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(12) Patent Application Publication (10) Pub. No.: US 2004/0209807 A1 Quay Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0209807 A1 Quay Et Al US 200402098.07A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0209807 A1 Quay et al. (43) Pub. Date: Oct. 21, 2004 (54) COMPOSITIONS AND METHODS FOR (60) Provisional application No. 60/493,226, filed on Aug. ENHANCED MUCOSAL DELIVERY OF Y2 7, 2003. Provisional application No. 60/501,170, filed RECEPTOR-BINDING PEPTDES AND on Sep. 8, 2003. Provisional application No. 60/510, METHODS FOR TREATING AND 785, filed on Oct. 10, 2003. Provisional application PREVENTING OBESTY No. 60/517,290, filed on Nov. 4, 2003. Provisional application No. 60/518,812, filed on Nov. 10, 2003. (75) Inventors: Steven C. Quay, Edmonds, WA (US); Gordon Brandt, Issaquah, WA (US); (30) Foreign Application Priority Data Mary S. Kleppe, Kingston, WA (US); Conor J. MacEvilly, Seattle, WA (US) Dec. 17, 2003 (WO)........................... PCT/USO3/40538 Correspondence Address: Publication Classification Paul G. Lunn Nastech Pharmaceutical Company Inc. (51) Int. Cl." ......................... A61K 38/22; A61K 31/70; 3450 Monte Villa Parkway A61K 31/7012; A61K 31/724; Bothell, WA 98021-8906 (US) A61K 31/045 (52) U.S. Cl. ................. 514/12; 514/23: 514/53; 514/58; (73) Assignee: Nastech Pharmaceutical Company Inc. 514/738 (21) Appl. No.: 10/768,288 (57) ABSTRACT (22) Filed: Jan. 30, 2004 Pharmaceutical compositions and methods are described comprising at least one Y2 receptor-binding peptide, Such as Related U.S. Application Data peptide YY(PYY), Neuropeptide Y (NPY) or Pancreatic Peptide (PP) and one or more mucosal delivery-enhancing (63) Continuation of application No. 10/745,069, filed on agents for enhanced nasal mucosal delivery of the peptide Dec. 23, 2003, which is a continuation-in-part of YY, for treating a variety of diseases and conditions in application No. 10/322,266, filed on Dec. 17, 2002. mammalian Subjects, including obesity. Patent Application Publication Oct. 21, 2004 Sheet 1 of 14 US 2004/0209807 A1 FIGURE 1 Effect of pH on stability of PYY 3-36 @ 40°C 100 75 9. 50 E H 25 O pH pH pH pH pH pH pH pH pH 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.4 FIGURE 2 % TEER Of Enhancers Tested % TEER Y U H SS 2. 2. 2. i. i i Patent Application Publication Oct. 21, 2004 Sheet 2 of 14 US 2004/0209807 A1 FIGURE 3 % MT 12O 1OO 80 60 40 2O O T T a so a so a o as as as as a FIGURE 4 LDH Assay 2 1.5 1 - LDH O.5 o , , , , , , , , , , , , , , , - - - - - Patent Application Publication Oct. 21, 2004 Sheet 3 of 14 US 2004/0209807 A1 FIGURES 9 % Permeation 8 7 6 5 S. 4. 3 2 1 O T t - ambus Current Current Current Current Current Cuttent Buffer Form. For . Form. Form. Forth. Form. and NaCl w/o EN 1 wifo EN2 w/o EX1 w/o EN 1 w/o EN 1, and EN2 EN2 and EX1 FIGURE 6 Patent Application Publication Oct. 21, 2004 Sheet 4 of 14 US 2004/0209807 A1 1200 1000 8 O O 6 O O -B- N 4.1 -e-IN 41 -G- IN 205 4.O O 200 O 5 10 15 20 25 30 35 40 45 Time (min) Patent Application Publication Oct. 21, 2004 Sheet 5 of 14 US 2004/0209807 A1 FIGURE 7 Dose Linearity Following intranasal Administration 1400 1200 1000 800 600 400 200 O 50 100 150 200 250 Dose, uglkg Patent Application Publication Oct. 21, 2004 Sheet 6 of 14 US 2004/0209807 A1 FIGURE 8 Dose Linearity Following intranasal Administration 30000 25000 20000 9 15000 10000 5000 O 50 100 150 200 250 Dose, uglkg Patent Application Publication Oct. 21, 2004 Sheet 7 of 14 US 2004/0209807 A1 FIGURE 9 Gr up 1: 20 Micrograms intranasal Dose Pharmac kinetic Profile 120 100 60 -0-Average of 3 Subjects 40 2O - O T O 20 40 60 8O 100 120 140 160 Time, Minutes post-dose FIGURE 10 Group 2: 50 Micrograms intranasal Dose Pharmacokinetic Profile 200 180 1 6 O 1 4. O 1 2O 10 O -0-Average of 3 Subjects 8 O 6 O 4.O 2 O - -T - - O 2O 40 60 80 100 120 140 160 Time, Minutes Post-Dose Patent Application Publication Oct. 21, 2004 Sheet 8 of 14 US 2004/0209807 A1 FIGURE 11 Group 3: 100 Micrograms Intranasal Dose Pharmacokinetic Profile 40 350 300 2 co T T re-au-------- 0. 2. 40 SO 8 Oc 120 140 16 Tirne, Minutes Post-Dose Patent Application Publication Oct. 21, 2004 Sheet 9 of 14 US 2004/0209807 A1 FIGURE 12 Gr up 4: 150 Micr grams intranasal Dose Pharmacokinetic Profile 7O O 600 500 400 -0-Average of 3 Subjects 300 200 O 2O 40 60 80 1OO 120 140 160 Time, Minutes Post-Dose FIGURE 13 Group 5: 200 Micrograms intranasal Dose Pharmacokinetic Profile O 80 700 600 500 / Y O 40 I N. 300 L 200 o -- y --- - O 20 40 80 80 10 12 14 1so Time, Minutes Post-Dose Patent Application Publication Oct. 21, 2004 Sheet 10 of 14 US 2004/0209807 A1 FIGURE 14 PYY Plasma Levels, pmol/L. - S e 1 4O E l -e-200 ug us 1 2O -- 150 ug 1 O O - A - 100 ug E -X - 50 Ug ol -Xe - 20 ug > > Patent Application Publication Oct. 21, 2004 Sheet 11 of 14 US 2004/0209807 A1 FIGURE 15 Dose linearity: mean Cmax vs dose y = 3.9387x - 81.333 R* = 0.9872 6 O O 5 O O S E 400 > L 3 O O 2 O O Patent Application Publication Oct. 21, 2004 Sheet 12 of 14 US 2004/0209807 A1 FIGURE 16 Dose linearity: mean AUC 0-tws dose y = 189.43x + 815.42 R2 = 0.8249 3 O O O O 2 5 O O O 2 O O O O FIGURE 17 Visual Analog Scale (VAS) results: Visual Analog Scale Question: How hungry are you? (Lower score = less hungry, 100 point scale) O 50 100 150 200 Dose Patent Application Publication Oct. 21, 2004 Sheet 13 of 14 US 2004/0209807 A1 FIGURE 18 Visual Analog Scale Question: How much c uldy u eat? (L wer score F less hungry, 100 p int scale) 200 15.0 10.O 5. O | O.O. FIGURE 19 Visual Analog Scale Question: How full do you feel? (Lower score = less full, 100 point scale) 35.0 30.0 25.0 200 15 O 1. S.O. OO O 50 OO 150 2OO Dose Patent Application Publication Oct. 21, 2004 Sheet 14 of 14 US 2004/0209807 A1 FIGURE 20 % Permeation of Regular PYY Vs. Endotoxin-free PYY Regular PYY Endotoxin free PYY US 2004/0209807 A1 Oct. 21, 2004 COMPOSITIONS AND METHODS FOR peripheral nervous Systems and influences a diverse range of ENHANCED MUCOSAL DELIVERY OF Y2 physiological parameters, including effects on psychomotor RECEPTOR-BINDING PEPTDES AND METHODS activity, food intake, central endocrine Secretion, and Vaso FOR TREATING AND PREVENTING OBESITY activity in the cardiovascular System. High concentrations of NPY are found in the sympathetic nerves supplying the CROSS REFERENCE TO RELATED coronary, cerebral, and renal vasculature and have contrib APPLICATIONS uted to vasoconstriction. NPY binding sites have been identified in a variety of tissues, including Spleen, intestinal 0001. This is a continuation application and claims pri membranes, brain, aortic Smooth muscle, kidney, testis, and ority under 35 U.S.C. S 120 of co-pending U.S. patent placenta. application Ser. No. 10/745,069 filed Dec. 23, 2003, which is a continuation-in-part of U.S. patent application Ser. No. 0006 Neuropeptide Y (NPY) receptor pharmacology is 10/322,266, filed Dec. 17, 2002, and claims priority under currently defined by structure activity relationships within 35 U.S.C. S 119 (e) of U.S. Provisional Application No. the pancreatic polypeptide family. This family includes 60/493,226, filed Aug. 7, 2003, U.S. Provisional Application NPY, which is synthesized primarily in neurons; PYY, which No. 60/501,170, filed Sep. 8, 2003, U.S. Provisional Appli is Synthesized primarily by endocrine cells in the gut, and cation No. 60/510,785, filed Oct. 10, 2003, U.S. Provisional PP, which is synthesized primarily by endocrine cells in the Application No. 60/517,290, filed Nov. 4, 2003; U.S. Pro pancreas. These approximately 36 amino acid peptides have visional Application No. 60/518,812, filed on Nov. 10, 2003; a compact helical structure involving a “PP-fold' in the and PCT/USO3/40538, filed on Dec. 17, 2003; the entire middle of the peptide. Specific features include a polypro contents of these applications are incorporated herein by line helix in residues 1 through 8, a B-turn in residues 9 reference. through 14, an O.-helix in residues 15 through 30, an outward-projecting C-terminus in residues 30 through 36, BACKGROUND OF THE INVENTION and a carboxyl terminal amide, which appears to be critical for biological activity. The peptides have been used to define 0002 The teachings of all the references cited in the at least five receptor subtypes known as Y1, Y2, Y3, Y4 and present specification are incorporated in their entirety by Y5. Y1 receptor recognition by NPY involves both N- and reference. C-terminal regions of the peptide; exchange of Gln' with 0003) Obesity and its associated disorders are common Pro is fairly well tolerated. Y2 receptor recognition by NPY and very serious public health problems in the United States depends primarily upon the four C-terminal residues of the and throughout the world.
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