AU2005244475A1

AU2005244475A1 - A composition comprising pyy for the treatment of gastrointestinal disorders

Info

Publication number: AU2005244475A1
Application number: AU2005244475A
Authority: AU
Inventors: Henrik Nilsson
Original assignee: ADITECH PHARMA AB
Current assignee: ADITECH PHARMA AB
Priority date: 2004-05-18
Filing date: 2005-05-18
Publication date: 2005-11-24
Also published as: JP2007538017A; EP1750753A1; WO2005110467A1

Description

WO 2005/110467 PCT/DK2005/000327 A composition comprising PYY for the treatment of gastrointestinal disorders All patent and non-patent references cited in the application, or in the present appli cation, are also hereby incorporated by reference in their entirety. 5 Field of invention The present invention relates to a composition comprising PYY for the treatment of gastrointestinal disorders. The composition of the invention is for the production of a 10 pharmaceutical composition for the treatment of IBS, FD and/or abdominal pain. The invention further relates to a method of treatment comprising administration of said pharmaceutical composition, alone or in combination with a second active ingredient. 15 Background of invention Gastrointestinal disorders are very common in the population. Some of these are very well characterised and thus suitable treatment regimes have been developed. It is more difficult to develop treatments for functional gastrointestinal disorder. This term refers to a disorders or diseases where the primary abnormality is an altered 20 physiological function (the way the body works) rather than an identifiable structural or biochemical cause. Thus, these types of gastrointestinal disorders have unknown aetiology, e.g. are lacking a biological explanation. Generally, this type of disorder can not be diagnosed in a traditional way; that is, as an inflammatory, infectious, or structural abnormality that can be seen by commonly used examination, x-ray, or 25 laboratory test. Gastrointestinal disorders with unknown aetiology include irritable bowel syndrome (IBS) also called irritable colon, functional dyspepsia (FD) or Non-ulcer syspepsia. Therefore the diagnosis and development of suitable treatment for this subset of 30 gastrointestinal disorders have so far not been sufficiently successful. Irritable Bowel Syndrome The predominant symptoms of IBS are abdominal pain, altered bowel habit, discomfort associated with disturbed defecation and bloating. Patients have an 35 increased mucus and nausea and feeling of constipation and distension. The criteria for irritable bowel syndrome are pain or discomfort for 12 weeks of the previous 12 WO 2005/110467 PCT/DK2005/000327 2 months associated with two of the following; relief with defecation, looser or more frequent stools, harder or less frequent stools, according to Rome II (se below) reviewed by Talley, NJ and Spiller R (2002) and Talley, NJ (2003). The symptoms may be chronic and impair the quality of life for the patient. 5 ROME 11 SYMPTOM CRITERIA FOR IBS At least 12 weeks or more, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features: 1) Relieved with defecation; and/or 10 2) Onset associated with a change in frequency of stool; and/or 3) Onset associated with a change in form (appearance) of stool. Other symptoms that are not essential but support the diagnosis of IBS: Abnormal stool frequency (greater than 3 bowel movements/day or less than 3 bowel movements/week); 15 Abnormal stool form (lumpy/hard or loose/watery stool); Abnormal stool passage(straining, urgency, or feeling of incomplete evacuation); Passage of mucus; Bloating or feeling -of abdominal distension. 20 It is estimated that 10-15 % of the population experience IBS symptoms. The patients are grouped in three groups based on there predominat bowel habit (diarrhoea and/or constipation): 25 IBS associated with abdominal pain, fecal urgency and diarrhoea IBS associated with abdominal discomfort, bloating and constipation IBS associated with alternating diarrhoea and constipation Functional dyspepsia 30 The symptoms of functional dyspepsia (FD) are partially overlapping with the symptoms of IBS. Dyspepsia refers to persisten or recurrent epigastric pain or subjective upper abdominal discomfort that may be characterized by early satiety, prostprandial fullness, or bloating. Dyspepsia is not restricted to meal-related symptoms. Patients are grouped in dysmotility-like FD and ulcer-like FD based on 35 the prevalent symptom centred in the upper abdomen (discomfort and pain WO 2005/110467 PCT/DK2005/000327 3 respectively . Many patients experience symptoms after meal ingestion, including epigastric discomfort, fullness and pain. Further symptoms include inability to finish a normal-sized meal, bloating, belching, nausea and vomiting (Feinle-Bisset, C. et al. 2003). The underlying mechanism of functional dyspepsia is unclear. The role of 5 delay gastric emptying is debated and currently not the favoured model. Central nervous system, visceral hypersensitivity and stress The brain-gut interaction plays a prominent role in the modulation of gut function in health and disease. The central nervous system (CNS) regulates the functions of 10 the gastrointestinal tract, such as motility, secretion and blood flow. This occurs unperceived by the individual. In case of irregularities of the gastrointestinal an individual may experience short periods of pain. In the case of patients with gastrointestinal diseases the pain may be very strong and durable. There appears to be a connection with visceral hypersensitivity in the pathophysiology of functional 15 gastrointestinal diseases including IBS and FD (Feinle-Bisset, C. et al. 2003). Furthermore, stress, anxiety or recall of aversive memories can enhance perception of painful events. Thus stress might have an inducing effect on hyperalgesia (Drossman DA, et al. 2002). 20 Psycholoqical factors Psychological and sociological factors appears relevant for the onset and severity of symptoms (Drossman DA, et al. 2002), it further appears that the most effective drugs for treatment of irritable bowel syndrome so far have been antidepressants (Talley, N.J. and Spiller R). 25 Treatments Until now treatments of gastrointestinal disorders with unknown aetiology as irritable bowel syndrome and functional dyspepsia have been based on empirical findings and aims for control of symptoms. The complexity of the symptoms indicates that a 30 single cure will not be beneficial for all patients. Symptoms relating to diarrhoea and constipation may be treated using laxatives an antidiarrhoeals but the success is modest. Furthermore, drugs as Loperamide may minimise diarrhoea but does not modulate the abdominal pain (review by Talley, WO 2005/110467 PCT/DK2005/000327 4 N.J. 2003), suggesting that the irregular bowel habit and the experienced abdominal pain is not directly linked. As mentioned above antidepressants have some effect on IBS, mostly patient with 5 diarrhoea associated IBS may benefit from a treatment of tricycclic antidepressant, such as disipramine, nortyptiline and fluphenzine, but the trials have been of variably quality. It is further expected that selective serotonin reuptake inhibitors (SSRI) maybe useful in IBS patients with constipation (review by Talley, N.J. 2003). 10 Gut hormones Several gut hormones have been suggested to be related to symptoms of gastrointestinal disorders. VIP, CCK, and motilin relates to the motility of the upper gastrointestinal tract whereas polypeptide YY (PYY) and Neuropeptide Y (NPY) affect the absorption in the intestine. The latter (both PYY and NPY) have been 15 suggested as treatment for diarrhoea (US 6,588, 708) by prolonging of the residence time. PYY 20 The gut hormone peptide YY (PYY), and the neuropeptide, neuropeptide Y (NPY), are structurally related to pancreatic polypeptide (PP) (figure 1). PYY and NPY exert their action through NPY receptors (Y1 R, Y2R, Y4R and Y5R). The PP, NPY and PYY peptides consist of 36 amino acids with an amidated C-terminal. Two forms of PYY, PYYI-36 and PYY3-36, the latter being a truncated form of the former, have 25 been found in circulation. PYY3-36 is produced by the cleavage of PYY1 -36 by the enzyme dipeptidyl peptidase IV (DPP-IV). PYY1-36 binds to and activates at least three NPY receptor subtypes (Y1, Y2 and Y5) whereas PYY3-36 is more selective for the Y2 receptor (Y2R). Only the C-terminal part of the PYY3-36 peptide is required for the binding to the Y2 receptor. Throughout this document, the notation 30 PYY covers both PYY1 -36 and PYY3-36 (Berglund, M.M. et al., 2003). PYY was initially isolated from porcine intestine (Tatemoto, K. and Mutt, C., 1980) and named Peptide YY due to the tyrosine residues present in the N- and C terminal of the molecule. 35 WO 2005/110467 PCT/DK2005/000327 5 PYY is expressed in endocrine cells lining the gastrointestinal tract and particularly in the distal portion. PYY is secreted in response to food ingestion. Within 15 minutes the plasma level of PYY rise and the level of PYY will reach a plateau after approximately 90 min. The maximum level of PYY reached is proportional to the 5 calories ingested, suggesting that PYY may function as a sensor of food ingestion. In addition PYY is also expressed by neurones, such as in peripheral neurons, particularly enteric neurons. Furthermore, PYY is found in a restricted set of central neurons. The expression pattern of PYY in both endocrine cells and neurons suggest that PYY may be involved in regulation of multiple functions in the individual 10 (Ekblad, E. and Sundler, F., 2002). A suggested role of PYY may be to regulate the secretion and absorbance of fluid and electrolytes in the gastrointestinal tract and intestine and PYY have therefore been suggested as treatment of diarrhoea (US 6,588, 708) by prolonging of the 15 residence time. Furthermore, PYY3-36 has been suggested to be involved in the system regulating feeding behaviour. It has been found that peripheral administration of PYY3-36 inhibited food intake in rodents. Moreover, direct intra arcuate administration of PYY3-36 inhibited food intake. A linkage between the PYY - effect on feeding behaviour and the NPY 2 receptor have been suggested- by the 20 demonstration that NPY receptor Y2 null mice are resistant to the anorectic effects of peripherally administered PYY3-36 (Batterham, R.L. and Bloom, S.R., 2003). The hypothalamic arcuate nucleus, a key brain area regulating appetite, has access to nutrients and hormones within the peripheral circulation. NPY neurons within the 25 arcuate nucleus express the Y2R. The arcuate nucleus contains two distinct sub groups of neurons that control food intake. On group of neurons produces NPY, which acts in the brain to stimulate feeding (Stanley, B. G. et al, 1986), whereas an adjacent subgroup of neurones produces melanocortin peptides, which act in the same brain areas as NPY, but inhibit eating (Fan, W. et al, 1997). Typically, when 30 one of these subsets is activated, the other one is inhibited. References 35 Batterham, R.L. and Bloom, S.R. (2003). The gut hormone peptide YY regulates appetite. Ann. N. Y. Acad. Sci. Jun;994:162-8.

WO 2005/110467 PCT/DK2005/000327 6 Berglund, M.M.; Hipskind, P.A. and Gehlert, D.R. (2003). Recent developments in our understanding of the physiological role of PP-fold peptide receptor subtypes. Exp Biol Med (Maywood). Mar;228(3):217-44. 5 Drossman, D.A.; Camilleri, M.; Mayer, E.A.; Whitehead WE (2002). AGA technical review on irritable bowel syndrome. Gastroenterology. Dec;123(6):2108-31. Ekblad, E. and Sundler, F. (2002). Distribution of pancreatic polypeptide and peptide 10 YY. Peptides. Feb;23(2):251-61. Fan, W.; Boston, B.A.; Kesterson, R.A.; Hruby, V.J.; Cone, R.D (1997). Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. Jan 9;385(6612):165-168. 15 Feinle-Bisset, C.; Vozzo, R.; Horowitz, M., and Talley, N.J.(2003). . American Journal of Gastroenterology, Jan.;99 (1):170-181 Stanley, B. G:; Kyrkouli, S. E.; Lampert, S. and Leibowitz; -S F(1986). Peptides 7; 20 1189-1192). Talley, N.J. and Spiller R (2002). Irritable bowel syndrome: a little understood organic bowel disease. The Lancet, Vol 360, August 17, 555-564. 25 Talley, N.J.(2003). Evaluation of drug treatment in irritable bowel syndrome. J. Clin. Pharmacol, 56, 362-369. Tatemoto, K. and Mutt, V. (1980). Isolation of two novel candidate hormones using a chemical method for finding naturally occurring polypeptides. Nature, Jun 30 5;285(5764):417-8. Summary of invention The invention relates to a composition comprising PYY for the production of a medicament for the treatment of functional gastrointestinal disorders. Said 35 medicament may be used for the treatment of irritable bowel syndrome wherein, WO 2005/110467 PCT/DK2005/000327 7 a) the predominant bowel habit is constipation and/or b) the predominant bowel habit is alternating diarrhoea and constipation and/or c) the treatment is administered parenterally. 5 Said medicament may further be for the treatment of abdominal and visceral pain associated with functional gastrointestinal disorders as irritable bowel syndrome and functional dyspepsia. Said medicament may further be for the treatment of functional dyspepsia, for the 10 relief of the symptom(s) a) sensation of fullness and/or b) inability to finish a normal sized meal and/or c) pain after food intake and/or d) nausea and/or 15 e) vomiting and/or f) bloating and/or g) belching and/or h) regurgitation and/or - - i) epigastric pain and/or 20 j) feeling of distention and/or k) exess flatus and any combination of the above. It is further contemplated that the composition according to the invention 25 The invention further relates to a method of treatment comprising administration of said composition. 30 Description of Drawings Figure 1. Structure of the family of the PP-fold peptides Figure 2. Plasma concentration of PYY1-36 Figure 3. Plasma concentration of PYY3-36 35 Sequence listing WO 2005/110467 PCT/DK2005/000327 8 SEQ ID 1: Human PYY Definitions: AA: See "Amino acid". 5 Amino acid: Entity comprising an amino terminal part (NH 2 ) and a carboxy terminal part (COOH) separated by a central part comprising a carbon atom, or a chain of carbon atoms, comprising at least one side chain or functional group. NH 2 refers to the amino group present at the amino terminal end of an amino acid or peptide, and COOH refers to the carboxy group present at the carboxy terminal end of an amino 10 acid or peptide. The generic term amino acid comprises both natural and non natural amino acids. Natural amino acids of standard nomenclature as listed in J. Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.F.R., section 1.822(b)(2) be long to the group of amino acids listed in Table 1 herein below. Non-natural amino acids are those not listed in Table 1. Examples of non-natural amino acids are those 15 listed e.g. in 37 C.F.R. section 1.822(b) (4), all of which are incorporated herein by reference. Amino acid residues described herein can be in the "D" or "L" isomeric form. 20 Symbols Amino acid 1-Letter 3-Letter Y Tyr tyrosine G Gly glycine 25 F Phe phenylalanine M Met methionine A Ala alanine S Ser serine I Ile isoleucine 30 L Leu leucine T Thr threonine V Val valine P Pro proline K Lys lysine 35 H His histidine WO 2005/110467 PCT/DK2005/000327 9 Q Gin glutamine E Glu glutamic acid W Trp tryptophan R Arg arginine 5 D Asp aspartic acid N Asn asparagine C Cys cysteine Table 1. Natural amino acids and their respective codes. 10 Amino acid residue: the term "amino acid residue" is meant to encompass amino acids, either standard amino acids, non-standard amino acids or pseudo-amino ac ids, which have been reacted with at least one other species, such as 2, for example 3, such as more than 3 other species. In particular amino acid residues may com 15 prise an acyl bond in place of a free carboxyl group and/or an amine-bond and/or amide bond in place of a free amine group. Furthermore, reacted amino acid resi dues may comprise an ester or thioester bond in place of an amide bond. Antibody: Are immunoglobulin molecules and active portions of immunoglobulin molecules. Antibodies are for example intact immunoglobulin molecules or frag 20 ments thereof retaining the immunologic activity. Antigen: The molecule recognised by an antibody. Usually a peptide, polypeptide or a multimeric polypeptide. Antigens are preferably capable of eliciting an immune response. Chimera: A molecule consisting of at least two parts not found together in nature. A 25 chimeric peptide or protein is a peptide or protein constructed by the fusion of two peptides or proteins. A chimeric DNA molecule is a DNA molecule that encodes a chimeric protein. Concentration equivalent: A concentration equivalent is an equivalent dosage be ing defined as the dosage of a compound having the same response (as evaluated 30 e.g. from a dosage-response curve) in vitro and/or in vivo as a known compound. Frequency: The number of occurrences of a certain event within a certain period of time (e.g. the number of occurrences per day or per week). Individual: A living animal or human. In preferred embodiments, the subject is a mammal, including humans and non-human mammals such as dogs, cats, pigs, WO 2005/110467 PCT/DK2005/000327 10 cows, sheep, goats, horses, rats, and mice. In the most preferred embodiment, the subject is a human. Isolated: is used to describe any of the various secretagogues, polypeptides and nucleotides disclosed herein, that have been identified and separated and/or recov 5 ered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified. 10 Ligand: A molecule, for example a peptide, capable of specific binding to one or more cognate receptors. An antigen is, for example, a ligand to its cognate anti bodies. Medical disorder: By the term "medical disorder" is meant any disease or syn drome having a detrimental effect on an individual's physical and/or mental health. 15 MTD: Maximum tolerated dose. The maximum tolerated dose of a substance in a given test period should not induce a) overt toxicity, such as appreciable death of cells or organ dysfunction; b) a material reduction in life span, except by cancer induction; c) 10% or greater retardation of body weight gain (in growing animals). Parenteral: For the purpose of this document "parenteral" is defined as being out 20 side the alimentary canal. Thus, the term "parenteral administration" of a compound encompasses e.g. subcutaneous, intramuscular, intravenous, intranasal, buccal, intradermal and transdermal administration, as well as inhalation of said compound. Peptide: Plurality of covalently linked amino acid residues defining a sequence and linked by amide bonds. The term is used analogously with oligopeptide and poly 25 peptide. The amino acids may be both natural amino acids and non-natural amino acids, including any combination thereof. The natural and/or non-natural amino acids may be linked by peptide bonds or by non-peptide bonds. The term peptide also embraces post-translational modifications introduced by chemical or enzyme catalyzed reactions, as are known in the art. 30 PYY: Peptide YY. Herein PYY represents both PYY1-36 and PYY3-36, the full length and a truncated version of PYY, respectively. Receptor: A receptor is a molecule, such as a protein, glycoprotein and the like, that can specifically (non-randomly) bind to another molecule Recombinant DNA (rDNA) molecule: A DNA molecule produced by operatively 35 linking two DNA segments. Thus, a recombinant DNA molecule is a hybrid DNA WO 2005/110467 PCT/DK2005/000327 11 molecule comprising at least two nucleotide sequences not normally found together in nature.

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2 : The half-life is the time for the concentration of a compound to decrease 50 %. 5 Detailed description of the drawings Figure 1. Structure of the family of the PP-fold peptides 10 NPY, PYY, and PP share a common hairpin-like three-dimensional structure called the PP-fold (Fuhlendorf, J. et al. (1990) J. Biol. Chem.). All four peptides are 36 amino acids long with an amidated carboxy-terminus. The general structure of the PP-fold peptides has been established using x-ray crystallography of avian PP and confirmed in several studies using nuclear magnetic resonance (Keire D. A. et al. 15 (2000) Biochemistry). Amino acid residues 1-8 form a type Il proline helix followed by a loop. Residues 15-32 form an a-helix, and the four most carboxy-terminal resi dues are in a flexible loop conformation. NPY is one of the most evolutionary con served peptides known. Despite a low degree of conservation in amino acid se quence between PP from different species as well as between PP and PYY and 20 NPY, the general three-dimensional structure seems to be conserved in all PP-fold peptides. Figure 2 25 PYY plasma concentration in response to subcutaneous PYY1-36 administration. PYY1-36 was administered to subjects as described in example 3. The plasma level of PYY was measured during a 4 hour time period following injection. The plasma level of PYY increases with in15 minutes after administration. 30 A plasma level of 80-100 pmol/l is obtained using a dosage of 200 pmol/kg FFM. Figure 3 PYY plasma concentration in response to subcutaneous PYY3-36 administration. 35 WO 2005/110467 PCT/DK2005/000327 12 PYY3-36 was administered to subjects as described in example 3. The plasma level of PYY was measured during a 4 hour time period following injection. The plasma level of PYY increases with in15 minutes after administration. A plasma level of 100-120 pmol/l is obtained using a dosage of 100 pmol/kg FFM. 5 Detailed description of the invention Gastrointestinal disorders The gastrointestinal disorders described in the background section of the application 10 are characterised by the lack of known aetiology, and are subsequently diagnosed based on patients report of symptoms. The prevalent symptoms are abdominal dis comfort and abdominal pain that may be accompanied by irregular stool frequency. The symptoms of the patient may include; constipation, diarrhoea, abdominal pain, 15 sensing of fullness, inability to finish a normal sized meal, bloating, vomiting, nausea, and epigastric pain. Individual in need 20 According to the invention, any individual who may draw benefit from the composi tions of the present invention may be treated with said compositions. Thus an indi vidual who would draw benefit of the treatment are considered an individual in need of treatment. 25 Preferably, said individual is suffering from a gastrointestinal disorder. An individual in need may suffer from a disorder such as any of the above mentioned. An individ ual in need may suffer from any of the symptoms of the above mentioned disorders, such as abdominal pain, visceral pain, abdominal discomfort, diarrhoea, constipa tion, nausea, vomiting, bloating, belching or feeling of distension. 30 An individual in need may be an individual in risk of acquiring any of the above men tioned disorders. As described above the symptoms associated with such gastrointestinal disorders 35 have been difficult to treat. Surprisingly, the present invention discloses successful use of PYY and functional equivalents thereof for the treatment of gastrointestinal disorders.

WO 2005/110467 PCT/DK2005/000327 13 PYY Throughout this document, peptide YY (PYY) is used as a general term covering PYY1-36 and PYY3-36. PYY1-36 is a 36 AA polypeptide with C- as well as N-termi 5 nal tyrosine amino acid residues. The polypeptide is produced by cleavage of a pre polypeptide and is furthermore cleaved by depeptidyl peptidase IV yielding PYY3 36, as described above. Surprisingly, PYY has subsequently been found to be capable of suppressing symptoms of several gastrointestinal disorders such as IBS and functional dyspepsia. 10 Functional equivalents Human PYY1-36 is identified by SEQ ID NO: 1. PYY3-36 is a truncated form of PYY where the two most N-terminal residues are deleted. Functional equivalents of PYY 15 include PYY molecules originating from different species, such as mouse, rat, mon key, swine, bovine or other mammalian species. A functional equivalent may also be a homologue to PYY. The invention relates to a composition comprising PYY or a functional equivalent 20 thereof, for the preparation of a pharmaceutical composition for the treatment of an gastrointestinal disorder with unknown aetiology. In an embodiment of the invention the composition is for the preparation of a pharmaceutical composition for the treatment a gastrointestinal disorder with 25 unknown aetiology characterized by the symptoms a) constipation and/or b) diarrhoea and/or c) abdominal pain 30 In one embodiment the composition comprising PYY or a functional equivalent thereof is for the preparation of a pharmaceutical composition for the treatment of irritable bowel syndrome wherein a) the predominant bowel habit is constipation and/or b) the predominant bowel habit is alternating diarrhoea and constipation and/or 35 c) the treatment is administered parenterally.

WO 2005/110467 PCT/DK2005/000327 14 In a further embodiment the composition is for the treatment of functional dyspepsia. In a further embodiment the composition is for the treatment of abdominal pain, visceral pain, such as pain in the left upper quadrant, such as pain in the right upper 5 quadrant, such as pain in the left lower quadrant, such as pain in the right lower quadrant. In an embodiment the composition is for the treatment of 10 In an embodiment the composition is the treatment of pain associated with either IBS or functional dyspepsia. In an embodiment the composition is for the relief of the symptom(s) I) sensation of fullness and/or 15 m) inability to finish a normal sized meal and/or n) pain after food intake and/or o) nausea and/or p) vomiting and/or q) bloating and/or 20 r) belching and/or s) regurgitation and/or t) epigastric pain and/or u) feeling of distention and/or v) exess flatus 25 and any combinations hereof. In a preferred embodiment the composition comprises human PYY. In a more preferred embodiment the composition comprises human PYY1- 36 as defined by SEQ ID NO 1. In a further preferred embodiment the composition comprises human 30 PYY3-36 as defined by amino acid 3-3 in SEQ ID NO. 1. Homoloques A homologue shall be construed as a molecule that shares some identity to the molecule, here PYY represented by both PYY1-36 and PYY3-36. The homology 35 may be expressed as the percentage of amino acid residues in the candidate se- WO 2005/110467 PCT/DK2005/000327 15 quence that are identical with the residue of a corresponding sequence to which it is compared, after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent identity for the entire sequence, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C 5 terminal extensions nor insertions shall be construed as reducing identity or homol ogy. Methods and computer programs for the alignment are well known in the art. Sequence identity may be measured using sequence analysis software (e.g., Se quence Analysis Software Package, Genetics Computer Group, University of Wis consin Biotechnology Centre, 1710 University Ave., Madison, Wis. 53705). This 10 software matches similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications. A homologue of one or more of the sequences specified herein may vary in one or more amino acids as compared to the sequences defined, but is capable of perform 15 ing the same function, i.e. a homologue may be envisaged as a "functional equiva lent" of a predetermined sequence. As described above a functional equivalent of any of the predetermined sequences herein may be defined as: 20 i) homologues comprising an amino acid sequence capable of being recog nised by an antibody, said antibody also recognising PYY (PYY1-36 and/or PYY3-36), and/or 25 ii) homologues comprising an amino acid sequence capable of binding selec tively to an NPY receptor (for example measured as described in example 1), and/or iii) homologues having a substantially similar or higher binding affinity to NPY 30 receptors than PYY (PYY1-36 or PYY3-36) and with a binding affinity pref erably high than 100 nM and/or iv) homologues with at least 60 % identity to human PYY identified by SEQ ID NO 1 and/or 35 WO 2005/110467 PCT/DK2005/000327 16 v) homologues consisting of fragments of human PYY identified by SEQ ID NO 1, wherein the fragments comprise a stretch of at least 6 continuous amino acids of SEQ ID NO 1. 5 Human PYY1-36 has the sequence shown in SEQ ID NO: 1. Human PYY3-36 is 34 amino acids long and has the sequence shown in SEQ ID NO: 1 except for the dele tion of the two N-terminal amino acids. Examples of homologues comprise one or more conservative amino acid substitu 10 tions including one or more conservative amino acid substitutions within the same group of predetermined amino acids, or a plurality of conservative amino acid substi tutions, wherein each conservative substitution is generated by substitution within a different group of predetermined amino acids. 15 Homologues may thus comprise conservative substitutions independently of one another, wherein at least one glycine (Gly) of said homologue is substituted with an amino acid selected from the group of amino acids consisting of Ala, Val, Leu, and lle, and independently thereof, homologues, wherein at least one of said alanines (Ala)-of said homologue thereof is substituted with an amino acid selected from the 20 group of amino acids consisting of Gly, Val, Leu, and lie, and independently thereof, homologues, wherein at least one valine (Val) of said homologue thereof is substi tuted with an amino acid selected from the group of amino acids consisting of Gly, Ala, Leu, and Ile, and independently thereof, homologues thereof, wherein at least one of said leucines (Leu) of said homologue thereof is substituted with an amino 25 acid selected from the group of amino acids consisting of Gly, Ala, Val, and lie, and independently thereof, homologues thereof, wherein at least one isoleucine (Ile) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Gly, Ala, Val and Leu, and independently thereof, homologues thereof wherein at least one of said aspartic acids (Asp) of said homo 30 logue thereof is substituted with an amino acid selected from the group of amino acids consisting of Glu, Asn, and GIn, and independently thereof, homologues thereof, wherein at least one of said phenylalanines (Phe) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Tyr, Trp, His, Pro, and preferably selected from the group of amino 35 acids consisting of Tyr and Trp, and independently thereof, homologues thereof, WO 2005/110467 PCT/DK2005/000327 17 wherein at least one of said tyrosines (Tyr) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Phe, Trp, His, Pro, preferably an amino acid selected from the group of amino acids consisting of Phe and Trp, and independently thereof, homologues thereof, wherein at least 5 one of said arginines (Arg) of said fragment is substituted with an amino acid se lected from the group of amino acids consisting of Lys and His, and independently thereof, homologues thereof, wherein at least one lysine (Lys) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Arg and His, and independently thereof, homologues thereof, wherein 10 at least one of said aspargines (Asn) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Asp, Glu, and GIn, and independently thereof, homologues thereof, wherein at least one glutamine (GIn) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Asp, Glu, and Asn, and independently thereof, 15 homologues thereof, wherein at least one proline (Pro) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Phe, Tyr, Trp, and His, and independently thereof, homologues thereof, wherein at least one of said cysteines (Cys) of said homologues thereof is substituted with an amino acid selected from the group of amino acids consisting of Asp, Glu, Lys, 20 Arg, His, Asn, GIn, Ser, Thr, and Tyr. Conservative substitutions may be introduced in any position of a preferred prede termined sequence. It may however also be desirable to introduce non-conservative substitutions, particularly, but not limited to, a non-conservative substitution in any 25 one or more positions. A non-conservative substitution leading to the formation of a functionally equivalent homologue of the sequences herein would for example i) differ substantially in pola rity, for example a residue with a non-polar side chain (Ala, Leu, Pro, Trp, Val, lle, 30 Leu, Phe or Met) substituted for a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gln or a charged amino acid such as Asp, Glu, Arg, or Lys, or substituting a charged or a polar residue for a non-polar one; and/or ii) differ sub stantially in its effect on polypeptide backbone orientation such as substitution of or for Pro or Gly by another residue; and/or iii) differ substantially in electric charge, for 35 example substitution of a negatively charged residue such as Glu or Asp for a posi- WO 2005/110467 PCT/DK2005/000327 18 tively charged residue such as Lys, His or Arg (and vice versa); and/or iv) differ sub stantially in steric bulk, for example substitution of a bulky residue such as His, Trp, Phe or Tyr for one having a minor side chain, e.g. Ala, Gly or Ser (and vice versa). 5 Substitution of amino acids may in one embodiment be made based upon their hy drophobicity and hydrophilicity values and the relative similarity of the amino acid side-chain substitutions, including charge, size, and the like. Exemplary amino acid substitutions which take one of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and 10 aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine. In a preferred embodiment the homologue has an amino acid sequence at least 60 % identical to SEQ ID NO 1. 15 More preferably the identity is at least 65 %, such as at least 70 % identical, such as at least 75 % identical, such as at least 80 % identical, such as at least 85 % identi cal, such as at least 90 % identical, such as at least 95 % identical, such as at least 98 % identical to SEQ ID NO 1. 20 In a preferred embodiment the functional equivalent comprise the amino acids corresponding to the 6 N- terminal amino acids of PYY1-36 as defined in SEQ ID NO.1 (Tyr Pro Ile Lys Pro Glu). The functional equivalent may comprise 8 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lIe Lys Pro Glu Ala Pro), or 25 such as 10 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro IlIe Lys Pro Glu Ala Pro Gly Glu) or such as 12 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lIe Lys Pro Glu Ala Pro Gly Glu Asp Ala), or such as 14 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro) ), or such as 16 N-terminal amino acids of PYY1 30 36 as defined in SEQ ID (Tyr Pro lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu), or such as 18 N-terminal amino acids of PYY1 -36 as defined in SEQ ID (Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn), or such as 20 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr), or such as 22 N 35 terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro Ile Lys Pro Glu Ala WO 2005/110467 PCT/DK2005/000327 19 Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala), or such as 24 N terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu), or such as 26 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lIe Lys Pro Glu 5 Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His), or such as 28 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro IlIe Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu), or such as 30 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lIe Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn 10 Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu), or such as 32 N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lIe Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr), or such as 34N-terminal amino acids of PYY1-36 as defined in SEQ ID (Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr 15 Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin). In a further preferred embodiment the functional equivalent comprise the amino acids corresponding to the 6 N- terminal amino acids of PYY3-36 as defined in SEQ ID NO.1 (Ile Lys Pro Glu Ala Pro), or such as 8 N-terminal amino acids of PYY3-36 20 as defined in SEQ ID (Ile Lys Pro Glu Ala Pro Gly Glu) or such as 10 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lie Lys Pro Glu Ala Pro Gly Glu Asp Ala), or such as 12 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lle Lys Pro Glu Ala Pro Gly GIu Asp Ala Ser Pro) ), or such as 14 N-terminal amino acids of PYY3-36 as defined in SEQ ID (Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu 25 Glu), or such as 16 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lIle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn), or such as 18 N terminal amino acids of PYY3-36 as defined in SEQ ID (Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr), or such as 20 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser 30 Pro Glu Glu Leu Asn Arg Tyr Tyr Ala), or such as 22 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu), or such as 24 N-terminal amino acids of PYY3-36 as defined in SEQ ID (Tyr Pro lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His), or such as 26 N-terminal 35 amino acids of PYY3-36 as defined in SEQ ID (lie Lys Pro Glu Ala Pro Gly Glu Asp WO 2005/110467 PCT/DK2005/000327 20 Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu), or such as 28 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu), or such as 30 N-terminal amino acids of PYY3-36 as defined in SEQ ID 5 (lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr), or such as 32 N-terminal amino acids of PYY3-36 as defined in SEQ ID (lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin). 10 In a preferred embodiment the functional equivalent comprise the amino acids corresponding to the 6 C- terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Val Thr Arg Gin Arg Tyr), or such as the 8 C-terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Asn Leu Val Thr Arg Gin Arg Tyr), or such as the 10 C terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Tyr Leu Asn Leu Val 15 Thr Arg GIn Arg Tyr), or such as the 12 C-terminal amino acids of PYY1 -36 as defined in SEQ ID NO I (Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr), or such as the 14 C- terminal amino acids of PYY1-36 as defined in SEQ ID NO I (Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg GIn Arg Tyr), or such as the 16 C- terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Ser Leu Arg His Tyr Leu Asn 20 Leu Val Thr Arg GIn Arg Tyr Tyr Ala), or such as the 18 C-terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr Tyr Ala), or such as the 20 C- terminal amino acids of PYY1 -36 as defined in SEQ ID NO 1 (Leu Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg GIn Arg Tyr Tyr Ala), or such as the 22 C-terminal amino acids of PYYI-36 25 as defined in SEQ ID NO 1 (Glu Glu Leu Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr Tyr Ala), or such as the 24 C-terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Ser Pro Glu Glu Leu Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr Tyr Ala), or such as the 26 C-terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Asp Ala Ser Pro Glu Glu Leu 30 Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu.Val Thr Arg GIn Arg Tyr Tyr Ala), or such as the 28 C-terminal amino acids of PYY1-36 as defined in SEQ ID NO I (Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr Tyr Ala), or such as the 30 C-terminal amino acids of PYYI-36 as defined in SEQ ID NO 1 (Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg 35 Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg GIn Arg Tyr Tyr Ala), or such as WO 2005/110467 PCT/DK2005/000327 21 the 32 C-terminal amino acids of PYY1-36 as defined in SEQ ID NO 1 (Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr Tyr Ala), or such as the 34 C-terminal amino acids of PYY1 -36 as defined in SEQ ID NO 1 (Tyr Ala lIe Lys Pro Glu Ala Pro Gly Glu Asp 5 Ala Ser Pro Glu Glu Leu Asn Arg Tyr Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg GIn Arg Tyr). In another preferred embodiment the functional equivalent may comprise internal amino acids of PYY1-36 such as amino acid 16-21 of PYY 1-36 as defined in 10 sequence ID NO 1 (Glu Leu Asn Arg Tyr Tyr), or such as amino acid 15-22 of PYY 1-36 as defined in sequence ID NO 1 (Glu Glu Leu Asn Arg Tyr Tyr Ala), or such as amino acid 14-23 of PYY 1-36 as defined in sequence ID NO 1 (Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser), or such as amino acid 13-24 of PYY 1-36 as defined in sequence ID NO 1 (Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu), or such as 15. amino acid 12-25 of PYY 1-36 as defined in sequence ID NO 1 (Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg), or such as amino acid 11-26 of PYY 1-36 as defined in sequence ID NO 1 (Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His), or such as amino acid 10-27 of PYY 1-36 as defined in sequence ID NO 1 (Glu Asp-Ala-Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr), or 20 such as amino acid 9-28 of PYY 1-36 as defined in sequence ID NO 1 (Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu), or such as amino acid 8-29 of PYY 1-36 as defined in sequence ID NO 1 (Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn), or such as amino acid 7-30 of PYY 1-36 as defined in sequence ID NO 1 (Ala Pro Gly Glu Asp 25 Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu), or such as amino acid 6-31 of PYY 1-36 as defined in sequence ID NO 1 (Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val), or such as amino acid 5-32 of PYY 1-36 as defined in sequence ID NO 1 (Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser 30 Leu Arg His Tyr Leu Asn Leu Val Thr), or such as amino acid 4-33 of PYY 1-36 as defined in sequence ID NO 1 (Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg), or such as amino acid 3-34 of PYY 1-36 as defined in sequence ID NO 1 (lle Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr 35 Leu Asn Leu Val Thr Arg GIn), or such as amino acid 2-35 of PYY 1-36 as defined in WO 2005/110467 PCT/DK2005/000327 22 sequence ID NO 1 (Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg) or such as amino acid 2-36 of PYY 1-36 as defined in sequence ID NO 1 (Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu 5 Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr), or such as amino acid 4-36 of PYY 1-36 as defined in sequence ID NO 1 (Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gin Arg Tyr). 10 In an embodiment the functional equivalent comprise any of the above sequences with conservative amino acid substitutions, such as one substitution, or such as two substitutions, or such as two substitutions, or such as more than two substitutions, or such as more than four substitutions. 15 Further included are functional equivalent know from the literature, such as the PYY agonists described in WO 03/057235 and references therein. Covalent modifications 20 The functional equivalent may comprise any type of modifications. Nearly 200 struc turally distinct covalent modifications have been identified thus far, ranging in size and complexity from conversion of amides to carboxylic acids, to the attachment of multiple complex oligosaccharides. Such modifications include phosphorylation, acetylation, ubiquination, lipidation (acetylation, prenylation, farnesylation, geranyla 25 tion, palmitoylation, myristoylation), methylation, carboxylation, sulfunation and 0- or N-glycosylations. A subset of modifications is dependent on vitamin C as a cofactor. This include proline and lysine hydroxylations and carboxy terminal amidation. 30 In an embodiment PYY or the functional equivalent comprise a C-terminal amida tion. In a preferred embodiment the C-terminal tyrosine residue of PYY or a func tional equivalent is amidated. 35 Protectinq qroup WO 2005/110467 PCT/DK2005/000327 23 The functional equivalent may according to the invention comprise protecting group at the N-terminus or the C-terminus or at both. A protecting group covalently joined to the N-terminal amino group reduces the re 5 activity of the amino terminus under in vivo conditions. Amino protecting groups in clude - C1-10 alkyl, -C1-10 substituted alkyl, -C2-10 alkenyl, -C2-10 substituted al kenyl, aryl, -C1-6 alkyl aryl, -C(O)- (CH2) 1-6-COOH, -C(0)-C1-6 alkyl, -C(O)-aryl, -C (0)-O-Cl -6 alkyl, or-C (0)-O-aryl. Preferably, the amino terminus protecting group is acetyl, propyl, succinyl, benzyl, benzyloxycarbonyl or tbutyloxycarbonyl. 10 A protecting group covalently joined to the C-terminal carboxy group reduces the reactivity of the carboxy terminus under in vivo conditions. The carboxy terminus protecting group is preferably attached to the a-carbonyl group of the last amino acid. Carboxy terminus protecting groups include amide, methylamide, and ethyla 15 mide. Conjuqates PYY or the functional equivalent of PYY may conjugated to another entity, in order for example,-to prolong its half-life. -Conjugation can improve the delivery of targeted 20 doses, prevent breakdown, and increase bioavailablity in circulation.The conjugate may be any molecule. The preparation of conjugates is well known in the art se for example Hermanson GT. Bioconjugate Techniques. New York: Academic Press; 1996, Aslam M, Dent 25 AH. Bioconjugation: protein coupling techniques for the biomedical sciences. Houndsmills, England: Macmillan Publishers; 1999, and Wong SS. Chemistry of protein conjugation and crossinking. Boca Raton, FL: CRC Press; 1991. Most methods use amine-reactive reagents or thiol-reactive reagent. In the prepara 30 tion of conjugates advantages may be achieved through the use of certain linkers. For example, linkers that contain a disulfide bond that is sterically "hindered" are often preferred, due to their greater stability in vivo, thus preventing release of the toxin moiety prior to binding at the site of action. It is generally desired to have a conjugate that will remain intact under conditions found everywhere in the body ex- WO 2005/110467 PCT/DK2005/000327 24 cept the intended site of action, at which point it is desirable that the conjugate have good "release" characteristics. Different conjugates have been described, for examplen, use of the A chain of ricin 5 is described in US Pat. No. 4,340,535 incorporated herein by reference. Examples of peptide conjugates based on Ac-RYY(RK)(WI)RK)-NH 2 (where the brackets show allowable variation of amino acid residues) may be found in US patent application 2003040472. 10 In an embodiment of the invention PYY or the functional equivalent is conjugated to another entity. The molecules may be conjugated as described above, or by peptide bonds, before or after synthesis and purification. The fusion may be obtained by any suitable 15 methods, for example, but not exclusively, by recombinant DNA technology. In a preferred embodiment the fusion of is made by recombinant DNA technology, such as a fusion of the nucleotide sequence encoding the binding member and the nu cleotide sequence encoding the ligand is made and the fusion is thereby encoded by a single nucleotide sequence. The fusion polypeptide may be expressed and 20 purified as a single polypeptide molecule, using any suitable method, as described for the purification of a binding member. The fusion polypeptide may include inser tion of a linker, such as a peptide of at least 2 AA, such as at least 5 AA, such as at least 8 AA, such as at least 15 AA, such as at least 20 AA 25 In one embodiment PYY or a functional equivalent there of is conjugated with an other entity using a linker of at least 2AA. Methods for production of PYY PYY or a functional equivalent thereof can be produced using techniques well 30 known in the art. For example, a polypeptide region of a PYY can be chemically or biochemically synthesized and modified. Techniques for chemical synthesis of poly peptides are well known in the art such as solid phase peptide synthesis (see e. g., Vincent in Peptide and Protein Drug Delivery, New York, N. Y., Dekker, 1990.) Ex amples of techniques for biochemical synthesis involving the introduction of a nu- WO 2005/110467 PCT/DK2005/000327 25 cleic acid into a cell and expression of nucleic acids are provided in Ausubel, Cur rent Protocols in Molecular Biology, John Wiley, 1987-1998, and Sambrook et al., in Molecular Cloning, A Laboratory Manual, 2 d Edition, Cold Spring Harbor Laboratory Press, 1989. 5 PYY may according to the invention by synthesised by solid phase peptide synthe sis (se example 1). An second example of how PYY according to the invention is produced is described 10 in brief below. The human PYY of the present invention may be produced by the following process: (a) constructing, by conventional techniques, an expression vector containing an operon with a DNA sequence encoding human PYY or a functional equivalent 15 thereof, thereby producing the vector of the invention; (b) transfecting the expression vectors into a host cell by conventional techniques to produce the transfected host cell of the invention; and 20 (c) culturing the transfected cell by conventional techniques to produce the human PYY of the invention. The host cell may be cotransfected with a second vector for optimization of the pro duction process. The two vectors may contain different selectable markers. The cod 25 ing sequences of PYY may comprise cDNA or genomic DNA or both. The host cell used to express the PYY of the invention may be either a bacterial cell such as Escherichia coli, or a eukaryotic cell, such as S. cerevisiea or P. pastoris. In particular a mammalian cell line may be used, such as Hela, CHO or any other 30 suitable host cell known by the person skilled in the art. The general methods by which the vectors of the invention may be constructed, transfection methods required to produce the host cell of the invention and culture methods required to produce the polypeptide of the invention from such host cells WO 2005/110467 PCT/DK2005/000327 26 are all conventional techniques. Likewise, once produced, the polypeptide of the invention may be purified according to standard procedures as described below. Purification of PYY 5 After production, PYY or a functional equivalent thereof is preferably purified. The method of purification used is dependent upon several factors, including the purity required, the source of PYY or a functional equivalent, the intended use and the species in which PYY or a functional equivalent was produced. 10 Any suitable conventional methods of purifying polypeptides including precipitation and column chromatography are well known to one of skill in the purification arts, including cross-flow filtration, ammonium sulphate precipitation, affinity column chromatography, gel electrophoresis and the like may be used. 15 PYY composition According to the invention, a composition comprising PYY or a functional equivalent thereof may preferably be produced by chemical or biochemical synthesized or re combinant methods, and may preferably be free of any contaminants present in blood such as infectious agents. 20 In a preferred embodiment the PYY composition have a concentration of at least 10 nM such as at least 50 nM, such as at least 0.2 pM, such as at least 0.5 pM, such as -at least 1 pM, such as at least 2 pM, such as at least 5 pM, such as at least 10 pM, such as at least 20 pM, such as at least 50 pM, such as at least 0.2 mM, such 25 as at least 0.5 pM, such as at least 1 mM, such as at least 2 mM, such as at least 5 mM of PYY or a functional equivalent thereof.. The PYY composition may be stored as a dry composition, for example lyophilized (freeze-dried) or spray dried to improve the stability of PYY. Such compositions are 30 reconstituted with liquid solutions prior to use. Generally, the protein concentration of the reconstituted formulation is about 2-40 times greater than the protein concen tration in the mixture before lyophilization; thus this allows the production of a PYY composition of a high concentration. When reconstituted with a diluent comprising a preservative (such as bacteriostatic water for injection, BWFI), the reconstituted WO 2005/110467 PCT/DK2005/000327 27 formulation may be used as a multi-dose formulation. Such a formulation is useful, for example, where the patient requires frequent subcutaneous administrations. In another embodiment the PYY composition may be a liquid composition of high 5 stability. The PYY composition may be meant for mixing with a suitable diluent prior to use. The PYY composition may further comprise pharmaceutically acceptable salts, as well as pharmaceutically acceptable carriers and diluents. 10 Pharmaceutical compositions Pharmaceutical compositions of the present invention may be prepared by conven tional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, 15 Easton, Pa. The compositions may appear in conventional forms, for example solu tions or suspensions. As used herein, the terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, as they refer to compositions, carriers, diluents 20 and reagents, are used interchangeably and represent that the materials are capa ble of administration to or upon an individual without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like. According to the present invention, the pharmaceutical composition may comprise 25 PYY or a functional equivalent thereof and pharmaceutical acceptable salts. The pharmaceutical composition according to the present invention further prefera bly comprises pharmaceutically acceptable salts, a pharmaceutically acceptable carrier and/or a diluent. The pharmaceutical composition may further comprise vehi 30 cles, excipients and/or transport molecules. The pharmaceutical composition may be produced prior to use by mixing a PYY composition with an appropriate diluent.

WO 2005/110467 PCT/DK2005/000327 28 The compositions of the present invention may preferably be administered to an individual in any way so as to achieve a beneficial effect, preferably for treatment of a gastrointestinal disorder. 5 An aspect of the invention relates to a method of treatment comprising administra tion of the pharmaceutical composition according to the invention. The pharmaceutical composition according to the invention may be formulated for administered by any suitable route, such as peripherally, parenterally or orally. 10 The pharmaceutical composition according to the invention is preferably formulated for parenteral administration, such as via a subcutaneous, intramuscular, intrave nous, intranasal, inhalation, buccal, intradermal and transdermal administration route. Further including formulation for administration via rectal suppositories. 15 Second active ingredient The patient suffering from an eating disorder event may benefit from additional treat ments. This may e.g. involve anti-depressants, such as selective serotonin reuptake -inhibitors (SSRIs), serotonin noradrenalin reuptake inhibitors (SNRIs), norepi 20 nephrine serotonin reuptake inhibitors (NSRIs), selective noradrenalin reuptake inhi bitors, tetracyclic antidepressants, non-selective monoamine reuptake inhibitors including tricyclic antidepressants (TCAs), selective reversible monoamine reuptake inhibitors and antidepressants with other mechanisms of action, e.g. mirtazapin. Examples of SSRIs are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxet 25 ine and sertraline. An example of an SNRI is venlafaxine. An example of an NSRI is miinacipran. In an embodiment of the invention, the composition comprises a second active in gredient in addition to PYY or a functional equivalent thereof. 30 In another embodiment, an anti-emetic may be used as a second active ingredient. This is of particular interest in cases where the treatment with PYY or a functional equivalent thereof gives rise to nausea and/or emesis. 35 Anti-emetic drugs WO 2005/110467 PCT/DK2005/000327 29 In the present context, an "anti-emetic" drug is one which counteracts (i.e. reduces or removes) nausea or emesis (vomiting). The experience of nausea and emesis may have many causes and the relief or reduction of the symptoms may be ob tained by various mechanisms. The major groups of drugs useful for the treatment 5 of nausea and emesis are; Neuroleptics/anti-psychotics, Antihistamines, Anticho linergic agents, Steroids (corticosteroids), 5HT3-receptor antagonists (serotonin receptor antagonist), NK1 -receptor antagonists (Neurokinin 1 substance P receptor antagonists), Antidopaminergic agents/dopamine receptor antagonists, Benzodi azapines, Cannabinoids. Here below is a non-exhaustive list of members of the dif 10 ferent groups of compounds. 1. Neuroleptics/anti-psychotics a. Dixyrazine b. Haloperidol 15 c. Prochlorperazine (Compazine@) 2. Antihistamines a. Piperazine derivatives i. cyclizine 20 ii. meclizine iii. cinnarizine b. Promethazine c. Dimenhydrinate d. Diphenhydramine 25 e. Hydroxyzine f. Buclizine g. Meclizine hydrochloride (Bonine, Antivert) 3. Anticholinergic agents (Inhibitors of the acetylcholine receptors.) 30 a. Scopolamine b. Glycopyrron c. Hyoscine i. Artane (Trihexy-5 trihexyphenidyl hydrochloride) ii. Cogentin (benztropine mesylate) 35 iii. Akineton (biperiden hydrochloride) iv. Disipal (Norflex orphenadrine citrate) v. Kemadrin (procyclidine hydrochloride) 4. Steroids (corticosteroids) 40 a. Betamethasone b. Dexamethasone c. Methylprednisolone d. Prednisone@, e. Trimethobenzamide (Tigan) 45 5. 5HT3-receptor antagonists (serotonin receptor antagonist) a. Granisetron WO 2005/110467 PCT/DK2005/000327 30 b. Dolasetron c. Ondansetron (hydrochloride) d. Tropisetron e. Ramosetron 5 f. Palonosetron g. Alosetron h. Bemesetron i. Zatisetron j. Batanopirde 10 k. MDL-73147EF; 1. Metoclopramide m. N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-y-1 H indazole-3-carboxamide dihydrochloride), n. Y-25130 hydrochloride 15 o. MDL 72222 p. Tropanyl-3,5-d imethylbenzoate q. 3-(4-Allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate r. Zacopride hydrochloride s. Mirtazepine (Antidepressant) 20 6. NK1-receptor antagonists (Neurokinin 1 substance P receptor antagonists) a. Aprepitant b. MPC-4505 c. GW597599 25 d. MPC-4505 e. GR205171 (a selective tachykinin NK1 receptor antagonist) f. L-759274 -g. SR 140333 h. CP-96,345 30 i. BIlF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (Nolpitan tium besilate/chloride), LY 303870 (Lanepitant), MDL-1 05172A, MDL 103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM 44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-1 1974, L-758298, DNK-33A, 6b-1, 35 CJ-11974. j. Benserazide and carbidopa k. TAK-637 [(aR, 9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 tetrahyd ro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2, 1 -g] [1,7]naphthyridine-6,13-dione] 40 1. PD 154075 ([(2-benzofuran)-CH20CO]-(R)-alpha-MeTrp-(S) NHCH(CH3) Ph) m. FK888, chemical modification of the parent compound, (D-Pro4, D Trp7, 9, 10, Phel1) SP4-11. 45 7. Antidopaminergic agents/dopamine receptor antagonists a. Domperidone b. Prochlorperazine c. Metoclopramide d. Chlorpromazine (Thorazine) 50 e. Droperidol (Inapsine) f. Promethazine (Phenergan) 8. Benzodiazapines(Valium@ and others) WO 2005/110467 PCT/DK2005/000327 31 9. Non-psychoactive cannabinoids, a. Cannabidiol (CBD) b. Cannabidiol dimethylheptyl (CBD-DMH) 5 c. Tetra-hydro-cannabinol (THC) d. Cannabinoid agonists such as WIN 55-212 (a CB1 and CB2 receptor agonist) e. Dronabinol (Marinol@) 10 10. Further cannabinoids a. Nabilone (Cesamet) 11. c-9280 (Merck) 15 A 5HT3-recpetor antagonist is particularly preferred. The anti-emetic is used in an effective amount which is sufficient to either remove or reduce the nausea and/or emesis to an acceptable level. A preferred embodiment 20 The pharmaceutical composition may also be a kit-in-part further including anti depressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin nor adrenalin reuptake inhibitors (SNRIs), norepinephrine serotonin reuptake inhibitors (NSRIs), selective noradrenalin reuptake inhibitors, tetracyclic antidepressants, non 25 selective monoamine reuptake inhibitors including tricyclic antidepressants (TCAs), selective reversible monoamine reuptake inhibitors and antidepressants with other mechanisms of action, e.g. mirtazapin. Examples of SSRIs are citalopram, escitalo pram, fluoxetine, fluvoxamine, paroxetine and sertraline. An example of an SNRI is venlafaxine. The kit-in-part may be used for simultaneous, sequential or separate 30 administration. An example of an NSRI is milnacipran. In a preferred embodiment the pharmaceutical composition may be a kit-in-part. Pharmaceutically acceptable salts 35 Pharmaceutically acceptable salts of the present compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating dis 40 eases.

WO 2005/110467 PCT/DK2005/000327 32 Pharmaceutically acceptable salts are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or 5 organic base in a suitable solvent. The compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form 10 of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (in cluding subcutaneous) route, in an effective amount. Examples of pharmaceutically acceptable acid addition salts for use in the present inventive pharmaceutical composition include those derived from mineral acids, 15 such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, ben zoic, glycolic, gluconic, succinic, p-toluenesulphonic acids, and arylsulphonic, for example. 20 The pharmaceutical composition of the present invention can include pharmaceuti cally acceptable salts of the compounds therein. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypep tide). 25 Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addi tion salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydriodic, phosphoric, sulpfuric and nitric acids and the like. Representative examples of suit 30 able organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, as partic, stearic, palmitic, ethylenediaminetetraacetic (EDTA), p-aminobenzoic, glu 35 tamic, benzenesulfonic and p-toluenesulfonic acids and the like. Further examples WO 2005/110467 PCT/DK2005/000327 33 of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutical acceptable salts listed in J. Pharm. Sci. 1977,66,2, which is incorpo rated herein by reference. Examples of metal salts include lithium, sodium, potas sium and magnesium salts and the like. 5 According to the invention organic acid salts of organic acids such as for example acetic acid is preferred. Examples of ammonium and alkylated ammonium salts include ammonium, methyl 10 ammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxy ethylammonium, diethylammonium, butylammonium and tetramethylammonium salts and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases 15 such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like. -Also included within the scope- of compounds or pharmaceutical acceptable acid 20 addition salts thereof in the context of the present invention are any hydrates (hy drated forms) thereof. The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art. Typically such composi 25 tions are prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non-aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified. Pharmaceutically acceptable carriers and diluents 30 The active ingredient can be mixed with excipients which are pharmaceutically ac ceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, wa ter, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addi tion, if desired, the'composition can contain minor amounts of auxiliary substances WO 2005/110467 PCT/DK2005/000327 34 such as wetting or emulsifying agents, pH buffering agents and the like which en hance the effectiveness of the active ingredient. Liquid compositions can also contain liquid phases in addition to and to the exclu 5 sion of water. Exemplary of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra 10 alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. 15 The pharmaceutical compositions formed by combining the compounds of the inven tion and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The com positions may conveniently be presented in unit dosage form or in multiple dosage form -by methods known in-the art of pharmacy. 20 In a still further aspect, the invention relates to a pharmaceutical composition com prising, as an active ingredient, a compound as defined above or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier. 25 Stabilizers The active compound of the invention may be unstable, thus the composition pref erably contain stabilizers, preservatives or conservatives to increase the stability of the compounds. 30 A pH-buffering agent may be used to stabilize the active compound of the composi tion. The buffering agent may be acetate, carbonate, bicarbonate, phosphate, cit rate, tris or hepes. In a preferred embodiment the buffering agent is acetate. According to the invention the composition preferably has a pH between 2.0 and 35 9.0, or such as between 2.5 and 8.0, or such as 3.0 and 7.0, or such as between 3.5 WO 2005/110467 PCT/DK2005/000327 35 and 6.0, or such as between 3.5 and 5.0 or such as between 4.0 and 5.5, or such as between 4.0 and 5.0, or such as between 4.0 and 4.5. Preferably the pH of the com positions is less than 6, preferably less than 5.5, preferably less than 5, preferably less than 4.8, preferably less than 4.6, preferably less than 4.4, preferably less than 5 4.2. Tween 20, Tween 60, Tween 80, Span 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate, manitol, polysorbates and sodium lauryl sulphate are possible stabilizers. 10 In a preferred embodiment manitol may be used as stabilizers Tween 60, Span 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate, mannitol and sodium lauryl sulphate are possible stabilizers. 15 In a preferred embodiment mannitol may be used as stabilizer. For the preparation of a lyophilised composition ad lyoprotectant may be used to stabilize the active ingredient (Townsend and DeLuca, "Use of lyoprotectants in the 20 freeze-drying of a model protein, ribonuclease A" Journal of Parenteral Science & Technology 42 (6): 190-199 (Nov.-Dec. 1988)). The lyoprotectant may preferably be a sugar such as sucrose or trehalose such as sucrose, dextran, or hydroxypropyl-/142-cyclodextrin. 25 Transport molecules Transport molecules act by having incorporated into or anchored to it the compound according to the invention. Any suitable transport molecules known to the skilled 30 person may be used. Examples of transport molecules may be liposomes, micelles, and/or microspheres. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980), U.S. Pat. Nos. 4,235,871, 35 4,501,728 and 4,837,028, all of which are incorporated herein by reference.

WO 2005/110467 PCT/DK2005/000327 36 Micelles are formed by surfactants (molecules that contain a hydrophobic portion and one or more ionic or otherwise strongly hydrophilic groups) in aqueous solution. As the concentration of a solid surfactant increases, its monolayers adsorbed at the 5 air/water or glass/water interfaces become so tightly packed that further occupancy requires excessive compression of the surfactant molecules already in the two monolayers. Further increments in the amount of dissolved surfactant beyond that concentration cause amounts equivalent to the new molecules to aggregate into micelles. This process begins at a characteristic concentration called "critical micelle 10 concentration". The shape of micelles formed in dilute surfactant solutions is approximately spheri cal. The polar head groups of the surfactant molecules are arranged in an outer spherical shell whereas their hydrocarbon chains are oriented toward the centre, 15 forming a spherical core for the micelle. The hydrocarbon chains are randomly coiled and entangled and the micellar interior has a nonpolar, liquid-like character. In the micelles of polyoxyethylated nonionic detergents, the polyoxyethylene moieties are oriented outward and permeated by water. This arrangement is energetically favourable since the hydrophilic head groups are in contact with water and the 20 hydrocarbon moieties are removed from the aqueous medium and partly shielded from contact with water by the polar head groups. The hydrocarbon tails of the surfactant molecules, located in the interior of the micelle, interact with one another by weak van der Waals forces. 25 The size of a micelle or its aggregation number is governed largely by geometric factors. The radius of the hydrocarbon core cannot exceed the length of the extended hydrocarbon chain of the surfactant molecule. Therefore, increasing the chain length or ascending homologous series increases the aggregation number of spherical micelles. If the surfactant concentration is increased beyond a few percent 30 and if electrolytes are added (in the case of ionic surfactants) or the temperature is raised (in the case of nonionic surfactants), the micelles increase in size. Under these conditions, the micelles are too large to remain spherical and become ellip soidal, cylindrical or finally lamellar in shape. 35 Common surfactants well known to one of skill in the art can be used in the micelles WO 2005/110467 PCT/DK2005/000327 37 of the present invention. Suitable surfactants include sodium laureate, sodium ole ate, sodium lauryl sulfate, octaoxyethylene glycol monododecyl ether, octoxynol 9 and PLURONIC F-127 (Wyandotte Chemicals Corp.). Preferred surfactants are non ionic polyoxyethylene and polyoxypropylene detergents compatible with IV injection 5 such as, TWEEN-80, PLURONIC F-68, n-octyl-beta-D-glucopyranoside, and the like. In addition, phospholipids, such as those described for use in the production of liposomes, may also be used for micelle formation. Compositions for oral administration 10 The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise the compounds of the invention or its pharmaceutically acceptable salt or a crystal form thereof as the active component. The pharmaceutically accept able carriers can be either solid or liquid. Solid form preparations include powders, 15 tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid car rier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material. 20 Preferably, the 0.00002% to 2 % by weight of a compound or compounds of the invention, with the remainder consisting of suitable pharmaceutical excipients. For oral administration, such excipients include pharmaceutical grades of mannitol, lac tose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. 25 In powders, the carrier is a finely divided solid which is a mixture with the finely di vided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably containing from one to 30 about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the compo sition of the active compound with encapsulating material as carrier providing a cap 35 sule in which the active component, with or without carriers, is surrounded by a car- WO 2005/110467 PCT/DK2005/000327 38 rier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suit able for oral administration. 5 Drops according to the present invention may comprise sterile or non-sterile aque ous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent. The resulting solution may then be clarified by filtration, 10 transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 0C for half an hour. Alternatively, the solution may be steril ized by filtration and transferred to the container aseptically. Examples of bacteri cidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine ace 15 tate (0.01%). Suitable solvents for the preparation of an oily solution include glyc erol, diluted alcohol and propylene glycol. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations -for oral administration. Such- liquid 20 forms include solutions, suspensions, and emulsions. These preparations may con tain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. 25 Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, toothpaste, gel dentrifrice, chewing gum, or solid form preparations which are intended to be con verted shortly before use to liquid form preparations. Emulsions may be prepared in solutions in aqueous propylene glycol solutions or may contain emulsifying agents 30 such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents. Aqueous suspensions can be prepared by dis persing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, 35 and other well known suspending agents. Solid form preparations include solutions, WO 2005/110467 PCT/DK2005/000327 39 suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. 5 Compositions for parenteral administration The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Ex amples of oily or nonaqueous carriers, diluents, solvents or vehicles include propyl ene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic 10 esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alterna tively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suit able vehicle, e.g., sterile, pyrogen-free water. Aqueous solutions should be suitably 15 buffered if necessary, and the liquid diluents first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous -media employed are all readily available by standard techniques known to those skilled in the art. 20 In a preferred embodiment of the invention, the composition comprising PYY or a functional equivalent thereof or a salt thereof, is a lyophilised composition and the composition may further comprise a solvent. In another embodiment the composi tion is a solution of PYY or a functional equivalent thereof according to the invention 25 or a salt thereof. Preferably, the solvent may be any suitable solvents, such as de scribed herein, and preferably the solvent is saline or a physiological buffer like phosphate buffer. The pharmaceutical composition comprises PYY or a functional equivalent thereof 30 or a pharmaceutically acceptable salt thereof, (and for example antigenic epitopes and protease inhibitors). Such compositions can be prepared in water or saline, and optionally mixed with a nontoxic surfactant. Compositions for intravenous or intra arterial administration may include sterile aqueous solutions that may also contain buffers, liposomes, diluents and other suitable additives.

WO 2005/110467 PCT/DK2005/000327 40 Oils useful in parenteral compositions include petroleum, animal, vegetable, or syn thetic oils. Specific examples of oils useful in such compositions include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty 5 acids for use in parenteral compositions include oleic acid, stearic acid, and isoste aric acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral compositions include fatty alkali metal, ammo 10 nium, and triethanolamine salts, and suitable detergents include (a) cationic deter gents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, f6r example, alkyl, aryl, and olefin sulfo nates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) non ionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, 15 and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary am monium salts, and (e) mixtures thereof. The parenteral compositions typically will contain from about 0.5 to about 25% by 20 weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such compositions will typically range from about 5 to about 15% by weight. Suitable surfactants in 25 clude polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral composi tions can be presented in unit-dose or multi-dose sealed containers, such as am pules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring 30 only the addition of the sterile liquid excipient, for example, water, for injections, im mediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously de scribed.

WO 2005/110467 PCT/DK2005/000327 41 The pharmaceutical dosage forms suitable for injection can include sterile aqueous solutions or dispersions comprising the active ingredient that are adapted for admini stration by encapsulation in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. 5 Sterile injectable solutions are prepared by incorporating PYY or a functional equi valent thereof or pharmaceutically acceptable salt thereof in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filter sterilization. 10 Compositions for topical administration The compounds of the invention can also be delivered topically. Regions for topical administration include the skin surface and also mucous membrane tissues of the rectum, nose, mouth, and throat. Compositions for topical administration via the skin 15 and mucous membranes should not give rise to signs of irritation, such as swelling or redness. The topical composition may include a pharmaceutically acceptable carrier adapted for topical administration. Thus, the composition may take the form of a suspension, 20 solution, ointment, lotion, cream, foam, aerosol, spray, suppository, implant, inha lant, tablet, capsule, dry powder, syrup, balm or lozenge, for example. Methods for preparing such compositions are well known in the pharmaceutical industry. The compounds of the present invention may be formulated for topical administra 25 tion to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, 30 thickening agents, or colouring agents. Compositions suitable for topical administra tion in the mouth include lozenges comprising active agents in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth washes comprising the active ingredient in a suitable liquid carrier. 35 WO 2005/110467 PCT/DK2005/000327 42 Creams, ointments or pastes according to the present invention are semi-solid com positions of the active ingredient for external application. They may be made by mix ing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, 5 with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its deriva tives or a fatty acid such as steric or oleic acid together with an alcohol such as pro pylene glycol or a macrogel. The compositionmay incorporate any suitable surface 10 active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. 15 Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include - an agent to hasten drying and to cool the skin, such as an alcohol or acetone, 20 and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil. The pharmaceutical agent-chemical modifier complexes described herein can be administered transdermally. Transdermal administration typically involves the deliv ery of a pharmaceutical agent for percutaneous passage of the drug into the sys 25 temic circulation of the patient. The skin sites include anatomic regions for trans dermally administering the drug and include the forearm, abdomen, chest, back, buttock, mastoidal area, and the like. Transdermal delivery is accomplished by exposing a source of the complex to a 30 patient's skin for an extended period of time. Transdermal patches have the added advantage of providing controlled delivery of a pharmaceutical agent-chemical modi fier complex to the body. See Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Hadgraft and Guy (eds.), Marcel Dekker, Inc., (1989); Con trolled Drug Delivery: Fundamentals and Applications, Robinson and Lee (eds.), 35 Marcel Dekker Inc., (1987); and Transdermal Delivery of Drugs, Vols. 1-3, Kydo- WO 2005/110467 PCT/DK2005/000327 43 nieus and Berner (eds.), CRC Press, (1987). Such dosage forms can be made by dissolving, dispersing, or otherwise incorporating the pharmaceutical agent-chemical modifier complex in a proper medium, such as an elastomeric matrix material. Ab sorption enhancers can also be used to increase the flux of the compound across 5 the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. A variety of types of transdermal patches will find use in the methods described herein. For example, a simple adhesive patch can be prepared from a backing ma 10 terial and an acrylate adhesive. The pharmaceutical agent-chemical modifier com plex and any enhancer are formulated into the adhesive casting solution and al lowed to mix thoroughly. The solution is cast directly onto the backing material and the casting solvent is evaporated in an oven, leaving an adhesive film. The release liner can be attached to complete the system. 15 Alternatively, a polyurethane matrix patch can be employed to deliver the pharma ceutical agent-chemical modifier complex. The layers of this patch comprise a back ing, a polyurethane drug/enhancer matrix, a membrane, an adhesive, and a release - liner. The polyurethane matrix is prepared using a room temperature curing polyure 20 thane prepolymer. Addition of water, alcohol, and complex to the prepolymer results in the formation of a tacky firm elastomer that can be directly cast only the backing material. A further embodiment of this invention will utilize a hydrogel matrix patch. Typically, 25 the hydrogel matrix will comprise alcohol, water, drug, and several hydrophilic poly mers. This hydrogel matrix can be incorporated into a transdermal patch between the backing and the adhesive layer. The liquid reservoir patch will also find use in the methods described herein. This 30 patch comprises an impermeable or semipermeable, heat sealable backing material, a heat sealable membrane, an acrylate based pressure sensitive skin adhesive, and a siliconized release liner. The backing is heat sealed to the membrane to form a reservoir which can then be filled with a solution of the complex, enhancers, gelling agent, and other excipients. 35 WO 2005/110467 PCT/DK2005/000327 44 Foam matrix patches are similar in design and components to the liquid reservoir system, except that the gelled pharmaceutical agent-chemical modifier solution is constrained in a thin foam layer, typically a polyurethane. This foam layer is situated between the backing and the membrane which have been heat sealed at the pe 5 riphery of the patch. For passive delivery systems, the rate of release is typically controlled by a mem brane placed between the reservoir and the skin, by diffusion from a monolithic de vice, or by the skin itself serving as a rate-controlling barrier in the delivery 'system. 10 See U.S. Pat. Nos. 4,816,258; 4,927,408; 4,904,475; 4,588,580, 4,788,062; and the like. The rate of drug delivery will be dependent, in part, upon the nature of the membrane. For example, the rate of drug delivery across membranes within the body is generally higher than across dermal barriers. The rate at which the complex is delivered from the device to the membrane is most advantageously controlled by 15 the use of rate-limiting membranes which are placed between the reservoir and the skin. Assuming that the skin is sufficiently permeable to the complex (i.e., absorption through the skin is greater than the rate of passage through the membrane), the membrane will serve to control the dosage rate experienced by the patient. 20 Suitable permeable membrane materials may be selected based on the desired degree of permeability, the nature of the complex, and the mechanical considera tions related to constructing the device. Exemplary permeable membrane materials include a wide variety of natural and synthetic polymers, such as polydimethylsilox anes (silicone rubbers), ethylenevinylacetate copolymer (EVA), polyurethanes, poly 25 urethane-polyether copolymers, polyethylenes, polyamides, polyvinylchlorides (PVC), polypropylenes, polycarbonates, polytetrafluoroethylenes (PTFE), cellulosic materials, e.g., cellulose triacetate and cellulose nitrate/acetate, and hydrogels, e.g., 2-hydroxyethylmethacrylate (HEMA). 30 Other items may be contained in the device, such as other conventional compo nents of therapeutic products, depending upon the desired device characteristics. For example, the compositions according to this invention may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, and the like. These phar 35 maceutical compositions also can contain other active ingredients such as antim- WO 2005/110467 PCT/DK2005/000327 45 icrobial agents, particularly antibiotics, anesthetics, analgesics, and antipruritic agents. Compositions for administration as suppositories 5 The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for ex ample, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify. 10 The active compound may be formulated into a suppository comprising, for exam ple, about 0.5% to about 50% of a compound of the invention, disposed in a poly ethylene glycol (PEG) carrier (e.g., PEG 1000 [96%] and PEG 4000 [4%]). 15 Compounds for nasal administration The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be pro vided in a single or multidose form. In the latter case of a dropper or pipette this may 20 be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray this may be achieved for example by means of a metering atomizing spray pump. Compounds for aerosol administration 25 The compounds of the present invention may be formulated for aerosol administra tion, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of 5 mi crons or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack 30 with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichloro difluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon diox ide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alterna tively the active ingredients may be provided in a form of a dry powder, for example WO 2005/110467 PCT/DK2005/000327 46 a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composi tion may be presented in unit dose form for example in capsules or cartridges of 5 e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler. Compositions administered by aerosols may be prepared, for example, as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption pro 10 moters to enhance bioavailability, employing fluorocarbons, and/or employing other solubilizing or dispersing agents. Combinations It is further envisaged that the composition of the present invention can be adminis 15 tered in combination with a second active ingredient. Said second active ingredient may be co-formulated with the other compound(s) according to the invention. It is further envisaged that the active ingredient of the present invention can be ad -ministered in combination with a second active ingredient. By "in combination" is 20 meant that said composition may be co-formulated with other compounds in the same composition, and/or that said second active ingreedient and/or pharmaceutical composition(s) are administered before, during (including concurrently with) and/or after administration of the compositions of the present invention. 25 Thus an embodiment of the present invention relates to a composition comprising PYY or a functional equivalent there of and a second active ingredient. Thus an embodiment of the present invention relates to a composition comprising PYY or a functional equivalent thereof as defined herein and a second active ingre 30 dient. Said second active ingredient may be selected from the group of; anti hypertensives including (but not limited to) beta-adrenoceptor antagonists, alpha adrenoceptor antagonists, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin 11 receptor antagonists and diuretics (including, but not limited to, thiazide diuretics and loop diuretics), insulin, DPP-IV inhibitors, anti 35 depressant medications including (but not limited to) selective serotonin reuptake WO 2005/110467 PCT/DK2005/000327 47 inhibitors (SSRIs), mianserine and mirtazapine, classical as well as atypical antipsy chotic drugs (neuroleptics), corticosteroids as well as any other drug(s) that may increase body weight or body fat mass or that may be indicated for the treatment of hypertension, overweight, obesity, the metabolic syndrome (syndrome X) and/or 5 diabetes mellitus. Administration Furthermore are provided in the scope of the present invention methods of treat 10 ment of an individual in need thereof, comprising administering to said individual an effective amount of one or more of the pharmaceutical compositions described herein. Said individual is preferably suffering, or at risk of, one or more of the health problems described earlier herein such as gastrointestinal disorders. By "treatment" is also meant prophylaxis and aftercare, and/or lessening of disease symptoms 15 and/or possible disease prevention and/or cure. Said method of treatment may comprise improving the sense of well-being and the quality of life in an individual. Said method may involve one or more of the combination treatments as disclosed herein. 20 The pharmaceutical compositions of the invention may be used both prophylactically as well as for therapeutic administration. Thus, the pharmaceutical composition comprising PYY or a functional equivalent there of can be administered to patients in order to prevent the development of a gastrointestinal disorder, in order to mini mise the severity of a disorder or to patients already suffering from a disorder. Fur 25 thermore the therapeutic method may prevent reoccurrence of disorders of the gas trointestine. The pharmaceutical composition may be prepared so it is suitable for one or more particular administration methods. The composition according to the invention may 30 be administered parenterally, orally, nasally (inhalation or intranasal application), topically (to the skin or to the eye), rectally using suppositories or by intravaginal absorption. The pharmaceutical composition comprising PYY or a functional equivalent thereof 35 may be administered to an individual in need thereof.

WO 2005/110467 PCT/DK2005/000327 48 The composition comprising PYY or a functional equivalent thereof can, according to the invention, be administered parenterally, e.g. by injection. Thus, PYY or a func tional equivalent thereof may, according to the invention, be administered parenter 5 ally, such as intravenously, intra-arterially, intraperitoneally, intramuscularly, subcu taneously, intranasally or transdermally. The composition may further be adminis tered by inhalation, topical application to the eye, intranasal application, intravaginal absorption, application to the skin, and rectal suppositories. Other drug administration methods, which are effective to deliver the drug to a target site or to 10 introduce the drug into the bloodstream, are also contemplated. The pharmaceutical compositions containing PYY or a functional equivalent thereof may be administered intravenously, for example by injection of a unit dose. The term "unit dose" when used in reference to a pharmaceutical composition of the present 15 invention refers to physically discrete units suitable as unitary dosage for the sub ject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e. carrier, or vehicle. Alternatively, the pharmaceutical composition may be prepared in a multiple dose form and, by use of the multi-dose delivery device, single doses can 20 be administered when needed. As an alternative to standard injections the pharma ceutical composition may be administrated by infusions, such infusions are prefera bly short. The effect of PYY or functional equivalents according to the invention is believed to 25 be mediated via actions of PYY outside the central nervous system, with the excep tion of the NPY neurons located in the hypothalamus. Thereby PYY or functional equivalents do not affect NPY neurons located elsewhere in the central nervous system. 30 Accordingly, PYY or functional equivalents capable of binding to the NPY Y2 recep tor may circulate in the bloodstream to the receptors in the hypothalamus; however, these molecules should preferably not be capable of crossing the blood-brain bar rier, and thereby not be able to enter into other parts of the central nervous system.

WO 2005/110467 PCT/DK2005/000327 49 The composition according to the invention may be administrated in combination with a second pharmaceutical composition. By "in combination" is meant that said composition may be co-formulated with other compounds in the same composition, and/or that said other compound(s) and/or pharmaceutical composition(s) are ad 5 ministered before, during (including concurrently with) and/or after administration of the compositions of the present invention. Thus in an embodiment the composition of the invention may be administered in combination with a second pharmaceutical composition. The compositions may be 10 administered simultaneously, either as separate compositions or combined in a unit dosage form, or administered sequentially as two separate pharmaceutical composi tions. In an embodiment the pharmaceutical composition according to the invention is ad 15 ministered in combination with a second pharmaceutical composition selected from the group of pharmaceutical composition comprising ; anti-depressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenalin reuptake inhibitors (SNRIs), norepinephrine serotonin reuptake inhibitors (NSRIs), selective noradrenalin reuptake inhibitors, tetracyclic antidepressants, non-selective monoam 20 ine reuptake inhibitors including tricyclic antidepressants (TCAs), selective reversi ble monoamine reuptake inhibitors and antidepressants with other mechanisms of action, e.g. mirtazapin. Examples of SSRIs are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. An example of an SNRI is venlafaxine. An example of an NSRI is milnacipran. 25 Method of treatment The method of treatment may aim at reducing the symptoms of the gastrointestinal disorder. 30 The compositions are preferably administered after sensing of symptoms, such as 5 minutes after sensing of symptoms, such as 10 minutes after sensing of symptoms, such as 15 minutes after sensing of symptoms, such as up to 20 minutes after sens ing of symptoms, such as up to 30 minutes after sensing of symptoms, such as up 35 to 45 minutes after sensing of symptoms, such as up to 60 minutes after sensing of WO 2005/110467 PCT/DK2005/000327 50 symptoms, such as up to 75 minutes after sensing of symptoms, such as up to 90 minutes after sensing of symptoms, such as up to 120 minutes after sensing of symptoms, such as up to 150 minutes after sensing of symptoms, such as up to 180 minutes after sensing of symptoms. 5 The composition may administered once a day, or every second day or twice a week or once a week. Administration of said pharmaceutical composition may be once a day, or twice a day, or three times a day. 10 The pharmaceutical composition may be administered prior to a meal, such as within 5 minutes of a meal, such as within 20 minutes of a meal, such as within 60 minutes of a meal. The pharmaceutical preparations described herein may also be arranged in unit 15 dosage forms. In such a form, the preparation is subdivided into unit doses contain ing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as powders in compartments. In this embodiment the powders may be mixed -- with a solvent prior to or during use. 20 In one aspect of the present invention, a suitable dose of the compositions de scribed herein is administered in pharmaceutically effective amounts to an individual in need of such treatment. Herein, "pharmaceutically effective amounts", is defined as an administration involving a total amount of each active component of the phar 25 maceutical composition or pharmaceutical composition or method that is sufficient to show a meaningful patient benefit. The term "unit dosage form" as used herein re fers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a compound, alone or in combination with other agents, calculated in an amount sufficient to produce the 30 desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host. The dose administered should be an "effective amount" or an amount necessary to 35 achieve an "effective level" in the individual patient.

WO 2005/110467 PCT/DK2005/000327 51 The pharmaceutical compositions may be administrated by intravenous infusion. The duration of an infusion may be less than 120 minutes, such as less than 100 minutes, such as less than 80 minutes, such as less than 60 minutes, such as less 5 than 40 minutes, such as less than 20 minutes, such as less than 10 minutes or such as less than 5 minutes. The dosage requirements will vary with the particular drug composition employed, the route of administration and the particular subject being treated. Ideally, a patient 10 to be treated by the present method will receive a pharmaceutically effective amount of the compound not exceeding the maximum tolerated dose (MTD), which is gene rally no higher than that required before drug resistance develops. Suitable dosing regimens are preferably determined taking into account factors well 15 known in the art including type of subject being dosed; age, weight, sex and medical condition of the subject; the route of administration; the renal and hepatic function of the subject; the desired effect; and the particular compound employed. Optimal precision in achieving concentrations-of drug-within the range that yields 20 efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equili brium, and elimination of a drug. For the present invention the dosage will vary depending on the compound employed and the mode of administration. 25 The dosage may be calculated based on the body weight of the subject but in cer tain situations the dosages may be calculated base on the fat free mass (FFM) of the subject. Thus the dosage may be in concentration equivalent to PYY1-36 or PYY3-36. 30 For the present invention the dosage will vary depending on the compound em ployed and the mode of administration. Dosage levels may vary between about 4 ng/kg body weight to 20 ptg/kg body weight daily, preferably between about 10 ng/kg body weight to 1 gg/kg body weight, more preferably between 50 to 750 ng/kg body weight. Alternative dosages in relation to FFM may vary between about 5 ng/kg FFM 35 to 25 pg/kg FFMdaily, preferably between about I12.5 ng/kg FFM to 1.25 pg/kg WO 2005/110467 PCT/DK2005/000327 52 FFM, more preferably between 62.5 to 875 ng/kg FFM. To obtain dosages in rela tion to FFM the dosage/kg bodyweight should be multiplied by the factor 1.25. The dosage may be administered when needed, such as up to ten times daily, such 5 as one to five times daily, such as two or three times daily, or preferably such as once a day, thus the daily dosage maybe up to 2-5 times the dosages mentioned above. Alternatively, the dosage may be administered less frequently than once daily as described herein above. 10 A preferred dosage of a composition employed according to the invention is in a concentration equivalent to PYY or a functional equivalent there of from 4 ng to about 20 pg per kg bodyweight, or such as from 10 ng to 1 pg per kg bodyweight, more preferably from 50 to 750 ng per kg bodyweight. The dosage of PYY is pref erably 20-200 ng/kg, 20-160 ng/kg, 40-160 ng/kg, 40-120 ng/kg, 40-80 ng/kg, 60 15 120 ng/kg or such as approximately 60 ng/kg or 80 ng/kg. The preferred dosages may be in a concentration equivalent to PYY or a functional equivalent there of from 1 pmol/kg to 5 nmol/ kg, such as from 5 pmol/kg to 1 nmol/kg, or such as from 20 pmol/kg to 500 pmol/kg alternativly-such as from -40 to 20 160 pmol/kg or such as from 75 to 120 pmol/kg. PYY1-36 is preferably administered in dosages of, such as from 50-400 pmol/kg, such as 80320 pmol/kg, such as 150 250 pmol/kg, such as about 200 pmol/kg. PYY3-36 is preferably administered in dosages of-such as from 30-350 pmol/kg, such as 50-280 pmol/kg, such as 80- 200 pmol/kg, such as about 120 pmol/kg. Dosages in relation to FFM may be calculated 25 by multiplying the indicated dosages with 1.25. In a second embodiment the dosage may be 5-50 pmol/kg, 5-40 pmol/kg, 5 to 30 pmol/kg, 10-40 pmol/kg, 10-30 pmol/kg such as 5 to 25 pmol/kg, such as 5 to 20 pmol/kg, and most preferably 10-20 pmol/kg, 15-30 pmol/kg or approximately 15 30 pmol/kg or 20 pmol/kg. The dosages are preferably administrated once a day, or such as two times a day, or such as three times a day, or such as four times a day, or such as five times a day, or such as more than five times a day. 35 WO 2005/110467 PCT/DK2005/000327 53 In one preferred embodiment of the present invention, the compositions are admin istered in dosages of PYY or a functional equivalent from about 400 ng to about 2 mg, more preferably from about 10 pg to about 200 pg, or from about 5 gg to about 250 pg, more preferably from about 20 ig to about 200 pg, more preferably from 5 about 20 pg to about 100 pg. Most preferably the dosage may be 1-20 pg, 2-16 pg, 4-16 pg, 4-12 pg, 4-8 pg, 6-12 pg, 6-10 pg or approximately 8 pg. In a preferred embodiment the composition is administered in dosages of PYY or a functional equivalent from 100 pmol to 500 nmole, or such from 500 pmol to 100 10 nmol, or such as from 1 nmol to 50 nmol, or such as from 2 to 25 nmol, or such as from 4 to 20 nmol. Alternatively the preferred dosage may be 0,25-5 nmol, 0,5-4 nmol, 1-4 nmol, 1-3 nmol, 1-2 nmol, 1,5-3 nmol or more preferably 1,5-2,5 nmol or most preferably approximately 2 nmol. In a further preferred embodiment a PYY1-36 dosages includes such as from 5-40 nmol, such as 8-32 nmol, such as 15- 25 nmol, 15 such as about 20 nmol, wheras a dosage of PYY3-36 includes such as from 3-35 nmol, such as 5-28 nmol, such as 8-200 nmol, such as about 12 nmol. In another embodiment, the PYY or functional equivalent is administered subcuta neously in a dosage of 5-30 prnol/kg, such as 5-25pmol/kg, such-as 5-20 pmol/kg or 20 such as 10-20 pmol/kg bodyweight, in order to achieve an effective level in the indi vidual treated. The presently preferred dosage is 10-20 pmol/kg bodyweight of ' PYY1 -36 or PYY 3-36. In second preferred embodiment the dosages of PYY1 -36 is 150-250 pmol/kg and/or the dosages of PYY3-36 is 80-150 pmol/kg. 25 The dosages of PYY or the functional equivalent is preferably administered once a day, or such as two times a day, or such as three times a day, or such as four times a day, or such as five times a day. The pharmaceutical preparations described herein may also be arranged in unit 30 dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as powders in compartments. In this embodiment the powders may be mixed with a solvent prior to or during use. 35 WO 2005/110467 PCT/DK2005/000327 54 In a preferred embodiment the PYY composition is administrated in unit dosage form, from about 400 ng to about 2 mg of PYY or a functional equivalent thereof, more preferably from about 10 ptg to about 206 ptg, or from about 5 pg to about 250 gg, more preferably from about 20 pg to about 200 tg, more preferably from about 5 20 pg to about 100 ptg. The unit dosage form may comprise from 100 pmol to 500 nmole, or such from 500 pmol to 100 nmol, or such as from 1 nmol to 50 nmol, or such as from 2 to 25, such as from 4 nmol to 20 nmol. of PYY or a functional equiva lent thereof. The compositions are preferably administered once a day, or such as two times a day, or such as three times a day, or such as four times a day, or such 10 as five times a day. In a further preferred embodiment a unit dosage of PYY1-36 includes such as from 5-40 nmol, such as 8-32 nmol, such as 15- 25 nmol, such as about 20 nmol, wheras a unit dosage of PYY3-36 includes such as from 3-35 nmol, such as 5-28 nmol, such as 8-200 nmol, such as about 12 nmol. 15 In certain embodiment the pharmaceutical composition may be administered by in fusions. The dosages of PYY or a functional equivalent for infusion may be from 0.01 pmol/kg minute to 500 pmol/kg minute such as from 0.05 pmol/kg minute to 100 pmol/kg minute, or such as from 0.1 pmol/kg minute to 50 pmol/kg minute, or such as from 1 pmol/kg min. to 25 prnol/kg minute. 20 The compositions are preferably administered after sensing of symptoms, such as 5 minutes after sensing of symptoms, such as 10 minutes after sensing of symptoms, such as 15 minutes after sensing of symptoms, such as up to 20 minutes after sens ing of symptoms, such as up to 30 minutes after sensing of symptoms, such as up 25 to 45 minutes after sensing of symptoms, such as up to 60 minutes after sensing of symptoms, such as up to 75 minutes after sensing of symptoms, such as up to 90 minutes after sensing of symptoms, such as up to 120 minutes after sensing of symptoms, such as up to 150 minutes after sensing of symptoms, such as up to 180 minutes after sensing of symptoms. 30 The PYY composition of the present invention may be administered admixed with a pharmaceutically acceptable carrier or diluent. It is thereby included that the treatment may be administered during the night. Fur 35 thermore, since the "effective level" is used as the preferred endpoint for dosing, the WO 2005/110467 PCT/DK2005/000327 55 actual dose and schedule can vary, depending on individual differences in pharma cokinetics, drug distribution, and metabolism. The "effective level" can be defined, for example, as the blood or tissue level desired in the patient that corresponds to a concentration of one or more compounds according to the invention. 5 The effective level may refer to an amount of the active ingredient of the composi tion according to the invention that is able to obtain certain blood or tissue levels of a desired compound in the patient. The effective level may be the amount of the active ingredient of the composition according to the invention that is able to diminish the 10 symptoms in the patient. The pharmaceutical composition may be administration during hospitalization. In addition it may be beneficial for the patient if the composition can be self administered. 15 In one embodiment of the invention, the compositions of the present invention are self-administered. The pharmaceutical composition may be administered by use of an injection device, for example by the use of a system similar to insulin pens. 20 In one embodiment of the invention the composition is administered by use of a single or a multi-dose injection device. The pharmaceutical composition may also be a kit-in-part further including anti depressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin nor 25 adrenalin reuptake inhibitors (SNRIs), norepinephrine serotonin reuptake inhibitors (NSRIs), selective noradrenalin reuptake inhibitors, tetracyclic antidepressants, non selective monoamine reuptake inhibitors including tricyclic antidepressants (TCAs), selective reversible monoamine reuptake inhibitors and antidepressants with other mechanisms of action, e.g. mirtazapin. Examples of SSRIs are citalopram, escitalo 30 pram, fluoxetine, fluvoxamine, paroxetine and sertraline. An example of an SNRI is venlafaxine. The kit-in-part may be used for simultaneous, sequential or separate administration. An example of an NSRI is milnacipran. In a preferred embodiment the pharmaceutical composition may be a kit-in-part. 35 WO 2005/110467 PCT/DK2005/000327 56 Examples The following examples illustrate the invention without limiting it thereto. 5 Example 1 Binding assay and functional assay Transfections and tissue culture: COS-7 cells can be grown Dulbecco's Modified Eagle'e Medium 1885 supplemented with 10% fetal calf serum, 2mM glutamine and 10 0.01 mg/mI gentamicin. The expression plasmids containing the cDNAs encoding the wild type or the mutated receptors can be transiently expressed after transfetion according to the calcium phosphate precipitation method and assay can be.per formed 48 hour after transfection. Binding assay: One day after transfection the cells will be transferred and seeded in 15 multi-well plates for assay. The number of cells to be plated per well will be chosen so as to obtain 5 to 10% binding of the radioligand added. Two days after transfec tion the cells will be assayed in competition binding assays using 1251. PYY(3-36) as a tracer. Radioligand will be bound in a buffer composed of 0.5 ml of 50 mM Hepes buffer, pH 7.4, supplemented with 1-mM CaC 2 ,-5 mM -MgCl 2 , and 0.1% BSA, and 20 displaced in a dose dependent manner by unlabelled ligands. The assay will be per formed in duplicate for 3 hours at 4 0C, and stopped by washing twice in the buffer. Cell associated, receptor bound radioligand will be determined by the addition of lysis buffer (48% urea, 2% NP-40 in 3M acetic acid). The concentration of radioli gand in the assay corresponds to a final concentration of approximately 20 pM. 25 Functional assay. COS-7 can be cultured as described above and contransfections can be performed. The activation of Phospholipase C by chimeric G-proteins (Conklin B) formed be tween both Gaq and Gai the Y2 receptor can be measured through the inositol phosphate (IP) turnover in the cell. The IP turnover may be recorded by use of fol 30 lowing assay: One day after transfection COS-7 cells are incubated for 24 hours with 5 :Ci of [ 3

H]

myo-inositol (Amersham, PT6-271) in 1 ml medium supplemented with 10% fetal calf serum, 2 mM glutamine and 0.01 mg/ml gentamicin per well. Cells are washed twice in buffer, 20 mM HEPES, pH 7.4, supplemented with 140 mM NaCl, 5 mM 35 KCl, 1 mM MgSO 4 , 1 mM CaCl 2 , 10 mM glucose, 0.05 % (w/v) bovine serum; and WO 2005/110467 PCT/DK2005/000327 57 are incubated in 0.5 ml buffer supplemented with 10 mM LiCl at 37EC for 30 min. The indicated curves are furthermore incubated with adenosine deaminase ADA (200U/mg, Boeringer Mannheim, Germany) for 30 min in a concentration of 1 U/ml . After stimulation with various concentrations of peptide for 45 min at 37 C, cells will 5 be extracted with 10 % ice-cold perchloric acid followed by incubation on ice for 30 min. The resulting supernatants are neutralized with KOH in HEPES buffer, and the generated [ 3 H]-inositol phosphate is purified on Bio-Rad AG 1-X8 anion-exchange resin. Determinations will be made in duplicates. 10 Example 2 Synthetic production of PYY and functional equivalents thereof The polypeptide of the present invention may be produced by a conventional peptide synthesis method. 15 Amino acid derivatives and synthesis reagents, can be obtained from commercial sources. Peptide chain extension is performed by mainly using Applied Biosystem 433A synthesizer produced by Perkin Elmer, and a protected peptide derivative - resin is constructed by the Boc or Fmoc method. The protected peptide resin ob tained by the Boc method is deprotected with anhydrous hydrogen fluoride (HF) in 20 the presence of p-cresol thereby releasing the peptide, which is then purified. The protected peptide resin obtained by the Fmoc method is deprotected with trifluoroacetic acid (TFA) or dilute with TFA containing various scavengers, and the released peptide is purified. Purification is performed in reversed phase HPLC on a C4 or C18 column. The purity of the purified product is confirmed by reverse phase 25 HPLC, and its structure is confirmed by amino acid composition analysis and mass spectrometry. Example 3 30 Measurements of PYY plasma levels. The experiment is performed by subcutaneous injections of placebo and 4 escalat ing doses of PYY1 -36 or PYY3-36 as set out in table 1. The dosages of PYY is cal culated base on the fat free mass (FFM) of the subject.

WO 2005/110467 PCT/DK2005/000327 58 Stof Dosis, pmol/kg FFM Number of subjects (n) PYY1-36 12,5 2 25 2 50 12 100 12 150 10 200 10 PYY3-36 12,5 2 25 12 50 12 75 10 100 12 Table 1. Dosages of PYY and number of subjects (n) The results are presented as mean±SE, paired t-test (SAS) and repeated measures 5 (SAS). The PYY injections is performed at time 0 minutes and the plasma concentrations of PYY upon PYY1 -36 and PYY3-36 administration is measured at t=0, 15, 30, 45, 60, 75, 90, 120, 150, 180, 210 and 240 minutes. 10 PYY assay The plasma concentration of PYY is measured using radioimmunoassay of PYY. The assays are performed using PYY antiserum (code no. 8412-5) (Euro Diagnostica, Malmoe, Sweden). The antiserum recognizes both human PYY 1-36 15 and PYY 3-36. Synthetic human PYY 1-36 (Peninsula, Merseyside, UK) and porcine 125 Pyy (code no. IM259) is purchased from Amersham Biosciences, Buckingham shire UK) for use as standards. Detection limit of the assay is below 2 pmol/l and 50 % inhibition is obtained with 40 pmol/l PYY. Recovery of PYY added to plasma in concentrations between 5 and 50 pmol/l deviates less than 15 % from expected val 20 ues. Intra-assay coefficient of variation is below 5 %. The antiserum shows no cross reaction with human NPY or human PP in concentrations up to 500 pmol/l. The results are shown in figure 2 and 3.

WO 2005/110467 PCT/DK2005/000327 59 Example 4 5 In vivo measuring of the effect of PYY on migrating myoelectric complexes Method Rats are supplied with bipolar electrodes at 5 (duodenum ), 15 and 25 cm (jejunum) distal to pylorus for electromyography of small intestine. The natural ligands peptide 10 YY1 -36 and peptide YY 3-36 are infused IV at doses of 0.5-400 pmol/kg min for 60 min. The mechanisms of action are studied in bilaterally vagotomised animals after pre-treatment with N-nitro-L-arginine (L-NNA) 1 mg/kg and guanethidine 3 mg/kg. The experimental protocol was approved by the local Ethics committee for animal 15 experimentation in northern Stockholm, Sweden. Materials Male Sprague-Dawley rats (B&K, Sollentuna, Sweden) weighing 300-350 g were used for-the study. 20 Preparation of rats for electromyography. The rats are anaesthetized with pentobarbital (Apoteksbolaget, Umes, Sweden) using 50 mg/kg intraperitoneally. Through a midline incision, three bipolar stainless steel electrodes (SS-5T, Clark Electromedical Instruments, Reading, UK) are im 25 planted into the muscular wall of the small intestine 5 (D), 15 (J1), and 25 (J2) cm distal to the pylorus. All animals are supplied with a jugular vein catheters for ad ministration of drugs. The electrodes and catheters are tunneled subcutaneously to exit at the back of the animal's neck. After surgery the animals are housed singly and allowed to recover for at least 7 days before experiments are undertaken. During 30 recovery the rats are trained to accept experimental conditions. Experiments are then carried out in conscious animals after an 8-h fasting period in wire-bottomed cages with free access to water. During the experiments, the rats are placed in Bollman cages. The electrodes are connected to an EEG preamplifier (7P5B) oper ating a Grass Polygraph 7B (Grass Instruments, Quincy, MA). The time constant is 35 set at 0.015 s and the low and high cut-off frequencies is set at 10 and 35 Hz, re spectively.

WO 2005/110467 PCT/DK2005/000327 60 Design of electromyography studies. All experiments are started with a control recording of basal myoelectric activity with four activity fronts propagated over all three recording sites during a period of 60 5 min. Infusions are started immediately after the fourth activity front has passed the first electrode site using a microinjection pump (CMA 100, Carnegie Medicine, Stock holm, Sweden). In a first series of experiments, the natural ligands PYY1-36 or PYY3-36 at doses of 10 0.5 to 400 pmol/kg min is administered intravenously for 60 min. A second series of experiments is performed with administration of a NO synthase inhibitor N"-nitro-L-arginine (L-NNA) at 1 mg/kg given as a bolus injection 45 min before infusion of PYY1 -36 or PYY3-36 at 100 pmol/kg min. In a third series of experiments 3 mg/kg guanethidine is administered on day one 15 and the following day the effect of PYY1 -36 or PYY3-36 at 100 pmol/kg min is stud ied. In a forth series of experiments the effect of infusion of PYY1-36 or PYY3-36 at 100 pmol/kg min is studied in vagotomized and sham-vagotomized animals. 20 Drugs RatPYY1-36 and ratPYY3-36 is purchased from Neosystem (Strasbourg, France), L-NNA from Sigma-Aldrich, (St. Louis, Mo, USA) and guanethidine from Apoteksbo laget (Stockholm, Sweden). 25 Data analysis The main characteristic feature of myoelectric activity of the small intestine in the fasted state, the activity front, or phase Ill of MMC, is identified as a period of clearly distinguishable intense spiking activity with an amplitude at least twice that of the preceding baseline, propagating aborally through the whole recording segment and 30 followed by a period of quiescence, phase I of MMC. The percent of the recording periods occupied by phase Ill activity fronts is calcu lated for stimulatory periods (60 min). The effects of the peptides is expressed as per cent of time occupied by activity fronts. Dose-response curves are generated by Graph-Pad Prism 4 (GraphPad, San Diego, WO 2005/110467 PCT/DK2005/000327 61 Ca, USA). Data are expressed as mean ± SEM. Differences between individual data groups are determined using ANOVA, followed by Dunnet's test or students T-test, as appropriate, with statistical significance at p<0.05. 5 Example 5 Clinical protocol Gastro intestinal disorders 45 subjects that meet the proposed diagnostic criteria of IBS or functional dyspep 10 sias are included in the study. The study is performed in a double-blinded, placebo-controlled fashion. Subjects are divided into three groups (n=15 in each), groups A, B and C. The subjects are given diaries where they note their symptoms (bowel habits/pain/nausea etc) and eating 15 information. This initial phase of the study is 4 weeks ("Run-in Phase"), after which the subjects start treatment with one of three regimens, as defined below. The sub jects keep diaries where they note the timing, type and severity of experienced symptoms throughout the treatment phase. The treatment duration is 4 weeks ("Treatment Phase"). 20 Dosing: The subjects of group A receive subcutaneous placebo injections (NaCl) three times daily (distributed evenly over the hours awake). The subjects of group B receive 60 pmol/kg body weight of PYY 3-36 s.c. three times daily and the subjects of group C receive 100 pmol/kg body weight of PYY 3-36 s.c. three times daily. 25 The subjects' diaries are reviewed by the investigators and the severity of symptoms is determined in relation to food intake and timing. The effect on symptoms is evaluated by comparing the results during the 4-week 30 Treatment Phase with the results during the Run-in Phase for each subject, and then statistically comparing the result from group B with group A, and the result from group C with group A.

WO 2005/110467 PCT/DK2005/000327 62 Example 6 Effects of PYY on pain sensation and the spontaneous motor activity in the rectum. 5 12 patients (men or women between 18 and 60 years of age) meeting the Rome II criterias is included in the study. Conduct of the study All patients will come to the clinic after a 12-hour fasting period. Before the study 10 patients will be given a tap water enema. A probe (Barostat bag) will be inserted in the rectum and connected to an electronic barostat that is programmed to automatically perform distensions with fixed time lags and bag pressure increments. 15 The study is performed as 3-way cross-over study with approx. 7 days between treatments. A) S.c. administration of PYY1-36 in 0.9% NaCI solution. B) S.c. administration of PYY3-36 in 0.9% NaCI solution. 20 C) S.c. administration of saline (0.9% NaCI solution). After administration of PYY or saline the distension according to a fixed protocol will begin. The patients will note the discomfort and pain using a visual analog scale (VAS). Patients will be given control over the protocol by their ability to deflate the 25 bag instantaneously at any time of significant discomfort or pain. The threshold pressure and volume will be written down. After a fixed period of time e.g. 20 or 30 minutes a saline meal with fixed energy content will be given p.o. 30 Hereafter a second distension similar to the first will begin. In between to two distensions a fixed low pressure will be kept in the barostat bag. This will allow recording of the volume in the bag as a measure of the motor activity 35 in the rectum.

WO 2005/110467 PCT/DK2005/000327 63 Primary endpoint Comparison of the pain threshold with or without food intake in patients with IBS and the effect of PYY compared to placebo. 5 Second endpoint Study of the physiological effects of PYY on the spontaneous motor activity in the rectum compared to placebo. 10 The effect on symptoms is evaluated by statistically comparing the result from group B with group A, and the result from group C with group A. Statistical analysis is performed by a non-parametric analysis of variance (Kruskal Wallis test).

Claims

1. A composition comprising PYY or a functional equivalent thereof or a pharma ceutical acceptable salt thereof, for the production of a medicament for the treatment of functional gastrointestinal disorders. 5

2. The composition according to claim 1, wherein the functional gastrointestinal disorder is irritable bowel syndrome wherein, a) the predominant bowel habit is constipation and/or b) the predominant bowel habit is alternating diarrhoea and 10 constipation and/or c) the treatment is administered parenterally.

3. The composition according to claim I for the treatment of abdominal pain 15

4. The composition according to claim 3 for the treatment of visceral pain.

5. The composition according to claim 3-4, wherein the functional gastrointestinal disorder is irritable bowel syndrome or functional dyspepsia. 20

6. The composition according to claim 1, wherein the functional gastrointestinal disorder is functional dyspepsia.

7. The composition according to claim 6 for the relief of the symptom(s) a) sensation of fullness and/or 25 b) inability to finish a normal sized meal and/or c) pain after food intake and/or d) nausea and/or e) vomiting and/or f) bloating and/or 30 g) belching and/or h) regurgitation and/or i) epigastric pain and/or j) feeling of distention and/or k) exess flatus 35 and any combination of the above. WO 2005/110467 PCT/DK2005/000327 65

8. The composition according to claim to any of the preceding claims, wherein the symptoms are predominantly upper GI symptoms. 5

9. The composition according to claim to any of the preceding claims, wherein the symptoms are predominantly lower GI symptoms.

10. The composition according to claim to any of the preceding claims, comprising 10 human PYY

11. The composition according to claim to any of the preceding claims, comprising human PYY1-36. 15

12. The composition according to claim to any of the preceding claims, comprising human PYY3-36.

13. The composition according to any of the preceding claims, wherein the pH of the composition is-between 2.0 and 9.0 20

14. The composition according to any of the preceding claims, wherein the pharmaceutical composition is for parenteral administration.

15. The composition according to any of the preceding claims, wherein the 25 pharmaceutical composition is for subcutaneous administration.

16. The composition according to any of the preceding claims, wherein the pharmaceutical composition is for intranasal administration. 30

17. The composition according to any of the preceding claims, wherein the compo sition comprises a second active ingredient.

18. The composition according to claim 18, wherein the second pharmaceutical composition is selected from the group of; anti-depressants, such as SSRls 35 (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), WO 2005/110467 PCT/DK2005/000327 66 SNRIs such as venlafaxine, NSRls, tetracyclic antidepressants, non-selective monoamine reuptake inhibitors including tricyclic antidepressants (TCAs), selective reversible monoamine reuptake inhibitors and mirtazapin. 5

19. The composition according to claim 18, wherein the second pharmaceutical composition is an anti-emetic drug.

20. The composition according to claim 20 for the treatment of IBS and/or FD. 10

21. A method of treatment comprising administration of the pharmaceutical composition according to any of the preceding claims.