CN1787830A - Compositions for delivering peptide YY and PYY agonists - Google Patents

Abstract

This invention provides a composition (e.g., a pharmaceutical composition) comprising at least one delivery compound and at least one of peptide YY (PYY) and a PYY agonist. Preferably, the composition comprises a therapeutically effective amount of peptide YY or a PYY agonist and a delivery compound. Compared to administration without a delivery compound, the compositions of this invention facilitate the delivery of PYY, a PYY agonist, or a mixture thereof, and improve their bioavailability. PPY and PYY agonists have the same activity as drugs that reduce nutrient utilization, including reducing food intake.

Description

Compositions for the delivery of peptide YY and PYY agonists

This application claims priority to U.S. Provisional Patent Application No. 60/470,905, filed May 14, 2003; U.S. Provisional Patent Application No. 60/471,114, filed May 15, 2003; U.S. Provisional Patent Application No. 60/506,702, filed September 25, 2004, and U.S. Provisional Patent Application No. 60/536,697, filed January 14, 2004, all of which are incorporated herein by reference.

field of invention

The present invention relates to compositions for delivering peptide YY (PYY) and PYY agonists to a target. These compositions include compounds well suited to form non-covalent mixtures with PYY and PYY agonists administered orally to animals. The invention also discloses methods of preparation, administration and treatment.

Background of the invention

Current anti-obesity drugs have limited efficacy and various side effects. Crowley, V.E., Yeo, G.S. & O'Rahilly, S., Nat. Rev. Drug Discov 1, 276-86 (2002). As obesity becomes more prevalent worldwide, there is an urgent need to develop suitable drugs in this field. treat. In recent years, hormones and neuropeptides involved in the regulation of appetite, energy expenditure, and fat mass accumulation have emerged as potential anti-obesity drugs. McMinn, J.E., Baskin, D.G. & Schwartz, M.W., Obes Rev 1:37-46 (2000), Drazen, D.L. & Woods, S.C., Curr Opin ClinNutr Metab Care 6:621-629 (2003). However, these peptides currently require parenteral administration. The prospects for daily injections to control obesity are dim and may limit the use of these drugs.

One such peptide, PYY, is secreted after meals by endocrine cells of the terminal gastrointestinal tract and acts on the hypothalamus signaling satiety center. Batterham, R.L. et al., Nature 418:650-654 (2002). Recent studies have shown that obese patients have lower fasting and postprandial PYY levels, which may explain their high appetite and high food consumption. When administered intravenously, it suppresses appetite and food intake in lean and obese patients. Batterham, R.L. et al., N Engl J Med 349:941-948 (2003). Other peptides derived from the pancreatic peptide (PP) family such as peptide YY fragments (eg, PYY[3-36]) and PYY agonists (including peptides not belonging to the PP family) also suppress appetite. However, its oral activity is negligible due to poor absorption and rapid degradation in the gastrointestinal tract.

During the delivery of PYY and PYY agonists to animals, the body imposes various barriers. Examples of physical barriers are skin, lipid bilayers, and various organ membranes, which are relatively impermeable to certain active agents but must pass through them before reaching a target such as the circulatory system. Chemical barriers include, but are not limited to, pH changes and degradative enzymes of the gastrointestinal (GI) tract.

These barriers are of particular importance in the design of oral delivery systems. Were it not for these biological, chemical and physical barriers, oral delivery of PYY and PYY agonists would be the route of choice for animal administration. These therapeutic agents may be rapidly inactivated or destroyed in the gastrointestinal tract due to acid hydrolysis, enzymes, etc. In addition, the size and structure of macromolecular drugs may prevent absorption. As a result, oral administration of protein and peptide drugs is challenging in part due to their poor absorption and rapid degradation.

Early methods of oral administration of fragile pharmacotherapeutics relied on the co-administration of adjuvants (e.g., resorcinol and nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyvinyl ether) to artificially Increase the permeability of the intestinal wall, and co-administer enzyme inhibitors to inhibit enzymatic degradation. Liposomes have also been described as delivery systems for insulin and heparin. However, the widespread use of such drug delivery systems has been hampered in part because: (1) the system requires toxic amounts of adjuvants or inhibitors; (2) the inability to obtain a suitable low molecular weight deliverable, i.e., the active agent; (3) ) the system exhibits poor stability and an insufficient shelf life; (4) the system is difficult to prepare; (5) the system does not protect the active agent (deliverable); (6) the system adversely alters the active agent; or (7) ) The system does not allow or facilitates the absorption of the active agent.

More recently, proteinoid microspheres have been used to deliver drugs. See, eg, US Patents 5,401,516, 5,443,841 and Re. 35,862. In addition, certain modified amino acids have been used to deliver drugs. See, eg, US Patents 5,629,020, 5,643,957, 5,766,633, 5,776,888, and 5,866,536.

According to Batterham et al., Nature 418:650-654 (2002) (incorporated herein by reference), the peptide YY [3-36] system may provide a therapeutic target for the treatment of obesity.

International application WO 02/47712 and US patent 2002/0141985 disclose methods of treating obesity and diabetes with peptide YY and peptide YY agonists such as peptide YY [3-36].

However, there is a need for simple, inexpensive drug delivery systems for delivering peptide YY and PYY agonists.

There is a need for a non-invasive route of delivery of peptide YY [3-36] to ensure patient compliance, preferably an oral route.

Summary of the invention

The invention provides compositions (eg, pharmaceutical compositions) comprising (a) at least one delivery agent compound and (b) peptide YY (PYY), a PYY agonist, or a mixture thereof. Preferably the composition comprises a therapeutically effective amount of a peptide YY and/or PYY agonist and a delivery agent compound. The compositions of the invention facilitate the delivery of PYY and/or PYY agonists and increase their bioavailability compared to administration without the delivery agent compound. PPY and PYY agonists have the same activity as drugs that reduce nutrient availability, including reducing food intake.

Preferred delivery agent compounds include, but are not limited to, N-(8-[2-hydroxybenzoyl]amino)caprylic acid and N-(10-[2-hydroxybenzoyl]amino)decanoic acid and their salts, solvates and hydrate. In a preferred embodiment, the salt is a sodium salt, such as the monosodium salt.

In a preferred embodiment, the composition comprises peptide YY, a PYY agonist or a mixture thereof and at least one delivery agent having the following structure or a salt thereof,

式A

Formula A

in:

Ar is phenyl or naphthyl;

Ar is optionally replaced by one or more of -OH, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ haloalkoxy group substitution;

R ⁷ is selected from C ₄ -C ₂₀ alkyl, C ₄ -C ₂₀ alkenyl, phenyl, naphthyl, (C ₁ -C ₁₀ alkyl) phenyl, (C ₁ -C ₁₀ alkenyl) benzene base, (C ₁ -C ₁₀ alkyl) naphthyl, (C ₁ -C ₁₀ alkenyl) naphthyl, phenyl (C ₁ -C ₁₀ alkyl), phenyl (C ₁ -C ₁₀ alkenyl ), naphthyl (C ₁ -C ₁₀ alkyl) or naphthyl (C ₁ -C ₁₀ alkenyl);

R ^is selected from hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy;

R ⁷ is optionally replaced by C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, -OH, -SH, -CO ₂ R ⁹ or any combination thereof;

R ⁹ is hydrogen, C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl;

^R7 is optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; provided that the compound is not substituted with an amino group alpha to the acid group.

In another preferred embodiment, the composition comprises peptide YY, a PYY agonist or a mixture thereof and at least one delivery agent having the following structure or a salt thereof:

Formula B

in,

R ¹ , R ² , R ³ and R ⁴ are independently H, -OH, halogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy, -C( O) R ⁸ , -NO ₂ , -NR ⁹ R ¹⁰ or -N ⁺ R ⁹ R ¹⁰ R ¹¹ (R ¹² ) ^- ;

R ⁵ is ^H , -OH, -NO ₂ , halogen, -CF ₃ , -NR ¹⁴ R ¹⁵ , -N ⁺ R ¹⁴ R ¹⁵ R ¹⁶ (R ¹³ ) ^- , amido, C ₁ -C ₁₂ alkoxy , C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, carbamate, carbonate, ureido or -C(O)R ¹⁸ ;

^R is optionally substituted by halogen, -OH, -SH or -COOH;

R is ^optionally interrupted by O, N, S or -C(O)-;

R ⁶ is C ₁ -C ₁₂ alkylene, C ₂ -C ₁₂ alkenylene or arylene;

R ⁶ is optionally substituted by C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ alkoxy, -OH, -SH, halogen, -NH ₂ or -CO ₂ R ⁸ ;

R ^{is optionally} interrupted by O or N;

R ⁷ is a bond or an arylene group;

R ⁷ is optionally substituted by -OH, halogen, -C(O)CH ₃ , -NR ¹⁰ R ¹¹ or -N ⁺ R ¹⁰ R ¹¹ R ¹² (R ¹³ )-;

Each occurrence of R ⁸ is independently H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl or -NH ₂ ;

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are independently H or C ₁ -C ₁₀ alkyl;

R ¹³ is halide, hydroxide, sulfate, tetrafluoroborate or phosphate;

R ¹⁴ , R ¹⁵ and R ¹⁶ are independently H, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkyl substituted by -COOH, C ₂ -C ₁₂ alkenyl, C ₂ substituted by -COOH -C ₁₂ alkenyl or -C(O)R ¹⁷ ;

R ¹⁷ is -OH, C ₁ -C ₁₀ alkyl or C ₂ -C ₁₂ alkenyl; and

R ¹⁸ is H, C ₁ -C ₆ alkyl, -OH, -NR ¹⁴ R ¹⁵ or N ⁺ R ¹⁴ R ¹⁵ R ¹⁶ (R ¹³ ) ^- .

Optionally, when R ¹ , R ² , R ³ , R ⁴ and R ⁵ are H and R ⁷ is a bond, R ⁶ is not C ₁ -C ₆ , C ₉ or C ₁₀ alkyl.

Optionally, when R ¹ , R ² , R ³ and R ⁴ are H, R ⁵ is -OH and R ⁷ is a bond, R ⁶ is not C ₁ -C ₃ alkyl.

Optionally, when at least one of R ¹ , R ² , R ³ and R ⁴ is not H, R ⁵ is -OH, and R ⁷ is a bond, R ⁶ is not C ₁ -C ₄ alkyl.

Optionally, when R ¹ , R ² and R ³ are H, R ⁴ is -OCH ₃ , R ⁵ is -C(O)CH ₃ , and R ⁶ is a bond, R ⁷ is not C ₃ alkyl.

Optionally, when R ¹ , R ² , R ⁴ and R ⁵ are H, R ³ is -OH, and R ⁷ is a bond, R ⁶ is other than methyl.

In another embodiment, the composition comprises peptide YY, a PYY agonist or a mixture thereof and at least one delivery agent having the structure or a salt thereof,

Compound C

in:

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are independently H, -CN, -OH, -OCH ₃ or halogen, and at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is -CN; and

R ⁶ is C ₁ -C ₁₂ linear or branched alkylene, alkenylene, arylene, alkyl (arylene) or aryl (alkylene).

According to one embodiment, when R ¹ is -CN, R ⁴ is H or -CN, and R ² , R ³ and R ⁵ are H, R ⁶ is not methylene ((CH ₂ ) ₁ ).

The invention also provides dosage unit forms (eg, oral dosage unit forms) comprising compositions of the invention. Dosage unit forms can be in liquid or solid form, such as tablets, capsules or granules, including powders or sachets.

Another embodiment is a method of administering peptide YY, a PYY agonist, or a mixture thereof to an animal in need thereof by administering to the animal a composition or dosage unit form of the invention. The preferred route of administration is oral administration.

Another embodiment is a method of administering Peptide YY, a PYY agonist, or a mixture thereof to an animal in need thereof by administering a composition or dosage unit form of the invention in such a way as to minimize or prevent peptide YY and/or PYY agonist Antibody formation is carried out by administering to animals.

Another embodiment is a method of reducing body weight in an animal, such as a human, in need thereof by administering to the animal an effective amount of a composition or dosage unit form of the invention. In other words, an effective amount of a delivery agent compound that facilitates delivery of PYY or a PYY agonist and an effective amount (eg, a therapeutically effective amount) of PYY or a PYY agonist are administered.

Another embodiment is a method of treating obesity in an animal in need thereof, such as a human, by administering to the animal an effective amount of a composition of the invention.

Another embodiment is a method of treating a condition or disorder that can be alleviated by reduced nutrient availability in an animal, such as a human, by administering to the animal a therapeutically effective amount of a composition or dosage unit form of the invention. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, risk of cardiovascular disease, eating disorders, insulin resistance, obesity, and diabetes.

Another embodiment is a method of improving the lipid profile of an animal, such as a human, by administering to the animal an effective amount of a composition or dosage unit form of the invention.

Another embodiment is a method of preparing a composition of the invention by admixing at least one delivery agent compound with at least one of peptide YY and a PYY agonist.

Brief description of the drawings

Figure 1 is a graph of PYY[3-36] plasma concentrations (pg/ml ± standard deviation) versus time following oral administration of PYY[3-36] following the procedure described in Example 1 with and without the delivery agent SNAC.

Figure 2 is a graph of PYY[3-36] plasma concentration (pg/ml±standard deviation)-time after oral administration of PYY[3-36] with and without the delivery agent SNAD according to the procedure described in Example 1 .

Figure 3 is a graph of PYY[3-36] plasma concentrations (pg/ml ± standard deviation) versus time following intraperitoneal injection of PYY[3-36] following the procedure described in Example 2 without delivery agent compound.

Fig. 4 is according to the step described in embodiment 3 to rat orally administers PYY [3-36] and multiple delivery agents, only uses delivery agent 3 and uses PYY and mannitol after PYY [3-36] plasma concentration ( pg/ml±standard deviation)-time graph.

Figure 5 is a graph of PYY[3-36] plasma concentrations (pg/ml ± standard deviation) after oral administration of PYY[3-36] to non-human primates following the procedure described in Example 4 )-time graph.

Figure 6 is a graph of PYY[3-36] plasma concentration over time following oral administration of the combination of PYY[3-36] and SNAD following the procedure described in Example 3c.

Figure 7 is a graph of food intake compared to placebo during the 4 days of treatment of male Sprague Dawley rats with the combination of PYY[3-36] and SNAD according to the procedure described in Example 5.

Figure 8a is a graph of cumulative body weight gain compared to placebo during 7 days of treatment of male Sprague Dawley rats with PYY[3-36]-combination with SNAD according to the procedure described in Example 6.

Figure 8b is a graph of cumulative food intake and body weight gain compared to placebo during 7 days of treatment of male Sprague Dawley rats with the combination of PYY[3-36] and SNAD according to the procedure described in Example 6.

Detailed description of the invention

definition

The term "hydrate" as used herein includes, but is not limited to: (i) a material containing molecularly bound water and (ii) a crystalline material containing one or more crystal water molecules or a crystalline material containing free water.

The term "solvate" as used herein includes, but is not limited to, molecular or ion complexes of molecules or ions of a solvent with molecules or ions of a delivery agent compound or a salt thereof or a hydrate or solvate thereof.

The term "delivery agent" refers to any delivery agent compound disclosed herein.

The term "SNAC" refers to N-(8-[2-hydroxybenzoyl]-amino)octanoic acid monosodium salt.

The term "SNAD" refers to N-(10-[2-hydroxybenzoyl]-amino)decanoic acid monosodium salt. The term "SNAD disodium salt" refers to N-(10-[2-hydroxybenzoyl]-amino)decanoic acid disodium salt.

An "effective amount of PYY, a PYY agonist, or a mixture thereof" is an amount of PYY, a PYY agonist, or a mixture thereof that is effective to treat or prevent a condition when administered to a living organism for a period of time, e.g., provides a therapeutic Effect.

An "effective amount of a delivery agent" is one that the delivery agent allows and/or facilitates via any route (such as those detailed in this application, including but not limited to oral (e.g., through biofilms of the gastrointestinal tract), nasal, pulmonary , dermal, buccal, vaginal and/or ocular routes) administered the expected amount of PYY or the amount of a PYY agonist absorbed.

The term "AUC" as used herein refers to the area under the plasma concentration-time curve, as calculated by the trapezoidal method over the entire dosing period, eg, over a 24-hour period.

Unless otherwise stated, the term "average" when preceded by a pharmacokinetic value (eg mean peak value) means the arithmetic mean of the pharmacokinetic value.

As used herein and in the appended claims, the singular forms "a" and "an" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" includes one or more such molecules, "an agent" includes one or more such different agents, "an antibody" includes one or more such different antibodies, A "method" includes equivalent steps and methods known to those of ordinary skill in the art that may be modified or substituted for the methods described herein.

The term "about" generally means within 10%, preferably 5%, more preferably 1% variation of a given value or range.

The terms "alkyl" and "alkenyl" as used herein include straight and branched chain alkyl and alkenyl substituents, respectively.

The term "patient" as used herein refers to a mammal, and preferably a human.

The phrase "pharmaceutically acceptable" refers to an additive or composition that is physiologically tolerable and generally does not produce allergic or similar adverse reactions such as stomach upset, dizziness and the like when administered to a mammal.

PYY and PYY agonists

"Peptide YY" or "PYY" refers to a Peptide YY polypeptide obtained or derived from any species. Thus, the term "PYY" includes human full-length, 36 amino acid peptides, such as International Application WO 02/47712 (which is the corresponding PCT application to U.S. Patent Publication No. 2002/0141985, which is incorporated herein by reference) and Tatemoto, Proc Natl Acad Sci U.S.A. 79: 2514-8, 1982, shown in SEQ ID NO: 2, and variants including PYY in different species, such as PYY including murine, hamster, chicken, cow, rat and dog. "PYY agonist" refers to any compound that causes the effect of PYY to reduce nutrient availability, such as compounds: (1) described in WO 02/47712 and US Patent Publication No. 2002/0141985 in Examples 1, 2, 5 or 6 Compounds that are active in assays of food intake, gastric emptying, pancreatic juice secretion, or weight loss, and (2) in the Y receptor assay (WO02/47712 and Example 10 of U.S. Patent Publication No. 2002/0141985) or In a competitive binding assay specifically binds to markers PYY or PYY [3- 36], wherein the PYY agonist is not pancreatic polypeptide. Preferred PYY agonists have an affinity of greater than about 1 [mu]M in an assay such as this, more preferably an affinity of greater than about 1 to about 5 nM.

Such agonists may include polypeptides containing PYY functional domains, active fragments of PYY, or chemical or small molecules. PYY agonists may be peptide or non-peptide compounds, including "PYY agonist analogs", which refers to any compound that is structurally similar to PYY and has PYY activity, usually due to interaction with PYY receptors or PYY itself binds or otherwise interacts directly or indirectly with other receptors to which it interacts to produce a biological response. Such compounds include PYY derivatives, PYY fragments, extended PYY molecules containing more than 36 amino acids, truncated PYY molecules containing less than 36 amino acids, and substituted PYY molecules containing one or more different amino acids or described above any combination of . Such compounds may also be modified by methods such as pegylation, amidation, glycosylation, acylation, sulfation, phosphorylation, acetylation and cyclization.

One such PYY agonist analogue is PYY[3-36], identified as SEQ ID NO:3 in WO 02/47712 and U.S. Patent Publication No. 2002/0141985; Eberlein Eysselein et al., Peptides 10:797-803 (1989); and Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994). A polypeptide with a number in brackets refers to a truncated polypeptide having the sequence of the full-length peptide at the bracketed amino acid position. Therefore, PYY[3-36] has the same sequence as amino acids 3 to 36 of PYY. PYY[3-36] contains about 40% of the total peptide YY-like immunoreactivity of human and canine intestinal extracts and about 36% of the total plasma peptide YY immunoreactivity in the fasted state to slightly more than 50% (postprandial ). It is apparently a dipeptidyl peptidase-IV (DPP4) cleavage product of peptide YY. Peptide YY [3-36] is reported to be a selective ligand for the Y2 and Y5 receptors, which show pharmacological activity in the preferred N-terminal truncated (i.e. C-terminal fragment) neuropeptide Y analogues. unique. PYY agonists may bind to PYY receptors with higher or lower affinity, indicating a longer or shorter half-life in vivo or in vitro, or be more or less potent than native PYY.

Other suitable PYY agonists include those described in International Application Publication No. WO 98/20885, which is incorporated herein by reference.

"Condition or disorder that can be mitigated by reduced caloric (or nutrient) availability" means any condition or disorder in an animal that results from, is complicated by, or is exacerbated by relatively high Any condition or disorder that is alleviated by food intake. Such conditions or disorders include, but are not limited to, obesity, diabetes and including type 2 diabetes, eating disorders, and insulin resistance syndrome.

In one aspect, the invention provides a method of treating obesity in an obese or overweight animal by administering a therapeutically effective amount of PYY, a PYY agonist, or a mixture thereof, and at least one delivery agent compound. Although "obesity" is generally defined as a body mass index over 30, for purposes of the present disclosure, any subject in need or desire to lose weight, including subjects with a body mass index below 30, includes "obesity" within range. Patients suffering from insulin resistance, glucose intolerance or any form of diabetes such as type 1, type 2 or gestational diabetes may benefit from this approach.

In other aspects, the invention features methods of reducing food intake, treating diabetes, and improving lipid profile, including lowering LDL cholesterol and triglyceride levels and/or altering HDL cholesterol levels, comprising administering to a subject A therapeutically effective amount of PYY, a PYY agonist, or a mixture thereof and at least one delivery agent compound. In a preferred embodiment, the methods of the invention are used to treat a condition or disorder that can be alleviated by reducing nutrient availability to a subject in need thereof, comprising administering to said subject a therapeutically effective amount of PYY, a PYY agonist, agent or mixture thereof and at least one delivery agent compound. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, insulin resistance, obesity, and diabetes of any type.

In the methods of the invention, preferred PYY agonists are PYY agonists that have a higher effect than NPY in one of the assays described in WO 02/47712 and U.S. Patent Publication No. 2002/0141985 in the same assay.

In one embodiment, for the treatment of all conditions and disorders described herein, the preferred PYY agonist is PYY [3-36] administered (peripherally) from about 1 pg to about 5 mg per day in single or divided doses. Alternatively, PYY[3-36] may be administered in single or divided doses at about 0.01 μg/kg to about 500 μg/kg, about 0.05 μg/kg to about 250 μg/kg, or less than about 50 μg per day, depending on the total body weight of the subject. /kg dose. Dosages within these ranges will of course vary with the potency of the various agonists and are readily ascertainable by those skilled in the art.

In the methods of the present invention, PYY and PYY agonist and delivery agent compounds may be administered alone or in combination with one or more other compounds and compositions that exhibit long-term or short-term effects that reduce nutrient availability. Including but not limited to including amylin or amylin agonist, cholecystokinin (CCK) or CCK agonist, leptin (OB protein)) leptin agonist, exendin or exendin agonist or GLP-1 or Other compounds and compositions that are GLP-1 agonists. For example, suitable amylin agonists include [25,28,29Pro-]-human amylin (also known as "pramlintide", described in U.S. Patent Nos. 5,686,511 and 5,998,367), calcitonin ( eg salmon calcitonin), including those described in US Pat. No. 5,739,106, which is incorporated herein by reference. The CCK used is preferably CCK octapeptide (CCK-8). Leptin is for example found in Pelleymounter, C. et al., Science 269:540-543 (1995), Halaas, G. et al., Science 269:543-6 (1995) and Campfield, S. et al., Science 269:546-549 ( 1995) are discussed. Suitable CCK agonists include those described in US Patent No. 5,739,106, which is incorporated herein by reference. Suitable exendins include exendin-3 and exendin-4, and exendin agonist compounds include, for example, those described in PCT Application Publications WO 99/07404, WO 99/25727 and WO 99/25728, all of which are incorporated herein by reference. According to one embodiment, the composition of the invention comprises at least one delivery agent compound, PYY, a PYY agonist or a mixture thereof, at least one amylin agonist and a CCK agonist. Suitable combinations of an amylin agonist and a CCK agonist include, but are not limited to, the combinations described in US Pat. No. 5,739,106, which is incorporated herein by reference.

PYY and PYY[3-36] are C-terminally amidated when expressed physiologically, but this need not be the case for the purposes of the present invention. These peptides may also undergo other post-translational modifications.

The PYY and peptide-based PYY agonists described herein can be prepared using standard recombinant expression or chemical peptide synthesis techniques known in the art, eg, using an automated or semi-automated peptide synthesizer. The PYY described herein includes PYY [3-36] in any form, including PYY [3-36] obtained by freeze-drying, crystallization, reconstitution, spray-drying, and supercritical fluidization processes.

Solid-phase peptide synthesis can be performed using an automated peptide synthesizer (e.g., Model 430A, Applied Biosystems Inc., Foster City, CA) using the NMP/HOBt (option 1) system and capped tBoc or Fmoc chemistry (see Applied Biosystems User's Manual for the ABI 430A Peptide Synthesizer, Version 1.3B, Jul 1, 1988, 6:4970, Applied Biosystems, Inc, Foster City, CA). It can also be assembled using an Advanced ChemTech Synthesizer (Advanced ChemTech Synthesizer, Model MPS 350, Louisville, KY). Peptides can be purified by RP-HPLC (preparative and analytical) using, for example, a Waters Delta Prep 3000 system and a _C4 , C8 or C18 preparative column (10p, 2.2 x 25 cm; Vydac, Hesperia, CA).

Peptide compounds useful in the present invention can also be prepared using recombinant DNA techniques using methods now known in the art. See, eg, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor (1989). Non-peptidic compounds useful in the present invention can be prepared by methods known in the art. For example, phosphate-containing amino acids and peptides containing such amino acids can be prepared using methods known in the art. See, eg, Bartlett and Landen, Biorg Chem. 14:356-377 (1986).

Compositions for use in the present invention may be provided, for example, as parenteral compositions for injection or infusion. For example, they can be suspended in an aqueous carrier, for example, in an isotonic buffer solution having a pH of about 3.0 to about 8.0. Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid and sodium acetate/acetate buffers. A depot or "depot" sustained release formulation may be used to deliver a therapeutically effective amount of the formulation into the bloodstream for hours or days following transdermal injection or delivery.

Since PYY and various PYY agonists are amphoteric, they can be used as free bases, as acid addition salts, or as metal salts. The salts are preferably pharmaceutically acceptable salts, and these salts will include metal salts, especially alkali metal and alkaline earth metal salts, such as potassium or sodium salts. A wide variety of pharmaceutically acceptable acid addition salts are available. Such products are readily prepared by methods well known to those skilled in the art.

Therapeutically effective amounts of PYY or PYY agonists for reducing nutrient availability are those that suppress appetite to the desired extent. As will be appreciated by those skilled in the art, an effective amount of a therapeutic agent will vary with a variety of factors, including the age and weight of the patient, the patient's physical health, blood glucose levels, weight levels to be gained, and other factors.

For a patient weighing 50 kg, an effective daily dose of PYY, a PYY agonist, or a mixture thereof to suppress appetite is from about 1 to 30 μg to about 50 mg/day, or from about 10 to 30 μg to about 20 mg/day, or from about 5 to 100 μg to About 10 mg/day, or about 5 μg to about 5 mg/day. An effective amount of PYY or a PYY agonist can be administered in a single dose or in divided doses. Dosages may be from about 0.01 to about 1 mg/kg/dose. The precise dose to be administered can be determined by one skilled in the art and will depend on the potency of PYY, the PYY agonist or mixture thereof and on the age, weight and physical condition of the individual. Drugs should be initiated whenever inhibition of nutrient availability, food intake, body weight, blood glucose, or lowering of blood lipids is desired, eg, at the onset of first symptoms or shortly after a diagnosis of obesity, diabetes, or insulin resistance syndrome.

Screening for other PYY agonists

Other PYY agonists can be detected by using receptor binding assays described below (e.g. WO 02/47712 and Examples 9 and 10 of U.S. Patent Publication No. 2002/0141985) or known in the art in combination with WO 02/47712 and Physiological screening methods described in the Examples of US Patent Publication No. 2002/0141985 were identified. Potential PYY agonists were compared with the activity of PYY or PYY [3-36].

Alternatively, once one or more PYY-preferred (Y7) receptors have been characterized and cloned, alternative assays and high-throughput screening can be performed as detailed below or as known in the art. Y7 receptors are those receptors that have a higher affinity for PYY or PYY [3-36] than their affinity for neuropeptide Y (NPY). A method of screening for compounds that modulate the activity of a PYY receptor comprises contacting a test compound with a PYY receptor and detecting the presence of a complex between the compound and the PYY receptor. In such assays, the test ligand is usually labeled. After appropriate incubation, free ligand is separated from ligand present in bound form and the amount of free or uncomplexed label is a measure of the ability of a particular compound to bind the PYY receptor.

Alternatively, bound labeled ligand can be measured (eg, by expressing a membrane-bound Y7 receptor).

High throughput screening for PYY agonists with suitable PYY receptor binding affinity can be performed. For example, large numbers of different small peptide test compounds are synthesized on solid substrates. These peptide test compounds were contacted with PYY receptors, followed by washing. Bound PYY receptors are then detected using methods known in the art. Purified test compounds can also be directly coated on plates used in the aforementioned drug screening techniques. Additionally, if the test compound is a protein, antibodies can be used to capture the protein and immobilize it on a solid support by methods known in the art.

Competitive screening assays can be used in which neutralizing antibodies that specifically bind a polypeptide of the invention compete with test compounds for binding to the polypeptide. In this method, antibodies can be used to detect the presence of any peptide that shares one or more antigenic determinants with the PYY agonist. Competitive binding studies of radiolabels are described in Lin, A.H. et al., Antimicrobial Agents and Chemotherapy 41(10):2127-2131 (1997), the disclosure of which is incorporated herein by reference in its entirety.

delivery agent compound

The delivery agent compound can be any of the compounds described in U.S. Patent Nos. 5,650,386 and 5,866,536 and International Application Publication Nos. 12473, WO96/12475, WO96/30036, WO96/33699, WO97/31938, WO97/36480, WO98/21951, WO98/25589, WO98/34632, WO98/49135, WO99/16427, WO00/06534, WO00/07979, WO00/40203, WO00/46182, WO00/47188, WO00/48589, WO00/50386, WO00/59863, WO00/59480, WO01/32130, WO01/32596, WO01/34114, WO01/44199, WO01/51454, WO01/ 70219, WO01/92206, WO02/02509, WO02/15959, WO02/16309, WO02/20466, WO02/19969, WO02/070438, WO03/026582, WO02/100338, WO03/045306 and WO0326582, all of which are incorporated herein Reference.

Non-limiting examples of delivery agent compounds include N-(8-[2-hydroxybenzoyl]-amino)octanoic acid, N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, 8-(2 -Hydroxy-4-methoxybenzamido) octanoic acid, 8-(2,6-dihydroxybenzamido) octanoic acid, 8-(2-hydroxy-5-bromobenzamido) octanoic acid, 8- (2-Hydroxy-5-chlorobenzamido) octanoic acid, 8-(2-hydroxy-5-iodobenzamido) octanoic acid, 8-(2-hydroxy-5-methylbenzamido) octanoic acid, 8-(2-Hydroxy-5-fluorobenzamido) octanoic acid, 8-(2-hydroxy-5-methoxybenzamido) octanoic acid, 8-(3-hydroxyphenoxy) octanoic acid, 8- (4-Hydroxyphenoxy)octanoic acid, 6-(2-cyanophenoxy)hexanoic acid, 8-(2-hydroxyphenoxy)octyl-diethanolamine, 8-(4-hydroxyphenoxy) Octanoate, 8-(4-hydroxyphenoxy)octanoate, 8-(2-hydroxy-4-methoxybenzamido)octanoic acid, 8-(2-hydroxy-5-methoxy Benzamido)-octanoic acid and their salts. Preferred salts include, but are not limited to, the monosodium and disodium salts.

The delivery agent compound may be in the form of a carboxylic acid or a pharmaceutically acceptable salt thereof, such as sodium salt, as well as hydrates and solvates thereof. These salts may be monovalent or polyvalent salts, such as monosodium and disodium salts. These delivery agent compounds may contain different counterions selected for example due to their effect on modifying the dissolution properties of the carrier.

Delivery agent compounds can be prepared by methods known in the art, as disclosed in the aforementioned applications (e.g. International Publication Nos. /045306). SNAC, SNAD, and their free acids and other salts can be prepared by any method known in the art, for example by the methods described in US Patent Nos. 5,650,386 and 5,866,536.

Salts of the delivery agent compounds of the present invention can be prepared by methods known in the art. For example, the sodium salt can be prepared by dissolving the delivery agent compound in ethanol and adding aqueous sodium hydroxide.

The transporter compound can be purified by recrystallization or by fractional distillation on one or more solid-state chromatographic stationary phases, either alone or in series. Suitable solvent systems for recrystallization include, but are not limited to, acetonitrile, methanol, and tetrahydrofuran. Fractional distillation can be carried out as follows: on a suitable chromatographic stationary phase such as alumina using a methanol/n-propanol mixture as the mobile phase; reverse phase chromatography using a trifluoroacetic acid/acetonitrile mixture as the mobile phase; and separation using water or a suitable The buffer was used as the mobile phase for ion exchange chromatography. When anion exchange chromatography is performed, a sodium chloride gradient of 0-500 mM is preferably employed.

delivery system

Compositions of the invention comprise one or more delivery agent compounds of the invention and/or one or more PYY and PYY agonists. The delivery agent compound and PYY and/or PYY agonist are usually mixed to form a dosing composition prior to administration.

The composition may comprise one or more therapeutic agents that reduce food intake, lower plasma glucose, or alter plasma lipids, such as amylin, an amylin agonist, CCK or a CCK agonist, leptin or leptin Agonist or exendin or exendin agonist.

Compositions for administration may be in liquid form. The solution medium can be water, 25% propylene glycol in water or phosphate buffered saline. Other administration carriers include polyethylene glycols. Dosing solutions can be prepared by mixing a solution of the delivery agent compound with a solution of the active agent just prior to administration. Alternatively, a solution of a delivery agent compound (or PYY, a PYY agonist or a mixture thereof) may be mixed with PYY or a PYY agonist (or delivery agent compound) in solid form. The delivery agent compound can also be mixed with PYY, a PYY agonist, or a mixture thereof as a dry powder. The delivery agent compound can also be mixed with PYY, a PYY agonist, or mixtures thereof during the manufacturing process.

Administration solutions may optionally contain additives such as phosphate buffered saline, citric acid, glycol or other dispersing agents. Stabilizing additives may be incorporated into the solution, preferably at a concentration of about 0.1-20% (w/v).

Alternatively, the administration composition may be in the form of a solid, such as a tablet, capsule or granules, such as a powder or sachets. Solid dosage forms can be prepared by admixing solid form of the compound with solid form of PYY, a PYY agonist, or mixtures thereof. Alternatively, solids can be obtained from solutions of compounds and PYY, PYY agonists or mixtures thereof by methods known in the art such as lyophilization (freeze drying), precipitation, crystallization and solid dispersion. Alternatively, the administration composition may be semi-solid, in the form of a gel, paste, colloid, gelatin, emulsion or suspension, and the like.

The administration compositions of the invention may also contain one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof. Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitors.

The amount of PYY and/or PYY agonist used in the administered compositions of the present invention is an amount effective to treat the intended indication. However, when the composition is used in dosage unit form, the amount may be lower than the above amounts, since a dosage unit form may contain multiple combinations of delivery agent compound/PYY or PYY agonist or may contain separate effective amounts. Thus, the total effective amount can be administered in cumulative units that collectively contain an effective amount of PYY, a PYY agonist, or a mixture thereof. Furthermore, those skilled in the art will recognize that an effective amount of PYY, a PYY agonist, or a mixture thereof will vary with a variety of factors, including the age and weight of the patient, the patient's physical condition, blood glucose levels, desired body weight level, and other factors.

The total amount of PYY or PYY agonist used can be determined by methods known to those skilled in the art. However, because the compositions of the present invention can deliver PYY or a PYY agonist more effectively than compositions containing only PYY or a PYY agonist, patients can be administered less than previously used dosage unit forms or delivery systems. PYY or a PYY agonist while still achieving the same blood levels and/or therapeutic effect.

According to one embodiment, the amount of PYY, PYY agonist, or mixture thereof administered with the delivery agent is an amount sufficient to suppress appetite to a desired level. For a patient weighing 50 kg, an effective daily dose of PYY, a PYY agonist, or a mixture thereof to suppress appetite is generally from about 1 μg to about 5 mg/day, preferably from about 5 μg to about 2 mg/day, more preferably about 5 mg/day, in single or divided doses. 5 μg to 500 μg/day. Preferably, dosage forms of the present invention contain from about 0.01 to about 10 [mu]g/kg/dose of PYY, a PYY agonist, or a mixture thereof.

The present invention also includes pharmaceutical compositions and dosage forms comprising the above-mentioned amounts of PYY, PYY agonists or mixtures thereof and at least one delivery agent.

Typically, an effective amount of a delivery agent to facilitate delivery of PYY and/or a PYY agonist is administered with PYY, a PYY agonist, or a mixture thereof. Typically, the molar ratio of delivery agent to PYY, PYY agonist or mixture thereof is from about 25000:1 to about 50:1, preferably from about 8000:1 to about 100:1, most preferably from about 4000:1 to about 300:1.

The delivery agent compounds disclosed herein facilitate the delivery of PYY, PYY agonists, or mixtures thereof, especially oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary , percutaneous, intradermal, parenteral, intraperitoneal, intravenous, intramuscular, and ocular, as well as cross the blood-brain barrier. The compositions and dosage unit forms of the invention may be administered by any of the routes described above.

The compositions and dosage unit forms of the present invention achieve known therapeutic levels of PYY [3-36] in vivo when administered orally to humans, as set forth in Batterham et al., Nature 418:650-654 (2002) Those ones.

The dosage unit form may also contain any one of excipients, diluents, disintegrants, lubricants, plasticizers, colorants, flavors, taste-masking agents, sugars, sweeteners, salts, and administration carriers or Combinations thereof include but are not limited to water, 1,2-propanediol, ethanol, olive oil or any combination thereof.

The compounds and compositions of the present invention are useful for administering biologically or chemically active therapeutic agents to any animal including, but not limited to, birds such as chickens; fish, reptiles, mammals such as rodents, cattle, pigs, dogs, cats, squirrels Long species and especially humans, and insects.

Example

The following examples serve to illustrate the invention without limitation. All parts are given by weight unless otherwise stated.

Example 1 - Liquid Oral Delivery of PYY[3-36] in Rats

Oral gavage (PO) dosing solutions of the delivery agent compound and peptide YY residues 3-36 (PYY[3-36]) (available from Bachem California Inc., Torrance, Canada) in deionized water were prepared as follows .

Dosing solutions of Delivery Agent 1 (SNAC) and PYY[3-36] were prepared as follows. Dissolve SNAC monosodium salt solid in water. The pH of this solution was close to 7.5, so no pH adjustment was necessary. An aliquot of this SNAC solution was mixed with an aliquot of the PYY solution (pH 7.5). Follow this procedure to prepare solutions of 100 or 200 mg/kg SNAC and 0.1 or 0.5 mg/kg PYY[3-36]. The final pH of these solutions was 7.5.

Dosing solutions of delivery agent 2 monosodium salt (SNAD) and PYY[3-36] were prepared as follows. Dissolve the solid disodium salt of SNAD in water. The resulting solution had a pH of 11.1. Its pH was then adjusted down to 7.7 by adding HCl (5N). An aliquot of the SNAD solution was then mixed with an aliquot of the PYY[3-36] solution (pH 7.5). Follow this procedure to prepare solutions of 100 or 200 mg/kg SNAD and 0.1 or 0.5 mg/kg PYY[3-36]. The final pH of these solutions varied between 7.5-7.6.

Dosing solutions of delivery agents 4-15 monosodium salt and PYY[3-36] were prepared as follows. Each delivery agent compound (free acid or monosodium salt form) was dissolved in water. The pH was adjusted to about 7.5 by adding HCl (5N) and NaOH (5N) as needed. An aliquot of the delivery agent solution was then mixed with an aliquot of the PYY[3-36] solution (pH 7.5). Follow this procedure to prepare a solution of 200 mg/kg of delivery agent and 0.3 mg/kg of PYY[3-36]. The final pH of these solutions was about 7.5.

A typical dosing and sampling protocol is as follows. Male Sprague-Dawley rats weighing 240-320 g were fasted for up to 24 hours prior to testing, and ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) were administered intramuscularly prior to administration of the test article. Thereafter, the test article is administered to anesthetized animals by oral gavage. One of the dosing solutions was administered to five animals of the dosing group. For oral gavage (PO) an 11 cm Rusch 8 French catheter fitted to a 1 ml syringe with a straw tip was used. Aspirate the solution through the catheter, fill the syringe with the dosing solution, and wipe the catheter dry. The catheter was inserted into the esophagus, leaving 1 cm of the test tube through the incisor. Depress the syringe plunger to administer the dosing solution.

Blood samples were collected serially via tail artery or cardiac puncture, typically at time = 0, 15, 30, 45, 60 and 90 minutes. Serum PYY concentrations were measured using the PYY[3-36] radioimmunoassay (Cat. No. RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA). The results obtained from each group of animals at each time point were averaged. The maximum of these means (ie mean peak serum PYY[3-36] concentration ± standard deviation (SD)) is reported in Table 1 below. When animals were given PYY only orally [3-36], no significant PYY was detected in the blood [3-36]. The results (± SD) obtained with the delivery agents SNAC and SNAD are also shown in Figures 1 and 2, respectively.

Table 1. Oral delivery of PYY[3-36] in rats Delivery agent Delivery Agent Dose (mg/kg) PYY[3-36] dose (mg/kg) Volume dose (ml/kg) Mean serum [PYY(3-36)] peak (pg/ml) ± SD 1 100 0.5 1 235.75±181.7 1 200 0.5 1 442.098±78.4 1 100 0.1 1 233.03±127.5 1 200 0.1 1 313.14±151.8 2 100 0.5 1 273.69±457.5 2 200 0.5 1 430.29±364.6 2 100 0.1 1 44.63±53.53 2 200 0.1 1 134.37±236.708 3(none) 0 0.5 1 8.8925±8.290 4 200 0.3 1 830.246±71.382

5 200 0.3 1 800.318±40.61 6 200 0.3 1 812.946±53.616 7 200 0.3 1 663.472±135.394 8 200 0.3 1 276.82±425.45 9 200 0.3 1 732.912±266.578 10 200 0.3 1 846.416±55.993 11 200 0.3 1 871.484±119.461 12 200 0.3 1 845.682±69.846 12 200 0.3 1 1047.46±36.93 13 200 0.3 1 826.48±379.12 14 200 0.3 1 913.536±33.688 14 200 0.3 1 1083.38±78.878 15 200 0.3 1 705.106±75.906

Delivery Agent 1 was N-(8-[2-hydroxybenzoyl]-amino)caprylic acid monosodium salt (SNAC).

Delivery agent 2 was N-(10-[2-hydroxybenzoyl]-amino)decanoic acid monosodium salt (SNAD).

Delivery agent 4 was 8-(2-hydroxy-4-methoxybenzamido) octanoic acid monosodium salt.

Delivery agent 5 was 8-(2,6-dihydroxybenzamido) octanoic acid monosodium salt.

Delivery agent 6 was 8-(2-hydroxy-5-bromobenzamido) octanoic acid monosodium salt.

Delivery agent 7 was 8-(2-hydroxy-5-chlorobenzamido) octanoic acid monosodium salt.

Delivery agent 8 was 8-(2-hydroxy-5-iodobenzamido) octanoic acid monosodium salt.

Delivery agent 9 was 8-(2-hydroxy-5-methylbenzamido) octanoic acid monosodium salt.

Delivery agent 10 was 8-(2-hydroxy-5-fluorobenzamido) octanoic acid monosodium salt.

Delivery agent 11 was 8-(2-hydroxy-5-methoxybenzamido) octanoic acid monosodium salt.

Delivery agent 12 was 8-(3-hydroxyphenoxy) octanoic acid monosodium salt.

Delivery agent 13 was 8-(4-hydroxyphenoxy) octanoic acid monosodium salt.

Delivery agent 14 was 6-(2-cyanophenoxy)hexanoic acid monosodium salt.

Delivery agent 15 was 8-(2-hydroxyphenoxy)octyl-diethanolamine monosodium salt.

Example 2 Intraperitoneal Delivery of Peptide YY [3-36] in Rats

Solutions for intraperitoneal administration of PYY[3-36] were prepared in sterile saline solution (0.9% sodium chloride, pH 7.5). A typical dosing and sampling protocol is as follows. Males weighing 240-320g

Sprague-Dawley rats were fasted for a maximum of 24 hours prior to testing, and ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) were administered intramuscularly prior to administration of the test article. Thereafter, the test article is administered to anesthetized animals by intraperitoneal injection. One of the dosing solutions was administered to five animals of the dosing group.

Blood samples were collected serially via tail artery or cardiac puncture, typically at time = 0, 15, 30, 45, 60 and 90 minutes. Serum PYY concentrations were measured using the PYY[3-36] radioimmunoassay (Cat. No. RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA). The results obtained from each group of animals at each time point were averaged. The maximum of these means (ie, the mean peak serum PYY concentration) is reported in Table 2 below. The obtained results (± standard deviation) are also shown in FIG. 3 .

Table 2. Intraperitoneal (IP) Delivery of PYY[3-36] in Rats Method of administration PYY[3-36] dose (mg/kg) Volume dose (ml/kg) Average serum [PYY] peak (pg/ml) ± SD IP 0.005 0.5 435.19±56.07 IP 0.05 0.5 521.02±111.54 IP 0.1 0.5 464.48±77.48

Example 3 - Solid Oral Delivery of PYY[3-36] in Rats

Example 3a. Administration of Solid PYY3-36 to Restricted Rats

A stock solution of PYY[3-36] (80 mg/ml) prepared in deionized water was used.

About 0.08 mg/tablet (about 0.3 mg/kg) of PYY (about 1 μl) was added and mixed with about 13.5 or about 27 mg/tablet (about 50 or 100 mg/kg) of delivery agent. The punches, punches, and dies of a Carver 4350 manual tablet press with small capsule-shaped dies sold by Natoli Engineering Company, Inc. were treated with magnesium stearate (0.1%). About 13.58 or about 27.08 mg of the blended powder was fed into a die and prepared into small spherical tablets under a pressure of about 1000 PSI bar. The resulting solid dosage form was about the size of a standard size 9 capsule (about 2.65 mm in diameter and about 8.40 mm in length) at 27.08 mg and about 2.65 mm in diameter and about 4.20 mm in length at 13.58 mg solid.

Male Sprague Dawley rats (approximately 260 to approximately 280 g) were fasted overnight and then anesthetized for approximately 10 to 30 seconds using standard _CO2 inhalation techniques, allowing them to remain under anesthesia for approximately less than one minute, preferably approximately 10 seconds to approximately 30 seconds .

Use an oral tube. The dosing tube is inserted into the rat's mouth and carefully inserted about 8 cm to about 15 cm along the rat's pharynx and esophagus, depending on the rat's body weight (usually about 11 cm). The solid dosage form is delivered into the distal esophagus and/or stomach by depressing the plunger of the oral administration tube.

Blood samples were collected serially via tail artery or cardiac puncture, or in this case retro-orbital bleeding, typically at time = 0, 15, 30, 60 and 90 minutes. Serum PYY concentrations were measured using the PYY[3-36] radioimmunoassay (Cat. No. RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA). The results obtained from each group of animals at each time point were averaged. The maximum of these means (ie mean peak serum PYY[3-36] concentration) is reported in Table 3 below.

Table 3. Oral delivery of PYY[3-36] in fed-restricted rats Delivery agent Method of administration Delivery Agent Dose (mg/kg) PYY[3-36] dose (mg/kg) Mean serum [PYY] peak (pg/ml) ± SD 1 Oral, solid administration, 1 tablet per animal 100 0.3 830.24±341.32 1 Oral, solid administration, 1 tablet per animal 50 0.3 511.5±493.5 2 Oral, solid administration, 1 tablet per animal 100 0.3 512.4±484.2 2 Oral, solid administration, 1 tablet per animal 50 0.3 536.3±424.7 7 Oral, solid administration, 1 tablet per animal 100 0.3 1064.18±363.8 7 Oral, solid administration, 1 tablet per animal 50 0.3 725.96±110.78 7 Oral., solid administration, 1 tablet per animal 100 0 14.35±19.71 16 Oral, solid administration, 1 tablet per animal 100 0.3 1294.2±351.4 16 Oral, solid administration, 1 tablet per animal 100 0.3 1560±883.4 16 Oral, solid administration, 1 tablet per animal 100 0.3 980.7±49.7 16 Oral, solid administration, 1 tablet per animal 50 0.3 617.4±272.1 16 Oral, solid administration, 1 tablet per animal 50 0.3 988.7±288.2 16 Oral, solid administration, 1 tablet per animal 50 0.3 847.3±152 16 Oral, solid administration, 1 tablet per animal 75 0.3 754.7±539.8 16 Oral, solid administration, 1 tablet per animal 25 0.1 274.1±118.6 16 Oral, solid administration, 1 tablet per animal 50 0.1 249.3±144.0 16 Oral, solid administration, 1 tablet per animal 25 0.3 953.8±660.3 16 Oral, solid administration, 1 tablet per animal 25 0.5 494.6±318.2 16 Oral, solid administration, 1 tablet per animal 50 0.5 715±208.0 16 Oral, solid administration, 1 tablet per animal 100 0.5 852.2±1119 16 Oral, solid administration, 1 tablet per animal 50 1 739.6±409.6 2 and 16 Oral, solid administration, 1 tablet per animal 25 and 25 0.3 791.22±453.4 2 and 16 Oral, solid administration, 1 tablet per animal 50 and 50 0.3 644.18±595.4 16 Oral, solid administration, 1 tablet per animal 50 0.3 421.08±389.2 16 Oral, solid administration, 1 tablet per animal 100 0.3 939.88±166.61 17 Oral, solid administration, 1 tablet per animal 100 0.3 897.18±549.5 17 Oral, solid administration, 1 tablet per animal 50 0.3 581.62±236.94 18 Oral, solid administration, 1 tablet per animal 100 0.3 1216.13±661.31 18 Oral, solid administration, 1 tablet per animal 50 0.3 940.33±1090.65 control Oral, solid administration, 1 tablet per animal 10mg/kg mannitol, no delivery agent 0.3 5.55±12.40 19 Oral, solid administration, 1 tablet per animal 100 0.3 728.4±364.4 4 Oral, solid administration, 1 tablet per animal 100 0.3 1821.82±1513.84 9 Oral, solid administration, 1 tablet per animal 100 0.3 1309.8±836.33 10 Oral, solid administration, 1 tablet per animal 50 0.3 897.18±549.5 20 Oral, solid administration, 1 tablet per animal 100 0.3 695.8±274.3 11 Oral, solid administration, 1 tablet per animal 100 0.3 2330.63±963.7

Delivery agent 16 is N-(10-[2-hydroxybenzoyl]-amino)decanoic acid disodium salt (SNAD).

Delivery agent 17 was 8-(4-hydroxyphenoxy) octanoic acid disodium salt.

Delivery agent 18 was 8-(4-hydroxyphenoxy) caprylate monosodium salt.

Delivery agent 19 was 8-(2-hydroxy-4-methoxybenzamido) octanoic acid disodium salt.

Delivery agent 20 was 8-(2-hydroxy-5-methoxybenzamido) octanoic acid disodium salt.

Mannitol was used as a control.

Example 3b. Administration of solid PYY[3-36] to non-restricted fed rats

Rats received a solid oral dosage form consisting of PYY [3-36] and vehicle as described in Example 3a, except that no food restriction was imposed on the rats prior to administration of the solid dosage form. The serum PYY concentration of each animal was measured at each time point, and the results obtained from each group of animals at each time point were averaged. The maximum of these means (ie mean peak serum PYY[3-36] concentration ± standard deviation (SD)) is reported in Table 4 below.

Table 4. Oral delivery of PYY[3-36] in non-restricted fed rats Delivery agent Method of administration Delivery Agent Dose (mg/kg) PYY[3-36] dose (mg/kg) Mean serum [PYY] peak (pg/ml) ± SD 16 Oral, solid administration, 1 tablet per animal 50 0.3 1101±1197 16 Oral, solid administration, 1 tablet per animal 100 0.3 1011.5±1287 16 Oral, solid administration, 1 tablet per animal 100 0.5 1735.6±1108

Example 3c. Administration of Minitablets in Restricted-Fed Rats

Male Sprague Dawley rats were fasted overnight. Microtablets (about 2.5 mm in diameter) containing PYY[3-36] and SNAD were prepared by physical mixing and compression, and then administered to rats by oral gavage. Serum PYY[3-36] levels were measured by radioimmunoassay. Serum PYY[3-36] increased to 940±74 pg/ml after administration of one microtablet containing 0.3 and 100 mg/kg (body weight) of PYY[3-36] and SNAD, respectively (n=5, mean±s.e.m.) , and remain above baseline for 90 minutes. No changes in serum PYY[3-36] were detected when PYY[3-36] or SNAD were administered alone.

The results during the 90 minute test period are shown in FIG. 6 .

Peptide YY (PYY[3-36] Solid Oral Delivery in Rhesus Monkey (Rhesus Monkey)) in Example 4

About 1 mg/tablet of PYY solid powder was gradually added and mixed with 50 or 100 mg/tablet delivery agent. The punches, punches, and dies of a Carver 4350 manual tablet press with small capsule-shaped dies sold by Natoli Engineering Company, Inc. were treated with magnesium stearate (0.1%). About 51 or about 101 mg of the blended powder was fed into a die and prepared into small spherical tablets under a pressure of about 1000 PSI bar. The resulting solid dosage form was about 3 mm in diameter and about 1 mm in height at 51 mg solids and about 3 mm in diameter and about 2 mm in height at 101 mg solids.

For each dose level, 2 male and 2 female rhesus monkeys weighing 3.5-5.0 kg were fasted overnight prior to testing and resumed approximately 2 hours after solid administration. During the 30 minutes before and after dosing, water feeding was stopped except for the water used for dosing.

Each solid dosage form was delivered to the back of the mouth using a pellet gun. After release of the solid dosage form, 5 ml of reverse osmosis water was administered to the oral cavity to facilitate swallowing. After delivery, check the mouth to ensure solids have been swallowed.

Serial blood samples (approximately 1.3 ml) were collected from the femoral, brachial, or saphenous veins, typically at time = 0 (pre-dose) and 10, 20, 30, 45, 60, 90, 150, 240, and 360 minutes post-dose when collected. Place samples in serum separation tubes and allow to clot at room temperature for 30-45 minutes. The samples were then centrifuged at about 2-8°C for 10 minutes at 2500 rpm. The resulting sera were transferred into test tubes and placed on dry ice, then stored frozen at -70±10°C until assayed. Serum PYY concentrations were measured using the PYY[3-36] radioimmunoassay (Cat. No. RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA). The results obtained from each group of animals at each time point were averaged. The maximum of these means (ie mean peak serum PYY[3-36] concentrations ± standard deviation) is reported in Table 4 below. The results (± standard deviation) are also shown in FIG. 5 .

Table 4. Oral delivery of PYY in macaques Delivery agent Method of administration Delivery agent dose (mg/tablet) PYY[3-36] dose (mg/tablet) Dose per animal: Delivery agent (mg)/PYY[3-36] (mg) Mean serum [PYY] peak (pg/ml) ± SD 1 Oral, solid administration, 1 tablet per animal 50 1 50/1 969±60.72 1 Oral, solid administration, 1 tablet per animal 50 1 100/2 1030.9±76.88 1 Oral, solid administration, 1 tablet per animal 100 1 100/1 757.8±441.02

Delivery Agent 1 was N-(8-[2-hydroxybenzoyl]-amino)caprylic acid monosodium salt (SNAC).

Example 5 - Effect of Oral Administration of PYY[3-36] on 4-Hour Food Intake

A stock solution of PYY[3-36] (80 mg/ml) prepared in deionized water was used to prepare PYY[3-36] tablets.

About 0.132 mg/tablet (about 0.5 mg/kg) of PYY[3-36] (about 1.7 μl) was added and mixed with about 27 mg/tablet (100 mg/kg) of the delivery agent SNAD. The punches, punches, and dies of a Carver 4350 manual tablet press (available from Natoli Engineering Company, Inc.) with caplet-shaped dies were treated with magnesium stearate (0.1%). About 27.132 mg of blended PYY[3-36]/SNAD powder was fed into a die and prepared into small spherical tablets under a pressure of about 1000 PSI bar. The size of the resulting solid dosage form was about the size of a standard size 9 capsule (about 2.65 mm in diameter and about 8.40 mm in length).

Placebo tablets containing only SNAD, approximately 27 mg/tablet (100 mg/kg), were prepared in the same manner.

Male Sprague Dawley rats (about 260 to about 280 g) were fasted for 24 hours prior to dosing. Each rat was given either one PYY[3-36]/SNAD tablet or one placebo tablet.

Use an oral tube. The dosing tube is inserted into the rat's mouth and carefully inserted about 8 cm to about 15 cm along the rat's pharynx and esophagus, depending on the rat's body weight (usually about 11 cm). The solid dosage form is delivered into the distal esophagus and/or stomach by depressing the plunger of the oral administration tube. No anesthesia was used during the administration.

Food was weighed and given to rats one hour after dosing. After four hours, food was removed and weighed. The amount of food consumed was determined from the difference in food weight.

Cumulative 4-hour food intake in grams (mean ± s.e.m.) is shown in Table 5 and Figure 7. Double asterisks indicate P<0.01.

Table 5. 4-Hour Food Intake Group 4-hour food intake (g) standard deviation no PYY[3-36]/SNAD 4.09 0.33 9 placebo 6.69 0.76 9

As shown in the table above and Figure 7, rats receiving one PYY[3-36] tablet consumed significantly less food than rats receiving one placebo tablet.

Example 6 - Effect of oral administration of PYY[3-36] on body weight gain and food intake after 7 days of treatment

A stock solution of PYY[3-36] (110 mg/ml) prepared in deionized water was used to prepare PYY[3-36] tablets.

Microspherical tablets containing about 0.11 mg/tablet (about 0.5 mg/kg) of PYY [3-36] and about 16.5 mg/tablet (75 mg/kg) of the delivery agent SNAD were prepared following the procedure described in Example 6.

Placebo tablets containing only SNAD, about 16.5 mg/tablet (75 mg/kg), were also prepared according to the procedure described in Example 6.

Male Sprague Dawley rats (approximately 220 g) were administered either one PYY[3-36] tablet or one placebo tablet twice daily for 7 days. Prior to dosing, rats are anesthetized for about 10 to 30 seconds using standard _CO2 inhalation techniques and are allowed to remain under anesthesia for about less than one minute, preferably for about 10 seconds to about 30 seconds. Withdraw food prior to dosing and resume 30 minutes after dosing.

Use an oral tube. The dosing tube is inserted into the rat's mouth and carefully inserted about 8 cm to about 15 cm along the rat's pharynx and esophagus, depending on the rat's body weight (usually about 11 cm). The solid dosage form is delivered into the distal esophagus and/or stomach by depressing the plunger of the oral administration tube.

Food consumption was determined every 24 hours from the difference in weight between the food given to each rat and the remaining food. The body weight of each rat was measured every 24 hours.

The results are shown in Table 6 and Figures 8a and 8b. Body weight gain (expressed in grams) during the 7-day treatment period is shown in Figure 8a. Asterisks indicate P<0.05. Cumulative food intake (in grams) during the 7-day treatment period (mean ± s.e.m.) is shown in Fig. 8b. Double asterisks indicate P<0.01.

Table 6. Weight gain during the 7-day treatment period Group Weight gain after 7 days of treatment (g) standard error Food intake (g) during the 7-day treatment period standard error no PYY[3-36]/SNAD 12 4 148 5 7 placebo twenty three 2 169 4 7

As shown in the table above and in Figures 8a and 8b, rats receiving PYY[3-36]/SNAD had significantly less body weight gain and food consumption compared to rats receiving placebo. PYY [3-36] had no effect on gastric emptying. At the end of the 7-day study, the amount of food in the stomach was minimal and comparable for placebo and treated animals. No pathology or other phenomena were observed in the gastrointestinal tract at the time of macroscopic autopsy after the end of the study.

Example 7 - Dosage Forms of SNAD Disodium Salt and PYY [3-36] and Intraperitoneal Administration of PYY [3-36]

Liquid dosage forms are prepared as follows. PYY[3-36] stock solution (80 mg/ml) prepared in deionized water. A liquid solution of the delivery agent is prepared by dissolving the disodium salt of SNAD in water. The pH of the resulting SNAD disodium salt solution was about 10. An aliquot of the SNAD disodium salt solution was mixed with an aliquot of the PYY[3-36] solution (pH about 8). This procedure is followed to prepare a liquid dosage form containing about 100-200 mg/kg SNAD disodium salt and about 0.3-1 mg/kg PYY [3-36]. The final pH of the liquid dosage form is about 9-10.

Solid dosage forms are prepared as follows. About 0.08 mg/tablet (about 0.3 mg/kg) of PYY (about 1 μl) was added and mixed with about 13.5 or about 27 mg/tablet (about 50 or 100 mg/kg) of delivery agent. The punches, punches, and dies of a Carver 4350 manual tablet press with small capsule-shaped dies sold by Natoli Engineering Company, Inc. were treated with magnesium stearate (0.1%). About 13.58 or about 27.08 mg of the blended powder was fed into a die and prepared into small spherical tablets under a pressure of about 1000 PSI bar. The resulting solid dosage form was about the size of a standard size 9 capsule (about 2.65 mm in diameter and about 8.40 mm in length) at 27.08 mg and about 2.65 mm in diameter and about 4.20 mm in length at 13.58 mg solid.

Male Sprague Dawley rats (approximately 260 to approximately 280 g) were fasted overnight and then anesthetized for approximately 10 to 30 seconds using standard _CO2 inhalation techniques, allowing them to remain under anesthesia for approximately less than one minute, preferably approximately 10 seconds to approximately 30 seconds .

Use an oral tube. The dosing tube is inserted into the rat's mouth and carefully inserted about 8 cm to about 15 cm along the rat's pharynx and esophagus, depending on the rat's body weight (usually about 11 cm). The solid dosage form is delivered into the distal esophagus and/or stomach by depressing the plunger of the oral administration tube.

Blood samples were collected serially via tail artery or cardiac puncture, or in this case retro-orbital bleeding, typically at time = 0, 15, 30, 60 and 90 minutes. Serum PYY concentrations were measured using the PYY[3-36] radioimmunoassay (Cat. No. RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA). The results obtained from each group of animals at each time point were averaged. The maximum of these means (ie, mean peak serum PYY concentration) is reported in Table 7 below.

Table 7. Transmission of PYY[3-36] in rats Method of administration SNAD disodium salt dosage (mg/tablet) PYY(3-36) dose (mg/tablet) Mean serum [PYY] peak (pg/ml) ± SD Oral, solid administration, 1 tablet per animal 100 0.5 1518.36±464.98 Oral, solid administration, 1 tablet per animal 100 0.5 3685.8±880.43 oral, liquid 150 0.5 2215.6±1543.01 oral, liquid 150 1 4697.8±3009.48 oral, liquid 150 1 2432.4±1702.55 oral, liquid 100 0.3 1008.2±145.16 oral, liquid 200 0.3 805.67±583.78 oral, liquid 200 0 0 intraperitoneal injection 0 0.05 3671±244.7 intraperitoneal injection 0 0.05 6292.8±1365.1

Example 8 - Peptide YY (PYY[3-36]), solid oral administration in Cynomoleus monkey send

Capsules are prepared as follows. Gradually add approximately 1 mg of PYY solid powder and mix with 50 or 100 mg of SNAD. Fill the pre-weighed size 2 capsule shells with this mixture using a clean metal medicine spoon. The final capsules were reweighed and determined to contain >98% of the transferred mixture.

Tablets are prepared as follows. About 1 mg/tablet of PYY solid powder was gradually added and mixed with about 50 mg/tablet of the delivery agent. The punches, punches, and dies of a Carver 4350 manual tablet press with small capsule-shaped dies sold by Natoli Engineering Company, Inc. were treated with magnesium stearate (0.1%). About 51 mg of the blended powder was fed into a die and prepared into small spherical tablets under a pressure of about 1000 PSI bar. The resulting solid dosage form was about 3 mm in diameter and about 1 mm in height.

For each dose level, 2 male and 2 female macaques weighing 3.5-5.0 kg were fasted overnight prior to testing and resumed approximately 2 hours after solid administration. During the 30 minutes before and after dosing, water feeding was stopped except for the water used for dosing.

Each solid dosage form was delivered directly into the stomach using a gavage tube. The capsule or tablet is ejected by blowing air.

Serial blood samples (approximately 1.3 ml) were collected from the femoral, brachial, or saphenous veins, typically at time = 0 (pre-dose) and 10, 20, 30, 45, 60, 90, 150, 240, and 360 minutes post-dose when collected. Place samples in serum separation tubes and allow to clot at room temperature for 30-45 minutes. The samples were then centrifuged at about 2-8°C for 10 minutes at 2500 rpm. The resulting sera were transferred into test tubes and placed on dry ice, then stored frozen at -70±10°C until assayed. Serum PYY concentrations were measured using the PYY[3-36] radioimmunoassay (Cat. No. RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont, CA). The results obtained from each group of animals at each time point were averaged. The maximum of these means (ie, mean peak serum PYY concentration) is reported in Table 8 below.

Table 8. Results of solid oral delivery of PYY[3-36] in macaques compound Method of administration Compound dose (mg/tablet) PYY(3-36) dose (mg/tablet) Mean serum [PYY] peak (pg/ml) ± SD SNAD Oral, solid administration, 1 capsule per animal 50 1 419.68±320.44 SNAD Oral, solid administration, 1 capsule per animal 100 1 432.02±309.47 SNAD Oral, solid administration, 1 tablet per animal 50 1 925.86±794.03

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The patents, applications, test procedures, and publications mentioned above are hereby incorporated by reference in their entirety.

From the above detailed description, various modifications of the present invention can themselves be suggested to those skilled in the art. All such obvious variations are within the fully intended scope of the appended claims.

Claims (20)

1. pharmaceutical composition, the transmission agent that comprises (a) peptide YY, peptide YY agonist or its mixture and (b) have following formula structure or its salt,

Wherein:

Ar is a phenyl or naphthyl;

Ar is randomly by-OH, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkenyl, C ₁-C ₄Alkoxyl or C ₁-C ₄One or more groups in the halogenated alkoxy replace;

R ⁷Be selected from C ₄-C ₂₀Alkyl, C ₄-C ₂₀Alkenyl, phenyl, naphthyl, (C ₁-C ₁₀Alkyl) phenyl, (C ₁-C ₁₀Alkenyl) phenyl, (C ₁-C ₁₀Alkyl) naphthyl, (C ₁-C ₁₀Alkenyl) naphthyl, phenyl (C ₁-C ₁₀Alkyl), phenyl (C ₁-C ₁₀Alkenyl), naphthyl (C ₁-C ₁₀Alkyl) or naphthyl (C ₁-C ₁₀Alkenyl);

R ⁸Be selected from hydrogen, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₁-C ₄Alkoxyl and C ₁-C ₄Halogenated alkoxy;

R ⁷Randomly by C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₁-C ₄Alkoxyl, C ₁-C ₄Halogenated alkoxy ,-OH ,-SH ,-CO ₂R ⁹Or their combination in any replaces;

R ⁹Be hydrogen, C ₁-C ₄Alkyl or C ₂-C ₄Alkenyl;

R ⁷Randomly at interval by oxygen, nitrogen, sulfur or their combination in any; Condition is that this chemical compound is not replaced by amino on the α position of acid groups.

2. pharmaceutical composition, the transmission agent that comprises (a) peptide YY, peptide YY agonist or its mixture and (b) have following formula structure or its salt,

Wherein,

R ¹, R ², R ³And R ⁴Be independently H ,-OH, halogen, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₁-C ₄Alkoxyl ,-C (O) R ⁸,-NO ₂,-NR ⁹R ¹⁰Or-N ⁺R ⁹R ¹⁰R ¹¹(R ¹²) ^-

R ⁵For H ,-OH ,-NO ₂, halogen ,-CF ₃,-NR ¹⁴R ¹⁵,-N ⁺R ¹⁴R ¹⁵R ¹⁶(R ¹³) ^-, acylamino-, C ₁-C ₁₂Alkoxyl, C ₁-C ₁₂Alkyl, C ₂-C ₁₂Alkenyl, carbamate groups, carbonate group, urea groups or-C (O) R ¹⁸

R ⁵Randomly by halogen ,-OH ,-SH or-COOH replaces;

R ⁵Randomly by O, N, S or-C (O)-at interval;

R ⁶Be C ₁-C ₁₂Alkylidene, C ₂-C ₁₂Alkenylene or arlydene;

R ⁶Randomly by C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₁-C ₄Alkoxyl ,-OH ,-SH, halogen ,-NH ₂Or-CO ₂R ⁸Replace;

R ⁶Randomly by O or N interval;

R ⁷Be key or arlydene;

R ⁷Randomly by-OH, halogen ,-C (O) CH ₃,-NR ¹⁰R ¹¹Or-N ⁺R ¹⁰R ¹¹R ¹²(R ¹³) ^-Replace;

R ⁸Be H, C when occurring independently at every turn ₁-C ₄Alkyl, C ₂-C ₄Alkenyl or-NH ₂

R ⁹, R ¹⁰, R ¹¹And R ¹²Be H or C independently ₁-C ₁₀Alkyl;

R ¹³Be halogen ion, hydroxyl, sulfate radical, tetrafluoroborate or phosphate radical; And

R ¹⁴, R ¹⁵And R ¹⁶Be H, C independently ₁-C ₁₀The C that alkyl, quilt-COOH replace ₁-C ₁₀Alkyl, C ₂-C ₁₂The C that alkenyl, quilt-COOH replace ₂-C ₁₂Alkenyl or-C (O) R ¹⁷

R ¹⁷For-OH, C ₁-C ₁₀Alkyl or C ₂-C ₁₂Alkenyl; And

R ¹⁸Be H, C ₁-C ₆Alkyl ,-OH ,-NR ¹⁴R ¹⁵Or N ⁺R ¹⁴R ¹⁵R ¹⁶(R ¹³).

3. pharmaceutical composition, the transmission agent that comprises (a) peptide YY, peptide YY agonist or its mixture and (b) have following formula structure or its salt,

Wherein,

R ¹, R ², R ³, R ⁴And R ⁵Be independently H ,-CN ,-OH ,-OCH ₃Or halogen, and R ¹, R ², R ³, R ⁴And R ⁵In at least one is-CN; And

R ⁶Be C ₁-C ₁₂Straight or branched alkylidene, alkenylene, arlydene, alkyl (arlydene) or aryl (alkylidene).

4. each pharmaceutical composition in the claim 1,2 or 3 wherein transmits agent and is selected from transmission agent 1-20.

5. the pharmaceutical composition of claim 1 wherein transmits agent and is sad or its officinal salt of N-(8-[2-hydroxy benzoyl]-amino).

6. the pharmaceutical composition of claim 1 wherein transmits agent and is N-(10-[2-hydroxy benzoyl]-amino) capric acid or its officinal salt.

7. each pharmaceutical composition in the aforementioned claim, wherein peptide YY agonist is selected from the functional domain of PYY, active fragment, PYY derivant, PYY fragment and the PYY analog of PYY.

8. each pharmaceutical composition in the aforementioned claim, wherein peptide YY agonist is PYY[3-36].

9. dosage unit form, it comprises:

(A) each pharmaceutical composition in the aforementioned claim; With

(B) (a) excipient,

(b) diluent,

(c) disintegrating agent,

(d) lubricant,

(e) plasticizer,

(f) coloring agent,

(g) drug administration carrier, or

(h) their combination in any.

10. the dosage unit form of claim 9, wherein dosage unit form is the form of tablet, capsule, granule, powder, wafer or liquid.

11. the dosage unit form of claim 9, wherein drug administration carrier is for being selected from water, aqueous solution of propylene glycol, phosphate buffer, 1, the liquid of 2-propylene glycol, ethanol and their combination in any.

12. with the method that the peptide YY or the peptide YY agonist of effective dose is applied to the patient who needs it, this method comprises the step of each pharmaceutical composition among the Orally administered claim 1-8.

13. the method for treatment of obesity in its patient of needs, this method comprise the step of using each pharmaceutical composition among the claim 1-8 of effective dose to the patient.

14. treatment can come demulcent disease or disorderly method by reducing the nutritional utilization degree in its patient of needs, this method comprises the step of using each pharmaceutical composition among the claim 1-8 of effective dose to animal.

15. the method for claim 14, wherein said disease or disorder are selected from hypertension, dyslipidemia disease, cardiovascular disease danger, eating disorders, insulin resistant, obesity and diabetes.

16. reduce the method for alimentation in its patient of needs, this method comprises the step of each pharmaceutical composition among the claim 1-8 that uses effective dose.

17. improve the method for lipid in nature in its patient of needs, this method comprises the step of each pharmaceutical composition among the claim 1-8 that uses effective dose.

18. each method among the claim 12-17, wherein peptide YY agonist is PYY[3-36] and to transmit agent be the sad or N-of N-(8-[2-hydroxy benzoyl]-amino) (10-[2-hydroxy benzoyl]-amino) capric acid or its officinal salt.

19. improve the method for the bioavailability of the peptide YY of animal or peptide YY agonist, this method comprises the step of the preparation of using claim 1 or 2.

20. the method for pharmaceutical compositions, this method comprise at least a blended step at least a transmission immunomodulator compounds and peptide YY and the peptide YY agonist.

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