypeptide synthe 0010 (iii) absence of breast enlargement during preg sized in pituitary lactotrophs, which constitute about 20 per nancy (Moon J et al. Breast engorgement: contributing vari cent of adenohypophysial cells (for review, see Harrison's ables and variables amenable to nursing intervention. J. Principles of Internal Medicine, 16th Ed., p. 2084; also Free Obstet. Gynecol. Neonatal Nurs. 18:309-315, 1989). man ME et al. Prolactin: Structure, function, and regulation 0011 (iv) history of breast surgery (Widdice L The effects of secretion. Physiol. Rev. 80: 1523 1631, 2000). Prolactin is of breast reduction and breast augmentation Surgery on lac also referred to in the art as Galactin, Lactogen, Lactoropin, tation: An annotated bibliography. J. Hum. Lact. 9:161-163, LMTH. LTH, Luteomammotrophic Hormone, Luteotrophic 1993). Hormone, Luteotropin, and Mammotrophin, although these (0012 (v) first time delivery of infant (Dewey KG et al. names are now obsolete. The best studied effects of prolactin Risk factors for suboptimal infant breastfeeding behavior, are on the mammary gland, and include growth and develop delayed onset of lactation, and excess neonatal weight loss. ment of the mammary gland (mammogenesis), synthesis of Pediatrics 112:607-619, 2003). milk (lactogenesis), and maintenance of milk secretion (ga 0013 (vi) premature delivery of infant (Ehrenkranz, RA et lactopoiesis). The endocrine control of lactation involves al. Metoclopramide effect on faltering milk production by multiple complex physiological mechanisms since mammo mothers of premature infants. Pediatrics; 78:614 20, 1986: genesis, lactogenesis, galactopoiesis, and galactokinesis are Feher S D K et al. Increasing breast milk production for all essential for proper lactation. Prolactin is the key hormone premature infants with a relaxation/imagery audiotape. Pedi of lactation and is believed to be the single most important atrics 83:57-60, 1989) galactopoietic hormone. Oxytocin, serotonin, opioid pep 0014 (vii) delivery of more than one infant (Leonard, L. tides, histamine, Substance P, and other physiological Sub Breastfeeding higher order multiples: Enhancing Support stances modulate prolactin release by means of an autocrine/ during the postpartum hospitalization period. J. Hum. Lact. paracrine mechanism at the level of the hypothalamus, 18:386-392, 2002). whereas estrogen and progesterone hormones can act at the (0015 (viii) adoption of infant (Cheales Siebenaler, N. hypothalamic and adenohypophysial levels. Human placental Induced lactation in an adoptive mother. J. Hum. Lact. 15:41 lactogen and growth factors play an essential role in Success 43, 1999). ful lactation during pregnancy, with oxytocin functioning as a 0016 (ix) retention of placental fragments (Neifert, M Ret key galactokinetic hormone. al. Failure of lactogenesis associated with placental retention. 0006 Normal adult serum prolactin levels are about 1025 Am. J. Obstet. Gynecol. 140:477-478, 1981) ng/ml in women and 1020 ng/ml in men. Prolactin is secreted 0017 (x) use of hormonal birth control (Tankeyoon Met in an episodic manner with a distinct 24 hour pattern. Circu al. Effects of hormonal contraceptives on milk volume and lating prolactin levels are lowest at midday, and a modest infant growth. WHO Special Programme of Research, Devel increase occurs during the afternoon. Prolactin levels opment and Research Training in Human Reproduction Task increase shortly after onset of sleep, peaking in the early force on oral contraceptives. Contraception 30:505-22, 1984) morning. Serum prolactin levels rise Substantially during 0018 (xi) use of certain OTC decongestants (Aljazaf Ket pregnancy (150 200 ng/ml) and decline rapidly within two al. Pseudoephedrine: effects on milk production in women weeks of parturition. Breastfeeding will normally cause pro and estimation of infant exposure via breastmilk. Br. J. Clin. lactin levels to remain elevated, due to Suckling induced acti Pharmacol. 56:18-24, 2003) vation of neural reflexes that that induce prolactin release. 0019 (xii) cigarette smoking (Andersen A N et al: Sup However, inadequate activation of prolactin release will inter pressed prolactin but normal neurophysin levels in cigarette fere with breastfeeding, with a variety of potentially delete Smoking breast feeding women. Clin. Endocrinol. (Oxf.) rious psychological and physiological consequences, e.g., a 17:363-8, 1982. failure of mother infant bonding and a failure to transmit 0020 (xiii) prepregnant overweight and obesity (Hilson J maternal protective antibodies to the infant (American Acad A et al. High prepregnant body mass index is associated with emy of Pediatrics, Section on Breastfeeding. Breastfeeding poor lactation outcomes among white, rural women indepen and the use of human milk. Pediatrics 115: 496 506, 2005). dent of psychosocial and demographic correlates. J. Hum. According to the American Academy of Pediatrics, in this Lact. 20:18-29, 2004; Rasmussen K M et al. Prepregnant US 2014/022 1277 A1 Aug. 7, 2014

overweight and obesity diminish the prolactin response to quality and serum testosterone. Arch. Androl. 23:259-65. suckling in the first week postpartum. Pediatrics 113:465-71, 1989), a finding that is supported by the observation that 2004). pharmacological Suppression of prolactin release for several 0021 (xiv) Cesarean delivery (Chapman DJ et al. Identi weeks in young men decreased Subsequent hCG stimulated fication of risk factors for delayed onset of lactation. J. Am. testosterone secretion (Oseko F et al. Effects of chronic bro Diet. Assoc. 99:450-454, 1999) mocriptine induced hypoprolactinemia on plasma testoster 0022 (XV) insulin dependent maternal diabetes (Neu one responses to human chorionic gonadotropin stimulation bauer, SH et al. Delayed lactogenesis in women with insulin in normal men. Fertil. Steril. 55:355-357, 1991). Hypopro dependent diabetes mellitus. Am. J. Nutr. 58:54-60, 1993) lactinemia could also contribute to age related changes in 0023 (xvi) medications to treat labor pain (Riordan Jet al. physiological functions. Serum prolactin concentrations tend The effect of labor pain relief medication on neonatal suck to fall with age, e.g. in older men and estrogen unreplaced ling and breastfeeding duration.J. Hum. Lact. 16:7-12, 2000; postmenopausal women (Maddox P et al. Bioactive and Ransjo Arvidson AB et al. Maternal analgesia during labor immunoactive prolactin levels after TRH stimulation in the disturbs newborn behavior: effects on breastfeeding, tem sera of normal women. Horm. Metab. Res. 24:181-184, 1992; perature, and crying. Birth 28:5-12; 2001). Maddox Petal. Basal prolactin and total lactogenic hormone 0024 (xvii) stress (Chen DC et al. Stress during labor and levels by microbioassay and immunoassay in normal human delivery and early lactation performance. Am. J. Clin. Nutr. sera. Acta Endocrinol. (Copenh.) 125:621-627, 1991). 68:335-344, 1998; Dewey K. Maternal and fetal stress are Remarkably, a comparable quantitative reduction in prolactin associated with impaired lactogenesis in humans. J. Nutr. secretion occurs in critically ill individuals (Van den Berghe 131:3012 S-3015S, 2001) Get al. Thyrotropin and prolactin release in prolonged critical 0025 Signs of insufficient lactation in a human infant illness—dynamics of spontaneous secretion and effects of include: (1) insufficient weight gain in an infant who is receiv growth hormone secretagogues. Clin. Endocrinol. (Oxf.) ing food only by breast feeding, even if the infant appears 47:599–612, 1998) as well as in patients with poorly con content; (2) infant latching on poorly; (3) infant Sucking trolled type I diabetes mellitus (Iranmanesh A et al. Attenu inconsistently; (4) inconsistency of let down reflex, and (5) ated pulsatile release of prolactin in men with insulin depen evidence of hunger, indicated by crying Soon after feedings. dent diabetes mellitus. J. Clin. Endocrinol. Metab. 71:73-78, 0026. Lactation failure in humans is a common clinical 1990). Hypoprolactinemia is also reported to be a risk factor event with serious emotional sequelae. It has been considered for prolonged lymphopenia and apoptosis associated deple to be a significant problem in 5 to 10% of all lactations. In tion of lymphoid organs in nosocomial sepsis related death in many instances this leads to premature initiation of Supple critically ill children (Felmet K Aetal. Prolonged lymphope ments or total weaning. This is considered to be an inferior nia, lymphoid depletion, and hypoprolactinemia in children child rearing practice and may be harmful to certain infants with nosocomial sepsis and multiple organ failure. J. Immu with an increased risk of gastritis and other disorders. Many mol. 174:3765-72, 2005). The findings reviewed above indi affected women are severely emotionally distressed by their cate that prolactin deficiency may contribute to impaired tes perceived inadequacy, thus affecting the parent child bond. tosterone dependent functioning and age related changes as Failure to thrive in infants is not uncommon if the mother well as vulnerability to illness. refuses to Supplement. 0029. In addition to the apparent roles of prolactin dis 0027. There has therefore been a long need for a medica cussed above, there is evidence that prolactin is important for ment that can promote human lactation, e.g., when there is maintenance of rapid eye movement sleep (REM sleep), insufficient lactation after the birth of the child. For animal which is essential for normal brain function. After observing breeders, the inability of their livestock, e.g., mares, to pro that pregnancy associated sleep enhancement is correlated duce and secrete milk after giving birth can be a significant with the daily Surges of prolactin, investigators found that problem. Should the breeding animals not lactate properly, administration of prolactin to female rats significantly the offspring must then be bottle fed, which is time consum increased REM sleep (Zhang SQetal. Effects of prolactin on ing, labor intensive, and costly; thus, there is a need for a sleep in cyclic rats. Psychiatry Clin. Neurosci. 53:101-3, medicament to safely and effectively promote breeding ani 1999). Consistent with these findings, induction of experi mal lactation. For commercial milk producing animals like mental hypoprolactinemia in male rats was found to decrease cows and goats, there is an economic need to safely and REM sleep (Obál Jr Fetal. Antiserum to prolactin decreases effectively increase their milk production above a normal rapid eye movement sleep (REM sleep) in the male rat. level. Physiol. Behav. 52:1063-1068, 1992). These findings indi 0028. A number of causes of reductions in prolactin levels cate that subjects experiencing insufficient REM sleep could that are associated with insufficient lactation were noted benefit from elevations in prolactin. above. Certain of these causes are also associated with 0030 Based on the findings reviewed above, there is a reduced prolactin levels in non lacting Subjects, e.g., cigarette need for a medicament that can safely and effectively elevate Smoking (FuXe K et al. Neuroendocrine actions of nicotine prolactin level in a variety of subjects with functional hypo and of exposure to cigarette Smoke: medical implications. prolactinemia, particularly including females experiencing Psychoneuroendocrinology 14: 1.9-41, 1989). Other causes insufficient lactation, but also males experiencing insufficient oflow prolactin levels (hypoprolactinemia) include the use of testosterone related functions, and both females and males various therapeutic agents, such as L deprenyl for the treat who are suffering from the effects of severe illness, including ment of migraine (Fanciullacci Met al. Dopamine involve type I diabetes, or who are suffering the effects of insufficient ment in the migraine attack. Funct Neurol. 15 Suppl 3:17.1- REM sleep, e.g., due to insomnia. 81, 2000). Hypoprolactinemia of unknown origin has also 0031. The citation of any reference herein should not be been associated with poor sperm motility in adult men construed as an admission that Such reference is available as (Gonzales G F et al. Hypoprolactinemia as related to seminal “Prior Art” to the instant application. US 2014/022 1277 A1 Aug. 7, 2014

SUMMARY OF THE INVENTION 0043 b) poor infant weight gain in relation to age/length; 0032. In general, the invention provides methods for treat 0044 c) lack of breast engorgement/leaking if feeding is ing a Subject Suffering from insufficient or inadequate serum missed; prolactin, such as functional hypoprolactinemia and the dis 0045 d) baby is satisfied by supplemental feeding follow orders disclosed herein and known in the art associated with ing breast feeding: insufficient or inadequate serum prolactin, as well as methods 0046 e) milk secretion of less than 500 ml/day. for treating a subject in need of elevated or stabilized levels of 0047. These methods involve systemic administration of prolactin. In one embodiment, a method employs a peripher compositions that contain one or more compounds that exert ally selective kappa opioid receptor agonist compound, prolactin elevating, increasing or stabilizing activity via optionally in a pharmaceutically acceptable vehicle for local, kappa receptors, but that do not exhibit a severe or regional or systemic administration, said compound possess significant side effect, such as a CNS or diuretic effect at ing prolactin elevating, increasing or stabilizing activity, effective dosages. optionally administered without causing a severe or a clini 0048. In various embodiments, methods use compositions cally significant side effect, such as CNS effects or diuretic containing peripherally selective kappa opioid receptor ago effects. nists that do not, upon systemic administration, evoke severe 0033. In another embodiment, the invention features a or clinically significant diuresis or CNS effects, as defined method of treating functional hypoprolactinemia in a subject herein, particularly at the prolactin elevating dosage. Com with a formulation of a peripherally selective kappa opioid positions that contain a peripherally selective kappa opioid receptor agonist, optionally Suitable for incorporation into a receptor agonist together with other prolactin elevating com controlled drug delivery device. In a particular aspect, a con pounds are also provided. trolled drug delivery device is applied to the skin of a subject. 0049. Typically, compounds intended for use in the com In certain embodiments, a controlled drug delivery device is positions and methods herein possess prolactin elevating, applied to the skin of a subject and optionally further utilizes increasing or stabilizing activity and reduced or tolerable iontophoresis to increase transdermal drug delivery. CNS effects, as defined herein, because, without being bound 0034. In certain embodiments, a formulation is a solid or by any theory, they do not substantially cross the blood brain liquid or gel. barrier. A relative or complete absence of substantial crossing 0035. In certain embodiments, a formulation includes a of the blood brain barrier lessens the occurrence of CNS liquid carrier. systemic effects. Kappa opioid receptors agonists that readily 0036. In certain embodiments, a therapeutically effective cross the blood brain barrier could be effective as prolactin dose of a peripherally selective kappa opioid receptoragonist elevating agents, but permeability through the blood brain is selected to produce elevated, increased or stabilized serum barrier can result in severe or intolerable side effects, such as prolactin levels without producing severe or significant diure dysphoria and hallucinations. sis and/or a CNS side effect. 0050 Peripherally selective kappa opioid receptor ago 0037. In certain embodiments, a peripherally selective nists include kappa opioid receptor agonists that do not Sub kappa opioid receptor agonist produces pharmacologically stantially cross the blood brain barrier as assessed by assays insignificant or physiologically tolerable levels of said ago described herein or known in the art. The peripherally selec nist in the plasma of an infant consuming the breast milk from tive kappa opioid receptoragonists for use in the methods and or produced by a Subject treated with said agonist. compositions provided herein also include any compound 0038. In certain embodiments, the peripherally selective that by virtue of its interaction, either directly or indirectly, kappa opioid receptor agonist is selected to avoid producing with peripheral kappa opioid receptor receptors ameliorates a severe or a clinically significant side effect in an infant failure of lactation, or elevates, increases or stabilizes levels consuming the breast milk from or produced by a subject of serum prolactin, without exhibiting medically severe or treated with said agonist. significant CNS effects, such as dysphoria and hallucinations, 0039. In certain aspects, the invention features methods of at effective doses. elevating, increasing or stabilizing plasma levels of prolactin 0051. As used herein, the term “peripherally selective.” to a subject in need of elevated, increased or stabilized pro when used in reference to a "kappa opioid receptor agonist' lactin. In one embodiment, a method includes administration refers to a chemical compound having a reduced ability to of a therapeutically effective dose of a peripherally selective cross (traverse) the blood-brain barrier, or that exhibits little kappa opioid receptor agonist to the Subject. In another or substantially no crossing of the blood-brain barrier when embodiment, a method includes administration ofatherapeu not administered to the CNS (brain and spinal cord). As a tically effective dose of a peripherally selective kappa opioid consequence of a reduced ability or inability to cross receptor agonist to the Subject, in combination with a prolac (traverse) the blood-brain barrier, a peripherally selective tin elevating-increasing or stabilizing dose of a second com kappa opioid receptoragonist typically exhibits fewer or less pound selected from a D2 dopamine receptor antagonist, mu severe (minor or tolerable) side effects in the CNS, such as opioid receptor agonist, or prolactin. dysphoria, hallucinations, or sedation. 0040. In various embodiments a Subject is: a person, e.g., 0.052 Various measures of the ability of a compound to a human patient, in need of elevated prolactin levels. E.g., the cross (traverse) the blood-brain barrier are known in the art Subject can be: a person in need of stimulation of lactation or and can be used to measure the amount or rate (kinetics) of stabilization of lactation, e.g., a mother. blood-brain barrier crossing (traversal). One non-limiting 0041. The invention features methods for treatment and/or example is to compare the ability of a compound to elicit prevention of lactational failure, which can be diagnosed by peripheral effects versus the ability of the compound to elicit various criteria, including: central effects following treatment with a particular com 0042 a) baby is dissatisfied and irritable after breastfeed pound (e.g., kappa opioid receptor agonist). Peripheral 1ng effects can be measured using the mouse writhing test (WT) US 2014/022 1277 A1 Aug. 7, 2014

and central effects, due to action of kappa opioid receptors ria, hallucinations and sedation) when used clinically. located in the brain and spinal cord, can be measured using the Accordingly, compounds useful in the invention have BPI mouse tail-flick test (TF). values typically greater than 5, or more, for example, BPI 0053. In brief, the mouse writhing test (WT) test (de values of 10, 15, 20, 25, 30, 40, 45, 50, 60, 75, 100, 125, 150, scribed in Bentley et al., Br. J. Phamac., 73:325 (1981)) 175, 200, 225, 250, 275,300, 400, 500, 600, 700, 800, 900, employs conscious male ICR mice (available from Harlan) 1000, 1500, 2000, or more. weighing about 20 to 30 grams. Mice are fasted for about 12 0.058 Particular non-limiting compounds of the invention to 16 hours prior to the test and writhing is induced by intra are disclosed in U.S. Pat. No. 5,965,701, are sequences of peritoneal administration of dilute acetic acid (10 ml of 0.6% four D-isomer amino acid residues having a C-terminus aqueous acetic acid/kg body weight). Writhing is scored dur which is a mono ordi-Substituted amide. Representative com ing the 15 minutes following acetic acid administration. pounds, which have an affinity for the kappa opioid receptor Compounds (e.g., kappa opioid receptor agonists) are typi at least 1,000 times their affinity for the mu opioid receptor cally tested at 3 to 4 increasing doses, given by intravenous and an EDso of not greater than about 0.5 mg/kg, include route, and at a unique pretreatment time (e.g., -5 minutes H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D-Phe-D-Phe-D- before acetic acidinjection). This step is used to determine the Nle-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg potency (WT-EDs) as well as a submaximal effective dose NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr, H-D- (about 80-90% antinociception). In a second step, a submaxi Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, H-D-Phe-D- mal effective dose for each specific compound is adminis Phe-D-Nle-D-Arg-NEt, H-D-Phe-D-Phe-D-Nle-D-Arg tered at various pretreatment times (e.g., -5 minutes, -60 NHMe, H-D-Phe-D-Phe-D-Leu-D-Orn-morpholinyl, H-D- minutes, -120 minutes and -180 minutes) prior to the admin Phe-D-Phe-D-Nle-D-Arg-NHhEt, H-D-Phe-D-Phe-D-Nle istration of the acetic acid in order to determine the duration D-Arg-NH-cyclopropyl, H-D-Ala(2Thi)-D-4Cpa-D-Leu-D- of action. Throughout the test, a control group of mice are Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg used which are administered only the vehicle without the piperidinyl, H-D-Phe-D-Phe-D-Leu-D-Orn-NHEt, H-D- compound. The number of writhes are counted over a 15 Phe-D-Phe-D-Leu-D-Lys-morpholinyl, and H-D-Phe-D- minute period, starting from the time of acetic acid injection, Phe-D-Nle-D-Arg-piperazinyl. and bioactivity, i.e. antinociception, is expressed as a percent 0059 Peripherally selective kappa opioid receptor ago age, and is calculated as follows: nists of the invention can be , such as those contain 100x(writhes in control group-writhes in treated ing D-amino acids instead of L-amino acids, and which group), writhes in control group optionally can have little to no sequence homology with 0054 Because each submaximal dose likely varies so as known mammalian endogenous opioid peptides, e.g., the not to be directly comparable, results are normalized math , endorphins, and . A peripherally ematically, to provide comparable values. Values higher than selective kappa opioid receptor agonist can comprise a tet 100% indicate greater antinociception than at the beginning rapeptide D-amino acid sequence. Peptides that are encom of the study. Compounds effective at reducing writhing by at passed by the criteria of the invention are any of the known least about 25% at a time of 1 hour are considered to have long mammalian endogenous opioid peptides, e.g., as identified in duration of in vivo action. Akil et al (1984), such as A(1-17), including natu 0055. In addition to using the writhing test to determine rally occurring, processed forms of these peptides, e.g., duration of antinociceptive activity, it is also used to measure (1-13) and dynorphin A (1-8). the in vivo biopotency (short term) of the . This value 0060. The invention, among other things, relates to the use is represented as WT-EDso in milligrams per kg of body of peripherally selective kappa opioid receptoragonists alone weight, a measure of the dosage necessary to reduce the or in conjunction with lactational enhancers, elevators, or number of writhes in the mouse being tested by 50% (as stabilizers for the treatment of lactation failure, or inadequate compared to a control mouse) over a period of 15 minutes. or insufficient lactation in a Subject. 0056. The tail-flick test (TF) is an assay of acute somatic 0061 The invention also relates to the use of peripherally pain, designed to evaluate potency and duration of action of selective kappa opioid agonists, alone or in conjunction with centrally acting (described, for example, in Van lactational enhancers elevators, or stabilizers for the manu derah, et al., J. Pharm. Exper. Therapeutics, 262:190 (1992)). facture of a medicament in treatment of lactation failure or Nociception induced by tail-dip into hot water (52°C.) results inadequate or insufficient lactation in a subject. in a rapid tail withdrawal, or a “tail-flick. Centrally acting 0062 Lactational enhancers, elevators, or stabilizers can compounds are expected to increase, in a dose-related man be chosen from among D2 dopamine receptor antagonists, ner, the latency for tail withdrawal. mu opioid receptor agonists, prolactin, or oxytocin, for 0057. “Brain Penetration Index” (BPI) can be used to pro example. vide a numerical representation of whethera compound func 0063. The invention further relates to a method for the tions centrally or peripherally. BPI is defined as: BPI-TF treatment of lactation failure, or inadequate or insufficient EDs/WT-EDs; where the EDso values are the doses that lactation in a Subject, characterized in that a peripherally produce half maximal effect in the mouse writhing test (WT selective kappa opioid receptor agonist, alone or in conjunc EDs) and the mouse tail-flick test (TF-EDs), respectively, tion with a lactational enhancer, elevator, or stabilizer is when administered intravenously. A high BPI value reflects administered to a female Subject. Non-limiting administra low brain penetration and, therefore, a compound that is less tion methods include Subcutaneous, intravenous, intramuscu likely to substantially cross the blood-brain barrier or produce lar, nasal, oral or transdermal administration. Severe CNS side effects. BPI values lower than 5 indicate 0064. The invention moreover relates to a composition significant or Substantial brain penetration, and, therefore, a comprising peripherally selective kappa opioid receptorago compound that is likely to substantially cross the blood-brain nist in conjunction with a lactational enhancer, elevators, or barrier, which can result in severe side effects (e.g., dyspho stabilizers, optionally including a pharmaceutically accept US 2014/022 1277 A1 Aug. 7, 2014

able carrier. These and other compositions set forth hereincan I0081. By “transdermal’ drug delivery is meant adminis be used in methods for the treatment of lactation failure, or tration of a drug to the skin surface of an individualso that the inadequate or insufficient lactation in a subject, in accordance drug passes through the skin tissue and into the individuals with the invention, as well as a method for the manufacture of blood stream, thereby providing a systemic effect. The term these compositions. “transdermal' is intended to include “transmucosal” drug 0065. By lactation failure is here meant both when a administration, i.e., administration of a drug to the mucosal female has no or insufficient amount of milk or is at risk for (e.g., Sublingual, buccal, vaginal, rectal) Surface of an indi none or insufficient amount of milk. vidualso that the drug passes through the mucosal tissue and 0066. Lactation can be promoted and, therefore, lactation into the individual’s blood stream. failure, or inadequate or insufficient lactation in a subject, I0082. The term “body surface” is used to refer to skin or methods are provided in the following situations: mucosal tissue. 0067 i) Normalize lactation volumes in women with lac I0083. By “predetermined area of skin or mucosal tissue, tational failure; which refers to the area of skin or mucosal tissue through 0068 ii) Maintain/enhance, increase lactation in females which a drug enhancer formulation is delivered, is intended a of premature babies who are being cared for in a neonatal defined area of intact unbroken living skin or mucosal tissue. unit; That area will usually be in the range of about 5 cm to about 0069 iii) Enhance lactational performance in females 200 cm, more usually in the range of about 5 cm to about with twins and triplets; 100 cm, typically in the range of about 20 cm to about 60 0070 iv) Promote and prolong (frequency or duration) cm. However, it will be appreciated by those skilled in the art lactation in females with offspring at risk of developing lac of drug delivery that the area of skin or mucosal tissue through tose intolerance or other milk allergies if formula milk was which drug is administered may vary significantly, depending used; on patch configuration, dose, and the like. 0071 v) Promote/prolong lactation in females where I0084) “Penetration enhancement” or “permeation adverse hygiene conditions would make the use of formula enhancement as used herein relates to an increase in the undesirable; permeability of the skin or mucosal tissue to a selected phar 0072 vi) Enhance, increase or stabilize lactation in macologically active agent, i.e., so that the rate at which the females where Suckling frequency is diminished during part agent permeates therethrough (i.e., the "flux of the agent of the day, e.g. working mothers; through the body surface) is increased relative to the rate that 0073 vii) To treat females prophylactically if they are at would be obtained in the absence of permeation enhance risk for having an insufficient or inadequate amount of milk ment. The enhanced permeation effected through the use of production. Such enhancers can be observed by measuring the rate of 0074 Certain embodiments of the invention involve pep diffusion of drug through animal or human skin using, for tides, optionally tetrapeptides containing four D-isomer example a Franz diffusion apparatus as known in the art and amino acid residues, which bind to kappa opioid receptor as employed in the Examples herein. receptors, which do not substantially cross the blood brain I0085. An “effective amount” or “an effective permeation barrier and enter the brain, which exhibit high affinity for the enhancing amount of a permeation enhancer refers to a kappa opioid receptor versus the mu opioid receptor, which nontoxic, nondamaging but sufficient amount of the enhancer have high potency and efficacy, and can exhibit a relative long composition to provide the desired increase in skin perme duration of action in vivo. ability and, correspondingly, the desired depth of penetration, 0075. It is an object herein to provide peripherally selec rate of administration, and amount of drug delivered. tive kappa opioid receptor agonists for systemic application I0086 A genus of peptides has been discovered which that have tolerable, minimal or few if any CNS or diuretic exhibit high selectivity for the kappa opioid receptor and effects at dosages that are Sufficient to elevate, increase or relative long duration of in vivo action and which can exhibit stabilize prolactin and thereby produce a benefit, such as reduced or Substantially little if any significant brain penetra increased lactation or prevent significant reductions, or tion. These peptides include sequences in which a sequence decreases in lactation, in a subject in need thereof. of four D-isomeramino acids having a C-terminus is either a 0.076 Mammals are defined herein as all animals, includ mono or disubstituted amide. These compounds have the ing humans, primates, and ungulates, for which the females of following general formula: the species have mammary glands and produce milk. HXaa1-Xaa-Xaa-Xaa1-Substituted amide 0077. As used herein, a “dairy animal' refers to a milk producing animal. In certain embodiments, the dairy animal wherein Xaa, is (A)D-Phe, (C' Me)D-Phe, D-Tyr, D-Tic produces large Volumes of milk and has a long period of or D-Ala(cyclopentyl or thienyl), with Abeing H, NO. F. Cl lactation, e.g., cows or goats. or CH; Xaa, is (A')D-Phe, D-1 Nal, D-2Nal, D-Tyror D-Trp. 0078. The term “pharmaceutically acceptable composi with A' being A or 3.4C1, Xaa is D-Nle, (B)D-Leu, D-Hle, tion” refers to compositions which comprise atherapeutically D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H effective amount of peripherally selective kappa opioid or C" Me: Xaa, is D-Arg, D-Har, D-nArg, D-Lys, D-Lys receptor agonist, formulated together with one or more phar (Ipr), D-Arg(Et), D-Har(Et), D-Amf(G), D-Dbu, (B)D-Orn maceutically acceptable carrier(s). or D-Orn(Ipr), and with G being Horamidino. Non-limiting 0079. As used herein, the term “formulation refers to a amides include ethylamide, morpholinylamide, 4-picolyla composition in Solid, e.g., powder, or liquid form, which mide, piperazineamide, propylamide, cyclopropylamide and includes a peripherally selective kappa opioid receptor ago diethylamide. nist. Formulations can provide therapeutic benefits. These formulations may contain a preservative to prevent growth of I0087. The invention also provides a method of treating a microorganisms. mammal in need of elevated prolactin by increasing levels of 0080. By “therapeutically effective” amount is meant a serum prolactin of said mammal, comprising administering tolerable (e.g., does not produce a severe side effect, which to said mammal an amount of a peripherally selective kappa can be relatively, Substantially, or completely nontoxic) opioid receptoragonist or a salt thereof or a pro-drug thereof amount of an active agent to provide the desired therapeutic effective to treat the mammal. In certain embodiments, the effect. method increases or stabilizes levels of serum prolactin to US 2014/022 1277 A1 Aug. 7, 2014

greater than 25, 50, 75, 100, 125, 150, 175, or 200 ng/ml centrations Following a 1 hour IV Infusion of CR665 at serum in the mammal. In other embodiments the method the various dosages in Male Subjects (Part A). peripherally selective kappa opioid receptor agonist or salt 0091 FIG. 2 is a graph showing the Arithmetic Mean thereof or prodrug thereof effective to treat the mammal is a Changes from Baseline (Pre dose) in Serum Prolactin Con peptide, or ionizes or is metabolized to form a peptide. The centrations Following a 1 hour IV Infusion of CR665 in peptide can comprise a pentapeptide or tetrapeptide, which Female Subjects (Part A). can include a sequence of four D-isomeramino acids having 0092 FIG. 3 is a graph showing the Arithmetic Mean a C-terminus that is either a mono- or di-substituted amide. In Changes from Baseline (Pre dose) in Serum Prolactin Con certain embodiments the peptide has a binding affinity for the centrations Following a 5 minute IV. Infusion of CR665 in kappa opioid receptor that is greater than its binding affinity Male Subjects (Part B). for non-kappa opioid receptors. In particular embodiments 0093 FIG. 4 is a graph showing the Geometric Mean the peptide has a binding affinity for the kappa opioid receptor Plasma Concentrations of CR665 Following a 1 hour IV at least 1,000 times greater than its binding affinity for the mu Infusion of CR665 in Male Subjects (Part A) (Linear Scale). opioid receptor. In some of these particular embodiments the 0094 FIG. 5 is a graph showing the Geometric Mean peptide has a binding affinity for the kappa opioid receptor at Plasma Concentrations of CR665 Following a 1 hour IV least 1,000 times greater than its binding affinity for the mu Infusion of CR665 in Male Subjects (Part A) (Semi logarith opioid receptor and in addition has an EDso for elevating mic Scale). prolactin of about 0.5 mg/kg or less. 0.095 FIG. 6 is a graph showing the Geometric Mean 0088 Particular compounds useful in the methods of the AUCOD for CR665Versus Dose Level Following a 1 hour IV present invention include the compound having the formula: Infusion of CR665 in Male Subjects (Part A). 0096 FIG. 7 is a graph showing the Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV Infusion of 0.24 mg/kg. CR665 in Female Subjects (Part A) (Linear Scale). 0097 FIG. 8 is a graph showing the Geometric Mean Plasma Concentrations of CR665 Following a 1 hour IV O GE) N N Infusion of 0.24 mg/kg. CR665 in Female Subjects (Part A) AcO HN1 1. N (Semi logarithmic Scale). O H. O H eN 0.098 FIG. 9 is a graph showing the Arithmetic Mean (SD) Plasma Concentrations of CR665 Following a 1-hour IV Infusion of 0.24 mg/kg. CR665 in Male and Female Sub HN jects (Part A) (Linear Scale). (0099 FIG. 10 is a graph showing the Geometric Mean NH Plasma. Concentrations of CR665 Following a 5-minute IV H.N. GE Infusion of CR665 in Male and Female Subjects (Part B) G AcO (Linear Scale). 0100 FIG. 11 is a graph showing the Geometric Mean Plasma Concentrations of CR665 Following a 5-minute IV H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolyl, or a picolyl Infusion of CR665 in Male and Female Subjects (Part B) N-oxide thereof, optionally excluding or including an acetate (Semi logarithmic Scale). counterion. 0101 FIG. 12 is a graph showing the Geometric Mean 0089 Another particular compound useful in the methods AUCo., a for CR665 Versus Dose Level Following a of the present invention is the compound having the formula: 5-minute IV infusion of CR665 in Male Subjects (Part B). 0102 FIG. 13 is a graph showing the Relationship Between AUCO 12 h of Changes from Baseline in Serum Prolactin and AUCo., ofCR665 over the 0.015 to 0.36 mg/kg Dose Range in Male Subjects (Part A). 0103 FIG. 14 is a graph showing the Relationship Between Cmax of Changes from Baseline in Serum Prolactin and Cmax of CR665 over the 0.015 to 0.36 mg/kg Dose. G. G.) N N Range in Male Subjects (Part A). AcO in-n 1. /NO O H O \-/ DETAILED DESCRIPTION 0104. The nomenclature used to define the peptides is O GE specified by Schroder & Lubke, The Peptides, Academic AcO NH Press, 1965, wherein, in accordance with conventional rep resentation, the N-terminus appears to the left and the C-ter H-D-Phe-D-Phe-D-Leu-D-Orn-Morpholinyl, optionally minus to the right. Where an amino acid residue has isomeric excluding or including an acetate counterion. forms, it is the L-isomer form of the amino acid that is being represented herein unless otherwise indicated. BRIEF DESCRIPTION OF THE FIGURES 0105. The invention provides methods, compositions, or dosage forms that employ and/or contain compounds, such as 0090 FIG. 1 is a graph showing the Arithmetic Mean peptides, that are selective for kappa opioid receptor and not Changes from Baseline (Pre dose) in Serum Prolactin Con only exhibit a strong affinity for the kappa opioid receptor but US 2014/022 1277 A1 Aug. 7, 2014

exhibit, optionally, long duration of in vivo prolactin elevat ing agent, said administration in an amount effective for ing activity in the absence of a severe or significant side effect, treating insufficient or inadequate lactation in the mammal. such as CNS side effects or diuresis. Exemplary kappa selec 0109. In other embodiments, the invention provides a tive opioid, receptor compounds (e.g., agonists) have a Ki method of for treating a mammal exhibiting insufficient or against a mammalian kappa opioid receptor, such as a human inadequate milk production or at risk of insufficient or inad kappa opioid receptor, of less than 1000 nM, or less than 100 equate milk production. The method includes administering nMorless than 10 nM, or less than 1 nM, optionally having a to said mammal an amount of a peripherally selective kappa selectivity for kappa opioid receptors over other mammalian opioid receptor agonist or salt thereof or prodrug thereof opioid receptor Subtypes greater than 100, or greater than effective to treat the mammal. The peripherally selective 1,000 or greater than 10,000 times greater affinity, measur kappa opioid receptor agonist or salt thereof or prodrug able in vitro by the ratio of their 1050 or Ki values against the thereof can include a peptide, or can ionize or metabolize to mammalian, e.g., human mu and delta opioid receptors, form a peptide. The peptide can include a tetrapeptide or a respectively. Kappa opioid receptoragonists can exhibit both pentapeptide. a lack of significant brain penetration and a prolonged dura 0110. In particular embodiments, the prolactin-elevating tion of in vivo activity. Therefore, in addition to the above agent useful in the methods of the present invention can be mentioned kappa opioid receptor affinity and selectivity, administered with a mu opioid receptoragonist selected from compounds also include those that exhibit no significant brain the group consisting of (i) , (ii) , penetration while preserving Substantial activity for measur (iii) , (iv) , (v) , (vi) able or detectable period of time, for example, at least about , (vii) , (viii) , (ix) morphine one hour, at least about two hours, for three hours or longer 6 glucuronide, (X) , (xi) meperidine, (xii) diphe (e.g., 4, 5, 6, 12, 24, 48 hours or days, or longer). noxylate, (xiii) , (xiv) , (XV) , 0106. In certain embodiments, the method of the invention (xvi) , (xvii) , (xviii) levomethadyl and can be practiced using a peripherally selective kappa opioid (Xviv) propoxyphene. receptor agonist, which when administered peripherally, is 0111. In certain embodiments of the method, the prolac effective to increase or stabilize levels of prolactin without tin-elevating agent can be a peptide having a binding affinity substantially crossing the blood-brain barrier of the subject. for the peripheral kappa opioid receptor that is greater than its In other embodiments, the amount of the peripherally selec binding affinity for non-peripheral kappa opioid receptor. tive kappa opioid receptoragonist administered is an amount Alternatively, the peptide can have a binding affinity for the effective to increase or stabilize levels of prolactin without peripheral kappa opioid receptor that is 10 times greater, 100 causing a severe side effect in the Subject. Alternatively, the times greater, 1,000 times greater, or more than its binding amount of the peripherally selective kappa opioid receptor affinity for a non-peripheral kappa opioid receptor. For agonist administered is an amount effective to increase or instance the peptide can have a binding affinity for the kappa stabilize levels of prolactin with minor or tolerable side opioid receptor which is at least 1,000 times greater than its effects in the subject. Side effects can include a neuropsychi binding affinity for the mu opioid receptor. In certain embodi atric side effect (such as but not limited to dysphoria or ments, the peptide has a binding affinity for the kappa opioid hallucinations), diuresis or sedation. receptor which is at least 1,000 times greater than its binding 0107. In some embodiments, according to the method of affinity for the mu opioid receptor and an EDso for elevating the invention for elevating levels of serum prolactin in a prolactin of about 0.5 mg/kg or less. mammal, the administered dose of the peripherally selective 0112. In a particular embodiment, the invention provides a kappa opioid receptoragonist is between about 1 microgram/ method of treating a mammal in need of elevated or stabilized kg of body weight to about 100 milligrams/kg of body weight prolactin levels, wherein the method includes administering of said mammal per hour, or per day, or per week or per to said mammal an amount of a peripherally selective kappa month. The prolactin levels can be elevated to greater than 10, opioid receptoragonist or a salt thereofor a pro-drug thereof, 15, 20, 25, 50, 75, 100, 125, 150, 175, or 200 ng/rnl serum in conjunction with an amount of an additional prolactin above the baseline level of serum prolactin. elevating compound, effective to treat the mammal. The addi 0108. In some embodiments, the method of the invention tional prolactin elevating compound can include a D2 dopam for treating insufficient or inadequate lactation in a mammal, ine receptor antagonist or mu opioid receptor agonist. includes administering, separately or in combination an 0113. In one embodiment, the D2 dopamine receptorago amount of a peripherally selective kappa opioid receptorago nist is selected from the group consisting of (i) domperidone, nist or a salt thereof or a pro-drug thereof, and an amount of (ii) metoclopramide, (iii) levosulpiride, (iv) sulpiride, (v) thi prolactin effective to treat insufficient or inadequate lactation ethylperazine, (vi) Ziprasidone, (vii) Zotepine, (viii) clozap in the mammal. In other embodiments, the invention provides ine, (ix) chlorpromazine, (X) acetophenazine, (xi) carphena a method for treating insufficient or inadequate lactation. The Zine (xii) chlorprothixene, (xiii) fluiphenazine, (xiv) loxapine, method includes administering an amount of a peripherally (XV) mesoridazine, (Xvi) molindone, (Xvii) perphenazine, selective kappa opioid receptor agonist or a salt thereof or a (Xviii) pimozide, (Xviv) piperacetazine, (XX) prochlorpera pro-drug thereof, to a mammal, separately or in combination, zine, (xxi) thioridazine, (xxii) thiothixene, (xxiii) trifluopera with (1) another prolactin-elevating agent, (2) prolactin, or Zine, (XXiv) triflupromazine, (XXV) pipamperone, (XXVi) (3) a non-drug therapy, the method effective to treat insuffi amperozide, (XXVii) quetiapine, (XXViii) melperone, (XXix) cient or inadequate lactation in the mammal. In still other remoxipride, (XXX) haloperidol, (XXXi) rispiridone, (XXXii) embodiments, the invention provides a method for treating olanzepine, (XXXiii) sertindole, and (XXXiv) prochlorperazine. insufficient or inadequate lactation in a mammal. The method 0114. In another embodiment the mu opioid receptorago includes administering separately or in combination 1) a nist is selected from the group consisting of (i) morphine, (ii) peripherally selective kappa opioid receptor agonist or a salt hydromorphone, (iii) oxymorphone, (iv) levorphanol, (v) thereofora pro-drug thereof, and; 2) another prolactin-elevat methadone, (vi) codeine, (vii) hydrocodone, (viii) oxyc US 2014/022 1277 A1 Aug. 7, 2014 odone, (ix) morphine-6-glucuronide, (X) tramadol, (xi) mep 0.120. As used herein, “pharmaceutically acceptable' eridine, (xii) , (xiii) loperamide, (xiv) fentanyl. refers to compounds, materials, compositions, and/or dosage (XV) sufentanil, (xvi) alfentanil, (xvii) remifentanil, (xviii) forms which are, within the scope of Sound medical judg levomethadyl, and (Xviv) propoxyphene. ment, Suitable for contact with the tissues of human beings 0115. As used herein, “prolactin elevating activity” refers and animals without severe toxicity, irritation, allergic to the pharmacological activity of a compound If it causes an response, or other complications commensurate with a rea elevation in circulating plasma or serum levels of prolactin in sonable benefit/risk ratio. a subject. A "prolactin increasing activity” refers to a com 0.121. As used herein, “in combination with’. “combina pound that causes a measurable or detectable, transient or tion therapy' and “combination products” refer, in certain longer term increase in circulating plasma or serum levels of embodiments, to the concurrent administration to a patient of prolactin in a subject. A “prolactin stabilizing activity” refers a peripherally selective kappa opioid receptor agonist of the to a compound that causes a measurable or detectable, tran invention and either or both of prolactin and a compound with sient or longer term, stabilization in circulating plasma or prolactin elevating, increasing or stabilizing activity but lack serum levels of prolactin in a subject, e.g., prevents or inhibits ing peripherally selective kappa opioid receptoragonist activ a reduction in prolactin levels, maintains a particular level of ity, e.g., a D2 dopamine receptor antagonist, e.g., domperi prolactin for a measurable period of time, prevents or inhibits done. When administered in combination, each component a reduction in prolactin levels below a certain amount (e.g., may be administered at the same time or sequentially in any below 200, 175, 150, 125, 100, 75, 50, 25 ng/ml serum), etc. order at different points in time. Thus, each component may 0116. As used herein, “functional hypoprolactinemia be administered separately but sufficiently closely in time so refers to a condition in which a subject has insufficient or as to provide a desired therapeutic effect. inadequate levels of circulating prolactin required to initiate, I0122. As used herein, a “D2 dopamine receptor antago maintain or enhance a physiological function, e.g. lactation. nist” refers to compounds with a binding affinity (K, or K.) The level of circulating prolactin required for a given physi for a mammalian D2 dopamine receptor of less than 10 micro ological function will vary, as is knownin the art, depending molar, regardless of binding affinity for other receptors. upon the function and the gender and physiological or patho Where there is ambiguity or an absence of useful information physiological status of the Subject. Thus, for example, a nor regarding whether the binding affinity of a compound for a mal pre pregnancy baseline level of circulating prolactin mammalian D2 dopamine receptor meets this definition, data would be insufficient to sustain lactation after delivery. Under from in vitro or in vivo functional studies, as are commonly these circumstances, the failure of lactation in a post pregnant employed by those with skill in the art, can be used to deter female with this level of prolactin would be characterized as mine whether a compound is a functional antagonist of a a functional hypoprolactinemia, even though the circulating mammalian D2 dopamine receptor. level of prolactin would be normal for a non lactating female. I0123. As used herein, “mu opioid receptoragonist” refers to compounds with a binding affinity (K, or K.) for a mam 0117. As used herein, “CNS side effect refers to a clini malian muopioid receptor of less than 10 micromolar, regard cally significant side effect of a compound in which the Symp less of binding affinity for other receptors. Where there is toms are psychiatric or neurological, e.g., visual or auditory ambiguity or an absence of useful information regarding hallucinations, delusions, impaired intellectual functioning, whether the binding affinity of a compound for a mammalian or impaired control of Voluntary movements. mu opioid receptor meets this definition, data from in vitro or 0118. As used herein, the term “subject' is intended to in vivo functional studies, as are commonly employed by include human and nonhuman mammals. Subjects include a those with skill in the art, can be used to determine whether a person, e.g., a patient, in need of elevated, increased or sta compound is a functional agonist of a mammalian mu opioid bilized levels of prolactin, e.g., a person in need of stimulation receptor. of lactation, e.g., a female (mother). The term “mammals' 0.124. As used herein, “dosage unit refers to a physically includes humans and all non human mammals, such as non discrete unit Suited as unitary dosages for a particular indi human primates, ungulates and ruminants. vidual or condition to be treated. Each unit may contain a 0119. As used herein, “effective amount or “sufficient predetermined quantity of active compound(s) calculated to amount refers to an amount of a compound as described produce the desired therapeutic effect(s), optionally in asso herein that may be therapeutically effective to inhibit, prevent ciation with a pharmaceutical carrier. The specification for or treat a symptom of a particular disease, disorder, condition, the dosage unit forms may be dictated by (a) the unique or side effect. Such diseases, disorders, conditions, and side characteristics of the active compound(s) and the particular effects include those conditions associated with insufficient, therapeutic effect(s) to be achieved, and (b) the limitations or inadequate circulating levels of prolactin, wherein the inherent in the art of compounding Such active compound(s). treatment comprises elevating, increasing or stabilizing cir 0.125. As used herein, “pharmaceutically acceptable salts' culating levels of prolactin by contacting cells, tissues or refer to derivatives of compounds wherein the parent com receptors with compounds as set forth herein. Thus, for pound is modified by making acid or base salts thereof. example, an "effective amount’, when used in connection Examples of pharmaceutically acceptable salts include, but with lactational insufficiency or inadequacy, for example, are not limited to, mineral or organic acid sals of basic resi refers to an amount of a compound required for treatment dues such as amines; alkali or organic salts of acidic residues and/or prevention of this condition. An “effective amount', Such as carboxylic acids; and the like. The pharmaceutically when used in connection with functional hypoprolactinemia, acceptable salts include the conventional nontoxic salts or the refers to the treatment and/or prevention of one or more quaternary ammonium salts of the parent compound formed, symptoms, diseases, disorders, and conditions associated for example, from non toxic inorganic or organic acids. For with circulating levels of prolactin that are undesirably low, example, such conventional non toxic salts include those for example, to optimally Sustain a physiological function. derived frominorganic acids such as hydrochloric, hydrobro US 2014/022 1277 A1 Aug. 7, 2014

mic, Sulfuric, Sulfamic, phosphoric, nitric and the like; and the ingredients that may be added to provide desirable color, salts prepared from organic acids such as acetic, propionic, taste, stability, buffering capacity, dispersion or other known Succinic, glycolic, Stearic, lactic, malic, tartaric, citric, ascor desirable features are red iron oxide, silica gel, Sodium lauryl bic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, sulfate, titanium dioxide, edible white ink and the like. Simi benzoic, Salicylic, Sulfanilic, 2 acetoxybenzoic, fumaric, lar diluents can be used to make compressed tablets. Both toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, tablets and capsules can be manufactured as Sustained release isethionic, and the like. These physiologically acceptable products to provide for continuous release of medication over salts are prepared by methods known in the art, e.g., by a period of hours. Compressed tablets can be Sugar coated or dissolving the free amine bases with an excess of the acid in film coated to mask any unpleasant taste and protect the tablet aqueous , or neutralizing a free carboxylic acid with from the atmosphere, or enteric coated for selective disinte an alkali metal base Such as a hydroxide, or with an amine. gration in the gastrointestinal tract. Liquid dosage forms for 0126 Compounds described herein, can be used or pre oral administration can contain coloring and flavoring to pared in alternate forms. For example, many amino contain increase patient acceptance. To facilitate drug stability and ing compounds can be used or prepared as an acid addition absorption, peptides of the invention can be released from a salt. Often such salts improve isolation and handling proper capsule after passing through the harsh proteolytic environ ties of the compound. For example, depending on the ment of the stomach. Methods for enhancing peptide stability reagents, reaction conditions and the like, compounds as and absorption after oral administration are well known in the described herein can be used or prepared, for example, as art (e.g., Mahato R I. Emerging trends in oral delivery of their hydrochloride or tosylate salts. Isomorphic crystalline peptide and protein drugs. Critical Reviews in Therapeutic forms, all chiral and racemic forms, N-oxide, hydrates, Sol Drug Carrier Systems. 20:153-214, 2003). In addition, oral Vates, and acid salt hydrates, are also contemplated to be delivery of compounds of the invention can be optimized within the scope of the present invention. through the use of remote controlled capsules as disclosed by 0127 Certain acidic or basic compounds of the present Wilding and Prior in Critical Reviews in Therapeutic Drug invention may exist as Zwitterions. All forms of the com Carrier Systems 20:405-431 (2003). pounds, including free acid, free base and Zwitterions, are I0131 For nasal administration, the peripherally selective contemplated to be within the scope of the present invention. kappa opioid receptoragonists can beformulated as aerosols. It is well known in the art that compounds containing both The term “aerosol includes any gas-borne Suspended phase amino and carboxyl groups often exist in equilibrium with of the compounds of the instant invention which is capable of their Zwitterionic forms. Thus, any of the compounds being inhaled into the bronchioles or nasal passages. Specifi described herein throughout that contain, for example, both cally, aerosol includes a gas-borne Suspension of droplets of amino and carboxyl groups, also include reference to their the compounds of the instant invention, as may be produced corresponding Zwitterions. in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition of a com Pharmaceutical Compositions pound of the instant invention Suspended in air or other carrier 0128. A peripherally selective kappa opioid receptor ago gas, which may be delivered by insufflation from an inhaler nist of the invention can be incorporated into a pharmaceuti device, for example. See Ganderton & Jones, Drug Delivery cal composition to ameliorate functional hypoprolactinemia to the Respiratory Tract, Ellis Horwood (1987); Gonda in a Subject, e.g., a Subject presenting with a deficiency, inad (1990) Critical Reviews in Therapeutic Drug Carrier Systems equacy or insufficiency in lactation associated with insuffi 6:273-313; and Raeburnet al. (1992).J. Pharmacol. Toxicol. cient or inadequate plasma levels of prolactin. The composi Methods 27:143-159. tions should contain an effective amount of a peripherally (0132 Parenteral administration of the formulations of the selective kappa opioid receptoragonist, in a pharmaceutically present invention includes intravenous, Subcutaneous, intra acceptable carrier. muscular and transdermal administrations. 0129. The pharmaceutical carrier can be any compatible, 0.133 Preparations for parenteral administration include non toxic substance suitable to deliver the peripherally selec sterile solutions ready for injection, sterile dry soluble prod tive kappa opioid receptor agonist to the Subject. Sterile ucts ready to be combined with a solvent just prior to use, water, alcohol, fats, waxes, and inert Solids may be used as the including hypodermic tablets, sterile Suspensions ready for carrier. Pharmaceutically acceptable adjuvants, buffering injection, sterile dry insoluble products ready to be combined agents, dispersing agents, and the like, may also be incorpo with a vehicle just prior to use and sterile emulsions. The rated into the pharmaceutical compositions. The concentra Solutions may be either aqueous or nonaqueous, and thereby tion of peripherally selective kappa opioid receptoragonist or formulated for delivery by injection, infusion, or using other active agent in the pharmaceutical composition can vary implantable pumps. For intravenous, Subcutaneous, and widely, i.e., from less than about 0.01% by weight, usually intramuscular administration, useful formulations of the being at least about 1% weight to as much as 50% by weight invention include microcapsule preparations with controlled O. O. release properties (R. Pwar et al. Protein and peptide 0130 For oral administration, an active ingredient can be parenteral controlled delivery. Expert Opin Biol Ther: 4(8): administered in Solid dosage forms, such as capsules, tablets, 1203-12, 2004) or encapsulation in liposomes, with an exem and powders, or in liquid dosage forms, such as elixirs, Syr plary form being polyethylene coated liposomes, which are ups, and Suspensions. Active component(s) can be encapsu known in the art to have an extended circulation time in the lated in gelatin capsules together with inactive ingredients vasculature (e.g.Koppal, T. "Drug delivery technologies are and powdered carriers, such as glucose, lactose, Sucrose, right on target'. Drug Discov. Dev. 6, 49-50, 2003). mannitol, Starch, cellulose or cellulose derivatives, magne 0.134 Preparations for transdermal delivery are incorpo sium Stearate, Stearic acid, sodium saccharin, talcum, magne rated into a device suitable for said delivery, said device sium carbonate and the like. Examples of additional inactive utilizing, e.g., iontophoresis (Kalia Y Net al. Iontophoretic US 2014/022 1277 A1 Aug. 7, 2014

drug delivery. Adv. Drug Deliv Rev. 56.619-58, 2004) or a desired species or agents. Each electrode assembly is com dermis penetrating surface (Prausnitz MR. Microneedles for prised of an electrically conductive electrode in ion-transmit transdermal drug delivery. Adv. Drug Deliv Rev. 56:581-7, ting relation with an ionically conductive liquid reservoir 2004), such as are known in the art to be useful for improving which in use is placed in contact with the patient’s skin. Gel the transdermal delivery of drugs. An electrotransport device reservoirs such as those described in Webster (U.S. Pat. No. and methods of operating same are disclosed in U.S. Pat. No. 4.383,529) are one form of reservoir since hydrated gels are 6,718,201. Methods for the use of iontophoresis to promote easier to handle and manufacture than liquid-filled contain transdermal delivery of peptides are disclosed in U.S. Pat. No. ers. Water is one liquid solvent that can be used in such 6,313,092 and U.S. Pat. No. 6,743,432. Herein the terms reservoirs, in part because the salts of the peptide compounds “electrotransport”, “iontophoresis', and “iontophoretic' are of the invention are water soluble and in part because water is used to refer to the delivery through a body Surface (e.g., skin non-irritating to the skin, thereby enabling prolonged contact or mucosa) of one or more pharmaceutically active com between the hydrogel reservoir and the skin. Examples of pounds by means of an applied electromotive force to an reservoirs and sources include a pouch as described in U.S. agent containing reservoir. The compound may be delivered Pat. No. 4,250.878, a pre-formed gel body as disclosed in by electromigration, electroporation, electroosmosis or any U.S. Pat. No. 4,382,529, and a glass or plastic container combination thereof. Electroosmosis has also been referred holding a liquid solution of the drug, as disclosed in the to as electrohydrokinesis, electro convection, and electrically figures of U.S. Pat. No. 4,722,726. For electrotransport, com induced osmosis. In general, electroosmosis of a compound pounds (e.g., peptides) the invention can be formulated with into a tissue results from the migration of solvent in which the flux enhancers such as ionic Surfactants (e.g., U.S. Pat. No. compound is contained, as a result of the application of elec 4,722.726) or cosolvents other than water (e.g., European tromotive force to the therapeutic species reservoir, i.e., Sol Patent Application 278.473). Alternatively the outer layer vent flow induced by electromigration of other ionic species. (i.e., the stratum corneum) of the skin can be mechanically During the electrotransport process, certain modifications or disrupted prior to electrotransport delivery therethrough (e.g., alterations of the skin may occur Such as the formation of transiently existing pores in the skin, also referred to as “elec U.S. Pat. No. 5,250,023). troporation.” Any electrically assisted transport of species 0.136 Peripherally selective kappa opioid receptor ago enhanced by modifications or alterations to the body surface nists that are well suited for electrotransport can be selected, (e.g., formation of pores in the skin) are also included in the by measuring their electrotransport flux through the body term "electrotransport” as used herein. Thus, as used herein, Surface (e.g., the skin or mucosa), e.g., as compared to a applied to the compounds of the instant invention, the terms standardized test peptide with known electrotransport flux “electrotransport”, “iontophoresis' and “iontophoretic' refer characteristics, e.g. thyrotropin releasing hormone (R. Bur to (1) the delivery of charged agents by electromigration, (2) nette et al. J. Pham. Sci. (1986) 75:738) or vasopressin (Nair the delivery of uncharged agents by the process of electroos et al., Pharmacol Res. 48:175-82, 2003). Transdermal elec mosis, (3) the delivery of charged or uncharged agents by trotransport flux can be determined using a number of in vivo electroporation, (4) the delivery of charged agents by the or in vitro methods well known in the art. In vitro methods combined processes of electromigration and electroosmosis, include clamping a piece of skin of an appropriate mammal and/or (5) the delivery of a mixture of charged and uncharged (e.g., human cadaver skin) between the donor and receptor agents by the combined processes of electromigration and compartments of an electrotransport flux cell, with the Stra electroosmosis. Electrotransport devices generally employ tum corneum side of the skin piece facing the donor compart two electrodes, both of which are positioned in close electri ment. A liquid Solution or gel containing the drug to be cal contact with some portion of the skin of the body. One delivered is placed in contact with the stratum corneum, and electrode, called the active or donor electrode, is the electrode electric current is applied to electrodes, one electrode in each from which the therapeutic agent is delivered into the body. compartment. The transdermal flux is calculated by sampling The other electrode, called the counter or return electrode, the amount of drug in the receptor compartment. Two Suc serves to close the electrical circuit through the body. In cessful models used to optimize transdermal electrotransport conjunction with the patient’s skin, the circuit is completed drug delivery are the isolated pigskin flap model (Heit MC et by connection of the electrodes to a source of electrical al. Transdermaliontophoretic peptide delivery: in vitro and in energy, e.g., a battery, and usually to circuitry capable of Vivo Studies with luteinizing hormone releasing hormone.J. controlling current passing through the device. Pharm. Sci. 82:2403, 1993), and the use of isolated hairless 0135 Depending upon the electrical charge of the com skin from hairless rodents or guinea pigs, for example. See pound to be delivered transdermally, either the anode or cath Hadzija BW et al. Effect of freezing on iontophoretic trans ode may be the active or donor electrode. Thus, if the com port through hairless rat skin. J. Pharm. Pharmacol. 44, 387 pound to be transported is positively charged, e.g., the 390, 1992. Compounds of the invention for transdermal ion compound exemplified in Example 1 herein, then the positive tophoretic delivery can have one, or typically, two charged electrode (the anode) will be the active electrode and the nitrogens, to facilitate their delivery. negative electrode (the cathode) will serve as the counter 0.137 The scope of the present invention also includes electrode, completing the circuit. However, if the compound methods of treating a mammal in need of elevated prolactin to be delivered is negatively charged, then the cathodic elec wherein the peripherally selective kappa opioid receptorago trode will be the active electrode and the anodic electrode will nist or a salt thereof or a pro-drug thereof is administered be the counter electrode. Electrotransport devices addition transdermally, for instance and without limitation, by an elec ally require a reservoir or source of the therapeutic agent that trotransport device. The electrotransport device can, in some is to be delivered into the body. Such drug reservoirs are embodiments, deliver the peripherally selective kappa opioid connected to the anode or the cathode of the electrotransport receptoragonist or a salt thereofora pro-drug thereof through device to provide a fixed or renewable source of one or more a body Surface. US 2014/022 1277 A1 Aug. 7, 2014

0.138. Other useful transdermal delivery devices employ cally active compound is adjusted so that administration pro high Velocity delivery under pressure to achieve skin penetra vides an effective amount to produce a desired effect. The tion without the use of a needle. Transdermal delivery can be exact dose depends on the age, weight and condition of the improved, as is known in the art, by the use of chemical patient or animal, as is known in the art. For any particular enhancers, sometimes referred to in the art as "permeation Subject, specific dosage regimens can be adjusted over time enhancers', i.e., compounds that are administered along with according to the individual need and the professional judg the drug (or in Some cases used to pretreat the skin, prior to ment of the person administering or Supervising the admin drug administration) in order to increase the permeability of istration of the formulations. Thus, the concentration ranges the stratum corneum, and thereby provide for enhanced pen set forth herein are exemplary only and are not intended to etration of the drug through the skin. Chemical penetration limit the scope or practice of the claimed invention. enhancers are compounds that are innocuous and serve 0142. The unit dose parenteral preparations include pack merely to facilitate diffusion of the drug through the stratum aging in an ampoule or a syringe with a needle. corneum, whether by passive diffusion or an energy driven 0.143 All preparations for parenteral administration are process Such as electrotransport. See, for example, Meidan V typically sterile, as is known and practiced in the art. Metal. Enhanced iontophoretic delivery of buspirone hydro 0144 Illustratively, intravenous infusion of a sterile aque chloride across human skin using chemical enhancers. Int. J. ous buffered solution containing an active compound is an Pharm. 264:73-83, 2003. effective mode of administration. Another embodiment is a 0139 Pharmaceutically acceptable carriers used in sterile aqueous or oily solution or Suspension containing an parenteral preparations include aqueous vehicles, nonaque active material injected as necessary to produce the desired ous vehicles, antimicrobial agents, isotonic agents, buffers, pharmacological effect. antioxidants, local anesthetics, Suspending and dispersing 0145 Compositions and methods of the invention can be agents, emulsifying agents, sequestering or chelating agents delivered or administered intravenously, transdermally, intra and other pharmaceutically acceptable Substances. nasally, Subcutaneously, intramuscularly, or orally. Compo 0140. Examples of aqueous vehicles include Sodium sitions can be administered for prophylactic treatment of Chloride Injection, Ringers Injection, Isotonic Dextrose individuals Suffering from, or at risk of a disease or a disorder, Injection, Sterile Water Injection, Dextrose and Lactated e.g., a female experiencing insufficient or inadequate lacta Ringers Injection. Nonacqueous parenteral vehicles include tion. For therapeutic applications, a pharmaceutical compo fixed oils of vegetable origin, cottonseed oil, corn oil, Sesame sition is typically administered to a subject Suffering from a oil and peanut oil. Antimicrobial agents in bacteriostatic or disease or disorder, e.g., a lactational deficiency, in an amount fungistatic concentrations must be added to parenteral prepa sufficient to inhibit, prevent, or ameliorate the disease or rations packaged in multiple dose containers which include disorder. An amount adequate to accomplish this is defined as phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, a “therapeutically effective dose.” methyl and propyl phydroxybenzoic acid esters, thimerosal, 0146 Although not wishing to be bound by any theory, it benzalkonium chloride and benzethonium chloride. Isotonic is believed that peripherally selective kappa opioid receptor agents include sodium chloride and dextrose. Buffers include agonist administered to Subjects stimulates release of the phosphate and citrate. Antioxidants include Sodium bisulfate. anterior pituitary hormone prolactin. The compound is typi Local anesthetics include procaine hydrochloride. Suspend cally administered in an amount Sufficient to stimulate secre ing and dispersing agents include sodium carboxymethylcel tion of prolactin, or stabilize or prevent or inhibit reductions luose, hydroxypropyl methylcellulose and polyvinylpyrroli or decreases in prolactin, without causing a severe side effect, done. Emulsifying agents include Polysorbate 80 (Tween 80). such as CNS side effects or diuresis. A useful dose range of a A sequestering or chelating agent of metal ions includes peripherally selective kappa opioid receptor agonist can be EDTA. Pharmaceutical carriers also include ethyl alcohol, determined by one of skill in the art through routine testing. polyethylene glycol and propylene glycol for water miscible One skilled in the art recognizes that a dose depends, in part, vehicles and sodium hydroxide, hydrochloric acid, citric acid upon physical characteristics of the patient to be treated, e.g., or lactic acid for pH adjustment. body weight, as well as the route of administration, e.g., 0141 Typically a therapeutically effective amount of a intravenous injection or transdermal delivery, and the bio peripherally selective kappa opioid receptoragonist is at least availability and plasma clearance of the compound by that about 0.01% w/w up to about 50% w/w or more, or more than route of administration, as well as the kappa opioid receptor 0.1% w/w of the active compound. The active ingredient may affinity of the compound. One method of approximating an be administered at once, or may be divided into a number of effective dose is to titrate the dose to achieve a plasma con Smaller doses to be administered at intervals of time, or as a centration of drug that exceeds the affinity constant (Kdor Ki) controlled release formulation. The term “controlled release of the drug for the kappa opioid receptor, e.g., as determined formulation' encompasses formulations that allow the con by a conventional radioreceptor assay as is routinely tinuous delivery of a peripherally selective kappa opioid employed in the art. One method is to titrate the dose to effect, receptor agonist to a Subject over a period of time, for e.g., to employ a dose that is found to effectively elevate example, several days to weeks. Such formulations may prolactin levels, as measured by an immunoassay selective administered Subcutaneously or intramuscularly and allow for prolactin. In this case, although only two samples of for the continual steady state release of a predetermined blood, before and after drug administration, are necessary to amount of compound in the subject over time. The controlled compare the basal prolactin level with the stimulated prolac release formulation of peripherally selective kappa opioid tin level, it is typical to measure the stimulated hormonal receptor agonist may be, for example, a formulation of drug levels at timed intervals so that the dosing interval can be containing polymeric microcapsules, such as those described adjusted to maintain a persistently elevated prolactin level. in U.S. Pat. Nos. 4,677,191 and 4,728,721, incorporated Serum prolactin concentrations can be assessed by any of herein by reference. The concentration of the pharmaceuti several, validated methods as are known in the art, e.g., a US 2014/022 1277 A1 Aug. 7, 2014

prolactin-specific immunoassay, e.g., the IMX prolactinassay 0150. The utility of the present invention is not limited to (Abbott Laboratories, Abbott Park, Ill.), a microparticle promoting, elevating, increasing or stabilizing lactation in enzyme immunoassay used in conjunction with an Abbott human and non human mammals. Although the prolactin IMx Automated Immunoassay Analyzer. When the desired receptor is indeed found in the mammary gland and the ovary, therapeutic effect is to increase lactation, an additional two of the best characterized sites of prolactin actions in method of dose titration is to employ a prolactin-elevating mammals, the receptor is also found in areas of the brain that dose that effectively increases the amount of milk that can be are outside the blood brain barrier, and are therefore acces expressed, for example, to between about 500 to 1000 ml per sible to circulating prolactin (Freeman ME et al. Prolactin: day for a nursing human mother, with the level of milk expres Structure, function, and regulation of secretion. Physiol. Rev. sion selected according to the needs of the nursing infant. The 80: 1523-1631, 2000). In particular, the prolactin receptor needs of the nursing infant can be assessed by methods known (and/or the mRNA encoding the prolactin receptor) is found to those with skill in the art, and which can include evidence in the choroid plexus the area postrema, and the mediobasal for adequate lactation: (1) infant is satisfied after breastfeed hypothalamus. Prolactin receptors are also present in a wide ing, (2) infant gains weight appropriately in relation to age/ range of peripheral tissues, including the pituitary gland, length, (3) breast engorgement and/or leaking occurs if infant heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal feeding is missed, and (4) milk is secreted in Volumes above gland, uterus; skeletal muscle, and skin. Accordingly, it is 500 ml/day. The volume of milk ingested by infants is com contemplated that peripherally selective kappa opioid recep monly estimated as 150 ml/kg/day. toragonists, as described herein, will be useful in preventing, 0147 The American Academy of Pediatrics has placed an ameliorating or modulating conditions associated with these emphasis on increasing breastfeeding in the United States, regions of the brain and periphery, as well. Thus, for example, and has noted that most drugs likely to be prescribed to the elevated circulating prolactin, caused by a compound of the nursing mother should have no effect on milk Supply or on instant invention, would have access to the mediobasal hypo infant well being (American Academy of Pediatrics, Com thalamus, a region outside the blood-brain barrier that mittee on Drugs. The Transfer of Drugs and Other Chemicals includes the anterior periventricular area, paraventricular Into Human Milk. Pediatrics 108:776-789, 2001). Methods nucleus, and arcuate nucleus (e.g., Merchenthaler I. Neurons of the invention therefore include those that minimize transfer with access to the general circulation in the central nervous of a compound or compounds of the invention into breast milk system of the rat: a retrograde tracing study with fluoro gold. that is fed to an offspring, Such as an infant. The transfer of Neuroscience 44:655-62; 1991). These hypothalamic nuclei drugs into breast milk is most commonly described quantita are critical for neuroendocrine regulation, and contain pro tively using the milk to plasma (M/P) concentration ratio. The lactin receptors, which would thereby be therapeutically accuracy of this value is improved if it is based on the area affected, e.g., in neuroendocrine related disorders, by eleva under the concentration time curves (AUC), of the drug in tions in circulating prolactin caused by a compound of the maternal milk and plasma. instant invention. 0148. The infant daily dose can be estimated with the 0151. A variety of assays may be employed to test whether following equation: the compounds of the invention exhibit high affinity and Estimated Daily Infant Dosage (mg/kg/day)=M/Px selectivity for the kappa opioid receptor, long duration of in average maternal serum concentrationX 150 vivo bioactivity, lack of CNS side effects, and prolactin mL/kg/day elevating activity. Receptor assays are known in the art and 0149. In this case M/P (milk to plasma ratio) is the ratio of kappa opioid receptors from several species have been AUC, to AUC, The average maternal serum concen cloned, as have mu and delta opioid receptors. Kappa opioid tration refers to AUC after maternal ingestion of a single dose receptors as well as mu and delta opioid receptors are classi of drug or at steady state during, chronic maternal dosing cal, seven transmembrane spanning, G-protein coupled (Bennett 1988, 1996). When using this approach to estimate receptors. Although these cloned receptors readily allow a daily infant dosage, the AUC is either the AUC from time Zero particular candidate compound, e.g., a peptide, to be to infinity after maternal ingestion of a single dose of drug or screened, natural sources of mammalian opioid receptors are the AUC within a dosing interval at Steady state during also useful for screening, as is well known in the art (Dooley chronic maternal dosing. The Volume of milk ingested by CT et al. Selective ligands for the mu, delta, and kappa opioid infants is commonly estimated as 150 ml/kg/day. The infant receptors identified from a single mixture based tetrapeptide dose (mg/kg) can then be expressed as a percentage of the positional scanning combinatorial library.J. Biol. Chem. 273: maternal dose (mg/kg). Compounds of the invention can 18848-56, 1998). Thus, screening against both kappa and mu result in an infant dose of less than 10% of the maternal dose, opioid receptors, whether of recombinant or natural origin, or less than 1% or less than 0.1% of the maternal dose. Since may be carried out in order to determine the selectivity of the compounds of the invention include peptides, they can be compound(s) for the kappa over the mu opioid receptor. In formulated, e.g., with polymeric microspheres, to protect general, a mammalian form of the opioid receptor is used for them from degradation and enhance absorption in the gas screening; typically, the species source of the receptors is the trointestinal tract (e.g., Mahato RI. Emerging trends in oral same as the species for which the compound of the invention delivery of peptide and protein drugs. Crit. Rev. Ther: Drug is being assessed, e.g., human placental tissue as a source of Carrier Syst. 20:153 214, 2003). Microsphere-encapsulated kappa opioid receptors (Porthe Get al. Kappa opiate binding peptides, for example typically do not survive the maternal sites in human placenta. Biochem. Biophys. Res. Commun. gastrointestinal environment and release free peptide into the 101:1-6, 1981) for screening if the contemplated use of the circulation, such that peptides would be orally bioavailable to screened compounds is for treatment of a human Subject. the offspring through breast milk in significant amounts, 0152 Binding affinity refers to the strength of interaction which can be readily confirmed by drug assay of infant between ligand and receptor. To demonstrate binding affinity plasma and/or urine. for opioid receptors, the compounds of the invention can be US 2014/022 1277 A1 Aug. 7, 2014 evaluated using competition binding studies. These studies D-2Fpa, D-3Fpa and D-4Fpa being typical. D-Npa means can be performed using cloned kappa and mu opioid recep nitro-D-Phe, and D-Mpa is used to represent methyl D-Phe. tors expressed in stable transfected cell lines or naturally D-34 Cpa means 3,4-dichloro-D-Phe. D-Acp represents occurring opioid receptors from a receptor-enriched tissue D-Ala(cyclopentyl). D-Orn represents D-ornithine, and Source, as noted above. In these studies, the test compounds D-Dbu represents alpha, gamma-diaminobutyric acid. CML (unlabeled or cold ligand) are used at increasing concentra represents C'methyl Leu, and CMP and CMO represent tions to displace the specific binding of a radiolabeled ligand C'P' Me Phe and C''' Me Orn. By D-4Amf is meant that has high affinity and selectivity for the receptor studied. D-4(NHCH)Phe, and by D-Gmf is meant Amf(amidino) Tritiated U-69,593 and DAMGO can be used as ligands in kappa and mu opioid receptor Studies, respectively. Both which represents D-Phe where the 4-position is substituted ligands are commercially available (NEN-Dupont). DAMGO with CH-NHC(NH)NH. Amd represents amidino, and the is an acronym for D-Ala, MePhe, Gly-ol-. symbol D-Amf(Amd) is also used. By D-Tic is meant D-1.2. The affinity of the radioligands is defined by the concentra 3,4-tetrahydroisoquinoline-3-carboxylic acid. In Ala(Thi), tion of radioligand that results in half-maximal specific bind Thirepresents the thienyl group, which is typically linked at ing (K) in Saturation studies. The affinity of the test com its 2-position to alanine, although 3-thienyl is an equivalent. pound (unlabeled or cold ligand) is determined in By Ily and Ior are respectively meant isopropyl Lys and competition binding studies by calculating the inhibitory con isopropyl Orn where the side chain amino group is alkylated stant (KO according to the following formula: with isopropyl. (O157 By lower alkyl is meant C to C for example, where ICs-Concentration of the cold ligand that inhibits C-C but including cyclopropyl and cyclobutyl. Me, Et, Pr, 50% of the specific binding of the radioligand Tpr Bu, Pn and BZl are used to represent methyl, ethyl, F=free radioligand concentration propyl, isopropyl, butyl, penty1 and benzyl. By Cyp is meant Kaffinity of the radioligand determined in Saturation stud cyclopropyl, and by Cyb is meant cyclobutyl. Although the 1CS linkage is typically to one end of an alkyl chain, the linkage 0153. When performing these assays under specific con may be elsewhere in the chain, e.g. 3-pentyl which may also ditions with relatively low concentrations of receptor, the be referred to as ethylpropyl. 4Nbz and 4Abz represent 4-ni calculated K, for the test compound is a good approximation trobenzyl and 4-aminobenzyl. By 2-, 3- and 4-picolyl (Pic) of its dissociation constant K, which represents the concen are meant methylpyridine groups with the attachment being tration of ligand necessary to occupy one-half (50%) of the via a methylene in the 2-, 3- or 4-position. binding sites. A low K, value in the nanomolar and Subnano 0158. By Mor is meant morpholinyl, molar range is considered to identify a high affinity ligand in the opioid field. Exemplary analogs have a K, for kappa opioid receptor of about 10 nanomolar (nM) or less, and typical analogs have a K, of about 1 nM or less. High affinity -N to compounds: (1) enable the use of relatively low doses of drug, \ / which minimizes the likelihood of side effects due to low affinity interactions, and (2) potentially reduce the cost of manufacturing a dose since a correspondingly smaller and by Timo is meant thiomorpholinyl, amount of a higher affinity compound would be required to produce the desired therapeutic effect, assuming equal absorption, distribution, metabolism, and excretion. 0154 These binding assays employing kappa opioid -N S. receptors and mu opioid receptors are straightforward to per form and can be readily carried out with large numbers of compounds to determine whether Such compounds are kappa opioid receptor selective and have high affinity. Such binding AhX is used to represent 4-aminocyclohexyl, and hEt is used assays can be carried out in a variety of ways as well known to represent hydroxyethyl, i.e. —CHCH, OH. Aeb is used to to one of skill in the art, and one detailed example of an assay represent 4-(2-amino-2-carboxyethyl)benzyl, i.e. of this general type is set forth in Young E A et al. H Dynorphin Abinding and kappa selectivity of peptides in rat, guinea pig and monkey brain. Eur. J. Pharma COOH col. 121:355-65, 1986. O155 Various abbreviations used herein are as follows: By D-Nle is meant D-norleucine, and D-Hle represents D-ho —cil ( )—cilCOOH moleucine. D-Har represents D-homoarginine, and D-nArg represents D-norarginine which is one carbon shorter than D-Arg. 0159. By Pip is meant piperidinyl, and by 4-HyP and OxP 0156 By D-NaI is meant the D-isomer of alanine which is are meant 4-hydroxypiperidinyl and 4-oxo-piperidinyl. By substituted by naphthyl on the n-carbon. Typically, D-2Nal is Pp.Z is meant piperazinyl. Ecp represents 4-ethylcarbam employed, i.e. the attachment to naphthalene is at the 2-posi oylpiperazinyl; quaternary ammonium moieties, such as tion on the ring structure; however, D-1 Nal may also be used. 4-dimethylpiperazinyl (Dmp) or other di-lower alkyl substi The abbreviations D-Cpa and D-Fpa are used to represent, tutions, may also be used. Substituted benzyl is typically respectively, chloro-D-Phe and fluoro-D-Phe, with D-4Cpa, 4-aminobenzyl, i.e. US 2014/022 1277 A1 Aug. 7, 2014 14

-continued

-CH2 NH2, CHART OF ADDITIONAL FORMULAABBREVIATIONS Abbreviation Definition D-Dbu Alpha, gamma-diaminobutyric acid and by 2-Tzl is meant 2-thiazolyl, i.e. D-Orn D-ornithine D-Ior Isopropyl-D-ornithine Aeb 4-(2-amino-2-carboxyethyl)benzyl S Ppz piperazinyl / \ Pep 4-phenyl carbamoyl piperazin-1-yl - C - C Aao 8-(acetylamino)-3,6-dioxaoct-1-yl || || Aoo 8-amino-3,6-dioxaoct-1-yl N-CH Hoh 6-(L-hydroorotylamino)-hex-1-yl: L-hydroorotic acid is CN2H5O)2-COOH Ghx 6-(D-gluconylamino)-hexyl Gao 6-(D-gluconylamino)-3,6-dioxa.oct-1-yl 0160. By Dor is meant 6-omithinyl where the side chain D-4Fpa 4-fluoro-D- amino group of L-ornithine is connected by an amide bond to D-4Cpa 4-chloro-D-phenylalanine the C-terminus. D-34Cpa 3,4-dichloro-D-phenylalanine D-CML C'methyl-D-Leucine 0161 D-Phe or substituted D-Phe is an example at the D-Acp D-Ala (cyclopentyl) 1-position. The phenyl ring may be substituted at the 2-, 3 Mor Morpholinyl and/or 4-positions, and commonly Substitutions by chlorine Tmo thiomorpholinyl or fluorine at the 2 or 4-position are particular examples. The Pip Piperidinyl 4-HyP 4-hydroxy piperidin-1-yl alpha-carbonatom may also be methylated. Other equivalent OxP 4-oxo-piperidin-1-yl residues which resemble D-Phe may also be used, and these Me Methyl include D-Ala(cyclopentyl), D-Ala(thienyl), D-Tyr and E Ethyl D-Tic. The 2-position residue can also be D-Phe or substi Pr Propyl Bu Butyl tuted D-Phe with such substitutions including a substituent on HEt Hydroxyethyl (i.e., —CHCH-OH) the 4-position carbon of the phenyl ring or the 3- and 4-posi Cyp Cyclopropyl tions. Alternatively, D-alanine substituted by naphthyl can be BZl Benzyl used, as well as D-Trp and D-Tyr. The 3-position can be D-2Fpa 2-fluoro-D-phenylalanine D-Ala (2Thi) 2-thienyl-D-alanine occupied by a residue such as D-Nle, D-Leu, D-CML, D-Hle, 4Pic 4-picolyl D-Met or D-Val; however, D-Ala(cyclopentyl) or D-Phe may C'methyl Methyl attached to the alpha carbon of an amino acid also be used. D-Arg and D-Har, which may be substituted with diethyl, are examples for the 4-position; however, D-nArg and other equivalent residues may be used. Such as 0162. In one embodiment, the invention provides a D-Lys or D-Orin (either of which can have its omega-amino method of treating a mammal exhibiting insufficient or inad group alkylated as by isopropyl or have its C-carbon group equate milk production or at risk of insufficient or inadequate methylated). Moreover, D-Dbu, D-4Amf (which is typically milk production; wherein the method includes administering substituted with amidino), and D-His may also be used. to the mammal an amount of a peripherally selective kappa opioid receptor agonist or salt thereof or prodrug thereof effective to treat the mammal, the peripherally selective CHART OF ADDITIONAL FORMULAABBREVIATIONS kappa opioid receptor agonist or salt thereof or prodrug thereof being a peptide, or ionizes or is metabolized to form a Abbreviation Definition peptide having the formula: D-Phe D-phenylalanine D-Tyr D-tyrosine D-Tic D-1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid D-Ala D-alanine wherein Xaa, is (A)D-Phe, (C'P' Me)D-Phe, D-Tyr, D-Tic D-1Na1 D-Alanine Substituted by naphthyl on the beta carbon or D-Ala(cyclopentyl or thienyl), with Abeing H, NO. F. Cl with the point of attachment at the 1-position on the naphthyl ring structure or CH; Xaa, is (A')D-Phe, D-1 Nal, D-2Nal, D-Tyror D-Trp. D-2Na1 D-Alanine Substituted by naphthyl on the beta carbon with A' being A or 3.4C1, Xaa is D-Nle, (B)D-Leu, D-Hle, with the point of attachment at the 2-position on the D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H naphthyl ring structure or Calpha Me: Xaa is D-Arg, D-Har, D-nArg, D-Lys, D-Lys D-Trp D-tryptophan D-Nle D-norleucine (Ipr), D-Arg(Et), D-Har(Et), D-Amf(G), D-Dbu, (B)D-Orn D-Leu D-leucine or D-Orn(Ipr), with G being Horamidino; and Q is NR. R. D-Hle D-homoleucine morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazinyl, D-Met D-methionine 4-mono- or 4.4-di-Substituted piperazinyl or delta-ornithinyl, D-Wal D-valine D-Arg D-arginine with R being lower alkyl, substituted lower alkyl, benzyl, D-Har D-homoarginine Substituted benzyl, aminocyclohexyl, 2-thiazolyl 2-picolyl, D-nArg D-norarginine 3-picolylor 4-picolyl, R being Hor lower alkyl; and C being D-Lys D-lysine H. 4-hydroxy or 4-oxo. In a particular embodiment Xaa is D-Ily sopropyl-D-lysine D-Arg(Et2) diethyl-D-arginine D-Phe, Xaa, is D-Nle and Xaa, is D-Arg. In another embodi D-Har(Et2) diethyl-D-homoarginine ment Q is NHR and R is ethyl, propyl, butyl, cyclopropyl or D-Amf D-(NH2CH2)-Phenylalanine cyclobutyl. In an alternative embodiment, Q is morpholinyl or D-Gmf D-(CH-NHC(NH)NH)-Phenylalanine thiomorpholinyl; or Q is NHR and R is 4-picolyl. In another embodiment, Xaa, is D-Ala (2-thienyl); alternatively, Xaa is US 2014/022 1277 A1 Aug. 7, 2014

D-4FPhe and Xaa, is D-4ClPhe. In still another embodiment, 0167. In one particular aspect, the method includes: (a) Xaa- is D-Nle or D-Leu and Xaa is D-Ornor D-Amf(Amd). providing a first electrode; (b) providing a second electrode: In another embodiment, Xaa, is D-Phe, Xaa is D-Leu or (c) providing a power source electrically connected to said D-CML and Xaa, is D-Orn. first and said second electrodes; (d) providing at least one 0163 The invention further provides a method of treating donor reservoir having the peripherally selective kappa a mammal exhibiting insufficient or inadequate milk produc opioid receptoragonist, wherein said donor reservoir is asso tion or at risk of insufficient or inadequate milk production; ciated with said first or second electrode; and (e) delivering a wherein the method includes administering to the mammalan therapeutically effective amount of said peripherally selec amount of a peripherally selective kappa opioid receptorago tive kappa opioid receptoragonist through said body Surface. nist or salt thereof or prodrug thereof effective to treat the 0.168. The peripherally selective kappa opioid receptor mammal, the peripherally selective kappa opioid receptor agonist can administered by any of these methods between agonist or salt thereof or prodrug thereof being a peptide, or about 1 microgram/kg of body weight to about 100 milli ionizes or is metabolized to form a peptide having the for grams/kg of body weight of said mammal per hour, day, week mula: or month. These methods of the invention delivering the peripherally selective kappa opioid receptor agonist admin istered can increase prolactinto levels greater than 10, 15, 20, wherein Xaa is D-Phe (unsubstituted or substituted by 25, 50, 75, 100, 125, 150, 175, or 200 ng/ml serum above the C', Me, 2F, 4F or 4C1) or D-Ala(cyclopentyl or thienyl); baseline level of serum prolactin. These methods are particu Xaa- is (A')D-Phe, D-1 Nal, D-2Nal or D-Trp, with A' being larly advantageous for the treatment of female animal Sub H, 4F, 4C1, 4NO or 3.4C1, Xaa, is D-Nle, D-Leu, D-CML, jects (particularly a mammal. Such as for instance a primate, D-Met or D-Acp; Xaa, is D-Arg, D-Arg(Et), D-Lys, D-Ily, ungulate, canine or feline) or human patients, especially preg D-Har, D-Har(Et), D-nArg, D-Orn, D-Ior, D-Dbu, D-Amf nant females or females that have given birth to an offspring and D-AmfAmd); and Q is NR. R. Mor, Tmo, Pip, 4-Hyp, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 12-24, 24-26, 36-48 OxP or Ppz, with R being Me, Et, Pr, Bu, hEt, Cyp, Bzl or hours, days, weeks, or months. Suitable primates include an 4-picolyl, and R being H or Et. In one embodiment, Xaa is ape, gorilla, monkey, macaque, chimpanzee, lemur or oran D-Phe, Xaa is D-Nle and Xaa, is D-Arg. In another embodi gutan. Suitable ungulates include a cow, pig, sheep, goat or ment, Q is NHRandR is ethyl, propyl, butyl, cyclopropylor horse. cyclobutyl. Alternatively, Q can be morpholinyl or thiomor 0169. The invention further provides a method of treating pholinyl. In a further embodiment, Q is NHR and R is a mammal exhibiting an insufficient or inadequate amount of 4-picolyl. Alternatively, Q is NR, RandR is ethyland R is milk production or at risk of exhibiting an insufficient or ethyl. In yet another embodiment, Xaa is D-Phe or D-Ala(2- inadequate amount of milk production, wherein the method thienyl) and Xaa, is D-4ClPhe. In another embodiment, Xaa includes administering to the Subject prior to or after child is D-Nle or D-Leu and Q is morpholinyl. birth an amount of a peripherally selective kappa opioid 0164. In a particular embodiment, Xaa is D-Phe, D-4Fpa, receptor agonist in conjunction with a lactation enhancer, D-2Fpa, D-Acp or D-Ala(2Thi); Xaa, is (A)D-Phe, D-1 Nal, such as for instance, oxitocin or a stabilizer effective to treat D-2Nal or D-Trp, with A being 4F or 4Cl: Xaa is D-Nle, the mammal. The oxytocin can be administered within one or D-Met or D-Leu; Xaa, is D-Arg, D-Har, D-nArg, D-Lys, more hours, days, or weeks following childbirth. In a particu D-Ornor D-Amf(Amd); and QNHR, Mor, Tmo, Pip or Ppz, lar embodiment, the lactation enhancer or stabilizer is admin with R being Et, Pr or 4Pic. istered within one or more hours, days, or weeks following 0.165. In another particular embodiment, the peptide has childbirth. the formula: H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D- 0170 This invention is further illustrated by the following Phe-D-Phe-D-Nle-D-Arg-morpholinyl, H-D-Phe-D-Phe-D- examples which in no way should be construed as being Nle-D-Arg-NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg further limiting. The contents of all cited references (includ NHPr, H-D-Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, ing literature references, issued patents, published patent H-D-Phe-D-Phe-D-Nle-D-Arg-Net, H-D-Phe-D-Phe-D- applications, and co pending patent applications) cited Nle-D-Arg-NHMe, H-D-Phe-D-Phe-D-Leu-D-Orn-mor throughout this application are hereby expressly incorporated pholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NHhEt, H-D-Phe by reference. D-Phe-D-Nle-D-Arg-NH-cyclopropyl, H-D-Ala(2Thi)-D-4 Cpa-D-Leu-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D- EXAMPLES Arg-piperidinyl, H-D-Phe-D-Phe-D-Leu-D-Orn-NHEt, 0171 The safety, tolerability, pharmacokinetics, and pro H-D-Phe-D-Phe-D-Leu-D-Lys-morpholinyl, or H-D-Phe-D- lactin-elevating activity of ascending single intravenous (IV) Phe-D-Nle-D-Arg-piperazinyl. doses of one of the compounds of the instant invention, 0166 Mammals exhibiting insufficient or inadequate milk D-phenylalanyl-D-phenylalanyl-D-norleucyl-N-(4-pyridi production or at risk of insufficient or inadequate milk pro nylmethyl)-D-argininamide, acetate salt, herein designated duction can be treated by a method according to the present as CR665, was assessed in healthy male and surgically sterile invention; the method includes administering to the mammal female human subjects following 1-hour or 5-minute infu an amount of a peripherally selective kappa opioid receptor sions. CR665, also referenced in the literature as FE 200665, agonist or salt thereof or prodrug thereof effective to treat the is a peripherally selective kappa opioid receptor agonist; see mammal, wherein the administration includes intravenous, U.S. Pat. No. 5,965,701; also Riviere P. J.-M. et al. Novel Subcutaneous, intramuscular, intranasal, oral, or transdermal D-amino acid tetrapeptides demonstrate unprecedented administration, Such as for instance by an electrotransport k-opioid receptor selectivity and antinociception. 30” Int. device. In one embodiment of the method the electrotransport Res. Conf. (INRC) 1999, Saratoga Springs, N.Y., device delivers the peripherally selective kappa opioid recep Jul. 10-12, 1999: Wisniewski Ketal. Long acting, selective, toragonist through a body Surface. peripheral kappa agonists. 26" European Peptide Sympo US 2014/022 1277 A1 Aug. 7, 2014

sium, Montpilier, France, Sep. 11-15, 2000; Binder Wet al. and antiinflammatory effects of two novel kappa Volume of 10 mg/mL CR665(mL) = opioid peptides. Anesthesiology. 94:1034-44, 2001; Riviere PJ. Peripheral kappa-opioid receptor agonists for visceral Dose level (mg/kg) Xbody weight (kg)x (40/30/10) pain. BrJ Pharmacol. 141:1331-4, 2004). Volume of buffer = 40 mL volume of CR665 required (mL) Study Design and Procedures 0172. This clinical study was conducted as a double blind, Table 2 provides some example dilutions, based on a 70 kg placebo controlled, ascending single intravenous (IV) dose, body weight. sequential group study. The results reported herein were obtained with 54 male and female human subjects in fifteen TABLE 2 groups as shown in Table X below. This study was double CR665 blind and placebo controlled in order to avoid bias in the CR665 dose dose collection and evaluation of data during its conduct. Placebo to be infused to be Concentration CR665 NaCl was chosen as the control treatment to assess whether any Dose for a 70 kg prepared of dose solution buffer observed effects were treatment related or simply reflected level person (mg/ solution volume volume the study conditions. In each group, subjects received CR665 (mg/kg) (mg/30 mL) 40 mL) (mg/mL) (mL) (mL) or placebo. Doses were administered as a single constant rate O.O15 1.OS 140 O.04 O.14 39.86 O.O3 2.10 2.80 O.O7 O.28 39.72 IV infusion over 1 hour (part A) or 5 minutes (part B) on the O.O6 4.20 5.60 O.14 O.S6 39.44 morning of Day 1. Doses were administered in an escalating O.12 840 11.20 O.28 1.12 38.88 manner following satisfactory review of the safety data and O.24 16.8O 22:40 O.S6 2.24 37.76 pharmacokinetic data from the lower dose levels. There was a minimum of 6 days between dose escalations to allow suffi Concentration 10 mg/mL cient time for an adequate safety review. 0177. The dose was administered via a cannula inserted (0173 Dose levels were as shown in Table 1: into a suitable vein of the forearm in the non dominant arm of the subject. The dose was infused over a 1 hour period in the TABLE 1. morning between 07:00 and 10:30, using an IMED Gemini Treatments PCI infusion pump operating at a constant rate of 0.5 ml/min (30 mL/h). A total of 30 mL of dosing solution (from 40 mL Infusion in the Syringe) was administered, and the Subjects remained Part Group Population Treatment duration Supine throughout the infusion. A. A1 Males 0.015 mg/kg placebo. 1 hour 0.178 From 24 hours after the start of the infusion, meals A2 Males 0.03 mg/kg placebo 1 hour were provided at appropriate times on each day. Other than A3 Males 0.06 mg/kg placebo 1 hour A4 Males 0.12 mg/kg placebo 1 hour the fluid restrictions on Day 1, water was freely available at all AS Males 0.24 mg/kg placebo 1 hour times. The Volume of fluid consumed up to 24 hours after the A6 Males 0.48 mg/kg placebo 1 hour start of the infusion was recorded as part of the fluid balance A7 Males 0.36 mg/kg placebo 1 hour assessment. Subjects fasted from food and beverages (other A8 Males 0.48 mg/kg placebo 1 hour A9 Females 0.24 mg/kg placebo 1 hour than water) from 22:00 on Day 1, until the clinical laboratory A10 Females 0.42 mg/kg placebo 1 hour samples had been taken on the following day, and for at least A12 Males 0.42 mg/kg placebo 1 hour 6 hours prior to the follow up visit. B B1 Males 0.03 mg/kg placebo 5 minutes B2 Females 0.06 mg/kg placebo 5 minutes 0179. On arrival at the clinical study center on Day -1, pre B3 Males 0.06 mg/kg placebo 5 minutes dose assessments were performed, including testing a urine B4 Males 0.09 mg/kg/placebo 5 minutes sample for the presence of illicit drugs, administering an alcohol breath test, and the recording of body weight (in 0.174 CR665 was prepared according to Good Manufac underclothes). Subjects then commenced a 24 hour urine turing Practice (GMP) standards and provided as bulk supply collection for assessment of creatinine clearance and fluid in 2 mL glass vials, each containing CR665 Solution (1.1 mL balance. Vitals signs and 12 lead ECG were also assessed, and at a concentration of 10 mg/mL free base in isotonic 0.04M all Subjects received a physical examination. acetate buffer, pH 4.5). Placebo solution (isotonic 0.04M 0180. The condition of each subject was monitored acetate buffer, pH 4.5) for IV administration, of identical throughout the study. In addition, any signs or symptoms appearance, i.e., a clear, colorless, Solution, was also pre were observed and elicited by open questioning, Such as pared. The TV dose solutions were stored at 2°C. to 8°C. “How have you been feeling since you were last asked?” at 0.175. The individual intravenous dose for each subject the following times for each part of the study: Pre dose, 0.5, 1. was prepared from bulk Supplies (2 mL vials containing 1.1 3, 12, 24, 36 and 48 hours after the start of the infusion (up to mL of CR665 or placebo solution). For each dose preparation, 24 hours only for Groups A1 to A4), and at Follow up assess an appropriate volume of CR665 solution (10 mg/mL) or ment. placebo Solution was withdrawn from one or more vials using 0181 Subjects were also encouraged to spontaneously a syringe, and injected into a 60 mL Plastipak polypropylene report adverse events occurring at any other time during the Syringe (Beckton Dickinson S.A., Spain) containing an study. Any adverse events and remedial action required were appropriate volume of sterile NaCl buffer. to be recorded for each subject. The nature, time of onset, 0176 For the 1 hour infusions, the final volume prepared duration and severity were documented, together with the was 40 mL, of which 30 mL was infused. The dose calculation Project Physician’s opinion of the relationship to drug admin was as follows: istration. US 2014/022 1277 A1 Aug. 7, 2014

0182. The condition of the dosing cannula site for each TABLE 3-continued Subject was monitored for erythema, pruritus and Swelling at the following times: Pre dose, 0.5, 1, 2 and 24 hours after the Units start of the infusion. Subjects were also encouraged to spon norganic phosphate mmol/L. taneously report adverse events relating to the infusion site at Glucose mmol/L. any other time during the study. Any adverse events and Urea mmol/L. Bilirubin (total) Imol/L. observations relating to the infusion site and remedial action Creatinine Imol/L. required were to be recorded for each subject. The nature, Total protein g/L time of onset, duration, and severity were to be documented, Albumin g/L together with the Project Physician's opinion of the relation Urinalysis: ship to drug administration. Microscopic examination -- 0183 Supine and standing blood pressure, supine pulse Specific gravity NA rate and oral body temperature were measured in duplicate at bH NA the following times: Day 1: Pre dose, 15 minutes (Part B Protein -- Glucose -- only), 30 minutes, 55 minutes, 1.5, 2, 2.5, 3, 4, 8, 12, 24 and Ketones -- 48 hours after the start of the infusion (up to 24 hours only for Blood -- Groups A1 to A4); and at Follow up visit. Supine vital signs Urobilinogen -- only were measured during the infusion period. Pre dose Hematology: blood pressure and pulse rate were measured in triplicate at White blood cell count (WBC) 109 L approximately 2 minute intervals. The median value was used Red blood cell count (RBC) 1012/L as the baseline value in the data analysis. All Subsequent Haemoglobin g/dL measurements were performed singly, but repeated in dupli Haematocrit (PCV) % Mean cell volume (MCV) fL cate if outside the relevant clinical reference ranges. If Mean cell haemoglobin (MCH) pg repeated, the median of the three values were used in the data MCH concentration (MCHC) g/dL analysis. Blood pressure and pulse rate were measured using Platelet count 109 L automated Critikon DinamapTM PRO400 monitors. Subjects Differential WBC 10/L & 9% were required to be supine for at least 5 minutes before blood Serology: pressure and pulse rate measurements. Standing blood pres Hepatitis B surface antigen (HBSAg) neg pos Sure and pulse rate were then measured singly after the Sub Hepatitis Cantibody' neg pos ject had been sitting for approximately 1 minute and then HIV antibodies' neg pos standing for approximately 2 minutes. Oral body temperature Direct bilirubin analyzed only if total bilirubin is elevated was measured singly using an Omron digital thermometer. To Analyzed at screening only assess drug effects on cardiovascular function, a 12 lead rest Neg=Negative ing ECG with a 10 second rhythm strip was recorded on a Pos = Positive Marquette MAC5000 ECG machine at the following times, 0185 Blood samples (2.5 mL) were collected for evalua after the subject has been supine for at least 5 minutes: Day 1: tion of serum prolactin at the following times: Pre dose (in Pre dose, 50 minutes, 2, 4, 8, 24 and 48 hours after the start of triplicate, with at least a 15 minute interval between each of the infusion (up to 24 hours only for Groups A1 to A4); and at the triplicate predose samples), 15 minutes, 30 minutes, 45 the follow up visit. The ECG machine computed the PR, QT minutes, 1 hour (immediately prior to the end of infusion), 1 and QTc intervals, QRS duration, and heart rate. The QT hour 5 minutes, 1 hour 10 minutes, 1 hour 15 minutes, 1.5, 2, interval was corrected for heart rate (QTc) using Bazett's 2.5, 3, 4, 6, 8 and 12 hours after the start of the infusion (18 formula. For continuous ECG measurements, continuous car samples). diac Holter monitoring of each Subject, using Reynolds 0186 Plasma and urine samples for the analysis of CR665 Tracker II Bolter monitors, was performed from 1 hour prior and N oxide metabolite were prepared by solid phase extrac to until 4 hours after the start of the infusion. Blood and urine tion. The centrifuged eluates were quantified by liquid chro samples were collected, after at leasta 6 hour fast, for clinical matography with tandem mass spectrometric detection (LC laboratory evaluations at the following times during the MS/MS). The lower limit of quantification was 1 ng/mL. study: Predose and 24 hours after the start of the infusion; and 0187. After collection of urine samples, following at the follow up visit. removal of the aliquots for drug assay and/or urinalysis, urine 0184 The following evaluations were performed, as was pooled over the following time intervals: 24 to 0 hours shown in Table 3. and 0 to 24 hours after the start of the infusion. A 10 mL aliquot was removed from the each pooled collection for TABLE 3 determination of urinary creatinine. Units 0188 An assessment of fluid balance (made by compari son of volume of fluid consumed and volume of fluid Serum biochemistry: excreted) was made over the following periods: 24 to 0 hours Aspartate aminotransferase (AST) IUL and 0 to 24 hours after the start of the infusion. During these Alanine aminotransferase (ALT) IUL periods, the volume of fluid consumed and the volume of Alkaline phosphatase IUL urine excreted was recorded. Gamma-glutamyl transferase (GGT) IUL 0189 A full physical examination, including a neurologi Sodium mmol/L. Potassium mmol/L. cal examination, was performed at the following times: Dis Chloride mmol/L. charge (Day 2 or 3) and at Follow up visit. Calcium mmol/L. 0190. For pharmacokinetic assessments, blood samples (1x3 mL) were taken from the contralateral forearm vein(s)at US 2014/022 1277 A1 Aug. 7, 2014 18 the following times: Pre-dose, 15 minutes, 30 minutes, 45 TABLE 4-continued minutes, 1 hour (immediately prior to the end of infusion), 1 hour 5 minutes, 1 hour 10 minutes, 1 hour 15 minutes, 1.5, 2, Pharmacokinetic Parameters Determined for CR665 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after the start of the and the N-Oxide Metabolite infusion). An indwelling cannula (Venflon R; BOC Ohmeda Parameter Definition AB, Sweden) was used for all blood collection pre-dose and Ae Amount of drug excreted in urine up to at least 12 hours after the start of the infusion. Other fe Percentage of dose excreted in urine wise, samples were collected using Venipuncture. Blood CLR Renal clearance samples were collected into pre-chilled 3 mL KEDTA Vacu tainerTM tubes (Becton Dickinson UK, Ltd., Oxford) and, after mixing, were placed in a cool box containing crushed 0194 Dose and body weight normalized values (norm) ice/water. The samples were centrifuged, within 30 minutes were determined for AUCo. AUCo., C, and C. Body of collection, at 1500 g for 10 minutes at approximately 4°C. weight normalized values norm were determined for V. For each sample, the separated plasma was transferred into V. CL and CL. two 5 mL suitably labeled polypropylene, tubes, and stored 0.195 The pharmacokinetic analysis was conducted using immediately at approximately -20°C. Plasma samples were model independent methods as implemented in WinNonlin analyzed for CR665 using liquid chromatography with tan software, based on plasma concentrations of CR665 from those subjects who have received CR665 and have evaluable dem mass spectrometric detection. plasma concentration-time profiles. 0191 Urine was collected into standard weight polyethyl 0196. The following plasma pharmacokinetic parameters ene containers over the following time intervals: Pre dose were determined for CR665: (-24 to 0), 0 to 4, 4 to 8, 8 to 12, 12 to 24 and 24 to 48 hours (0197) C. Maximum plasma concentration after the start of the infusion. During each collection period, 0198 to Time of maximum plasma concentration the containers were stored in a refrigerator at 2 to 8°C. The (0199 t Terminal half-life-ln(2)/ weight(g) of each collection was recorded prior to removal of 0200 AUC. Area under the plasma concentration two Sub samples (each approximately 4 mL) into Suitably time curve from time Zero to time t (time of last quanti labeled polypropylene containers, which were stored within2 fiable plasma concentration) hours of collection, at approximately -20°C. Additional ali 0201 AUC, Area under the plasma concentration quots (1x100 mL per collection period) were stored for pos time curve from time Zero to infinity calculated as sible future analyses. Any remaining urine from post close AUCo+(C/W) where C, is the estimated concen collection intervals was pooled with the rest of the urine tration at the last quantifiable concentration curve. collected during the 0 to 24 hour collection period, for analy 0202 W Terminal-phase rate constant, also known as sis of creatinine clearance. A nominal value for specific grav Ke ity of 1.018 was used to calculate urine volume. (0203. CL Total body clearance-Dose/AUC 0.192 The pharmacokinetic analysis was conducted using 0204 V. Volume of distribution based on terminal WinNonlin Enterprise Version 4.0.1. phase calculated as 0193 Pharmacokinetic parameters were determined from the plasma and urine concentrations of CR665 and the N-ox 0205 Individual elapsed sampling times were used in the ide metabolite using non compartmental procedures. The pharmacokinetic analysis. C, and t, were obtained pharmacokinetic parameters determined are presented in directly from the experimental observations. For the purpose Table 4 below. of calculating AUCo., when two consecutive plasma concen trations below the lower limit of quantification (LLOQ) were TABLE 4 encountered after t, all Subsequent values were excluded from the analysis. The exponential rate constant of the termi Pharmacokinetic Parameters Determined for CR665 nal-phase, W, was estimated by linear regression of the log and the N-Oxide Metabolite concentration-time data associated with the terminal phase of Parameter Definition the plasma concentration-time profile. The number of data AUCo. Area under the plasma concentration-time curve from time points included in the regression was determined by visual Zero up to the last quantifiable concentration inspection. A minimum of 3 data points in the terminal phase, AUCo Area under the plasma concentration-time curve from time excluding C, was required to estimate W. Zero to infinity 0206. An assessment of dose-proportionality of the phar % AUC Percentage of AUC that is due to extrapolation from t to infinity macokinetics of CR665 was also performed. Log-trans Cmax Maximum observed plasma concentration formed AUGo AUC, and C were derived and a model of Cinf Plasma concentration at end of the IV infusion the form: max Time of maximum observed plasma concentration t Time of last quantifiable plasma concentration Log(parameter)=Intercept--B'Log(Dose)+Error W. Apparent plasma terminal elimination rate constant t1/2 Apparent plasma terminal elimination half-life where dose is a fixed term was fitted to assess a between MRT Intrinsic mean residence time Subject estimate of the slope in order to assess dose-propor CL Total plasma clearance (CR665 only) tionality. A pointestimate of the slope B, with 90% confidence V. Apparent volume of distribution during the terminal intervals, provides a plausible range for which the true slope phase (CR665 only) V Apparent volume of distribution at steady-state (CR665 only) occurs. The interpretation of the slope is such that a conclu MR4C Metabolic ratio based on AUC (N-oxide metabolite only) sion of dose-proportionality for AUGo AUC and C, of MR. Metabolic ratio based on C (N-oxide metabolite only) CR665 will be made if the 90% CI for the slope contains the value 1. US 2014/022 1277 A1 Aug. 7, 2014

0207. The pharmacodynamic analysis was conducted tinine, for any subject during the study. The mean creatinine using WinNonlin Enterprise Version 4.0.1 (Pharsight Corpo clearance was generally similar prior to dosing and at 24 ration, Mountain View, Calif., USA). The following pharma hours after dosing for each dose level of CR665 and placebo. codynamic parameters were calculated from the serum con There were no apparent treatment or dose related trends in centrations of prolactin: fluid balance (urine excreted-fluid consumed) over the 0 to 0208 Change from baseline (mean of triplicate pre 24 hour period after the start of the infusion. However, an dose values) at each sampling time increase in the volume of urine excreted over the first 4 hours 0209 Maximum observed change from baseline (C) after the start of the infusion was observed at each dose level 0210 Area under the change from baseline time curve of CR655 compared to placebo in male and female subjects from 0 to 12 hours (AUCo.2 ) for Parts A and B of the study. 0211. This study was conducted under a MHRA Clinical Trials Authorization (CTA) in accordance with: (1) the rel Pharmacodynamics: Time Course of Prolactin evant articles of the Declaration of Helsinki as adopted by the Elevation by CR665 18th World Medical Assembly in 1964 and as revised in 0215. The administration of single IV doses of CR665 Tokyo (1975), Venice (1983), Hong Kong (1989), South caused a rapid and marked increase in serum concentrations Africa (1996) and Scotland (2000); and (2) the ICH Good of prolactin across all dose levels in male and female Subjects. Clinical Practices (GCP) consolidated guidelines adopted in Changes from baseline (pre dose) in serum concentrations of the EU by CPMP, July 1996, issued as CPMP/ICH/135/95. prolactin following 1-hour and 5-minute infusions of placebo and CR665 in male and female subjects are shown in FIGS. 1 Drug Safety to 3: 0212 All 54 subjects completed the treatment period with 0216. The derived pharmacodynamic parameters for no severe or serious adverse events. In particular, even at the serum prolactin following 1-hour and 5-minute infusions of highest dose levels, there were no signs of the more typical placebo and CR665 in male and female subjects are summa CNS symptoms (hallucinations or dysphoria) associated with rized in Tables 5 to 7: TABLE 5 Summary of the Pharmacodynamic Parameters of Serum Prolactin (Changes from Baseline) Following a 1 hour IV Infusion in Male Subjects PartA Dose of (mg/kg

Placebo O.O15 O.O3 O.O6 O.12 O.24 O.36 O.42 O48 males males males males males males males males males Parameter (N = 17) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 8) AUCo-12, O.760 30.8 57.4 43.6 89.5 119 140 132 131 (ng himL) (27.5) (87.6) (30.3) (32.2) (38.6) (22.3) (40.0) (51.5) (74.5) Cmax 4.61 22.2 18.8 25.3 39.3 36.3 45.5 44.2 47.2 (ngmL) (3.44) (6.44) (1.47) (6.41) (13.9) (17.3) (16.9) (10.8) (27.4) Arithmetic mean (SD) data are presented N = Number of subjects studied intolerable dose levels of previously tested kappa opioid TABLE 6 receptor agonists. For the 12-lead ECG evaluations, there were no treatment related trends, significant clinical changes, or abnormalities in the morphology of the 12 lead ECG. Summary of the Pharmacodynamic Parameters of Serum Similarly, for the clinical laboratory evaluations, there were Prolactin (Changes from Baseline) Following a 1 hour IV no treatment related trends or significant clinical findings in Infusion in Female Subjects (Part A) serum biochemistry, hematology, or urinalysis parameters. Physical examination of the subjects also revealed no treat Dose of (mg/kg) ment related findings. 0213. In Parts A and B of the study, there were no treat Placebo O.24 ment or dose related trends in mean Supine and standing females females systolic and diastolic blood pressure, Supine and standing Parameter (N = 3) (N = 3) pulse rate or oral body temperature. No apparent treatment or dose related trends in the 12 lead ECG parameters were noted AUCo-12, 19.7 209 in Parts A and B. In addition, there were no clinically impor tant findings in the morphology of the 12 lead ECGs for (ng himL) (23.5) (21.1) individual subjects at each dose level of CR665. There was no Cmax 3.67 68.2 evidence of prolongation of QTc interval (Bazett's and (ngmL) (2.27) (14.3) Friedericia's corrected) at each dose level of CR665 in male and female Subjects. Arithmetic mean (SD) data are presented 0214. For Parts A and B, there were no clinically important N = Number of subjects studied changes in creatinine clearance, estimated from serum crea US 2014/022 1277 A1 Aug. 7, 2014 20

TABLE 7 there was a dose-related decrease to baseline levels. Mean values had fallen to close to baseline values by 8 hours at the Summary of the Pharmacodynamic Parameters of 0.36, 0.42 and 0.48 mg/kg dose levels. Serum Prolactin (Changes from Baseline) Following a 0218. In Part A, following 1 hour infusions of 0.24 mg/kg 5 minute IV Infusion in Male and Female Subiects (Part B CR665 in female Subjects, maximum serum prolactin con Dose of (mg/kg centrations occurred at 1 hour after the start of the infusion. The mean C. values (change from baseline) in females males males males males females were higher than in male Subjects, with maximum serum Parameter (N = 5) (N = 4) (N = 4) (N = 4) (N = 4) prolactin levels being approximately 12-fold greater than baseline (pre dose) in females. AUCo-12, -0.876 24.3 74.3 68.5 96.8 (ng himL) (34.1) (35.4) (44.2) (13.5) (32.9) 0219. In Part B, following 5-minute infusions of 0.03 to Cmax 4.08 33.6 42.O 37.1 32.3 0.09 mg/kg. CR665 in male subjects, maximum serum pro (ng/mL) (3.63) (14.3) (22.8) (13.3) (14.8) lactin concentrations occurred at 30 minutes after the start of the infusion, i.e., 25 minutes after the end of the infusion. Arithmetic mean (SD) data are presented Mean C. values were generally similar at the 0.03, 0.06 and N = Number of subjects studied 0.09 mg/kg dose levels, with maximum serum prolactin lev 0217. In Part A, following 1-hour infusions of 0.015 to els being approximately 4- to 6-fold higher than baseline (pre 0.48 mg/kg. CR665 in male subjects, there was a rapid and dose) across these dose levels. In female Subjects, maximum marked increase in serum prolactin concentrations. At each serum prolactin concentrations occurred at 0.5 to 1 hour after dose level, maximum serum prolactin concentrations gener the start of the 5-minute infusion of 0.06 mg/kg. CR665. The ally occurred at 1 hour after the start of the infusion, i.e. at the mean C. value in females was similar to male Subjects, with end of the infusion. There was an apparent dose-related maximum serum prolactin levels being approximately 4-fold increase in mean values for C (maximum changes from greater than baseline (pre dose) in females. baseline in serum prolactin) up to the 0.36 mg/kg dose level. Mean C. values were generally similar at the 0.36, 0.42 and Part A: Pharmacokinetics of CR665 After a One 0.48 mg/kg dose levels, with maximum serum prolactin lev Hour Intravenous Infusion els being approximately 5- to 6-fold higher than baseline 0220. The plasma concentrations of CR665 following a 1 (pre-dose) across these dose levels. Mean values for AUCo hour infusion in male subjects are shown in FIGS. 4 and 5. h (changes from baseline) increased up to 0.36 mg/kg, and 0221) The pharmacokinetic parameters of CR665 follow thereafter were generally similar over the 0.36 to 0.48 mg/kg ing a 1-hour infusion in male Subjects are Summarized in dose range. Following maximum concentrations of prolactin, Table 8. TABLE 8 Summary of the Pharmacokinetic Parameters for CR665 Following a 1 hour IV Infusion in Male Subiects (PartA Dose of (mg/kg) males

O.O15 O.O3 O.O6 O.12 O.24 O.36 O42 O48 Parameter (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 4) (N = 8) AUCo. 3O.O 7O.O 129 267 474 808 1080 1120 (ng himL) (20.3) (14.2) (30.2) (7.17) (10.4) (8.39) (17.4) (20.5) AUCo. 31.4 72.5 132 270 478 812 1084 1125 (ng himL) (21.7) (15.5) (29.8) (7.11) (10.5) (8.37) (17.5) (20.4) Cmax 27.8 65.3 119 231 431 779 943 982 (ngmL) (15.2) (13.7) (24.8) (5.87) (8.30) (10.1) (13.7) (15.7) tmas 1.OO 1.00 0.875 0.750 1.00 1.OO 1.OO 0.875 (h) (0.750-1.02) (1.00-1.00) (0.733-1.35) (0.750-1.00) (1.00-1.00) (0.767-1.00) (0.750-1.00) (0.750-1.00) AUCo. 1979 2349 2161 2232 1979 2252 2573 2333 (norm) (20.5) (14.6) (30.1) (7.06) (10.2) (8.40) (17.0) (20.5) AUCo. 2O72 2430 22O1 2257 1994 2263 2582 2344 (norm) (22.0) (16.0) (29.7) (7.00) (10.3) (8.38) (17.1) (20.5) Cmax 1837 21.89 1991 1932 1797 2170 2248 2046 (norm) (15.1) (13.8) (24.7) (5.86) (8.12) (10.1) (13.2) (15.9) t12 O.691 0.732 O.728 1.65 1.37 1.64 1.78 1.87 (h) (73.2) (50.0) (14.4) (24.0) (17.6) (21.0) (41.8) (36.4) MRT O.S12 O.S10 O.S63 0.723 O.614 O.623 O618 O649 (h) (43.5) (35.8) (25.7) (23.1) (15.6) (19.8) (17.5) (20.8) CL S60 538 S64 533 629 569 SO4 576 (mL/min) (15.2) (16.0) (17.8) (8.71) (6.47) (11.5) (21.3) (18.6) V. 33.5 34.1 35.5 75.9 74.6 80.6 77.9 93.3 (L) (60.2) (42.2) (7.44) (20.9) (15.7) (13.3) (22.3) (39.1) V 17.2 16.5 19.0 23.1 23.2 21.2 8.7 22.4 (L) (35.4) (31.3) (32.1) (22.3) (18.0) (16.0) (8.42) (20.3) Geometric mean (CV%) data are presented Median (min - max) N = Number of subjects studied (norm) = Normalized for dose and body weight (mg/kg) US 2014/022 1277 A1 Aug. 7, 2014

0222. During the TV infusion of CR665 at dose levels of 0228 Geometric mean plasma concentrations of CR665 0.015 to 0.48 mg/kg in male Subjects, plasma concentrations following a 1-hour infusion of 0.24 mg. CR665 in female increased rapidly, with maximum concentrations generally subjects are summarized in FIGS. 7 and 8. occurring at the end of the 1 hour infusion. Plasma concen trations of CR665 were generally similar at 45 minutes and 1 0229 Arithmetic mean plasma concentrations of CR665 hour after the start of the infusion for individual subjects at following a 1-hour infusion of 0.24 mg/kg. CR665 in male and each dose level. female subjects are summarized in FIG. 9. 0223 Following the end of the IV infusion, plasma con 0230. The pharmacokinetic parameters of CR665 follow centrations of CR665 appeared to decline in an essentially ing a 1-hour infusion of 0.24 mg/kg. CR665 in male and biphasic manner with the start of the elimination phase occur female subjects are summarized in Table 9. ring between 1.25 and 6.0 hours after the start of the infusion. TABLE 9 0224. The mean apparent elimination half life was rela tively constant in the 0.015 to 0.06: mg/kg dose range, at Summary of the Pharmacokinetic Parameters for about 0.7 hours, but became longer across the 0.12 to 0.48 CR665 Following a 1-hour IV Infusion of 0.24 mg/kg mg/kg dose range, varying from 1.4 to 1.9 hours, with a trend CR665 in Male and Female Subiects (PartA toward longer half life values at higher doses. For individual 0.24 mg/kg Subjects across the 0.12 to 0.48 mg/kg dose range, the appar ent elimination half life ranged from 1.2 to 3.0 hours. This Males Females apparent increase inhalflife at higher dose levels is consistent Parameter (N = 4) (N = 3) with plasma concentrations of CR665 being quantifiable for a AUCo. 474 440 longer period of time at the higher dose levels, revealing more (ng himL) (10.4) (10.2) AUCo. 478 442 of true terminal elimination phase. As a result, statistical (ng himL) (10.5) (10.1) analysis showed that the elimination half life for CR665 was Cmax 431 384 dose dependent over the entire dose range. (ngmL) (8.30) (3.03) tna. 1.OO 0.750 0225 AUCo. and C generally appeared to increase in (h) (1.00-1.00) (0.750-1.00) a dose-proportional manner over the dose range of 0.015 to AUCo. 1979 1846 0.48 mg/kg. This observation was confirmed by statistical (norm) (10.2) (9.71) AUCo- 1994 1855 analysis, with the estimates of the slopes (95% CI) from the (norm) (10.3) (9.65) regression analysis for AUC and C being 1.02 (0.978 to Cmax 1797 1612 1.06) and 1.02 (0.984 to 1.05). FIG. 6 illustrates the dose (norm) (8.12) (2.33) proportional increase in AUC for CR665 over the dose t1/2 1.37 1.16 (h) (17.6) (15.9) range of 0.015 to 0.48 mg/kg. MRT O.614 0.515 (h) (15.6) (12.9) 0226. The dose proportionality of the increase in AUC was CL 629 557 found to be almost perfectly linear, as shown in FIG. 6, with (mL/min) (6.47) (9.21) an R value of 0.98, meaning that, for this data set, 98% of the V. 74.6 55.7 variation in systemic exposure to CR665 is due to variation in (L) (15.7) (12.4) the administered dose of CR665. The importance of this V 23.2 17.2 observation is that it enables the practitioner to predict, with (LS (18.0) (13.1) a high degree of accuracy, what drug exposures will occur Geometric mean (CV%) data are presented with a given dose of drug. In fact, one skilled in the art can use Median (min-max) this information, together with the calculated pharmacoki N = Number of subjects studied netic parameters of the drug (see Table 6), to accurately (norm) = Normalized for dose and body weight (mg/kg) estimate the plasma levels of drug that would result from intravenous infusions of different doses, at what time a steady 0231. Following administration of 0.24 mg/kg. CR665 in state concentration of drug would be achieved, and how to female Subjects, maximum plasma concentrations were design individualized dosage regimens to achieve steady state obtained at a similar time to those observed in males, i.e., drug concentrations for a particular patient (Bauer, L. A. close to the end of the IV infusion. Thereafter, the disposition Applied Clinical Pharmacokinetics, Chap. 2. “Clinical phar kinetics of CR655 were similar in male and female subjects, macokinetic equations and calculations', pp. 26 49, 2001). with a mean terminal elimination half-life of approximately Since controlled release formulations (e.g., microspheres) 1.2 to 1.4 hours. At the 0.24 mg/kg dose level, mean values for and devices (e.g., for electrotransport) are intended to provide AUCo., AUCo. (norm), C, and C (norm) were gener prolonged steady state drug concentrations, the skilled prac ally similar in male and female subjects. The between-subject titioner utilizes this pharmacokinetic information to define variability for AUCo. and C was low and similar in male the useful operating characteristics of modes of drug delivery. and female subjects at the 0.24 mg/kg dose level. These findings are important because they confirm the predictability 0227 Statistical analysis showed that total plasma clear of the pharmacokinetics of CR665, which assists the skilled ance of CR665 (CL) was dose-independent; however MRT practitioner in the design of alternative dosing regimens that and the volume of distribution (V and V) were found to be dose-dependent. This was due to the observed change in the are intended to achieve particular plasma levels of drug over elimination rate constant (W), which was probably due to the time. fact that the CR665 was quantifiable for a longer period of 0232. The urinary excretion of CR665 following a 1-hour time, post-injection, at the higher dose levels, rather than true infusion of 0.24 mg/kg. CR665 in male and female subjects is dose-dependency in the kinetics of CR665. summarized in Table 10. US 2014/022 1277 A1 Aug. 7, 2014 22

TABLE 10 0233. The fraction of the dose excreted in the urine as unchanged drug was low in female Subjects, and similar to Summary of the Urinary Excretion of CR665 Following a 1 hour IV that seen for male Subjects. Infusion of 0.24 mg/kg CR665 in Male and Female Subjects (Part A) Part B: Extrapolation of Part A PK Data to Design Brief IV Infusions of CR665 0.24 mg/kg 0234 For the Part B studies, five minute infusion dosing Males Females protocols were designed using conventional pharmacokinetic Parameter (N = 4) (N = 3) calculations (e.g., Bauer, L. A. Applied Clinical Pharmacoki netics, Chap. 2. “Clinical pharmacokinetic equations and cal Aeo-24, 631 446 culations”, pp. 2649, 2001), based on the results obtained in (Ig) (39.1) (30.0) the one hour infusion study (PartA). Doses were calculated to feo 24, 3.SO 3.02 produce systemic exposures to CR665 similar to those seen in (%) (26.2) (23.2) the one hour infusion study CLR 0-24 h 22.O 16.8 0235 Plasma concentrations of CR665 following a (mL/min) (27.9) (22.7) 5-minute infusion in male and female Subjects are shown in FIGS. 10 and 11. Geometric mean (CV%) data are presented 0236. The pharmacokinetic parameters of CR665 follow N = Number of subjects studied ing a 5-minute infusion in male and female Subjects are sum marized in Table 11. TABLE 11

Summary of the Pharmacokinetic Parameters for CR665 Following a 5-minute IV Infusion in Male and Female Subjects (Part B)

Dose of (mg/kg)

O.O3 O.O6 O.09 O.O6 males males males females Parameter (N = 3) (N = 4) (N = 4) (N = 3)

AUCo. 65.9 139 209 120 (ng himL) (12.6) (15.8) (16.2) (9.29) AUCo. 68.4 142 213 122 (ng himL) (11.8) (16.3) (16.4) (8.79) Cmax 233 624 783 52O (ng/mL) (14.5) (32.2) (19.6) (18.8) tna, O.0833 O.0833 O.O833 O.0833 (h) (0.0833-0.100) (0.0833-0.0833) (0.0833-0.0833) (0.0833-0.0833) AUCo. 2192 2327 2318 2013 (norm) (12.3) (16.0) (16.1) (8.92) AUCo. 2273 2372 2369 2044 (norm) (11.6) (16.5) (16.2) (8.43) Cmax 7751 10418 8701 8716 (norm) (14.4) (32.5) (19.8) (18.4) t1/2 1.31 1.00 1.14 O.833 (h) (18.3) (13.0) (23.9) (22.4) MRT O.615 OSO2 0.537 O419 (h) (448) (26.3) (21.0) (24.2) CL 473 553 575 544 (mL/min) (7.06) (15.5) (14.3) (9.47) V. S3.6 48.0 56.7 39.2 (L) (14.0) (13.4) (33.5) (21.5) V 17.4 16.6 18.5 13.7 (L) (3.13) (24.2) (24.3) (18.8)

Geometric mean (CV%) data are presented Median (min-max) N = Number of subjects studied (norm) = Normalized for dose and body weight (mg/kg) US 2014/022 1277 A1 Aug. 7, 2014 23

0237 Following the IV infusion of CR665 at dose levels of 0243 The urinary excretion of CR665 following a 0.03 to 0.09 mg/kg in male Subjects, plasma concentrations 5-minute infusion in male and female Subjects is Summarized increased rapidly with maximum concentrations generally in Table 12: occurring at the end of the 5-minute infusion. Similarly, maxi mum concentrations of CR665 following administration of TABLE 12 0.06 mg/kg. CR665 in female subjects were also attained at the end of the 5 minute infusion. Following the end of the IV infusion, plasma concentrations of CR665 appeared to Summary of the Urinary Excretion of CR665 Following a 5-minute IV decline in an essentially biphasic manner, with the start of the Infusion in Male and Female Subjects (PartB) elimination phase occurring between 1.0 to 2.0 hours after the start of the infusion in both male and female subjects. Dose of (mg/kg) 0238. In male subjects, the mean apparent elimination half life, about 1.0 to 1.3 hours, was similar across the 0.03 to 0.09 O.O3 O.O6 O.09 O.O6 mg/kg dose range. Statistical analysis confirmed that the males males males females elimination half life for CR665 was independent of dose. The Parameter (N = 3) (N = 4) (N = 4) (N = 3) disposition kinetics of CR655 were similar in male and female subjects, with the mean terminal elimination half life Aeo-24, 70.O 157 262 153 of CR665 being approximately 0.8 hours in females at the (Ig) (27.3) (25.8) (13.5) (16.9) 0.06 mg/kg dose level. 0239. In male Subjects, AUCo. and C generally feo 24, 3.60 3.33 3.56 3.83 appeared to increase in a dose-proportional manner over the (%) (29.6) (27.6) (7.29) (24.0) dose range 0.03 to 0.09 mg/kg. This was confirmed by statis CLR 0-24h 17.1 18.4 2O.S 20.9 tical analysis, with the estimates of the slopes (95% CI) from (mL/min) (22.7) (24.6) (12.0) (17.7) the regression analysis for AUCo. and C being 1.04 (0.853 to 1.22)and 1.12 (0.800 to 1.44). FIG. 12 illustrates the Geometric mean (CV%) data are presented dose-proportional increase in AUC for CR665 over the N = Number of subjects studied dose range of 0.03 to 0.09 mg/kg in male subjects. 0240. At the 0.06 mg/kg dose level, mean values for 0244. In male subjects, the fraction of the dose excreted in AUCo., AUCo. (norm), C and C (norm) were gener the urine as unchanged drug was low for all dose levels, with ally similar in male and female Subjects following a 5-minute approximately 3.5% being eliminated up to 24 hours post infusion. dose. The fraction of unchanged drug excreted in the urine 0241 Mean values for MRT CL, V and V were simi was also low in female subjects (3.8%), and similar to male lar across the 0.03 to 0.09 mg/kg dose range in male subjects, Subjects. which was confirmed by statistical analysis. Mean values for each parameter were also similar for male and female Subjects 0245. The amount of CR665 excreted in the urine at the 0.06 mg/kg dose level. increased in a dose proportional manner over the dose range 0242. In general, low between-subject variability was studied in male subjects. This was confirmed by statistical noted for AUCo. and C in male Subjects, with CV '% analysis, with the slopes of the regression not being signifi values ranging from 11.8 to 16.4% and 19.6% to 32.2%, cantly different from unity. Renal clearance was generally respectively. Across all doses in male Subjects, the pooled low and similar across all dose levels, with dose indepen between-subject variability for AUC and C was 15.3% and 24.1%, respectively. The between-subject variability for dence being confirmed by statistical analysis. AUCo. and C was also low in female Subjects at the 0.24 0246 The results of the statistical analyses to assess the mg/kg dose level, with CV '% values of 8.8% and 18.8%, effect of infusion time on the pharmacokinetic parameters of respectively. CR665 in male subjects are presented in Table 13. TABLE 13 Statistical Analysis of the Effect of Infusion Time on the Pharmacokinetic Parameters for CR665 in Male Subjects (Parts A & B

Geometric least Ratio of SClarOS IIlC3IS geometric least 5-minute 1-hour squares means 90% CI for the 95% CI for the Parameter infusion infusion 5-minute:1-hour ratio ratio AUCo. 2286 2238 1.02 O.957 to 1.09 O.944 to 1.11 (norm) AUCo. 2343 2260 1.04 O.971 to 1.11 O.957 to 112 (norm)

ex 90O2 2003 4.49 3.98 to S.O8 3.87 to S.22 (norm) t1/2 1.28 1.25 1.02 O.804 to 1.29 O.762 to 1.37 (h) MRT 0.558 O.6OS O.923 O.817 to 1.04 O.794 to 1.07 (h) US 2014/022 1277 A1 Aug. 7, 2014 24

TABLE 13-continued Statistical Analysis of the Effect of Infusion Time on the Pharmacokinetic Parameters for CR665 in Male Subjects (Parts A & B

Geometric least Ratio of SClareS IIlcallS geometric least 5-minute 1-hour squares means 90% CI for the 95% CI for the Parameter infusion infusion 5-minute:1-hour ratio ratio

CL 538 557 O.964 O.903 to 1.03 O.889 to 1.05 (mL/min) V. 61.O 59.1 1.03 O.825 to 1.29 O.784 to 1.36 (L) V 18.1 20.1 O.900 O.804 to 1.01 O.783 to 1.03 (L) feo 24, 3.48 3.46 1.01 O.908 to 1.12 O.887 to 1.15 (%) (norm) = Normalized for dose and body weight (mg/kg)

0247. In male subjects, the following pharmacokinetic would be expected, C, was significantly higher (5.3-fold) parameters for CR665 were similar following an IV infusion for the 5-minute compared to the 1-hour infusion. These time of 1-hour versus 5-minutes: AUCo., AUCo., t2, CL, findings reinforce the predictability of the pharmacokinetics V, V, and feo-2 . Suggesting that the overall Systemic of CR665, which aids the skilled practitioner in the design of exposure to CR665, based upon AUC and disposition kinet drug administration protocols that are designed to achieve a ics, were not affected by the different infusion times. The only parameter, however, for which the statistical analysis con particular level of systemic exposure to drug without undue firmed a significant difference was C, which was, as experimentation. expected, approximately 4.5-fold higher for the 5-minute compared to the 1-hour infusion. Pharmacodynamic-Pharmacokinetic Relationship 0248. The statistical analyses of the effect of infusion time on the pharmacokinetic parameters of CR665 in female sub 0250. The relationship between pharmacodynamic jects are presented in Table 14. parameters of serum prolactin (changes from baseline) and TABLE 1.4 Statistical Analysis of the Effect of Infusion Time on the Pharmacokinetic Parameters for CR665 in Female Subiects

Geometric least Ratio of SClareS IIlcallS geometric least 5-minute 1-hour squares means 90% CI for the 95% CI for the Parameter infusion infusion 5-minute:1-hour ratio ratio

AUCo. 2013 1936 1.04 O.918 to 1.18 O.893 to 1.21 (norm) AUCo. 2044 1943 1.OS O928 to 1.19 O.903 to 1.23 (norm) Cmax 8716 1655 5.27 4.17 to 6.66 3.96 to 7.01 (norm) t1/2 O.946 1.OS O.901 O.606 to 134 O554 to 1.47 (h) MRT O430 O498 O864 O.708 to 1.06 O.677 to 1.10 (h) CL 544 573 O.9SO O.837 to 1.08 O.813 to 1.11 (mL/min) V. 45.7 SO.2 O.911 O.628 to 1.32 O.577 to 1.44 (L) V 14.1 17.0 O.832 O.692 to 1.OO O.664 to 1.04 (L) feo 24, 3.83 2.70 1.42 1.16 to 1.73 1.11 to 1.81 (%) (norm) = Normalized for dose and body weight (mg/kg)

0249 In female Subjects, the following pharmacokinetic pharmacokinetic parameters of CR665 following IV infu parameters for CR665 were similar following an IV infusion sions of 0.015 to 0.36 mg/kg in male subjects is presented in time of 1-hour versus 5-minutes: AUCo., AUCo., t2, CL, FIGS. 13 and 14. and feo 24, Suggesting that the overall Systemic expo 0251. In Part A, there was a direct linear correlation sure to CR665, based upon AUC and disposition kinetics, between serum concentrations of prolactin (based on AUCo. were not affected by the different infusion times. However, as 12.h and C) and the plasma concentration of CR665 (based US 2014/022 1277 A1 Aug. 7, 2014

on AUCo. and C) over the 0.015 to 0.36 mg/kg dose range body at the same concentration it is present in the blood. In following a 1-hour infusion in male Subjects, with correlation general, a compound with a low volume of distribution will coefficients of 0.667 and 0.565 for AUC and C values, have physical characteristics that impede transport across respectively. The AUC and C values for serum pro biological membranes. Thus, a polar compound with a low lactin appeared to plateau at higher AUCo. and C values apparent volume of distribution, such as CR665, would not be for CR665 associated with dose levels of 0.36 to 0.48 mg/kg, expected to cross the blood-brain barrier as well as lipid indicating that the maximum increase in serum prolactin had soluble compounds that typically have a higher apparent Vol been achieved by 0.36 mg/kg CR665 administered as a 1-hour ume of distribution, and a greater propensity to cross the infusion. blood-brain barrier. 0252. In Part B, there was no apparent correlation between 0257 All patents and other references cited herein are serum prolactin concentrations and plasma CR665 concen hereby incorporated by reference. trations in male Subjects following a 5-minute infusion. A 0258 Other embodiments are within the following claims. likely cause of the absence of a correlation is the temporal What is claimed is: dissociation of pharmacokinetics and pharmacodynamics in 1. A method of elevating levels of serum prolactin in a these subjects: while plasma CR665 concentrations peaked at mammal in need of elevated or stabilized levels of serum the end of the 5-minute infusion and declined thereafter, prolactin, comprising administering to said mammal an serum prolactin concentrations only began to significantly amount of a peripherally selective kappa opioid receptorago rise at 10 minutes (5 minutes after the end of the infusion), and nist, a salt thereof or a pro-drug thereof effective to elevate or continued to rise at 30 minutes, with substantial but declining stabilize levels of serum prolactin in the mammal. levels measured at 60 minutes. Under these conditions, a 2. The method of claim 1, wherein said peripherally, selec correlation between plasma CR665 concentrations and serum tive kappa opioid receptoragonist, a salt thereofor a pro-drug prolactin concentrations would not be expected. However, thereof comprises a peptide. with longer (e.g., 1 hour) infusions of CR665, the plasma 3. The method of claim 2, wherein said peptide has a concentration of CR665 may better reflect the concentration binding affinity for the kappa opioid receptor that is 10 times of CR665 in the pharmacodynamically relevant compartment greater, 100 times greater, 1,000 times greater, or more than (i.e., high affinity kappa opioid receptors), and thereby yield its binding affinity for non-kappa opioid receptors. the significant linear relationship shown in FIGS. 13 and 14. 4. The method of claim 2, wherein said peptide has the 0253) Following administration of 0.015 to 0.48 mg/kg formula: CR665 as a 1-hour infusion in male subjects, AUCo. and Cincreased in a dose-proportional manner over the entire dose range. The between-subject variability in the pharmaco wherein Xaa, is (A)D-Phe, (C' Me)D-Phe, D-Tyr, D-Tic or D-Ala(cyclopentyl or thienyl), with Abeing H, NO. F. C. kinetics of CR665 was low in male subjects. or CH; Xaa, is (A')D-Phe, D-1 Nal, D-2Nal, D-Tyror D-Trp. 0254. In female Subjects, maximum plasma concentra with A' being A or 3.4C1, Xaa, is D-Nle, (B)D-Leu, D-Hle, tions of CR665 occurred at the end of the 1-hour infusion D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H period following a 0.24 mg/kg dose, which was similar to or Calpha Me: Xaa is D-Arg, D-Har, D-nArg, D-Lys, D-Lys male subjects. The systemic exposure of CR665, based on (Ipr), D-Arg(Et), D-Har(Et), D-Amf(G), D-Dbu, (B)D-Orn AUCo. and C, was similar in male and female Subjects. or D-Orn(Ipr), with G being Horamidino; and Q is NRR, The disposition of CR665 was also similar between genders, morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazinyl, with a mean terminal elimination half-life of 1.2 hours in 4-mono- or 4.4-di-Substituted piperazinyl or delta-ornithinyl, female subjects. Furthermore, similar between-subject vari with R being lower alkyl, substituted lower alkyl, benzyl, ability was observed in male and female subjects. Substituted benzyl, aminocyclohexyl, 2-thiazolyl 2-picolyl, 0255. The duration of infusion had no effect on the overall 3-picolylor 4-picolyl, R being Hor lower alkyl; and C being systemic exposure to CR665, with AUC. being similar H. 4-hydroxy or 4-oxo. following the 1-hour and 5-minute infusions in both male and 5. The method of claim 4, wherein Q is morpholinyl or female Subjects. However, maximum plasma concentrations thiomorpholinyl. of CR665 were notably higher following the 5-minute infu 6. The method of claim 4, wherein Q is NHR and R is sion compared to the 1-hour infusion, being approximately 4-picolyl. 4.5-fold higher in male subjects and 5.3-fold higher in female 7. The method of claim 2, wherein said peptide has the Subjects. The difference in C was expected because of the formula: higher rate of infusion used for the 5-minute infusion (360 mL/hour) compared to the 1-hour infusion (30 mL/hour). The disposition kinetics of CR665 was similar for the 1-hour and wherein Xaa is D-Phe (unsubstituted or substituted by 5-minute infusion, and low between-subject variability was C'P', Me, 2F, 4F or 4C1) or D-Ala(cyclopentyl or thienyl); observed for both infusion times. Xaa- is (A')D-Phe, D-1 Nal, D-2Nal or D-Trp, with A' being 0256 The apparent volume of distribution at steady state H, 4F, 4C1, 4NO or 3.4C1, Xaa, is D-Nle, D-Leu, D-CML, (V) of CR665 in male subjects ranged from 19 to 23 L over D-Met or D-Acp; Xaa, is D-Arg, D-Arg(Et), D-Lys, D-Ily, the 0.12 to 0.48 mg/kg dose range, which is similar to the D-Har, D-Har(Et), D-nArg, D-Orn, D-Ior, D-Dbu, D-Amf, volume of extracellular fluid, and is consistent for a peptide and D-Amf(Amd); and Q is NR. R. Mor, Tmo, Pip, 4-Hyp, with limited ability to penetrate lipid-containing membranes. OxP or Ppz, with R being Me, Et, Pr, Bu, hEt, Cyp, Bzl or This observation reflects another aspect of the present inven 4-picolyl, and R being H or Et. tion: a relatively low volume of distribution. The volume of 8. The method of claim 7, wherein Xaa, is D-Phe, Xaa is distribution is a quantitative measure of the extent of distri D-Nle and Xaa, is D-Arg. bution of drug outside the vasculature; it is the apparent 9. The method of claim 7, wherein Q is morpholinyl or volume which would contain the entire amount of drug in the thiomorpholinyl. US 2014/022 1277 A1 Aug. 7, 2014 26

10. The method of claim 7, wherein Q is NHR and R is (d) providing at least one donor reservoir having the 4-picolyl. peripherally selective kappa opioid receptor agonist, 11. The method of claim 7, wherein Xaa is D-Nle or wherein said donor reservoir is associated with said first D-Leu and Q is morpholinyl. or second electrode; and 12. The method of claim 7, wherein Xaa is D-Phe, (e) delivering a therapeutically effective amount of said D-4Fpa, D-2Fpa, D-Acp or D-Ala(2Thi); Xaa, is (A)D-Phe, peripherally selective kappa opioid receptor agonist D-1 Nal, D-2Nal or D-Trp, with A being 4F or 4Cl: Xaa is through said body Surface. D-Nle, D-Met or D-Leu; Xaa, is D-Arg, D-Har, D-nArg, 18. A method of treating a mammal in need of elevated or D-Lys, D-Ornor D-Amf(Amd); and Q is NHR, Mor, Tmo, stabilized prolactin levels, said method comprising adminis Pip or Ppz, with R being Et, Pr or 4Pic. tering to said mammal an amount of a peripherally selective 13. The method of claim 2, wherein said peptide has the kappa opioid receptor agonist or a salt thereof or a pro-drug formula: H-D-Phe-D-Phe-D-Nle-D-Arg-NHEt, H-D-Phe-D- thereof, and administering, either separately or in combina Phe-D-Nle-D-Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D- tion with said peripherally selective kappa opioid receptor Arg-NH-4-picolyl, H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr. agonist or a salt thereof or a pro-drug thereof, an amount of H-D-Phe-D-Phe-D-Nle-D-Arg-thiomorpholinyl, H-D-Phe an, additional prolactin elevating compound, effective to treat D-Phe-D-Nle-D-Arg-Net, H-D-Phe-D-Phe-D-Nle-D-Arg the mammal. NHMe, H-D-Phe-D-Phe-D-Leu-D-Orn-morpholinyl, H-D- 19. The method of claim 18, wherein the prolactin-elevat Phe-D-Phe-D-Nle-D-Arg-NHhEt, H-D-Phe-D-Phe-D-Nle ing agent is a D2 dopamine receptor antagonist or a muopioid D-Arg-NH-cyclopropyl, H-D-Ala(2Thi)-D-4Cpa-D-Leu-D- receptor agonist. Arg-morpholinyl, H-D-Phe-D-Phe-D-Nle-D-Arg 20. A method for treating reduced sperm motility, an age piperidinyl, H-D-Phe-D-Phe-D-Leu-D-Orn-NHEt, H-D- related disorder, type 1 diabetes, insomnia, or inadequate Phe-D-Phe-D-Leu-D-Lys-morpholinyl, or H-D-Phe-D-Phe REM sleep, insufficient or inadequate lactation, or for pre D-Nle-D-Arg-piperazinyl. venting insufficient or inadequate lactation, in a mammal, 14. The method of claim 1, wherein said peripherally selec comprising administering an amount of a peripherally selec tive kappa opioid receptor agonist, when administered tive kappa opioid receptor agonist or a salt thereof or a pro peripherally, does not substantially cross the blood-brain bar drug thereof, effective to treat or prevent insufficient or inad 1. equate lactation, or to treat reduced sperm motility, age 15. The method of claim 1, wherein said administration related disorder, type 1 diabetes, insomnia, or inadequate comprises intravenous, Subcutaneous, intramuscular, intrana sal, oral, or transdermal administration. REM sleep in the mammal. 16. The method of claim 15, wherein said transdermal 21. The method of claim 20, wherein such amount of a administration is provided by an electrotransport device. peripherally selective kappa opioid receptor agonist or a salt 17. The method of claim 16, wherein said administration thereof or a pro-drug thereof is administered to said mammal comprises: prior to or after childbirth in conjunction with a lactation (a) providing a first electrode; enhancer or stabilizer effective to treat said mammal. (b) providing a second electrode; 22. The method of claim 21, wherein the lactation enhancer (c) providing a power source electrically connected to said comprises oxytocin. first and said second electrodes;