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

Abstract

The present invention provides a composition (e.g., a pharmaceutical composition) comprising at least one delivery agent compound and at least one of peptide YY (PYY) and a PYY agonist. Preferably, the composition includes a therapeutically effective amount of peptide YY or the PYY agonist and the delivery agent compound. The composition of the present invention facilitates the delivery of PYY, a PYY agonist, or a mixture thereof and increases its bioavailability compared to administration without the delivery agent compound. PPY and PYY agonists possess activity as agents to reduce nutrient availability, including reduction of food intake.

Description

Be used to transmit the compositions of peptide YY and PYY agonist

The application requires to enjoy the priority of following application: the U.S. Provisional Patent Application No.60/470 that submits on May 14th, 2003,905, the U.S. Provisional Patent Application No.60/471 that submits on May 15th, 2003,114, in the U.S. Provisional Patent Application No.60/506 of JIUYUE in 2003 submission on the 25th, 702 and the U.S. Provisional Patent Application No.60/536 that submits on January 14th, 2004,697, above-mentioned all patent applications are incorporated herein by reference.

Invention field

The present invention relates to be used for peptide YY (PYY) and PYY agonist are sent to the compositions of target spot.These compositionss comprise and well being suitable for and the chemical compound that forms non-covalent mixture by oral administration to PYY and the PYY agonist of animal.The invention also discloses the method for preparation, administration and treatment.

Background of invention

The effect of present anti-obesity medicine is limited and multiple side effect arranged.Crowley, V.E., Yeo, G.S.﹠amp; O ' Rahilly, S., Nat.Rev.Drug Discov 1,276-86 (2002). along with obesity worldwide catches on, press in the suitable treatment of this field development.In recent years, hormone and the neuropeptide that relates in modulation of appetite, physical consumption and fat mass accumulation occurs as potential anti-obesity medicine.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)。Yet these peptides need be through the gastrointestinal tract external administration at present.Injection every day is not really optimistic with the prospect of controlling obesity, and may limit the application of these medicines.

A kind of such peptide, PYY is after the meal by the secretion of terminal gastrointestinal endocrine cell and act on hypothalamus signal satiety center.Batterham, people such as R.L., Nature 418:650-654 (2002). nearest studies show that obese patient's fasting and PYY content is lower after the meal, this can explain their honey stomach and the many reasons of food consumption.When intravenous administration, it suppresses thin weak person and obese patient's appetite and food intake.Batterham, people such as R.L., N Engl J Med 349:941-948 (2003).Being derived from other peptide of pancreas peptide (PP) family such as peptide YY fragment (for example PYY[3-36]) and PYY agonist (comprising the peptide that does not belong to PP family) also can appetite-suppressing.Yet because few and degraded is fast in gastrointestinal absorption, its Orally active can be ignored.

Be sent in the process of animal at PYY and PYY agonist, health has been given various barriers.The example of physical barrier has skin, double-layer of lipoid and various organ film, and they are impermeable relatively for some activating agent, but must pass them before arriving target spot such as blood circulation.Chemical barrier includes but not limited to that the pH in gastrointestinal (GI) road changes and digestive enzyme.

These barriers are particular importance in the design of oral transfer system.If it were not for because these biologies, chemistry and physical barriers, the oral transmission of PYY and PYY agonist will be the selection of animals administer approach.These therapeutic agents may be owing to acidolysis, enzyme etc. cause rapid inactivation or destroyed in gastrointestinal tract.In addition, the size of macromolecular drug and structure may stop absorption.As a result, the oral administration of protein and peptide medicament to a certain extent since their absorption less and degrade fast and challenging.

The method of early stage Orally administered easy ruined rem depend on give jointly adjuvant (for example, resorcinol and nonionic surfactant such as polyoxyethylene oleyl ether and n-hexadecyl polyvinylether) to increase intestinal wall artificially permeability and give enzyme inhibitor jointly to suppress enzymatic degradation.Liposome is also on the books as the drug-supplying system of insulin and heparin.Yet the extensive use of this class drug-supplying system is hindered, part because: (1) this system needs the adjuvant or the inhibitor of poisonous amount; (2) can not obtain the suitable low-molecular-weight thing that is transmitted, i.e. activating agent; (3) this system demonstrates poor stability and the shelf life falls short of; (4) this system is difficult to preparation; (5) this system can not protect activating agent (being transmitted thing); (6) this system changes activating agent unfriendly; Or (7) this system does not allow or promotes the absorption of activating agent.

Recently, proteinoid microsphere has been used to transmit medicine.For example referring to United States Patent (USP) 5,401,516,5,443,841 and Re.35,862.In addition, some modified amino acid has been used to transmit medicine.For example referring to United States Patent (USP) 5,629,020,5,643,957,5,766,633,5,776,888 and 5,866,536.

According to people such as Batterham, the description of Nature 418:650-654 (2002) (being incorporated herein by reference), peptide YY[3-36] system can provide the treatment target spot for the treatment of obesity.

International Application No. WO 02/47712 and United States Patent (USP) 2002/0141985 disclose with peptide YY and peptide YY agonist such as peptide YY[3-36] method of treatment of obesity and diabetes.

Yet, also need simple, the cheap transmission peptide YY and the delivery system of PYY agonist.

Need and non-invasively transmit peptide YY[3-36] approach to guarantee patient's compliance, the preferred oral approach.

Summary of the invention

The invention provides and comprise (a) at least a transmission agent (delivery agent) chemical compound and (b) compositions of peptide YY (PYY), PYY agonist or its mixture (for example pharmaceutical composition).Preferred said composition comprises the peptide YY and/or the PYY agonist for the treatment of effective dose and transmits immunomodulator compounds.Compare with the administration that does not transmit immunomodulator compounds, compositions of the present invention is convenient to the transmission of PYY and/or PYY agonist, and has improved its bioavailability.PPY has with the PYY agonist and reduces the nutritional utilization degree, comprises the identical activity of medicine that reduces food intake.

The preferred immunomodulator compounds that transmits includes but not limited to the sad and N-of N-(8-[2-hydroxy benzoyl] amino) (10-[2-hydroxy benzoyl] amino) capric acid and their salt, solvate and hydrate.In preferred embodiments, its salt is sodium salt, as a sodium salt.

In a preferred embodiment, said composition comprises peptide YY, PYY agonist or its mixture and at least a transmission agent with following formula structure or its salt,

Formula A

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.

In another embodiment preferred, said composition comprises peptide YY, PYY agonist or its mixture and at least a transmission agent with following formula structure or its salt:

Formula B

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;

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) ^-

Randomly, work as R ¹, R ², R ³, R ⁴And R ⁵Be H and R ⁷During for key, R ⁶Not C ₁-C ₆, C ₉Or C ₁₀Alkyl.

Randomly, work as R ¹, R ², R ³And R ⁴Be H, R ⁵For-OH and R ⁷During for key, R ⁶Not C ₁-C ₃Alkyl.

Randomly, work as R ¹, R ², R ³And R ⁴In at least one is not H, R ⁵For-OH, and R ⁷During for key, R ⁶Not C ₁-C ₄Alkyl.

Randomly, work as R ¹, R ²And R ³For being H, R ⁴For-OCH ₃, R ⁵For-C (O) CH ₃, and R ⁶During for key, R ⁷Not C ₃Alkyl.

Randomly, work as R ¹, R ², R ⁴And R ⁵Be H, R ³For-OH, and R ⁷During for key, R ⁶It or not methyl.

In another embodiment, said composition comprises peptide YY, PYY agonist or its mixture and at least a transmission agent with following formula structure or its salt,

Compound C

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).

According to an embodiment, work as R ¹For-CN, R ⁴For H or-CN, and R ², R ³And R ⁵During for H, R ⁶Not methylene ((CH ₂) ₁).

The present invention also provides the dosage unit form that comprises the present composition (for example, oral dosage unit form).Dosage unit form can be the form of liquid or solid, as tablet, capsule or granule, comprises powder or wafer.

Another embodiment is to its method for animal administration for peptides YY, PYY agonist or its mixture of needs, and this method is undertaken by compositions of the present invention or dosage unit form are applied to animal.Preferred route of administration is an oral administration.

Another embodiment is to its method for animal administration for peptides YY, PYY agonist or its mixture of needs, and this method is undertaken by compositions of the present invention or dosage unit form are applied to animal in the mode that minimizes or stop the antibody of peptide YY and/or PYY agonist to form.

Another embodiment is to make the slimming method of animal (as the people) that needs it, and this method is undertaken by the compositions of the present invention of effective dose or dosage unit form are applied to animal.That in other words, uses effective dose is convenient to the transmission immunomodulator compounds that PYY or PYY agonist transmit and the PYY or the PYY agonist of effective dose (for example treating effective dose).

Another embodiment is the method for the treatment of the obesity of the animal (as the people) that needs it, and this method is applied to animal by the compositions of the present invention with effective dose and carries out.

Another embodiment is that treatment can come demulcent disease or disorderly method by reducing the nutritional utilization degree in animal (as the people), and this method is undertaken by compositions of the present invention or the dosage unit form of giving animal administering therapeutic effective dose.This class disease and disorderly danger, eating disorders, insulin resistant, obesity and diabetes including, but not limited to hypertension, dyslipidemia disease, cardiovascular disease.

Another embodiment is to improve the method for the lipid in nature of animal (as the people), and this method is undertaken by compositions of the present invention or the dosage unit form of using effective dose to animal.

Another embodiment is the method for preparing the present composition, and this method is by carrying out with peptide YY at least a transmission immunomodulator compounds with at least a mixing the in the PYY agonist.

The accompanying drawing summary

Fig. 1 has and does not have an Orally administered PYY[3-36 under the situation that transmits agent SNAC according to the step of describing among the embodiment 1] back PYY[3-36] blood drug level (pg/ml ± standard deviation)-time diagram.

Fig. 2 is having and is not having an Orally administered PYY[3-36 under the situation that transmits agent SNAD according to the step of describing among the embodiment 1] back PYY[3-36] blood drug level (pg/ml ± standard deviation)-time diagram.

Fig. 3 is not having peritoneal injection PYY[3-36 under the situation that transmits immunomodulator compounds according to the step of describing among the embodiment 2] back PYY[3-36] blood drug level (pg/ml ± standard deviation)-time diagram.

Fig. 4 is to the Orally administered PYY[3-36 of rat according to the step of describing among the embodiment 3] and multiple transmission agent, only use transmission agent 3 and use PYY and mannitol after PYY[3-36] blood drug level (pg/ml ± standard deviation)-time diagram.

Fig. 5 is with PYY[3-36 according to the step of describing among the embodiment 4] with transmit agent 1 by oral administration to non-human primate after PYY[3-36] blood drug level (pg/ml ± standard deviation)-time diagram.

Fig. 6 is at Orally administered PYY[3-36 according to the step of describing among the embodiment 3c] with the combination of SNAD after PYY[3-36] blood drug level-time diagram.

Fig. 7 is the step PYY[3-36 that describes in according to embodiment 5] with 4 days of the male Sprague Dawley of the combined treatment of SNAD rat during the food intake figure that compares with placebo.

Fig. 8 a is the step PYY[3-36 that describes in according to embodiment 6]-with 7 days of the male Sprague Dawley of the combined treatment of SNAD rat during the accumulative total weight increase figure that compares with placebo.

Fig. 8 b is the step PYY[3-36 that describes in according to embodiment 6] with 7 days of the male Sprague Dawley of the combined treatment of SNAD rat during the accumulative total food intake and the weight increase figure that compare with placebo.

Detailed Description Of The Invention

Definition

Term " hydrate " includes but not limited to as used herein: (i) contain with the material of the water of molecular forms combination and (ii) contain the crystalline solid of one or more crystallization water molecules or contain the crystalline solid of free water.

Term " solvate " includes but not limited to molecule or the molecule of ion and transmission immunomodulator compounds or its salt or its hydrate or solvate or molecule or the ionic complex that ion forms of solvent as used herein.

Term " transmission agent " refers to any transmission immunomodulator compounds disclosed herein.

Term " SNAC " refers to the sad sodium salt of N-(8-[2-hydroxy benzoyl]-amino).

Term " SNAD " refers to N-(10-[2-hydroxy benzoyl]-amino) capric acid one sodium salt. Term " SNAD disodium salt " refers to N-(10-[2-hydroxy benzoyl]-amino) capric acid disodium salt.

" PYY of effective dose, PYY activator or its mixture " is PYY, PYY activator or its mixture being applied to live organism effective amount for the treatment of or prevention illness after a period of time, for example provides result for the treatment of in the administration time of expectation.

" the transmission agent of effective dose " is to transmit that agent allows and/or PYY or the absorbed amount of PYY activator of the desired amount being convenient to use through any approach (those that describe in detail in such as the application, include but not limited to oral (for example passing GI biomembrane), intranasal, through lung, skin, oral cavity, vagina and/or eye approach).

Term " AUC " refers to area under PC-time graph as used herein, as by trapezoidal method during the whole administration, for example calculate during 24 hours.

Except as otherwise noted, term " on average " is when the arithmetic mean of instantaneous value that is placed on pharmacokinetics numerical value (for example average peak) and represents before the time this pharmacokinetics numerical value.

The plural number that comprises related object such as the used singulative " " of this paper and appended claim and " a kind of " is unless context is clearly indicated in addition. Thereby, for example, " molecule " comprises one or more these molecules, " a kind of reagent " comprises the reagent that one or more these classes are different, " a kind of antibody " comprise the antibody that one or more these classes are different, " method " comprise known to persons of ordinary skill in the art can be flexible for or replace the equal step and method of described method herein.

Term " about " be often referred to set-point or scope 10%, preferred 5%, more preferably change within 1%.

Term " alkyl " and " alkenyl " comprise respectively alkyl and the alkenyl substitutents of straight chain and side chain as used herein.

Term " patient " refers to mammal as used herein, and preferred people.

Phrase " pharmaceutically useful " refers to when being applied to mammal be that physiology can tolerate and usually do not produce irritated or similar bad reaction as have a stomach upset, dizzy etc. additive or composition.

PYY and PYY activator

" PYY " or " PYY " refers to the PYY polypeptide that obtained or derived by any species. Therefore, term " PYY " comprises people's total length, 36 amino acid peptides, (it is U.S. Patent Publication No. 2002/0141985 corresponding PCT application such as International Application No. WO 02/47712, the document is incorporated herein by reference) and Tatemoto, Proc Natl Acad Sci U.S.A.79:2514-8, in 1982 shown in the SEQ ID NO:2, and the variant that comprises the PYY different genera, for example comprise the PYY of Muridae, hamster, chicken, ox, rat and dog. " PYY activator " guided PYY to reduce any compound of nutritional utilization degree effect, such compound for example: the activated compound of tool in food intake, gastric emptying, the pancreatic secretion that (1) is described in the embodiment 1,2,5 or 6 of WO 02/47712 and U.S. Patent Publication No. 2002/0141985 or the detection that loses weight, (2) the Y acceptor detect in (embodiment 10 of WO 02/47712 and U.S. Patent Publication No. 2002/0141985) or in competitive binding detects specific binding be derived from some tissue that is rich in the Y acceptor and (for example comprise the area postrema, the embodiment 9 of WO 02/47712 and U.S. Patent Publication No. 2002/0141985) mark PYY or PYY[3-36], wherein said PYY activator is not pancreatic polypeptide. Preferred PYY activator in suchlike detection affinity greater than about 1 μ M, more preferably affinity greater than about 1 to about 5nM.

This excitomotor can comprise the polypeptide that contains the PYY functional domain, active fragment or chemistry or the little molecule of PYY. The PYY activator can be peptide or non-peptide compound, comprise " PYY activator analog ", PYY activator analog refers to any structurally compound with PYY activity similar to PYY, this activity usually since with interact with it other receptors bind of producing biological response or directly or indirectly interact with it by alternate manner of pyy receptor or PYY itself. This compounds comprises PYY derivative, PYY fragment, contains more than 36 amino acid whose expansion PYY molecules, contains the replacement PYY molecule or the above-described any combination that are less than 36 amino acid whose brachymemma PYY molecules and contain one or more different aminoacids. This compounds can also be by modifying such as the method for Pegylation, amidatioon, glycosylation, acidylate, sulphation, phosphorylation, acetylation and cyclisation.

A kind of such PYY activator analog is PYY[3-36], be accredited as the SEQ ID NO:3 in WO 02/47712 and the U.S. Patent Publication No. 2002/0141985; Eberlein Eysselein etc., Peptides 10:797-803 (1989); And Grandy, Schimiczek etc., Regul Pept 51:151-9 (1994). The brachymemma polypeptide that has the polypeptide of number to refer to have the sequence on the amino acid position of full-length peptide in parantheses in the parantheses. Therefore, PYY[3-36] have with PYY 3 to the identical sequence of 36 amino acids. PYY[3-36] contain under the fasting state of total PYY of the intestines extract of about 40% people and dog-sample immunoreactivity and about 36% total blood plasma PYY immunoreactivity to being slightly larger than 50% (after the meal). Obviously it is dipeptidyl peptidase-IV (DPP4) pyrolysis product of PYY. It is reported that PYY[3-36] is the selective ligands of Y2 and Y5 acceptor, these two kinds of acceptors demonstrate pharmacological uniqueness in terminal brachymemma (being the C end fragment) the neuropeptide tyrosine analog of preferred N-. The PYY activator may be combined with pyy receptor with higher or lower affinity, and this expression has in the long or short body or vitro half-lives, and is perhaps greater or lesser than natural PYY effect.

Other suitable PYY activator comprises the PYY activator of describing among the International Publication No. WO 98/20885, and the document is incorporated herein by reference.

" illness or the disorder that can relax by reducing heat (or nutrition) availability " refer to animal by relatively high nutritional utilization degree caused, concurrent or any illness or the disorder that worsen, perhaps can be by any illness or the disorder that reduces the nutritional utilization degree, for example relaxes by the minimizing food intake. This class illness or disorder include but not limited to obesity, diabetes and comprise diabetes B, eating disorder and insuline resistance syndrome.

On the one hand, the invention provides the method for the obesity for the treatment of obesity or overweight animal, the method is by PYY, PYY activator or its mixture and at least a transmission immunomodulator compounds of administering therapeutic effective dose. Surpass 30 although " obesity " is generally defined as body mass index, for the purpose of the disclosure of invention, need or wish slimming any curee, comprise that body mass index is lower than 30 curee and all comprises in " obesity " scope. The patient who suffers from insulin resistance, glucose intolerance or any form diabetes (for example 1 type, 2 types or gestational diabetes) can be benefited from this method.

In other side, the present invention makes and reduces food intake, treats diabetes and improve the method for lipid in nature (comprise and reduce LDL-C and triglyceride levels and/or change the HDL cholesterol levels) characteristic, and the method comprises to the PYY of curee's administering therapeutic effective dose, PYY activator or its mixture and at least a transmission immunomodulator compounds. In preferred embodiments, method of the present invention is used for the treatment of illness or the disorder that can need its curee's nutritional utilization degree to relax by minimizing, comprises PYY, PYY activator or its mixture and at least a transmission immunomodulator compounds to described curee's administering therapeutic effective dose. This class illness and disorderly diabetes including, but not limited to hypertension, dyslipidemia, angiocardiopathy, eating disorder, insulin resistance, obesity and any type.

In the method for the present invention, the effect in one of detection that preferred PYY activator is description in WO 02/47712 and U.S. Patent Publication No. 2002/0141985 is higher than the PYY activator that NPY acts in same detection.

In one embodiment, for all illnesss of describing herein and disorderly treatment, preferred PYY activator is PYY[3-36], use (periphery) about 1pg to about 5mg every day with single dose or broken dose. Perhaps, PYY[3-36] can according to curee's TBW with single dose or broken dose by every day about 0.01 μ g/kg to about 500 μ g/kg, about 0.05 μ g/kg to about 250 μ g/kg or be lower than the amount administration of about 50 μ g/kg. Certainly the dosage in these scopes will change with the usefulness of various activators, and is easy to be determined by those skilled in the art.

In the method for the invention, PYY and PYY activator can demonstrate other compound and composition the administration long-term or effect of short-term reduction nutritional utilization degree separately or with one or more with transmitting immunomodulator compounds, and these compounds and composition include but not limited to comprise IAPP or IAPP activator, pancreozymin (CCK) or CCK activator, leptin (OB albumen)) other compound and the composition of leptin activator, exendin or exendin activator or GLP-1 or GLP-1 activator. For example, suitable IAPP activator comprises [25,28,29Pro-]-people's IAPP (has another name called " pramlintide ", at U.S. Patent number 5,686,511 and 5,998, description is arranged in 367), calcitonin (for example salmon calcitonin), comprise U.S. Patent number 5,739, those that describe in 106, the document is incorporated herein by reference. The preferred CCK octapeptide of used CCK (CCK-8). Leptin is for example at Pelleymounter, the people such as C., Science 269:540-543 (1995), Halaas, G. etc., Science 269:543-6 (1995) and Campfield, S. etc., Science 269:546-549 has discussion in (1995). Suitable CCK activator comprises U.S. Patent number 5,739, those that describe in 106, and the document is incorporated herein by reference. Suitable exendin comprises exendin-3 and exendin-4, the exendin agonist compound comprises that for example the PCT application discloses those that describe among WO 99/07404, WO 99/25727 and the WO 99/25728, and all these documents all are incorporated herein by reference. According to an embodiment, composition of the present invention comprises at least a transmission immunomodulator compounds, PYY, PYY activator or its mixture, at least a IAPP activator and CCK activator. Suitable IAPP activator and the combination of CCK activator include but not limited to U.S. Patent number 5,739, the combination of describing in 106, and the document is incorporated herein by reference.

PYY and PYY[3-36] when when physiology is expressed, being the C terminal amide, but there is no need for the purposes of this invention so. These peptides can also carry out other posttranslational modification.

The PYY that describes herein and can adopt standard restructuring body surface known in the art to reach or chemical peptide synthetic technology prepares based on the PYY activator of peptide for example uses automation or semi-automatic peptide synthesizer. The PYY that describes herein comprises the PYY[3-36 of any form], comprise the PYY[3-36 that obtains by freeze drying, crystallization, reconstruct, spray-drying and overcritical fluidisation process].

Solid-phase peptide is synthetic can use automatic peptide synthesizer (430A type for example, Applied Biosystems Inc., Foster City, CA) adopt NMP/HOBt (option one) system and add cap tBoc or Fmoc chemistry (referring to Applied Biosystems User ' s Manual for the ABI 430A Peptide Synthesizer, 1.3B version, on July 1st, 1988,6:4970, Applied Biosystems, Inc, Foster City, CA) carry out. Can also utilize Advanced ChemTech Synthesizer (the advanced synthesizer that learns a skill, MPS 350 types, Louisville, Kentucky) assembling. Peptide can adopt for example Waters Delta Prep 3000 systems and C₄, C8 or C18 preparative column (10p, 2.2 * 25cm; Vydac, Hesperia, CA) carry out purifying by RP-HPLC (preparation type and analytic type).

Useful peptides can also adopt recombinant DNA technology, use present methods known in the art preparation in the present invention. Such as referring to Sambrook etc., Molecular Cloning:A Laboratory Manual, the 2nd edition, Cold Spring Harbor (1989). Useful non-peptide compound can prepare by methods known in the art in the present invention. For example, the amino acid of phosphate ester-containing can adopt the methods known in the art preparation with the peptide that contains this amino acid. For example referring to Bartlett and Landen, Biorg Chem.14:356-377 (1986).

Being used for composition of the present invention can provide with the form of composition outside the intestines and stomach that for example are used for injection or transfusion. For example, they can be suspended in the moisture carrier, for example be suspended in pH and be in about 3.0 to about 8.0 the isotonic buffer solution. Useful buffer solution comprises natrium citricum-citric acid and sodium phosphate-phosphoric acid and acetate/acetic buffer solution. Can use the form of storage storehouse or " warehouse " sustained release preparation and after percutaneous injection or transmission, be sent to and reach a few hours or a couple of days in the blood flow in order to will treat the preparation of effective dose.

Because PYY and multiple PYY activator are both sexes, thus they can be with free alkali, use with acid-addition salts or with the form of slaine. Described salt is pharmaceutically useful salt preferably, and these salt will comprise slaine, especially alkali and alkaline earth metal ions salt, for example sylvite or sodium salt. Various pharmaceutically acceptable acid addition salts all can obtain. Be easy to prepare this class product by method well known to those skilled in the art.

The treatment effective dose be appetite-suppressing to those of expected degree for reducing the PYY of nutritional utilization degree or PYY activator. As those skilled in the art can recognize, the therapeutic agent of effective dose will become with many factors, comprise age of patient and body weight, patient's physical condition, blood sugar level, with the body weight level and other factor that obtain.

For the patient of body weight 50kg, effective daily dose of PYY, PYY activator or its mixture appetite-suppressing is that about 1 to 30 μ g was to about 50mg/ days, or about 10 to 30 μ g are to about 20mg/ days, or about 5 to 100 μ g are to about 10mg/ days, or about 5 μ g extremely about 5mg/ days. The PYY of effective dose or PYY activator can be with single dose or broken dose administrations. Dosage can be for about 0.01 to about 1mg/kg/ dosage. The exact dose of using can be determined that by those skilled in the art this depends on the drug effect of PYY, PYY activator or its mixture and depends on individual age, body weight and health. As long as expectation suppresses nutritional utilization degree, food intake, body weight, blood sugar or reduces blood fat, for example when initial symptom occurs or be diagnosed as after obesity, diabetes or the insuline resistance syndrome soon, just should begin medication.

The screening of other PYY activator

Other PYY activator can be identified by adopting the physiology screening method of describing among (for example embodiment 9 and 10 of WO 02/47712 and U.S. Patent Publication No. 2002/0141985) that hereinafter describe or receptors bind detection method known in the art and the embodiment in conjunction with WO 02/47712 and U.S. Patent Publication No. 2002/0141985. With potential PYY activator and PYY or PYY[3-36] activity compare.

Perhaps, in case preferred (Y7) acceptor of one or more PYY-is characterized and clones, just can implement selectable detection and high throughput screening by described in detail below or methods known in the art. The Y7 acceptor is to PYY or PYY[3-36] affinity be higher than them to those acceptors of neuropeptide tyrosine (NPY) affinity. The method that the compound of pyy receptor activity is regulated in screening comprises the existence that makes test compound contact and detect complex compound between this compound and the pyy receptor with pyy receptor. In this class detected, the test part was labeled usually. After suitable incubation, free part separates with the part that exists with combining form, free or not the amount of the label of complexing be particular compound measuring in conjunction with the pyy receptor ability.

Perhaps, can measure the tagged ligand (for example utilize and express membrane-bound Y7 acceptor) of institute's combination.

Can carry out the high throughput screening to the PYY activator with suitable pyy receptor binding affinity. For example, at the synthetic a large amount of different little peptide test compounds of solid matrix. These peptide test compounds are contacted, then flushing with pyy receptor. Then detect the pyy receptor of institute's combination with method well known in the art. The test compound of purifying can also directly be coated on the plate for aforementioned drug screening technology. In addition, if test compound is protein, then can catches this protein and be fixed on the solid carrier by methods known in the art with antibody.

Can use competition screening analytic approach, neutralizing antibody that wherein can specific binding polypeptide of the present invention and test compound be Binding peptide competitively. In the method, antibody can be used for detecting the existence of sharing any peptide of one or more antigenic determinants with the PYY activator. Radiolabeled competitive binding is studied at Lin, the people such as A.H., and Antimicrobial Agents and Chemotherapy 41 (10): 2127-2131 is described in (1997), and its disclosed content is incorporated herein by reference in full.

Transmit immunomodulator compounds

Transmitting immunomodulator compounds can be any compound of describing in the following document: United States Patent (USP) 5,650,386 and 5,866,536 and International Publication No. WO94/23767, WO95/11690, WO95/28920, WO95/28838, WO96/10396, WO96/09813, WO96/12473, 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 these documents all are incorporated herein by reference.

Transmit the nonrestrictive example of immunomodulator compounds and comprise that N-(8-[2-hydroxy benzoyl]-amino) is sad; N-(the 10-[2-hydroxy benzoyl]-amino) capric acid; 8-(2-hydroxyl-4-methoxybenzoyl is amino) is sad; 8-(2,6-protocatechuoyl is amino) is sad; 8-(2-hydroxyl-5-bromobenzene formamido group) is sad; 8-(2-hydroxyl-5-chlorobenzoyl is amino) is sad; 8-(2-hydroxyl-5-iodobenzene formamido group) is sad; 8-(2-hydroxy-5-methyl base benzamido) is sad; 8-(2-hydroxyl-5-fluorine benzamido) is sad; 8-(2-hydroxy-5-methyl oxygen base benzamido) is sad; 8-(3-hydroxyphenoxy) is sad; 8-(4-hydroxyphenoxy) is sad; 6-(2-cyano-benzene oxygen) caproic acid; 8-(2-hydroxyphenoxy) octyl group-diethanol amine; 8-(4-hydroxyphenoxy) caprylate salt; 8-(4-hydroxyphenoxy) caprylate; 8-(2-hydroxyl-4-methoxybenzoyl is amino) is sad; 8-(2-hydroxy-5-methyl oxygen base benzamido)-sad and their salt. Preferred salt includes but not limited to a sodium and disodium salt.

Transmit immunomodulator compounds and can be carboxylic acid or its officinal salt such as sodium salt, with and the form of hydrate and solvate. These salt can be unit price or multivalent salts, such as a sodium salt and disodium salt. These transmit immunomodulator compounds can contain the different counter ion counterionsl gegenions of for example owing to them effect of the Dissolution behaviours of modification carrier being selected.

Transmitting immunomodulator compounds can prepare by methods known in the art, those as describing in detail in aforesaid application open (for example international publication number WO 98/34632, WO 00/07979, WO 01/44199, WO 01/32596, WO 02/20466 and WO 03/045306). SNAC, SNAD and free acid thereof and other salt can prepare by any method known in the art, for example prepare by the method for describing in the U.S. Patent number 5,650,386 and 5,866,536.

The salt that the present invention transmits immunomodulator compounds can prepare by methods known in the art. For example, sodium salt can be dissolved in the ethanol and add sodium hydrate aqueous solution and prepare by transmitting immunomodulator compounds.

Transmitting immunomodulator compounds can be by recrystallization or by coming purifying in one or more solid-state chromatographic stationary phases fractionation independent or series connection. Suitable recrystallization solvent system includes but not limited to acetonitrile, methyl alcohol and oxolane. Fractionation can followingly be carried out: adopt methyl alcohol/normal propyl alcohol mixture to carry out as mobile phase at suitable chromatographic stationary phases such as aluminium oxide; Adopting trifluoroacetic acid/acetonitrile mixture to carry out RP chromatography as mobile phase separates; Carry out ion-exchange chromatography with employing water or suitable buffer solution as mobile phase. When carrying out anion-exchange chromatography, preferably adopt the sodium chloride gradient of 0-500mM.

Transfer system

Composition of the present invention comprises one or more transmission immunomodulator compounds of the present invention and/or one or more PYY and PYY activator. Transmit immunomodulator compounds and PYY and/or PYY agonists in general and before administration, mix the formation administration composition.

Said composition can comprise one or more therapeutic agents that reduces food intake, reduces plasma glucose or change blood plasma lipide, as Diabetes-associated peptide, Diabetes-associated peptide agonist, CCK or CCK agonist, leptin or leptin agonist or exendin or exendin agonist.

Administration composition can be the form of liquid.Solution medium can be water, 25% aqueous solution of propylene glycol or phosphate buffer.Other drug administration carrier comprises Polyethylene Glycol.Solution that can will transmit immunomodulator compounds just for drug solns before administration mixes with the solution of activating agent and prepares.Perhaps, the solution that transmits immunomodulator compounds (or PYY, PYY agonist or its mixture) can be mixed with the PYY or the PYY agonist (or transmitting immunomodulator compounds) of solid form.Also can mix with the form of dry powder with PYY, PYY agonist or its mixture transmitting immunomodulator compounds.Can also mix in preparation process with PYY, PYY agonist or its mixture transmitting immunomodulator compounds.

Can randomly contain additive such as phosphate buffer salt, citric acid, ethylene glycol or other dispersant for drug solns.Stabilization additives can be incorporated in this solution, and preferred concentration is about 0.1-20% (w/v).

Perhaps, this administration composition can be solid form, as tablet, capsule or granule, as powder or wafer.Solid dosage forms can be mixed with PYY, PYY agonist or its mixture of solid form by this chemical compound with solid form and be prepared.Perhaps, solid can obtain by methods known in the art such as lyophilizing (lyophilization), precipitation, crystallization and the solid dispersion solution by chemical compound and PYY, PYY agonist or its mixture.Perhaps, this administration composition can be semi-solid, is the form of gel (gel), paste, colloid, gelinite (gelatin), Emulsion or suspension etc.

Administration composition of the present invention can also comprise one or more enzyme inhibitors.This fermentoid inhibitor comprises but is not limited to chemical compound such as actinonin (actinonin) or table actinonin (epiactinonin) and derivant thereof.Other enzyme inhibitor includes but not limited to aprotinin (Trasylol) and Bowman-Birk inhibitor.

Being used for the PYY of administration composition of the present invention and/or the amount of PYY agonist is the amount of effective therapeutic goal indication.Yet when compositions was used with dosage unit form, this amount can be lower than above-mentioned amount, because dosage unit form may contain a plurality of compositionss of transmission immunomodulator compounds/PYY or PYY agonist or may contain separately effective dose.Therefore, total effective dose can add up unit to be used, and these units totally contain PYY, PYY agonist or its mixture of effective dose.And, those skilled in the art will recognize that the effective dose of PYY, PYY agonist or its mixture will change with multiple factor, comprise body weight level and other factors that patient's age and body weight, patient's body situation, blood sugar level, institute's desire obtain.

Total consumption of PYY or PYY agonist can be determined by method known to those skilled in the art.Yet, because comparing with the compositions that only contains PYY or PYY agonist, compositions of the present invention can more effectively transmit PYY or PYY agonist, therefore can use PYY or the PYY agonist that is less than consumption in dosage unit form in the past or the delivery system to the patient, and still obtain identical blood levels and/or therapeutic effect.

According to an embodiment, be to be enough to the amount of appetite-suppressing to aspiration level with the amount that transmits PYY, PYY agonist or its mixture that agent uses.For the patient of body weight 50kg, effective daily dose of PYY, PYY agonist or its mixture appetite-suppressing normally about 1 μ g of single dose or broken dose form to about 5mg/ days, preferred about 5 μ g extremely about 2mg/ days, more preferably from about 5 μ g to 500 μ g/ days.Preferred dosage form of the present invention contains have an appointment 0.01 PYY to about 10 μ g/kg/ dosage, PYY agonist or its mixture.

The present invention also comprises the PYY, PYY agonist or its mixture that wherein comprise above-mentioned amount and the pharmaceutical composition and the dosage form of at least a transmission agent.

Usually the transmission agent of being convenient to transmit the effective dose of PYY and/or PYY agonist is used with PYY, PYY agonist or its mixture.Usually, the mol ratio that transmits agent and PYY, PYY agonist or its mixture is about 25000: 1 to about 50: 1, preferred about 8000: 1 to about 100: 1, and most preferably from about 4000: 1 to about 300: 1.

Transmission immunomodulator compounds disclosed by the invention is convenient to the transmission of PYY, PYY agonist or its mixture, especially oral, intranasal, Sublingual, duodenum are interior, subcutaneous, oral cavity, colonic, rectum, vagina, mucosa, outside lung, percutaneous, Intradermal, gastrointestinal tract, in intraperitoneal, intravenous, intramuscular and the eye system time, and penetrate blood brain barrier.Compositions of the present invention and dosage unit form can be used through above-mentioned any approach.

Be applied to man-hour when oral, compositions of the present invention and dosage unit form can obtain PYY[3-36 in vivo] the known treatment level, as people such as Batterham, those that enumerate among the Nature 418:650-654 (2002).

Dosage unit form can also comprise any or its combination in excipient, diluent, disintegrating agent, lubricant, plasticizer, coloring agent, spice, odor mask, sugar, sweeting agent, salt and the drug administration carrier, include but not limited to water, 1,2-propylene glycol, ethanol, olive oil or their combination in any.

Chemical compound of the present invention and compositions can be used for the biological or chemical active therapeutic agent is applied to any animal, include but not limited to birds such as chicken; Fish, reptile, mammal such as Rodents, cattle, pig, Canis familiaris L., cat, primates and especially people, and insecticide.

Embodiment

Following examples are used for illustrating without limitation the present invention.Unless otherwise stated, all parts all provide by weight.

PYY[3-36 in the embodiment 1-rat] liquid oral transmit

Be prepared as follows and transmit immunomodulator compounds and peptide YY residue 3-36 (PYY[3-36]) (can obtain) oral raise by force (PO) in deionized water and give drug solns from the Bachem California Inc. of Canadian torrance.

Transmit agent 1 (SNAC) and PYY[3-36] give being prepared as follows of drug solns.SNAC one sodium salt solid is soluble in water.Therefore the pH of this solution needn't regulate pH near 7.5.This SNAC solution of aliquot is mixed with the PYY solution (pH7.5) of aliquot.According to the preparation 100 of this step or 200mg/kg SNAC and 0.1 or 0.5mg/kg PYY[3-36] solution.The final pH of these solution is 7.5.

Transmit agent 2 one sodium salts (SNAD) and PYY[3-36] give being prepared as follows of drug solns.Solid-state SNAD disodium salt is soluble in water.The pH of gained solution is 11.1.By adding HCl (5N) its pH is turned down 7.7 then.Then with the PYY[3-36 of the SNAD solution aliquot of aliquot] solution (pH7.5) mixes.According to the preparation 100 of this step or 200mg/kg SNAD and 0.1 or 0.5mg/kg PYY[3-36] solution.The final pH of these solution changes between 7.5-7.6.

Transmit agent 4-15 one sodium salt and PYY[3-36] give being prepared as follows of drug solns.It is soluble in water that each is transmitted immunomodulator compounds (free acid or a sodium-salt form).Add HCl (5N) as required and NaOH (5N) transfers to about 7.5 with its pH.Then with the transmission agent solution of aliquot and the PYY[3-36 of aliquot] solution (pH7.5) mixes.The transmission agent and the 0.3mg/kg PYY[3-36 that prepare 200mg/kg according to this step] solution.The final pH of these solution is about 7.5.

Typical administration and sampling plan are as follows.With the male Sprague-Dawley rat of body weight 240-320g before test fasting to maximum 24 hours, before using test product through intramuscular injection administration of ketamine to (44mg/kg) and chlorpromazine (1.5mg/kg).Afterwards, use test product by oral raising to anesthetized animal by force.Five animals of administration group are used described one of the drug solns of giving.For oral raise by force (PO), the Rusch 8 French conduits of employing 11cm are suitable for having the 1ml syringe of pipette tip.Through the conduit draw solution, syringe is filled with to drug solns, dry conduit then.Conduit is inserted esophagus, stay the 1cm test tube to pass through incisor.Press syringe plunger to be administered to drug solns.

Collect blood sample continuously through arteria caudalis or cardiac puncture, usually in time=0, collect 15,30,45,60 and 90 minutes the time.Adopt PYY[3-36] and radioimmunoassay (catalog number (Cat.No.) RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont CA) measures blood-serum P YY concentration.With the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (be average serum PYY[3-36] peak concentration ± standard deviation (SD)) be reported in the following table 1.As animal orally give PYY[3-36 only] time, in blood, do not detect tangible PYY[3-36].Also be shown among Fig. 1 and 2 respectively with the result's (± standard deviation) who transmits agent SNAC and SNAD gained.

Table 1. PYY[3-36 in the rat] oral transmission

Transmit agent	Transmit agent dose (mg/kg)	PYY[3-36] dosage (mg/kg)	Volume dose (ml/kg)	Average serum [PYY (3-36)] peak value (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 (nothings)	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

Transmit agent 1 and be N-(8-[2-hydroxy benzoyl]-amino) sad sodium salt (SNAC).

Transmit agent 2 and be N-(10-[2-hydroxy benzoyl]-amino) capric acid one sodium salt (SNAD).

Transmitting agent 4 is the sad sodium salt of 8-(2-hydroxyl-4-methoxybenzoyl amino).

Transmitting agent 5 is the sad sodium salt of 8-(2,6-dihydroxy benzenes formamido group).

Transmitting agent 6 is the sad sodium salt of 8-(2-hydroxyl-5-bromobenzene formamido group).

Transmitting agent 7 is the sad sodium salt of 8-(2-hydroxyl-5-chlorobenzoyl amino).

Transmitting agent 8 is the sad sodium salt of 8-(2-hydroxyl-5-iodobenzene formamido group).

Transmitting agent 9 is the sad sodium salt of 8-(2-hydroxy-5-methyl base benzamido).

Transmitting agent 10 is the sad sodium salt of 8-(2-hydroxyl-5-fluorobenzoyl amino).

Transmitting agent 11 is the sad sodium salt of 8-(2-hydroxy-5-methyl oxygen base benzamido).

Transmitting agent 12 is the sad sodium salt of 8-(3-hydroxyphenoxy).

Transmitting agent 13 is the sad sodium salt of 8-(4-hydroxyphenoxy).

Transmitting agent 14 is 6-(2-cyano-benzene oxygen) caproic acid one sodium salt.

Transmitting agent 15 is 8-(2-hydroxyphenoxy) octyl group-diethanolamine one sodium salt.

Peptide YY[3-36 in embodiment 2 rats] intraperitoneal transmit

Preparation PYY[3-36 in the sterile saline solution (0.9% sodium chloride, pH 7.5)] intraperitoneal give drug solns.Typical administration and sampling plan are as follows.Male with body weight 240-320g

The Sprague-Dawley rat before test fasting to maximum 24 hours, before using test product through intramuscular injection administration of ketamine to (44mg/kg) and chlorpromazine (1.5mg/kg).Afterwards, use test product by peritoneal injection to anesthetized animal.Five animals of administration group are used described one of the drug solns of giving.

Collect blood sample continuously through arteria caudalis or cardiac puncture, usually in time=0, collect 15,30,45,60 and 90 minutes the time.Adopt PYY[3-36] and radioimmunoassay (catalog number (Cat.No.) RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont CA) measures blood-serum P YY concentration.With the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (being average serum PYY peak concentration) is reported in following table 2.The result of gained (± standard deviation) also is shown among Fig. 3.

PYY[3-36 in table 2. rat] intraperitoneal (IP) transmit

Medication	PYY[3-36] dosage (mg/kg)	Volume dose (ml/kg)	Average serum [PYY] peak value (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

Embodiment 3-P of Rats YY[3-36] Peroral solid dosage form transmit

Embodiment 3a.Solid PYY3-36 feeds using of rat to restriction

Use is with the PYY[3-36 of deionized water preparation] storing solution (80mg/ml).

Add the PYY (about 1 μ l) of about 0.08mg/ sheet (about 0.3mg/kg) and mix with about 13.5 or the transmission agent of about 27mg/ sheet (about 50 or 100mg/kg).With Natoli Engineering Company, the upper punch of the Carver 4350 manual tablet machine that have Caplet shape mould that Inc. sells, following dashing and punch die magnesium stearate (0.1%) processing.With about 13.58 or the mixed-powder of about 27.08mg input punch die and under about 1000PSI bar pressure, be prepared into the pellet shapes tablet.Gained solid dosage forms its size when for 27.08mg is about No. 9 capsular sizes of standard (the about 2.65mm of diameter is about 8.40mm), when being the about 2.65mm of diameter when the 13.58mg solid and being about 4.20mm.

With male Sprague Dawley rat (the about 280g of about 260-) overnight fasting, use standard C O then ₂The suction technology was anaesthetized about 10 to 30 seconds, made it to be in narcotism approximately less than one minute, preferred about 10 seconds to about 30 seconds.

Use the oral administration pipe.Delivery tube inserted in the rat mouth and carefully insert extremely about 15cm of about 8cm along pharynx and the esophagus of rat, this depends on the body weight (about usually 11cm) of rat.By the plunger of pressing the oral administration pipe solid dosage forms is sent to terminal esophagus and/or gastric.

Collect blood sample continuously through arteria caudalis or cardiac puncture, perhaps get blood by posterior orbit in this case, usually in time=0, collect 15,30,60 and 90 minutes the time.Adopt PYY[3-36] and radioimmunoassay (catalog number (Cat.No.) RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont CA) measures blood-serum P YY concentration.With the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (be average serum PYY[3-36] peak concentration) is reported in following table 3.

Table 3. The restriction rat feeding in PYY[3-36] oral transmission

Transmit agent	Medication	Transmit agent dose (mg/kg)	PYY[3-36] dosage (mg/kg)	Average serum [PYY] peak value (pg/ml) ± SD
					1	Oral, solid administration, 1 of every animal	100	0.3	830.24±341.32
1	Oral, solid administration, 1 of every animal	50	0.3	511.5±493.5
					2	Oral, solid administration, 1 of every animal	100	0.3	512.4±484.2
2	Oral, solid administration, 1 of every animal	50	0.3	536.3±424.7
					7	Oral, solid administration, 1 of every animal	100	0.3	1064.18±363.8
7	Oral, solid administration, 1 of every animal	50	0.3	725.96±110.78
					7	It is oral., solid administration, 1 of every animal	100	0	14.35±19.71
16	Oral, solid administration, 1 of every animal	100	0.3	1294.2±351.4
					16	Oral, solid administration, 1 of every animal	100	0.3	1560±883.4
16	Oral, solid administration, 1 of every animal	100	0.3	980.7±49.7

16	Oral, solid administration, 1 of every animal	50	0.3	617.4±272.1
					16	Oral, solid administration, 1 of every animal	50	0.3	988.7±288.2
16	Oral, solid administration, 1 of every animal	50	0.3	847.3±152
					16	Oral, solid administration, 1 of every animal	75	0.3	754.7±539.8
16	Oral, solid administration, 1 of every animal	25	0.1	274.1±118.6
					16	Oral, solid administration, 1 of every animal	50	0.1	249.3±144.0
16	Oral, solid administration, 1 of every animal	25	0.3	953.8±660.3
					16	Oral, solid administration, 1 of every animal	25	0.5	494.6±318.2
16	Oral, solid administration, 1 of every animal	50	0.5	715±208.0
					16	Oral, solid administration, 1 of every animal	100	0.5	852.2±1119
16	Oral, solid administration, 1 of every animal	50	1	739.6±409.6
					2 and 16	Oral, solid administration, 1 of every animal	25 and 25	0.3	791.22±453.4
2 and 16	Oral, solid administration, 1 of every animal	50 and 50	0.3	644.18±595.4
					16	Oral, solid administration, 1 of every animal	50	0.3	421.08±389.2
16	Oral, solid administration, 1 of every animal	100	0.3	939.88±166.61
					17	Oral, solid administration, 1 of every animal	100	0.3	897.18±549.5
17	Oral, solid administration, 1 of every animal	50	0.3	581.62±236.94

18	Oral, solid administration, 1 of every animal	100	0.3	1216.13±661.31
					18	Oral, solid administration, 1 of every animal	50	0.3	940.33±1090.65
Contrast	Oral, solid administration, 1 of every animal	10mg/kg mannitol does not have the agent of transmission	0.3	5.55±12.40
					19	Oral, solid administration, 1 of every animal	100	0.3	728.4±364.4
4	Oral, solid administration, 1 of every animal	100	0.3	1821.82±1513.84
					9	Oral, solid administration, 1 of every animal	100	0.3	1309.8±836.33
10	Oral, solid administration, 1 of every animal	50	0.3	897.18±549.5
					20	Oral, solid administration, 1 of every animal	100	0.3	695.8±274.3
11	Oral, solid administration, 1 of every animal	100	0.3	2330.63±963.7

Transmit agent 16 and be N-(10-[2-hydroxy benzoyl]-amino) capric acid disodium salt (SNAD).

Transmitting agent 17 is the sad disodium salt of 8-(4-hydroxyphenoxy).

Transmitting agent 18 is 8-(4-hydroxyphenoxy) caprylate one sodium salt.

Transmitting agent 19 is the sad disodium salt of 8-(2-hydroxyl-4-methoxybenzoyl amino).

Transmitting agent 20 is the sad disodium salt of 8-(2-hydroxy-5-methyl oxygen base benzamido).

Mannitol is as placebo.

Embodiment 3b.Solid PYY[3-36] using unrestricted nursing rat

Except before using solid dosage forms, rat not being taked the food restriction, press description among the embodiment 3a to rat acceptance by PYY[3-36] and the solid oral dosage form formed of carrier.In the blood-serum P YY concentration of every animal of each time point determining, with the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (be average serum PYY[3-36] peak concentration ± standard deviation (SD)) is reported in following table 4.

Table 4. PYY[3-36 in the unrestricted rat feeding] oral transmission

Transmit agent	Medication	Transmit agent dose (mg/kg)	PYY[3-36] dosage (mg/kg)	Average serum [PYY] peak value (pg/ml) ± SD
					16	Oral, solid administration, 1 of every animal	50	0.3	1101±1197
16	Oral, solid administration, 1 of every animal	100	0.3	1011.5±1287
					16	Oral, solid administration, 1 of every animal	100	0.5	1735.6±1108

Embodiment 3c.Micro chip uses in the restriction nursing rat

With male Sprague Dawley rat overnight fasting.Contain PYY[3-36 by physical mixed and compacting preparation] and the micro chip (the about 2.5mm of diameter) of SNAD, be applied to rat by oral raising by force then.With radioimmunoassay method blood-serum P YY[3-36] level.Use contain respectively 0.3 and the PYY[3-36 of 100mg/kg (body weight)] and a slice micro chip of SNAD after, blood-serum P YY[3-36] increase to 940 ± 74pg/ml (n=5, mean value s.e.m.), and remain on and reach 90 minutes on the baseline values.When using PYY[3-36 separately] or do not detect blood-serum P YY[3-36 during SNAD] variation.

Result in 90 minute testing time as shown in Figure 6.

Peptide YY in the embodiment 4-macaque (Rhesus Monkey) (PYY[3-36] the Peroral solid dosage form transmission

Add the PYY pressed powder of about 1mg/ sheet gradually and mix with 50 or 100mg/ sheet transmission agent.With Natoli Engineering Company, the upper punch of the manual tablet machine of the Carver4350 that has Caplet shape mould of Inc. sale, following dashing and punch die magnesium stearate (0.1%) processing.With about 51 or the mixed-powder of about 101mg input punch die and under about 1000PSI bar pressure, be prepared into the pellet shapes tablet.The gained solid dosage forms is the about 3mm of its diameter and high about 1mm when for the 51mg solid, is the about 3mm of diameter and high about 2mm when for the 101mg solid.

For each dosage level, before test,, recover feed after about 2 hours in the solid administration with 2 male and 2 female macaque overnight fastings of heavy 3.5-5.0kg.Before and after administration, during 30 minutes, except that the water that is used for administration, stop to feed water.

Use pellet gun that each solid dosage forms is sent to the rear portion, oral cavity.After solid dosage forms discharges, give the 5ml reverse osmosis water to the oral cavity so that swallow.After the transmission, check that the oral cavity is to guarantee that solid is swallowed.

Collect blood sample (about 1.3ml) continuously from femoral vein, arm vein or saphena, after time=0 (before the administration) and administration, collect 10,20,30,45,60,90,150,240 and 360 minutes the time usually.Sample is placed serum separator tube, and at room temperature placed 30-45 minute so that it solidifies.Then that sample is centrifugal 10 minutes in about 2-8 ℃ under 2500rpm.With the gained serum transfers in vitro and place on the dry ice, then-70 ± 10 ℃ of following chilled storages to detecting.Adopt PYY[3-36] and radioimmunoassay (catalog number (Cat.No.) RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont CA) measures blood-serum P YY concentration.With the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (be average serum PYY[3-36] peak concentration ± standard deviation) is reported in following table 4.This result (± standard deviation) also is shown among Fig. 5.

Table 4. The oral transmission of PYY in the macaque

Transmit agent	Medication	Transmit agent dose (mg/ sheet)	PYY[3-36] dosage (mg/ sheet)	The dosage of every animal: transmit agent (mg)/PYY[3-36] (mg)	Average serum [PYY] peak value (pg/ml) ± SD
						1	Oral, solid administration, 1 of every animal	50	1	50/1	969±60.72
1	Oral, solid administration, 1 of every animal	50	1	100/2	1030.9± 76.88
						1	Oral, solid administration, 1 of every animal	100	1	100/1	757.8± 441.02

Transmit agent 1 and be N-(8-[2-hydroxy benzoyl]-amino) sad sodium salt (SNAC).

The Orally administered PYY[3-36 of embodiment 5-] to the influence of food intake in 4 hours

PYY[3-36 with deionized water preparation] storing solution (80mg/ml) is used to prepare PYY[3-36] tablet.

The PYY[3-36 that adds about 0.132mg/ sheet (about 0.5mg/kg)] (about 1.7 μ l) and mix with the transmission agent SNAD of about 27mg/ sheet (100mg/kg).To have the upper punch of the Carver 4350 manual tablet machine (can be from Natoli Engineering Company, Inc. obtains) of Caplet shape mould, following dashing and punch die magnesium stearate (0.1%) processing.Mixing PYY[3-36 with about 27.132mg]/SNAD powder input punch die and under about 1000PSI bar pressure, be prepared into the pellet shapes tablet.The size of gained solid dosage forms is about No. 9 capsular sizes of standard (the about 2.65mm of diameter is about 8.40mm).

Placebo tablet only contains SNAD, about 27mg/ sheet (100mg/kg), in kind preparation.

Male Sprague Dawley rat (about 260 to about 280g) fasting 24 hours before administration.Every rat gives a slice PYY[3-36]/SNAD tablet or a slice placebo tablet.

Use the oral administration pipe.Delivery tube inserted in the rat mouth and carefully insert extremely about 15cm of about 8cm along pharynx and the esophagus of rat, this depends on the body weight (about usually 11cm) of rat.By the plunger of pressing the oral administration pipe solid dosage forms is sent to terminal esophagus and/or gastric.Do not use anesthetis during administration.

Take by weighing food and after administration, gave rat in one hour.After four hours, remove food and weigh.Measure the quantity of food that consumes according to the food weight difference.

With the 4 hours accumulative total food intakes of gram expression (meansigma methods ± s.e.m.) as table 5 and shown in Figure 7.Double asterisk is represented P＜0.01.

Table 5. Food intake in 4 hours

Group	Food intake (g) in 4 hours	Standard deviation	n
				PYY[3-36]/SNAD	4.09	0.33	9
Placebo	6.69	0.76	9

As above harmony in the exterior is shown in Figure 7, accepts a slice PYY[3-36] food that rat consumed of tablet significantly is less than the rat of accepting a slice placebo tablet.

The Orally administered PYY[3-36 of embodiment 6-] handle the influence of weight increase and food intake after 7 days

PYY[3-36 with deionized water preparation] storing solution (110mg/ml) is used to prepare PYY[3-36] tablet.

Contain about 0.11mg/ sheet (about 0.5mg/kg) PYY[3-36 according to the step preparation of describing among the embodiment 6] and the microspheroidal tablet of about 16.5mg/ sheet (75mg/kg) transmission agent SNAD.

Placebo tablet only contains SNAD, and about 16.5mg/ sheet (75mg/kg) is pressed the step preparation that embodiment 6 describes equally.

Give a slice PYY[3-36 to male Sprague Dawley rat (about 220g)] tablet or a slice placebo tablet, every day twice, totally 7 days.Before administration, rat is used standard C O ₂The suction technology was anaesthetized about 10 to 30 seconds, made it to be in narcotism approximately less than one minute, preferred about 10 seconds to about 30 seconds.Before administration, remove food and recover after 30 minutes in administration.

Use the oral administration pipe.Delivery tube inserted in the rat mouth and carefully insert extremely about 15cm of about 8cm along pharynx and the esophagus of rat, this depends on the body weight (about usually 11cm) of rat.By the plunger of pressing the oral administration pipe solid dosage forms is sent to terminal esophagus and/or gastric.

Per 24 hours weight difference mensuration food consumptions by food that gives each rat and remaining food.Surveyed each rat body weight in per 24 hours.

The result is shown in table 6 and Fig. 8 a and 8b.Weight increase during treatment in 7 days (with the gram expression) is shown in Fig. 8 a.P＜0.05 represented in asterisk.Accumulative total food intake during treatment in 7 days (with the gram expression) (meansigma methods ± s.e.m.) shown in Fig. 8 b.Double asterisk is represented P＜0.01.

Weight increase during the table 6.7 day treatment

Group	Weight increase (g) after the treatment in 7 days	Standard error	Food intake (g) during the treatment in 7 days	Standard error	n
						PYY[3-36]/SNAD	12	4	148	5	7
Placebo	23	2	169	4	7

As above shown in harmony in the exterior Fig. 8 a and the 8b, compare, accept PYY[3-36 with the rat of accepting placebo]/weight increase and the food consumption of the rat of SNAD is significantly less.PYY[3-36] to not influence of gastric emptying.When research end in 7 days, the gastric quantity of food is few and suitable with its amount of treatment treated animal for placebo group.After research finishes, do not observe pathology or other phenomenon at gastrointestinal tract when carrying out gross necropsy.

Embodiment 7-SNAD disodium salt and PYY[3-36] dosage form and PYY[3-36] the intraperitoneal administration

Liquid dosage form is prepared as follows.PYY[3-36 with the deionized water preparation] storing solution (80mg/ml).By the preparation soluble in water of SNAD disodium salt is transmitted the liquid solution of agent.The pH of gained SNAD disodium salt solution is about 10.With the SNAD disodium salt solution of aliquot and the PYY[3-36 of aliquot] solution (pH about 8) mixes.Contain about 100-200mg/kg SNAD disodium salt and about 0.3-1mg/kg PYY[3-36 by the preparation of this step] liquid dosage form.The final pH of this liquid dosage form is about 9-10.

Solid dosage forms is prepared as follows.Add the PYY (about 1 μ l) of about 0.08mg/ sheet (about 0.3mg/kg) and mix with about 13.5 or the transmission agent of about 27mg/ sheet (about 50 or 100mg/kg).With NatoliEngineering Company, the upper punch of the Carver 4350 manual tablet machine that have Caplet shape mould that Inc. sells, following dashing and punch die magnesium stearate (0.1%) processing.With about 13.58 or the mixed-powder of about 27.08mg input punch die and under about 1000PSI bar pressure, be prepared into the pellet shapes tablet.Gained solid dosage forms its size when for 27.08mg is about No. 9 capsular sizes of standard (the about 2.65mm of diameter is about 8.40mm), when being the about 2.65mm of diameter when the 13.58mg solid and being about 4.20mm.

With male Sprague Dawley rat (the about 280g of about 260-) overnight fasting, use standard C O then ₂The suction technology was anaesthetized about 10 to 30 seconds, made it to be in narcotism approximately less than one minute, preferred about 10 seconds to about 30 seconds.

Use the oral administration pipe.Delivery tube inserted in the rat mouth and carefully insert extremely about 15cm of about 8cm along pharynx and the esophagus of rat, this depends on the body weight (about usually 11cm) of rat.By the plunger of pressing the oral administration pipe solid dosage forms is sent to terminal esophagus and/or gastric.

Collect blood sample continuously through arteria caudalis or cardiac puncture, perhaps get blood by posterior orbit in this case, usually in time=0, collect 15,30,60 and 90 minutes the time.Adopt PYY[3-36] and radioimmunoassay (catalog number (Cat.No.) RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont CA) measures blood-serum P YY concentration.With the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (being average serum PYY peak concentration) is reported in following table 7.

Table 7. PYY[3-36 in the rat] transmission

Medication	SNAD disodium salt dosage (mg/ sheet)	PYY (3-36) dosage (mg/ sheet)	Average serum [PYY] peak value (pg/ml) ± SD
				Oral, solid administration, 1 of every animal	100	0.5	1518.36±464.98
Oral, solid administration, 1 of every animal	100	0.5	3685.8±880.43
				Oral, the liquid administration	150	0.5	2215.6±1543.01
Oral, the liquid administration	150	1	4697.8±3009.48
				Oral, the liquid administration	150	1	2432.4±1702.55
Oral, the liquid administration	100	0.3	1008.2±145.16

Oral, the liquid administration	200	0.3	805.67±583.78
				Oral, the liquid administration	200	0	0
Peritoneal injection	0	0.05	3671±244.7
				Peritoneal injection	0	0.05	6292.8±1365.1

Embodiment 8-peptide YY (PYY[3-36]), the Peroral solid dosage form in the stump-tailed macaque (Cynomoleus monkey) Transmit

Capsule is prepared as follows.Add about 1mg PYY pressed powder gradually and mix with 50 or 100mgSNAD.Fill this mixture with No. 2 capsule shells that clean metal medicine spoon will be weighed in advance.Final capsule is weighed once more and determine to contain＞98% the mixture that is shifted.

Preparation tablets is as follows.Add the PYY pressed powder of about 1mg/ sheet gradually and mix with the transmission agent of about 50mg/ sheet.With Natoli Engineering Company, the upper punch of the Carver 4350 manual tablet machine that have Caplet shape mould that Inc. sells, following dashing and punch die magnesium stearate (0.1%) processing.The mixed-powder of about 51mg is imported punch die and be prepared into the pellet shapes tablet under about 1000PSI bar pressure.The about 3mm of gained solid dosage forms diameter and high about 1mm.

For each dosage level, before test,, recover feed after about 2 hours in the solid administration with 2 male and 2 female stump-tailed macaque overnight fastings of heavy 3.5-5.0kg.Before and after administration, during 30 minutes, except that the water that is used for administration, stop to feed water.

Use strong feeding tube that each solid dosage forms is directly delivered in the stomach.By blowing capsule or tablet are penetrated.

Collect blood sample (about 1.3ml) continuously from femoral vein, arm vein or saphena, after time=0 (before the administration) and administration, collect 10,20,30,45,60,90,150,240 and 360 minutes the time usually.Sample is placed serum separator tube, and at room temperature placed 30-45 minute so that it solidifies.Then that sample is centrifugal 10 minutes in about 2-8 ℃ under 2500rpm.With the gained serum transfers in vitro and place on the dry ice, then-70 ± 10 ℃ of following chilled storages to detecting.Adopt PYY[3-36] and radioimmunoassay (catalog number (Cat.No.) RK-059-02, Phoenix Pharmaceuticals, Inc., Belmont CA) measures blood-serum P YY concentration.With the results averaged of each time point by each treated animal acquisition.Maximum in these meansigma methodss (being average serum PYY peak concentration) is reported in following table 8.

Table 8. PYY[3-36 in the stump-tailed macaque] result that transmits of Peroral solid dosage form

Chemical compound	Medication	Chemical compound dosage (mg/ sheet)	PYY (3-36) dosage (mg/ sheet)	Average serum [PYY] peak value (pg/ml) ± SD
					SNAD	The oral cavity, solid administration, every animal 1 capsules	50	1	419.68± 320.44
SNAD	The oral cavity, solid administration, every animal 1 capsules	100	1	432.02± 309.47
					SNAD	The oral cavity, solid administration, 1 of every animal	50	1	925.86± 794.03

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Above-mentioned patent, application, test method and publication are incorporated herein by reference in full at this.

According to above-mentioned detailed description, multiple alternatives of the present invention itself can be prompted to those skilled in the art.All these conspicuous variations are all within the scope of the abundant expection of 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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