WO2022268213A1 - 含glp-1化合物的药物组合物 - Google Patents

含glp-1化合物的药物组合物 Download PDF

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WO2022268213A1
WO2022268213A1 PCT/CN2022/101272 CN2022101272W WO2022268213A1 WO 2022268213 A1 WO2022268213 A1 WO 2022268213A1 CN 2022101272 W CN2022101272 W CN 2022101272W WO 2022268213 A1 WO2022268213 A1 WO 2022268213A1
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Prior art keywords
ethoxy
glp
peptide
arg34
acetyl
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PCT/CN2022/101272
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English (en)
French (fr)
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张一宁
于永
陈伟
纪方舟
张蔓
王永春
薛方凯
牛江红
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甘李药业股份有限公司
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Priority to EP22827705.9A priority Critical patent/EP4360645A1/en
Priority to CN202280044104.5A priority patent/CN117561072A/zh
Publication of WO2022268213A1 publication Critical patent/WO2022268213A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the invention discloses a pharmaceutical composition of a GLP-1 compound and a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), a preparation method of the pharmaceutical composition and its application in medicine the use of.
  • NAC N-(8-(2-hydroxybenzoyl)amino)octanoic acid
  • Glucagon-like peptide 1 (GLP-1) and its analogs and derivatives are very effective in the treatment of type 1 and 2 diabetes, however high clearance limits the effectiveness of these compounds.
  • GLP-1 glucagon-like peptide 1
  • WO99/43708 discloses GLP-1(7-35) and GLP-1(7-36) derivatives with a lipophilic substitution attached to the C-terminal amino acid residue.
  • WO00/34331 discloses acylated GLP-1 analogs.
  • WO00/69911 discloses activated insulinotropic peptides for injection into a patient.
  • GLP-1 drugs include, for example: the natural GLP-1 analog Exenatide administered twice a day; Liraglutide and Lixisenatide administered once a day (Lixisenatide); and semaglutide (Semaglutide), albiglutide (Abiglutide), dulaglutide (D ⁇ laglutide), polyethylene glycol loxenatide, etc. administered once a week.
  • Most of the above-mentioned products are injections. This way of delivering GLP-1 compounds by subcutaneous injection will bring a lot of discomfort to patients, especially the treatment plan that requires multiple injections a day, which will reduce patient compliance; The use requires high technical proficiency of the injector, the preparation process is complicated, and the production cost is high.
  • WO2013/139694 discloses a salt pharmaceutical composition of GLP-1 peptide and N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC) and a preparation method thereof, which uses GLP-1 peptide and NAC
  • the salt is granulated separately, and then mixed and pressed into tablets, but the separate granulation is not conducive to the thorough mixing of the GLP-1 peptide and the NAC salt, and is not conducive to obtaining a pharmaceutical composition with better mixing uniformity.
  • semaglutide tablets an oral GLP-1 analog product
  • SNAC N-(8-(2-hydroxybenzoyl)amino)caprylic acid
  • NAC N-(8-(2-hydroxybenzoyl)amino)caprylic acid
  • semaglutide may have unknown and various potential side effects in the human body compared to natural amino acids, and clinical studies have proved that its bioavailability is about 1%, which is still There is room for further improvement.
  • the present invention provides a new GLP-1 pharmaceutical composition.
  • the new GLP-1 pharmaceutical composition has better or equivalent drug efficacy or efficacy, better or equivalent weight loss effect, longer or equivalent half-life, Faster or equivalent dissolution rate, higher or equivalent bioavailability, better or equivalent physical and chemical stability.
  • the pharmaceutical composition provided by the first aspect of the present invention comprises a GLP-1 compound and a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid (NAC), wherein the GLP-1 compound is formula B A compound, or a pharmaceutically acceptable salt, amide or ester thereof:
  • G1 is a GLP-1 analog with Arg at position 34 corresponding to GLP-1(7-37) (SEQ ID NO: 1) and Ala or Gly at position 8, [Acy-(L1) r ⁇ (L2) q ] is a substituent attached to the epsilon amino group of the Lys residue at position 26 of the GLP-1 analog, wherein
  • r is an integer of 1-10, and q is an integer of 0 or 1-10;
  • Acy is an aliphatic diacid comprising 20-24 carbon atoms, wherein formally the hydroxyl group has been removed from one of the carboxyl groups of said aliphatic diacid;
  • L1 is an amino acid residue selected from the group consisting of ⁇ Glu, ⁇ Glu, ⁇ Asp, ⁇ Asp, ⁇ -D-Glu, ⁇ -D-Glu, ⁇ -D-Asp or ⁇ -D-Asp;
  • L2 is a neutral, alkylene glycol-containing amino acid residue
  • G1 is [Gly8, Arg34]GLP-1-(7-37) peptide (SEQ ID NO:2) or [Arg34]GLP-1-(7-37) peptide (SEQ ID NO:3 ), preferably the [Gly8, Arg34]GLP-1-(7-37) peptide.
  • r is 1, 2, 3, 4, 5 or 6, preferably r is 1, 2, 3 or 4, preferably r is 1 or 2, preferably r is 1.
  • q is 0, 1, 2, 3, 4, 5, 6, 7 or 8, preferably, q is 0, 1, 2, 3 or 4, more preferably, q is 0, 1 , or 2.
  • Acy is an aliphatic diacid comprising 20-23 carbon atoms, preferably Acy is an aliphatic diacid comprising 20, 21, or 22 carbon atoms, wherein formally the hydroxyl group has been changed from the One of the carboxyl groups of the aliphatic diacid is removed.
  • L2 is: -HN-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -CO-, -HN-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CO-, -HN-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CO-, -HN-(CH 2 ) 2 -O-( CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 )2-O-
  • L1 is selected from ⁇ Glu or ⁇ Asp, preferably L1 is ⁇ Glu.
  • Acy is HOOC-(CH 2 ) 18 -CO-, HOOC-(CH 2 ) 19 -CO-, HOOC-(CH 2 ) 20 -CO-, HOOC-(CH 2 ) 21 - CO- or HOOC-(CH 2 ) 22 -CO-, preferably, Acy is HOOC-(CH 2 ) 18 -CO-, HOOC-(CH 2 ) 20 -CO- or HOOC-(CH 2 ) 22 -CO -.
  • Acy, L1, and L2 in formula (B) are sequentially linked by an amide bond, and the C-terminus of L2 is linked to the epsilon amino group of the Lys residue at position 26 of the GLP-1 analogue.
  • the GLP-1 compound in the pharmaceutical composition of the first aspect of the present invention is selected from the following compounds:
  • the GLP-1 compound in the pharmaceutical composition of the first aspect of the present invention is selected from the following compounds:
  • the GLP-1 pharmaceutical composition of the present invention comprises the GLP-1 compound of the above-mentioned formula (B) as an active ingredient, compared with the semaglutide tablets already on the market, it has unexpected Better or equivalent potency or efficacy, better or equivalent weight loss effect, longer or equivalent half-life, faster or equivalent dissolution rate, higher or equivalent bioavailability, better or equivalent physical chemical stability.
  • the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is N-(8-(2-hydroxybenzoyl)amino)octanoic acid sodium salt (SNAC ).
  • the composition comprises one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipient is one or more selected from glidants, binders, fillers, disintegrants and lubricants.
  • the glidant is selected from talc, and colloidal silicon dioxide, preferably colloidal silicon dioxide.
  • the binder is selected from povidone, copovidone and hydroxypropyl cellulose, preferably povidone, more preferably povidone K90.
  • the filler is selected from microcrystalline cellulose, cellulose powder, calcium hydrogen phosphate, corn starch, pregelatinized starch, anhydrous lactose, mannitol, erythritol, sucrose, sorbose One or more of alcohol, calcium phosphate, and dextrin, preferably microcrystalline cellulose or anhydrous lactose, more preferably microcrystalline cellulose.
  • the lubricant is selected from one or more of magnesium stearate, magnesium lauryl sulfate, stearic acid, sodium stearyl fumarate, glyceryl tribehenate, preferably for magnesium stearate.
  • Binder preferably the binder is selected from povidone, copovidone and hydroxypropyl cellulose, preferably povidone, more preferably povidone K90.
  • ⁇ comprising about 5%-40% (w/w), preferably about 10%-35% (w/w), preferably about 10%-30% (w/w), preferably about 10% -25% (w/w), preferably about 13%-17% (w/w), preferably about 13% (w/w), about 14% (w/w), about 15% (w/w), About 16% (w/w), about 17% (w/w), or about 20% (w/w) filler selected from microcrystalline cellulose, cellulose powder, calcium hydrogen phosphate, One or more of corn starch, pregelatinized starch, anhydrous lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate, and dextrin, preferably microcrystalline cellulose or anhydrous lactose , more preferably microcrystalline cellulose.
  • lubricant selected from magnesium stearate, lauryl sulfate One or more of magnesium, stearic acid, sodium stearyl fumarate, glyceryl tribehenate, preferably magnesium stearate.
  • glidant is selected from talcum powder and colloidal silicon dioxide, preferably colloidal silicon dioxide.
  • the GLP-1 compound is selected from N- ⁇ 26 -[2-(2-[2-(2-[2-(2-[2-(2-[4-(19-carboxydeca Nonalkanoylamino)-4(S)-carboxybuty)
  • binder is selected from povidone, copolyvinyl Ketone and hydroxypropyl cellulose, preferably povidone, more preferably povidone K90.
  • a filler selected from microcrystalline cellulose, cellulose powder, calcium hydrogen phosphate, corn starch, pregelatinized starch, anhydrous lactose, nectar One or more of alcohol, erythritol, sucrose, sorbitol, calcium phosphate, and dextrin, preferably microcrystalline cellulose or anhydrous lactose, more preferably microcrystalline cellulose.
  • a lubricant selected from the group consisting of magnesium stearate, magnesium lauryl sulfate, stearic acid, sodium stearyl fumarate, and glyceryl tribehenate or more, preferably magnesium stearate.
  • a glidant selected from talc comprising about 1-50 mg, preferably about 1-40 mg, preferably about 1-30 mg, preferably about 2-20 mg, preferably about 3-20 mg, preferably about 5-15 mg, preferably about 5-10 mg, preferably About 8 mg of a glidant selected from talc, and colloidal silicon dioxide, preferably colloidal silicon dioxide.
  • the pharmaceutical composition is in the form of tablets, granules or capsules, preferably, the pharmaceutical composition is in the form of tablets.
  • the composition has a hardness of less than about 130N, preferably about 80-130N, preferably about 90-130N, preferably about 100-125N, more preferably about 110-120N.
  • the particle size D90 of the composition is preferably no more than about 200 ⁇ m, preferably no more than about 130 ⁇ m, preferably about 15-130 ⁇ m, more preferably about 15-50 ⁇ m.
  • the pharmaceutical composition protected by the first aspect of the present invention contains the following ingredients:
  • the total weight of the pharmaceutical composition is about 150-1000 mg, preferably about 175-1000 mg, preferably about 200-800 mg, preferably about 400 mg-500 mg, preferably about 400 mg, about 403 mg, about 405 mg, about 408 mg, about 413 mg, about 418 mg, about 423 mg, about 428 mg, about 433 mg, about 438 mg, about 443 mg, about 448 mg, about 455 mg, about 500 mg, about 600 mg, or about 800 mg.
  • the second aspect of the present invention provides a preparation method, which is used to prepare the pharmaceutical composition provided by the first aspect of the present invention.
  • the preparation method comprises the step of one-time granulation after mixing the GLP-1 compound and the salt of NAC.
  • the preparation method comprises mixing the salt of NAC with a lubricant and/or a glidant prior to mixing the salt of NAC with the GLP-1 compound.
  • the preparation method comprises:
  • the GLP-1 compound is selected from N- ⁇ 26 -[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino) -4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8, Arg34]GLP-1-(7-37) peptide,
  • the salt of NAC is SNAC;
  • the binder is selected from povidone, copovidone and hydroxypropyl cellulose, preferably povidone, more preferably povidone K90; and/or
  • the filler is selected from microcrystalline cellulose, cellulose powder, calcium hydrogen phosphate, corn starch, pregelatinized starch, anhydrous lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate, and paste
  • microcrystalline cellulose preferably microcrystalline cellulose or anhydrous lactose, more preferably microcrystalline cellulose.
  • the lubricant is selected from one or more of magnesium stearate, magnesium lauryl sulfate, stearic acid, sodium stearyl fumarate, glyceryl tribehenate, preferably Magnesium stearate; and/or
  • the glidant is selected from talc, and colloidal silicon dioxide, preferably colloidal silicon dioxide.
  • the pharmaceutical composition of the present invention as described above is used as a medicine.
  • the above-mentioned pharmaceutical composition of the present invention is used for treating or preventing hyperglycemia, diabetes, and/or obesity.
  • the method for treating or preventing hyperglycemia, diabetes, and/or obesity comprises administering an effective amount of the above-mentioned pharmaceutical composition of the present invention.
  • Figure 1a shows the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on KM mice.
  • Figure 1b shows the AUC of the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on KM mice correspondingly to Figure 1a.
  • Figure 1c shows the control effect of a pharmaceutical composition comprising Compound 5 and SNAC, a pharmaceutical composition comprising semaglutide and SNAC, and a vehicle on the food intake of KM mice.
  • Figure 2a shows the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on db/db mice.
  • Figure 2b shows the AUC of the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on db/db mice correspondingly to Figure 2a.
  • Figure 3a shows the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on SD rats.
  • Figure 3b shows the AUC of the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on SD rats correspondingly to Figure 3a.
  • Figure 4a shows the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on ICR mice.
  • Figure 4b shows the AUC of the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, the pharmaceutical composition comprising semaglutide and SNAC, and the vehicle on ICR mice correspondingly to Figure 4a.
  • Fig. 5a shows the hypoglycemic effect of the title compound of Example 5 of the present invention, the title compound of Example 2 and vehicle on Kkay mice.
  • Figure 5b shows the AUC of the hypoglycemic effect of the title compound of Example 5 of the present invention, the title compound of Example 2 and the vehicle on Kkay mice corresponding to Figure 5a.
  • Figure 5c shows the HbA1c-lowering effect of the title compound of Example 5 of the present invention, the title compound of Example 2 and vehicle on Kkay mice.
  • Figure 6a shows the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, and the vehicle on db/db mice or normal mice.
  • Figure 6b shows the AUC of the hypoglycemic effect of the pharmaceutical composition comprising Compound 5 and SNAC, and the vehicle on db/db mice or normal mice correspondingly to Figure 6a.
  • Figure 7a shows the hypoglycemic effect of the pharmaceutical composition comprising compound 5 and SNAC, and the vehicle on db/db mice.
  • Figure 7b shows the AUC of the hypoglycemic effect of the pharmaceutical composition comprising Compound 5 and SNAC, and the vehicle on db/db mice corresponding to Figure 7a.
  • Figure 7c shows the body weight reducing effect of the pharmaceutical composition comprising compound 5 and SNAC, and the vehicle on db/db mice.
  • Figure 7d shows the food intake inhibitory effect of the pharmaceutical composition comprising compound 5 and SNAC, and vehicle on db/db mice.
  • Figure 8 shows the body weight control effect of the pharmaceutical composition comprising compound 5 and SNAC, and the vehicle on SD rats.
  • GLP-1 analogue or “analogue of GLP-1” refers to a peptide or compound that is a variant of human glucagon-like peptide-1 (GLP-1(7-37)), wherein One or more amino acid residues of GLP-1 (7-37) are replaced, and/or one or more amino acid residues are deleted, and/or one or more amino acid residues are added.
  • sequence of GLP-1(7-37) is shown in SEQ ID NO: 1 in the sequence listing.
  • a peptide having the sequence set forth in SEQ ID NO: 1 may also be referred to as "native" GLP-1 or "native" GLP-1 (7-37).
  • the amino acid residue numbering or position numbering of the GLP-1 (7-37) sequence referred to herein is the sequence starting from His at position 7 and ending at Gly at position 37.
  • [Gly8, Arg34]GLP-1-(7-37) peptide which is a GLP with Gly and Arg at positions corresponding to positions 8 and 34 of GLP-1(7-37) (SEQ ID NO: 1), respectively -1 analogue
  • [Arg34]GLP-1-(7-37) peptide is a GLP-1 analogue having an Arg at a position corresponding to position 34 of GLP-1(7-37) (SEQ ID NO: 1) thing.
  • the amino acid sequences of [Gly8, Arg34] GLP-1-(7-37) peptide and [Arg34] GLP-1-(7-37) peptide are respectively as SEQ ID NO in the sequence listing: 2 and SEQ ID NO :3 shown.
  • derivatives refers to chemically modified GLP-1 peptides or analogs wherein one or more substituents have been covalently attached to said peptide .
  • Substituents may also be referred to as side chains.
  • the GLP-1 derivatives of formula (B) of the present invention may exist in different stereoisomeric forms, which have the same molecular formula and linked atomic sequence, but differ only in the three-dimensional direction of their atomic space. Unless otherwise stated, the present invention relates to all stereoisomeric forms of the claimed derivatives.
  • peptide when applied to, for example, the GLP-1 analogs of the present invention refers to a compound comprising a series of amino acids linked to each other by amide (or peptide) bonds.
  • the peptide consists largely or essentially (eg at least 50%, 60%, 70%, 80% or at least 90% of the molar mass) of amino acids interconnected by amide bonds. In another specific embodiment, the peptide consists of amino acids interconnected by peptide bonds.
  • Amino acids are molecules containing an amino group and a carboxylic acid group, optionally with one or more additional groups, often called side chains.
  • amino acid includes proteinaceous amino acids (encoded by the genetic code, including natural and standard amino acids), as well as non-proteinaceous (not found in proteins, and/or not encoded in the standard genetic code), and synthetic amino acids .
  • a non-proteinogenic amino acid is a moiety that can be incorporated into a peptide via a peptide bond, but is not a proteinogenic amino acid.
  • Synthetic non-proteinogenic amino acids include amino acids produced by chemical synthesis, i.e.
  • D-isomers of amino acids encoded by the genetic code such as D-alanine and D-leucine, Aib (alpha-aminoisobutyric acid) , Abu ( ⁇ -aminobutyric acid), 3-aminomethylbenzoic acid, anthranilic acid, deamino-histidine, ⁇ analogs of amino acids such as ⁇ -alanine, etc., D-histidine, des Amino-histidine, 2-amino-histidine, ⁇ -hydroxy-histidine, homohistidine and the like.
  • Non-limiting examples of amino acids not encoded by the genetic code are gamma-carboxyglutamic acid, ornithine, D-alanine, D-glutamine, and phosphoserine.
  • Non-limiting examples of synthetic amino acids are the D-isomers of amino acids, such as D-alanine and D-leucine, Aib ( ⁇ -aminoisobutyric acid), ⁇ -alanine, and des-amino-group Amino acid (desH, alternative name imidazole propionic acid, abbreviated Imp).
  • the GLP-1 derivatives, analogs and intermediates of the present invention may be in the form of pharmaceutically acceptable salts, amides or esters.
  • a salt can be a basic salt, an acid salt, or a neutral salt.
  • Basic salts in water produce hydroxide ions, and acid salts produce hydronium ions.
  • Salts of the derivatives of the present invention may be formed with added cations or anions which react with anionic or cationic groups, respectively. These groups may be located within the peptide moiety and/or within the side chains of the derivatives of the invention.
  • Non-limiting examples of anionic groups of the derivatives of the invention include side chains (if any) and free carboxyl groups in the peptide moiety.
  • the peptide moiety usually includes a C-terminal free carboxylic acid, and it may also include free carboxyl groups on internal acidic amino acid residues such as Asp and Glu.
  • Non-limiting examples of cationic groups on the peptide moiety include the N-terminal free amino group, if any, and any free amino group on internal basic amino acid residues such as His, Arg and Lys.
  • Esters of the derivatives according to the invention can be formed, for example, by reaction of free carboxylic acid groups with alcohols or phenols, which results in the substitution of at least one hydroxyl group by an alkoxy or aryloxy group. Formation of the ester may involve the free carboxyl group at the C-terminus of the peptide, and/or any free carboxyl group in the side chain.
  • Amides of the derivatives according to the invention can be formed, for example, by reacting a free carboxylic acid group with an amine or a substituted amine, or by reacting a free or substituted amino group with a carboxylic acid.
  • Amide formation may involve a free carboxyl group at the C-terminus of the peptide, any free carboxyl group at the side chain, a free amino group at the N-terminus of the peptide, and/or any free or substituted peptide amino group in the peptide and/or in the side chain.
  • the GLP-1 compound or GLP-1 derivative of the invention is in the form of a pharmaceutically acceptable salt.
  • in the form of a pharmaceutically acceptable amide preferably with an amide group at the C-terminus of the peptide.
  • the peptide or derivative is in the form of a pharmaceutically acceptable ester.
  • amino acid residue includes amino acids from which a hydrogen atom has been removed from an amino group and/or a hydroxyl group has been removed from a carboxyl group and/or a hydrogen atom has been removed from a sulfhydryl group. Inexactly, an amino acid residue may be called an amino acid.
  • amino acids mentioned herein are L-amino acids.
  • alkylene glycol encompasses oligo- and polyalkylene glycol moieties as well as monoalkylene glycol moieties.
  • Mono- and polyalkylene glycols include, for example, mono- and polyethylene glycol-based, mono- and polypropylene glycol-based, and mono- and polytetramethylene glycol-based chains, i.e., based on the repeating unit -CH2CH2O- , -CH 2 CH 2 CH 2 O- or a chain of -CH 2 CH 2 CH 2 CH 2 O-.
  • the alkylene glycol moiety can be monodisperse (with a well-defined length/molecular weight) as well as polydisperse (with a less well-defined length/average molecular weight).
  • Monoalkylene glycol moieties include -OCH 2 CH 2 O-, -OCH 2 CH 2 CH 2 O-, or -OCH 2 CH 2 CH 2 CH 2 O- containing different groups at each end.
  • fatty acid includes straight or branched chain aliphatic carboxylic acids having at least two carbon atoms and being saturated or unsaturated.
  • Non-limiting examples of fatty acids are eg myristic acid, palmitic acid, stearic acid and eicosanoic acid.
  • aliphatic diacid includes linear or branched aliphatic dicarboxylic acids having at least two carbon atoms and being saturated or unsaturated.
  • Non-limiting examples of aliphatic diacids are adipic acid, suberic acid, sebacic acid, dodecanedioic acid, tetradecanedioic acid, hexadecandioic acid, heptadecandioic acid, octadecanedioic acid , eicosanedioic acid, docosanedioic acid and tetracosanedioic acid.
  • GLP-1 compounds are carried out according to the following principle: the names are given according to the mutations and modifications (eg acylation) relative to native GLP-1(7-37).
  • the nomenclature of the acyl moiety the nomenclature is followed by IUPAC nomenclature and in other cases by peptide nomenclature.
  • the following acyl moieties are named:
  • Eicosanedioyl- ⁇ Glu-OEG-OEG can be named, for example, "Eicosanedioyl- ⁇ Glu-OEG-OEG", “Eicosanedioyl- ⁇ Glu-2xOEG” or “Eicosanedioyl-gGlu-2xOEG”, "19-carboxynonadecanoyl - ⁇ Glu-2xOEG” or “19-carboxynonadecanoyl- ⁇ Glu-OEG-OEG", wherein OEG represents the group -NH(CH 2 ) 2 O(CH 2 ) 2 OCH 2 CO- (ie, 2-[ 2-(2-Aminoethoxy)ethoxy]acetyl) and ⁇ Glu (and gGlu) are shorthand for the amino acid ⁇ -glutamic acid in the L configuration.
  • the acyl moiety can be named according to IUPAC nomenclature (OpenEye, IUPAC format). According to this nomenclature, the aforementioned acyl moieties of the present invention are referred to by the following designations: “[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19- Carboxynonadecanoylamino)butyryl]-amino]-ethoxy]-ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]" or "[2-(2-[2 -(2-[2-(2-[4-(19-Carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy] ethoxy)acetyl]".
  • delivery agent or a salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid refers to an excipient capable of increasing the oral exposure of a GLP-1 compound.
  • the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid contains the anion N-(8-(2-hydroxybenzoyl)amino)octanoate.
  • the structural formula of N-(8-(2-hydroxybenzoyl)amino)octanoate is shown in formula (I).
  • the salt of N-(8-(2-hydroxybenzoyl)amino)octanoic acid is selected from sodium salts.
  • Salts of N-(8-(2-hydroxybenzoyl)amino)octanoic acid can be prepared for example using the methods described in WO96/030036, WO00/046182, WO01/092206 or WO2008/028859.
  • said pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.
  • excipient as used herein broadly refers to any ingredient other than the active therapeutic ingredient. Excipients can be inert substances, inactive substances and/or not pharmaceutically active substances. Excipients can serve a variety of purposes, eg, as carriers, vehicles, binders, lubricants, glidants, diluents, and/or to improve the administration, and/or absorption, of the active substance.
  • the formulation of pharmaceutical active ingredients with various excipients is known in the art, see for example Remington: The Science and Practice of Pharmacy (eg 19th Edition (1995), and any later editions).
  • a particular value referred to herein and given with respect to a number or interval may be understood as being at or about that particular value.
  • the term "about” means ⁇ 10% of the referred value, thus about 100 mM includes 100 mM ⁇ 10 mM, 10% includes 10% ⁇ 1%, and so on.
  • the concentration of each component in the pharmaceutical composition is expressed as % (w/w), which refers to the mass percentage of the component, such as 20% (w/w) of povidone, which means the content of povidone
  • % (w/w) refers to the mass percentage of the component, such as 20% (w/w) of povidone, which means the content of povidone
  • the mass ratio is 20% to the total mass of the pharmaceutical composition.
  • the GLP-1 derivatives and analogs of the present invention have GLP-1 activity. Having GLP-1 activity refers to the ability to bind to the GLP-1 receptor and trigger signal transduction pathways to produce insulin-stimulating effects or other physiological effects.
  • bioavailability refers to the fraction of an administered dose of active drug substance (API) in a formulation, such as a GLP-1 compound herein, that reaches the systemic circulation unchanged.
  • API active drug substance
  • a formulation such as a GLP-1 compound herein
  • pharmaceutical effect refers to the ability of a pharmaceutical composition to produce a certain action or effect (eg, lowering blood sugar).
  • Na 2 HPO 4 is disodium hydrogen phosphate
  • NaOH sodium hydroxide
  • OEG is the amino acid residue -NH(CH 2 ) 2 O(CH 2 ) 2 OCH 2 CO-;
  • OSu is succinimidyl-1-yloxy-2,5-dioxo-pyrrolidin-1-yloxy
  • OtBu is oxy-tert-butyl
  • HCl is hydrogen chloride
  • ⁇ Glu or gGlu is ⁇ L-glutamyl
  • NHS is N-hydroxysuccinimide
  • DCC is dicyclohexylcarbodiimide
  • AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid
  • Gly is glycine
  • Arg is arginine
  • TFA is trifluoroacetic acid
  • HbA1c is glycated hemoglobin
  • RD% is the relative deviation
  • [Gly8, Arg34]GLP-1-(7-37) peptide was prepared by general protein recombinant expression method (see Molecular Cloning: A Laboratory Manual (Fourth Edition), Michael R. Green, Cold Spring Harbor Press, 2012 for specific methods) .
  • [Gly8,Arg34]GLP-1-(7-37) peptide (5 g, 1.48 mmol) was dissolved in 100 mM Na 2 HPO 4 aqueous solution (150 mL) and acetonitrile (100 mL) was added and the pH was adjusted to pH 10 with 1 N NaOH -12.5.
  • tert-Butyleicosanedioyl- ⁇ Glu(2xOEG-OSu)-OtBu (1.59 g, 1.63 mmol) was dissolved in acetonitrile (50 mL) and [Gly8, Arg34]GLP-1-(7-37) was added slowly in the peptide solution. The pH was maintained at 10-12.5. After 120 minutes, the reaction mixture was added to water (150 mL), and the pH was adjusted to 5.0 with 1N aqueous HCl. The precipitate was isolated by centrifugation and lyophilized.
  • the crude product was added to a mixed solution of trifluoroacetic acid (60 mL) and dichloromethane (60 ml), and stirred at room temperature for 30 minutes.
  • the mixture was concentrated to about 30 ml, poured into ice-cold n-heptane (300 mL), and the precipitated product was isolated by filtration and washed twice with n-heptane.
  • the product was purified by ion exchange chromatography (Ressource Q, 0.25%-1.25% ammonium acetate gradient in 42.5% ethanol, pH 7.5), reverse phase chromatography (acetonitrile, water, TFA) , the purified fractions were combined, the pH was adjusted to 5.2 with 1N HCl, the precipitate was isolated, and lyophilized to give the title compound.
  • Ressource Q 0.25%-1.25% ammonium acetate gradient in 42.5% ethanol, pH 7.5
  • reverse phase chromatography acetonitrile, water, TFA
  • tert-butyleicosanedioyl- ⁇ Glu-OtBu (27.27g, 46.71mmol) was dissolved in dichloromethane (300mL), triethylamine (11.99mL) was added and stirred for 10 minutes, then NHS ( 5.38 g, 50.17 mmol), followed by DCC (10.60 g, 51.38 mmol). The mixture was stirred overnight at room temperature.
  • tert-butyleicosanedioyl- ⁇ Glu-(2xOEG-OH)-OtBu (30.75g, 35.18mmol) was dissolved in dichloromethane (300mL), triethylamine (9.03mL) was added and stirred for 10 Minutes, additional NHS (4.05 g, 35.18 mmol) was added followed by DCC (7.98 g, 38.70 mmol). The mixture was stirred overnight at room temperature.
  • tablets containing SNAC and GLP-1 compound, and tablets containing only SNAC without GLP-1 compound were prepared.
  • the semaglutide compound in this example was purchased from Gutuo Biotechnology Co., Ltd.
  • Compound 5 (mg) 7 10 7 7 7 7 20 0.7 - - Semaglutide (mg) - - - - - - 0.7 - SNAC (mg) 350 350 300 150 400 350 30 30 30
  • Premixing step 1 SNAC, colloidal silicon dioxide, and part of magnesium stearate were passed through a 40-mesh sieve, then added to a hopper mixer, and mixed at 20 rpm for 20 minutes to obtain premixed powder 1.
  • Premix step 2 GLP-1 compound, microcrystalline cellulose and povidone K90 were sieved together, added to the above premix powder 1, and mixed at 20 rpm for 20 minutes to obtain premix powder 2.
  • Granulation Put premixed powder 2 in a dry granulator for one-time granulation, horizontal screw feeding, roller speed 2rpm, roller pressure 40bar, feeding screw speed 40rpm, roller gap 0.5- 2mm, whole grain screen 1.2mm.
  • Tablet compression compress the blended granules to control tablet hardness and tablet weight to obtain tablet products.
  • contrast composition A by the following separate granulation process:
  • each component in granule 1 weighs SNAC, magnesium stearate, and colloidal silicon dioxide, place them in a mixer, and mix for 20 minutes; then add microcrystalline cellulose, place them in a mixer, and mix for 20 minutes, and take The mixed powder is granulated by a dry granulator into granule 1.
  • each component in granule 2 weigh compound 5, microcrystalline cellulose, and povidone K90, put them in a mixer, mix for 5 minutes, take the mixed powder and granulate it with a dry granulator to form granule 2.
  • Granule 1, granule 2 and magnesium stearate are placed in a mixer, mixed for 5 minutes, and the total mixed powder is taken and compressed on a rotary tablet press.
  • Embodiment 7 Dissolution test
  • composition B in embodiment 6 composition C, composition F and control group semaglutide tablet (Novo Nordisk The company’s product RYBELSUS) was used for dissolution determination, using 900ml of hydrochloric acid plus potassium chloride buffer solution (pH2.0) containing 0.8% Tween 80, and acetate buffer solution (pH4.5) containing 1.0% Tween 80 , phosphate buffer (pH6.8) containing 0.1% Tween 80, and purified water were used as the dissolution medium, and at 37° C., the dissolution test was carried out at a paddle speed of 50 rpm. The results are shown in Table 4-11.
  • the dissolution rate of the active substance and SNAC in the GLP-1 pharmaceutical composition of the present invention is comparable or even closer to that of the semaglutide oral tablet, that is, it has a comparable or higher F2 factor, suggesting that the dissolution rate of the present invention
  • the pharmaceutical composition has better bioavailability.
  • Dissolution medium/time (min) 0min 15min 30min 45min 60min F2 factor pH2.0+0.8% Tween 0.0% 56.3% 91.0% 99.8% 102.0% 69
  • Dissolution medium/time (min) 0min 15min 30min 45min 60min pH2.0+0.8% Tween 0.0% 57.6% 84.8% 90.3% 92.5% pH4.5+1.0% Tween 0.0% 50.1% 77.4% 86.9% 89.2% pH6.8+0.1% Tween 0.0% 49.0% 71.9% 80.0% 83.5%
  • Dissolution medium/time (min) 0min 15min 30min 45min 60min F2 factor pH2.0+0.8% Tween 0.0% 63.0% 88.5% 99.3% 101.4% 72 pH4.5+1.0% Tween 0.0% 52.4% 79.7% 93.2% 95.3% 85 pH6.8+0.1% Tween 0.0% 48.6% 73.6% 86.7% 93.1% 69
  • Dissolution medium/time (min) 0min 15min 30min 45min 60min pH2.0+0.8% Tween 0.0% 59.5% 84.4% 93.1% 95.4% pH4.5+1% Tween 0.0% 51.9% 78.1% 90.3% 91.7% pH6.8+0.1% Tween 0.0% 45.0% 69.7% 82.3% 88.5%
  • the purpose of this experiment is to test the dissolution performance of the GLP-1 pharmaceutical composition with different hardness of the present invention
  • Example 6 According to the steps similar to those in Example 7, the composition B in Example 6 with different hardness was tested for dissolution, using 500 ml of hydrochloric acid plus potassium chloride buffer (pH2.0) containing 0.8% Tween 80 As a dissolution medium, the dissolution test was carried out at 37° C. with a paddle speed of 50 rpm, and the results are shown in Table 16-17.
  • the GLP-1 pharmaceutical composition of the present invention has better dissolution performance when the hardness is lower than 130N.
  • the purpose of this experiment is to test the dissolution performance of the GLP-1 pharmaceutical composition that the active substance starting material of the present invention has different particle diameters D90
  • Example 7 the composition B in Example 6 with different particle diameters D90 of the active substance starting material was carried out for dissolution determination, using 500 ml of hydrochloric acid containing 0.8% Tween 80 plus potassium chloride buffer Solution (pH2.0) was used as the dissolution medium, and the dissolution test was carried out at 37° C. with a paddle speed of 50 rpm, and the results are shown in Table 18-19.
  • composition B Dissolution data of compound 5 in different dissolution media in table 18 composition B
  • composition B Dissolution data of SNAC in different dissolution media in Table 19 composition B
  • the purpose of this study is to confirm the control of the GLP-1 pharmaceutical composition of the present invention on blood sugar and food intake.
  • mice Male KM mice (purchased from Weitong Lihua) were raised in a breeding box of appropriate size in a barrier environment, free access to standard food and purified water, and the environmental conditions were controlled at a relative humidity of 40%-60% and a temperature of 22 °C-26°C. After an adaptation period of 1-2 weeks, it was used for experiments.
  • mice On the day before the experiment day, fasting was carried out, and the basal blood glucose was assessed and the mice were weighed before the experiment started. According to random blood sugar and body weight, the mice were matched and assigned to the treatment group, the control group or the vehicle group (SNAC group), a total of 6 groups, 6 in each group, and each group received the following treatment respectively: administration of intragastric suspension (10ml/ kg), the treatment group was administered Composition I, Composition II, Composition III and Composition IV, the control group was administered Composition V, and the vehicle group was administered Composition VI.
  • administration of intragastric suspension (10ml/ kg) administration of intragastric suspension (10ml/ kg)
  • the treatment group was administered Composition I, Composition II, Composition III and Composition IV
  • the control group was administered Composition V
  • vehicle group was administered Composition VI.
  • Figures 1a-1c show that the GLP-1 composition of the present invention has the effect of lowering blood sugar and inhibiting food intake after intragastric administration.
  • Figure 1a and Figure 1b show that the composition of the present invention comprising Compound 5 and SNAC has a hypoglycemic effect on KM mice, and when the mass ratio of Compound 5 to SNAC is 7:350 or 7:400, its hypoglycemic effect is comparable to that of Compositions comprising semaglutide were equivalent or superior.
  • Figure 1c shows that when the mass ratio of compound 5 to SNAC is 7:350, its effect on inhibiting food intake in mice is equivalent to that of semaglutide at the same dose.
  • the purpose of this study is to confirm the blood sugar control of the GLP-1 pharmaceutical composition of the present invention on db/db mice.
  • mice Male db/db mice (Cavens) were raised in a suitable size feeding box in a barrier environment, and had free access to standard food and purified water. The environmental conditions were controlled at a relative humidity of 40%-60%, and a temperature of 22°C- 26°C. After an adaptation period of 1-2 weeks, it was used for experiments.
  • the diabetic mice were matched and assigned to the treatment group, the control group or the vehicle group (SNAC group), a total of 3 groups, 6 in each group, and each group received the following treatment respectively: intragastric suspension administration (10ml /kg), Composition VII was administered to the treatment group, Composition VIII was administered to the control group, and Composition IX was administered to the vehicle group.
  • Adopt intragastric administration mode (10ml/kg body weight), measure blood glucose at 0 o'clock after administration 0.5 hours, carry out ipGTT experiment (10% glucose, 10mL/kg) with reference to embodiment 11 after administration 1 hour, monitor after giving sugar After 0.5 hour, 1 hour, and 2 hours, the blood glucose level of the mouse was measured, and two ipGTT experiments were carried out consecutively.
  • the GLP-1 composition of the present invention has unexpectedly increased hypoglycemic efficacy after administration. This further proves that the hypoglycemic effect of the composition comprising Compound 5 and SNAC of the present invention on db/db mice after administration is basically consistent with the hypoglycemic effect of semaglutide after intragastric administration of the same dose.
  • the purpose of this study is to confirm the control of blood sugar by the GLP-1 pharmaceutical composition of the present invention.
  • Adopt oral gavage tablet administration mode 3 tablets/only, carry out ipGTT (20% glucose, 10mL/kg) with reference to embodiment 11 2 hours after administration, monitor after giving sugar 0.5 hour, 1 hour, after 2 hours small Rat blood glucose levels.
  • FIGS 3a-3b show that the GLP-1 composition of the present invention has an unexpected better hypoglycemic effect in SD rats than the semaglutide composition after intragastric administration.
  • the purpose of this study is to confirm the control of blood sugar by the GLP-1 pharmaceutical composition of the present invention.
  • the ICR mice were raised in a feeding box of appropriate size in a barrier environment, free access to standard food and purified water, the environmental conditions were controlled at a relative humidity of 40%-60%, and a temperature of 22°C-26°C. After an adaptation period of 1-2 weeks, it was used for experiments.
  • mice were fasted for 16 hours before the experiment, and the basal blood glucose was assessed before the experiment, and the mice were weighed.
  • the ICR mice were matched and assigned to the treatment group, the control group or the vehicle group (SNAC group), a total of 3 groups, 6 in each group, and each group received the following treatment respectively: administration of intragastric suspension (10ml /kg), Composition X was administered to the treatment group, Composition XI was administered to the control group, and Composition XII was administered to the vehicle group.
  • Adopt intragastric administration mode measure blood glucose at 0 o'clock after administration 1.5 hours, carry out ipGTT (10% glucose, 10mL/kg) with reference to Example 11 2 hours after administration, monitor before giving sugar, after sugar 0.5 hour, Mouse blood glucose levels after 1 hour and 2 hours. Clean the tail of the rat with alcohol cotton balls, collect blood drops from the tail with a disposable blood collection needle, and measure it with a blood glucose meter (Roche) and supporting test paper. The ipGTT was performed again on the second day and the third day respectively.
  • Figures 4a-4b show that the composition comprising compound 5 and SNAC of the present invention has a hypoglycemic effect on ICR mice, which is comparable to the composition comprising semaglutide.
  • the purpose of this example is to illustrate the in vivo pharmacokinetic properties of the pharmaceutical composition of the present invention.
  • composition B low-dose group (10mg/kg)
  • composition B middle-dose group (15mg/kg)
  • composition B high-dose group (20mg/kg). kg
  • fast for about 16 hours before administration and take blood samples before administration (0min), 15min, 30min, 1hr, 2hr, 3hr, 5hr, 8hr, 12hr, 24hr, 48hr, and 72hr to measure the blood drug concentration.
  • the pharmacokinetic parameters C max , T max , T 1/2 , AUC 0-t , and MRT were calculated using the non-compartmental model of WinNonLin v6.4 software, and the test results are shown in Table 20.
  • C max maximum measured plasma concentration
  • T max time corresponding to maximum measured plasma concentration
  • T 1/2 terminal elimination half-life
  • AUC 0-t area under the 0-t time-blood glucose concentration time curve
  • MRT mean residence time stay time
  • composition of Compound 5 of the present invention and SNAC has a longer half-life and a longer average residence time in SD rats.
  • the purpose of this example is to illustrate the uniformity of the composition of the present invention obtained by different preparation methods.
  • composition C Prepare composition C according to the one-time granulation process in Example 6, and prepare comparative composition A in the separate granulation process in Comparative Example 1.
  • the respective mixers stop rotating, open the mixer cover, and use Multi-point sampling is carried out at the next three horizontal positions, the number of samples is not less than 6 points, and the sampling amount at each point is 1-3 times the weight of a single tablet.
  • the content is detected by high-performance liquid chromatography (HPLC). The detection steps as follows:
  • a phase is 0.1% trifluoroacetic acid aqueous solution
  • Phase B is a solution of 0.1% trifluoroacetic acid in acetonitrile.
  • the detection wavelength is 214nm/235nm
  • the flow rate is 1.0ml/min
  • the injection volume is 10 ⁇ l.
  • Table 21 shows the blend particle uniformity of samples obtained from separate granulation and one-time granulation.
  • the chemical stability of the preparation in this example can be expressed by the changes in the amount of related substances measured after storage at 30°C/65RH for 1 month and 2 months.
  • Phase A contains 90 mM potassium dihydrogen phosphate and 10% acetonitrile (v/v), pH 2.4
  • Phase B was 75% (v/v) acetonitrile.
  • the detection wavelength is 214nm
  • the flow rate is 1.0ml/min
  • the injection volume is 15 ⁇ l.
  • Table 22 shows the changes in the amount of related substances relative to day 0 when stored at 30° C. for 1 month and 2 months.
  • the purpose of this study is to confirm the hypoglycemic effect of the GLP-1 compound in the GLP-1 pharmaceutical composition of the present invention on type II diabetic Kkay mice
  • Compound 5 of Example 5 and Compound 2 of Example 2 were tested on type II diabetic Kkay mice. Compound 5 and compound 2 were administered to mice at different doses of 100 and 300 ⁇ g/kg, and the effect of the GLP-1 compound in the GLP-1 pharmaceutical composition of the present invention on lowering blood sugar and HbA1c was determined.
  • mice were matched and assigned to vehicle group or treatment group, and received the following treatment: subcutaneous injection of vehicle, or subcutaneous injection of GLP-1 compound 100 and 300 ⁇ g/kg in the GLP-1 pharmaceutical composition of the present invention.
  • the solvent contains: propylene glycol 14mg/ml, phenol 5.5mg/ml, disodium hydrogen phosphate 1.133mg/ml, pH 7.4.
  • Subcutaneous administration 50 ⁇ l/10g body weight
  • subcutaneous injection on the back of the neck administration of the GLP-1 compound or vehicle in the GLP-1 pharmaceutical composition of the present invention at about 10:00 in the morning (time 0), every 2
  • the drug was administered once a day and administered continuously for 16 times.
  • the blood glucose of the mice was evaluated 3 hours, 6 hours, 1 day and 2 days after the first administration, and EDTA anticoagulation was taken to detect HbA1c 48 hours after the last administration.
  • Figures 5a-5b show that the GLP-1 derivatives used in the pharmaceutical composition of the present invention have unexpectedly increased hypoglycemic efficacy, and the title compounds of Example 5 and Example 2 have significant hypoglycemic effects on Kkay mice. sugar effect.
  • Figure 5c shows that the title compounds of Example 5 and Example 2 of the present invention can significantly reduce HbA1c in type II diabetic Kkay mice.
  • Example 6 According to the content of each component shown in Table 23, referring to the preparation method in Example 6, a tablet containing SNAC and the GLP-1 compound of the present invention was prepared.
  • each component in Table 24 prepare a composition containing SNAC and the GLP-1 compound of the present invention, and a composition containing only SNAC without the GLP-1 compound.
  • the solvent of each composition is purified water, both in the form of a suspension.
  • Example 19 With reference to the experimental procedure in Example 7, the compositions K and L in Example 19 were tested for dissolution, using phosphate buffer (pH6.8) containing 0.1% Tween medium as the dissolution medium, and at 37°C , Dissolution test was carried out with a paddle speed of 70rpm, and the results are shown in Table 25-26.
  • the purpose of this study is to confirm the blood sugar control of the GLP-1 pharmaceutical composition of the present invention on db/db mice.
  • mice half male and half male
  • m/m mice half male and half female mice
  • the environmental conditions were controlled at a relative humidity of 40 %-60%, the temperature is 22°C-26°C. After an adaptation period of 1-2 weeks, it was used for experiments.
  • mice were weighed before the experiment started.
  • the m/m mice were used as the normal control group, and the db/db mice were assigned to the treatment group or the vehicle group (SNAC group) according to random blood sugar and body weight. There were 5 groups in total, 8 mice in each group.
  • the treatment was as follows: intragastric suspension administration (10 ml/kg), composition VIII, composition XIV, and composition XV were administered to the treatment group, and composition XVI was administered to the vehicle group.
  • Adopt intragastric administration mode (10ml/kg body weight), measure blood glucose at 0 o'clock after administration 0.5 hour, carry out ipGTT experiment (10% glucose, 1g/kg) with reference to embodiment 11 after administration 1 hour, monitor after giving sugar 15min, 30min, 60min, 75min, 90min, 120min, 150min, 210min, 240min, 360min mouse blood glucose level.
  • the GLP-1 composition of the present invention has an unexpected hypoglycemic effect after administration, and the composition of the title compound of Example 5 of the present invention and SNAC has an effect on db/db mice It has obvious hypoglycemic effect, improves the glucose tolerance of db/db mice, and presents a dose-dependent manner.
  • the purpose of this study is to confirm the control of the GLP-1 pharmaceutical composition of the present invention on the blood sugar and food intake of db/db mice.
  • diabetic mice are assigned to the treatment group or the vehicle group (SNAC group), totally 3 groups, 8 in each group, the treatment group and the vehicle group accept the following treatment respectively: intragastric administration of suspension (10ml /kg), Composition XIV and Composition XV were administered to the treatment group, and Composition XVI was administered to the vehicle group.
  • Oral administration (10ml/kg body weight) was adopted to monitor the blood glucose level of mice 1h, 2h, 4h, 6h, 12h, 24h, 48h after administration.
  • the diet was resumed immediately after the administration, and the body weight and food intake of the mice administered the composition XV and composition XVI before administration (0 min), and 12h, 24h, 48h, and 72h after administration were recorded.
  • the GLP-1 composition of the present invention has unexpected hypoglycemic effect, weight loss effect, and food intake inhibitory effect after administration.
  • the composition of the title compound of Example 5 of the present invention and SNAC has a significant hypoglycemic effect on db/db mice
  • Figure 7c and Figure 7d show the title compound of Example 5 of the present invention and The composition of SNAC has the effects of reducing body weight and controlling food intake in db/db mice.
  • the purpose of this example is to demonstrate the in vivo pharmacokinetic properties of the compositions of the present invention.
  • the oral formulation of compound 5 of the present invention exhibits a half-life comparable to or even longer than that of the oral formulation of semaglutide in the control group, and has a comparable average residence time.
  • the purpose of this study is to confirm the body weight control and pharmacokinetic properties of the GLP-1 pharmaceutical composition of the present invention in SD rats.
  • the rats were fasted the day before the experiment, and the basal blood glucose was assessed before the experiment, and the rats were weighed.
  • SD rats are matched and allocated to treatment group or vehicle group (SNAC group), totally 4 groups, each group has 8 rats, and each group accepts the following treatment respectively: gavage tablet administration (3 tablets/rat) , water supply 3m1), the particle diameters of 15.7 ⁇ m (small particle size group), 51.6 ⁇ m (medium particle size group), and 134 ⁇ m (large particle size group) were applied to the treatment group, and the composition P was applied to the vehicle group.
  • Adopt oral gavage tablet administration method 3 tablets/only, before administration (day0), after administration 12, 24, and 48 hours to detect body weight, and before administration (day-1), after administration 15min , 30min, 1hr, 2hr, 3hr, 8hr, 24hr, 48hr blood samples were taken to determine the blood drug concentration.
  • the pharmacokinetic parameters C max , T max , T 1/2 , AUC 0-t , and MRT were calculated using the non-compartmental model of WinNonLin v6.4 software, and the test results are shown in Table 28.
  • the oral formulation of Compound 5 of the present invention has an unexpected weight loss effect within the above particle size range.
  • the oral formulation of Compound 5 of the present invention has a longer half-life, a higher in vivo exposure, and a longer average residence time within the above particle size range.

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Abstract

本发明涉及一种GLP-1化合物的药物组合物及其制剂方法。具体而言，本发明涉及一种含有GLP-1化合物和N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐的药物组合物，该药物组合物具有优异的药效、良好的生物利用率、优异的溶出度、并且具有令人满意的物理稳定性、化学稳定性。

Description

含GLP-1化合物的药物组合物
相关申请的交叉引用
本申请要求2021年6月25日提交的第CN202110709288.X号中国发明专利申请的优先权，所述申请以引用的方式整体并入本文。
技术领域
本发明公开了一种GLP-1化合物和N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐的药物组合物，以及该药物组合物的制备方法及其在医药中的用途。
背景技术
胰高血糖素样肽1(GLP-1)及其类似物和衍生物在治疗1和2型糖尿病中非常有效，然而高清除率限制了这些化合物的有效性。为了提供在体内作用持续时间更长的GLP-1化合物，已经将一系列不同方法用于修饰胰高血糖素样肽1(GLP-1)的结构。例如WO99/43708公开了具有连接至C-端氨基酸残基的亲脂性取代物的GLP-1(7-35)和GLP-1(7-36)衍生物。WO00/34331公开了酰化的GLP-1类似物。WO00/69911公开了用于注射进患者体内的活化的促胰岛素肽。
目前已上市的GLP-1类药物有例如：每天给药两次的天然的GLP-1类似物艾塞那肽(Exenatide)；每天给药一次的利拉鲁肽(Liraglutide)和利司那肽(Lixisenatide)；和每周给药一次的索马鲁肽(Semaglutide)、阿必鲁肽(Abiglutide)、杜拉鲁肽(Dμlaglutide)、聚乙二醇洛塞那肽等。但上述这些产品多为注射剂，这种通过皮下注射来递送GLP-1化合物的方式会给患者带来诸多不适，尤其是需要一天多次注射的治疗方案，会降低患者的顺应性；并且注射剂的使用对注射人的技术熟练度要求高，制备过程复杂，生产成本高。到目前为止，口服给药是最广泛使用、最能为患者接受的给药途径，尤其是对于需要长期治疗的患者，并且其在生产过程的无菌要求比注射剂低，可以降低生产成本。但由于GLP-1化合物具有不易穿过胃肠道膜的特 性，因此如果以口服的方式进行给药，会使得GLP-1化合物的生物利用度极低。
WO2013/139694公开了GLP-1肽和N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐药物组合物及其制备方法，该制备方法采用了GLP-1肽和NAC盐分开制粒，再混合压片的方法，但分开制粒不利于GLP-1肽与NAC盐的充分混合，不利于得到混合均匀度较的药物组合物。
目前，市场上仅索马鲁肽片(RYBELSUS)这-款口服GLP-1类似物产品，其以SNAC作为N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐，在一定程度上保护活性物质索马鲁肽不被降解，并促进药物的跨膜吸收。但索马鲁肽中非蛋白质性氨基酸的存在，相对于天然的氨基酸，在人体内可能存在未知的、各种潜在的副作用风险，并且经临床研究证明了其生物利用度为1％左右，仍然有进一步提高的空间。
因此，仍需要与口服索马鲁肽片药效或功效更好或相当、减轻体重的效果更佳或相当、半衰期更长或相当、生物利用度更高或相当、物理化学稳定性更好或相当、和/或溶出速率相当或更快的GLP-1口服制剂。
发明内容
为克服或改善现有技术的至少一个缺点、或提供有用的替代品，本发明提供了新的GLP-1药物组合物。所述新的GLP-1药物组合物相比于已上市的索马鲁肽片，具有更好或相当的药效或功效、更好或相当的减轻体重的效果、更长或相当的半衰期、更迅速或相当的溶出速度、更高或相当的生物利用度、更好或相当的物理化学稳定性。
本发明第一方面提供的药物组合物，其包含GLP-1化合物和N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐，其中所述GLP-1化合物为式B的化合物，或其药学上可接受的盐、酰胺或酯：
[Acy-(L1) r-(L2) q]-G1      (B)，
其中G1为在对应于GLP-1(7-37)(SEQ ID NO：1)的位置34处具有Arg及位置8处具有Ala或Gly的GLP-1类似物，[Acy-(L1) r-(L2) q]是连接至所述GLP-1类似物的位置26的Lys残基的ε氨基上的取代基，其中
r为1-10的整数，q为0或1-10的整数；
Acy是包含20-24个碳原子的脂肪族二酸，其中在形式上羟基已从所述 脂肪族二酸的羧基之一中去除；
L1是选自下述的氨基酸残基：γGlu、αGlu、βAsp、αAsp、γ-D-Glu、α-D-Glu、β-D-Asp或α-D-Asp；
L2是中性的、包含亚烷基二醇的氨基酸残基；
Acy、L1、和L2之间以酰胺键连接；和
L1和L2在式(B)中出现的顺序可以独立地互换。
在一个实施方案中，G1为[Gly8，Arg34]GLP-1-(7-37)肽(SEQ ID NO：2)或[Arg34]GLP-1-(7-37)肽(SEQ ID NO：3)，优选为[Gly8，Arg34]GLP-1-(7-37)肽。
在另一个实施方案中，r为1、2、3、4、5或6，优选地，r为1、2、3或4，优选地，r为1或2，优选地，r为1。
在另一个实施方案中，q为0、1、2、3、4、5、6、7或8，优选地，q为0、1、2、3或4，更优选，q为0、1、或2。
在另一个实施方案中，Acy是包含20-23个碳原子的脂肪族二酸，优选Acy是包含20、21、或22个碳原子的脂肪族二酸，其中在形式上羟基已从所述脂肪族二酸的羧基之一中去除。
在一个实施方案中，L2是：-HN-(CH 2) 2-O-(CH 2) 2-O-CH 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2)2-O-(CH 2) 2-CO-、-HN-(CH 2) 3-O-(CH 2) 4-O-(CH 2) 3-NH-CO-、-HN-(CH 2) 3-O-(CH 2) 4-O-(CH 2) 3-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 4-O-(CH 2) 3-NH-CO-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-CH 2-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-NH-CO-(CH 2) 2-CO-、-HN-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-NH-CO-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 3-O-CH 2-CO-、或-HN-(CH 2) 4-O-(CH 2) 4-O-CH 2-CO-；优选L2是-HN-(CH 2) 2-O-(CH 2) 2-O-CH 2-CO-。
在另一个实施方案中，L1选自γGlu或βAsp，优选L1为γGlu。
在另一个实施方案中，Acy是HOOC-(CH 2) 18-CO-、HOOC-(CH 2) 19-CO-、HOOC-(CH 2) 20-CO-、HOOC-(CH 2) 21-CO-或HOOC-(CH 2) 22-CO-，优选地，Acy是HOOC-(CH 2) 18-CO-、HOOC-(CH 2) 20-CO-或HOOC-(CH 2) 22-CO-。
在一个实施方案中，式(B)中Acy、L1、和L2之间依次以酰胺键连接，L2的C末端连接至所述GLP-1类似物的位置26的Lys残基的ε氨基上。
在一个实施方案中，本发明第一方面所述药物组合物中的GLP-1化合物选自下述化合物：
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8， Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、或
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽；
在一个实施方案中，本发明第一方面所述药物组合物中的GLP-1化合物选自下述化合物：
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、或
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽。
发明人出乎意料的发现，本发明的GLP-1药物组合物包含上述式(B) 的GLP-1化合物作为活性成分时，相比于已上市的索马鲁肽片，具有预料不到的更好或相当的药效或功效、更好或相当的减轻体重的效果、更长或相当的半衰期、更迅速或相当的溶出速度、更高或相当的生物利用度、更好或相当的物理化学稳定性。
在一个实施方案中，所述N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐为N-(8-(2-羟基苯甲酰基)氨基)辛酸钠盐(SNAC)。
在一个实施方案中，所述组合物包含一种或多种可药用赋形剂。
在一个实施方案中，所述可药用赋形剂选自助流剂、粘合剂、填充剂、崩解剂和润滑剂中的一种或多种。
在一个实施方案中，所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
在另一个实施方案中，所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90。
在另一个实施方案中，所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素或无水乳糖，更优选为微晶纤维素。
在另一个实施方案中，所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁。
在一个实施方案中，包含至少约50％(w/w)、优选至少约55％(w/w)、优选至少约60％(w/w)、优选约50％-90％(w/w)、优选约55％-85％(w/w)、优选约60％-80％(w/w)、优选约61％(w/w)、约62％(w/w)、约63％(w/w)、约64％(w/w)、约65％(w/w)、约66％(w/w)、约67％(w/w)、约68％(w/w)、约69％(w/w)、约70％(w/w)、约71％(w/w)、约72％(w/w)、约73％(w/w)、约74％(w/w)、约75％(w/w)、约76％(w/w)、约77％(w/w)、约78％(w/w)、或约79％(w/w)的NAC的盐，优选，所述NAC的盐为SNAC。
在一个实施方案中，包含不超过25％，优选不超过20％(w/w)、优选不超过17％(w/w)、优选不超过15％(w/w)、优选约0.5％-20％(w/w)、优选约0.5％-18.5％(w/w)、优选约0.5％-16.5％(w/w)、优选约0.5％-15％(w/w)、优选约0.5％-13％(w/w)、优选约0.5％-12％(w/w)、优选约0.5％-11％(w/w)、优选约0.6％-11％(w/w)、优选约0.6％-10％(w/w)、优选约0.6％-9％(w/w)、 优选约0.6％-8％(w/w)、优选约0.6％-7％(w/w)、优选约0.6％-6％(w/w)、优选约0.7％-5％(w/w)、优选约1.2％-11％(w/w)、优选约1.2％-10％(w/w)、优选约1.2％-9％(w/w)、优选约1.2％-8％(w/w)、优选约1.2％-7％(w/w)、优选约1.2％-6％(w/w)、优选约1.2％-5％(w/w)、优选约1.2％-4.5％(w/w)、优选约1.4％-4％(w/w)、优选约1.4％-3.5％(w/w)、优选约1.4％-3％(w/w)，优选约1.5％(w/w)、约1.7％(w/w)、约2％(w/w)、约2.5％(w/w)、或2.8％(w/w)的所述GLP-1化合物，优选，所述GLP-1化合物选自N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基] 乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、和
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽。
在一个实施方案中，包含约0.1％-20％(w/w)、优选约0.2％-10％(w/w)、优选约0.3％-5％(w/w)、优选约0.5％-3％(w/w)、优选约0.7％-2％(w/w)、优选约1％-2％(w/w)、优选约1.6％(w/w)-约2.0％(w/w)、优选约1.6％(w/w)、约1.7％(w/w)、约1.8％(w/w)、约1.9％(w/w)、或约2.0％(w/w)的粘合剂，优选所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90。
在另一个实施方案中，包含约5％-40％(w/w)、优选约10％-35％(w/w)、优选约10％-30％(w/w)、优选约10％-25％(w/w)、优选约13％-17％(w/w)、优选约13％(w/w)、约14％(w/w)、约15％(w/w)、约16％(w/w)、约17％(w/w)、或约20％(w/w)的填充剂，所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素或无水乳糖，更优选为微晶纤维素。
在另一个实施方案中，包含约0.1％-10％(w/w)、优选约0.5％-10％(w/w)、优选约0.5％-5％(w/w)、优选约0.5％-3.5％(w/w)、优选约2.8％(w/w)、约2.9％(w/w)、约3％(w/w)、约3.1％(w/w)、约3.2％(w/w)、约3.3％(w/w)、约3.4％(w/w)、或约3.5％(w/w)的润滑剂，所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的 一种或多种，优选为硬脂酸镁。
在另一个实施方案中，包含约0.1％-20％(w/w)、优选约0.2％-10％(w/w)、优选约0.3％-5％(w/w)、优选约0.5％-3％(w/w)、优选约0.7％-2％(w/w)、优选约1％-2％(w/w)、优选约1.6％-2％(w/w)、优选约1.6％(w/w)、约1.7％(w/w)、约1.8％(w/w)、约1.9％(w/w)、或约2％(w/w)的助流剂，所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
在一个实施方案中，包含约1-100mg，优选约2-90mg，优选约3-80mg，优选约4-60mg，优选约5-55mg，优选约5-50mg，优选约5-45mg，优选约5-40mg，优选约5-35mg，优选约5-30mg，优选约5-25mg，优选约5-20mg，优选约5-15mg，优选约5-10mg，优选约7-50mg，优选约7-30mg，优选约7-25mg，优选约7-20mg，优选约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约14mg、约25mg、或约50mg的所述GLP-1化合物，优选，所述GLP-1化合物选自N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧 基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、和
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽。
在另一个实施方案中，包含至少约50mg、优选至少约100mg、优选至少约150mg、优选约50-600mg、优选约100-500mg、优选约150-450mg、优选175-425mg、优选约200-400mg、优选约250-400mg、更优选约300mg、350mg、400mg的NAC的盐，所述NAC的盐是SNAC。
在另一个实施方案中，包含约0.5-50mg，优选约1-40mg，优选约1-30mg，优选约1-25mg，优选约1-20mg，优选约1-15mg，优选约2-14mg，优选约3-13mg，优选约4-12mg，优选约5-11mg，优选约6-10mg，优选约7-9mg，优选约8mg的粘合剂，所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90。
在另一个实施方案中，包含约10-150mg，优选约20-140mg，优选约30-130mg，优选约40-120mg，优选约50-110mg，优选约50-100mg，优选约60-90mg，优选约60-80mg，优选约60-70mg，优选约68mg的填充剂，所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无 水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素、或无水乳糖，更优选为微晶纤维素。
在另一个实施方案中，包含约1-50mg，优选约1-40mg，优选约1-30mg，优选约2-20mg，优选约3-20mg，优选约5-20mg，优选约5-15mg，优选约10-15mg，优选约14mg的润滑剂，所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁。
在另一个实施方案中，包含约1-50mg，优选约1-40mg，优选约1-30mg，优选约2-20mg，优选约3-20mg，优选约5-15mg，优选约5-10mg，优选约8mg的助流剂，所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
在一个实施方案中，所述药物组合物为片剂、颗粒剂或胶囊剂形式，优选，所述药物组合物为片剂形式。
在一个实施方案中，所述组合物的硬度低于约130N，优选约80-130N，优选约90-130N，优选约100-125N，更优选约110-120N。
在一个实施方案中，所述组合物的粒径D90优选不超过约200μm，优选不超过约130μm，优选约15-130μm，更优选约15-50μm。
在一个实施方案中，本发明第一方面保护的药物组合物含有如下成分：
约5、10、15、20、25、30、35、40、45、50、55、60、70、80、90、或100mg、优选约7-10mg的N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽；约300、350或400mg的SNAC；约8mg的聚维酮K90；约68mg的微晶纤维素；约14mg的硬脂酸镁；和约8mg的胶态二氧化硅。
在一个实施方案中，所述药物组合物的总重为约150-1000mg、优选为约175-1000mg、优选为约200-800mg、优选为约400mg-500mg、优选为约400mg、约403mg、约405mg、约408mg、约413mg、约418mg、约423mg、约428mg、约433mg、约438mg、约443mg、约448mg、约455mg、约500mg、约600mg、或约800mg。
本发明的第二方面提供了一种制备方法，该方法用以制备本发明第一方面提供的药物组合物。
在一个实施方案中，所述制备方法包括将所述GLP-1化合物与NAC的 盐混合后进行一次性制粒的步骤。
在一个实施方案中，所述制备方法包括在将所述NAC的盐与所述GLP-1化合物混合之前，先将所述NAC的盐与润滑剂和/或助流剂混合。
在一个实施方案中，所述制备方法包括：
(1)将所述NAC的盐、助流剂和部分润滑剂混合，得到预混粉A；
(2)将所述GLP-1化合物、粘合剂和填充剂与所述预混粉A混合，得到预混粉B；
(3)将预混粉B制粒，优选采用干法制粒；
(4)将得到的颗粒与剩余润滑剂混合，得到总混颗粒；
(5)将总混颗粒进行压片。
在一个实施方案中，所述GLP-1化合物选自N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8， Arg34]GLP-1-(7-37)肽、
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、和
N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽。
在另一个实施方案中，所述NAC的盐是SNAC；和/或
所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90；和/或
所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素、或无水乳糖，更优选为微晶纤维素。
在一个实施方案中，所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁；和/或
所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
另一个方面，本发明如上所述的药物组合物，其用作药物。
另一个方面，本发明如上所述的药物组合物，其用于治疗或预防高血糖症、糖尿病、和/或肥胖症。
另一个方面，本发明如上所述的药物组合物，在制备用于治疗或预防高血糖症、糖尿病、和/或肥胖症的药物中的用途。
另一个方面，治疗或预防高血糖、糖尿病、和/或肥胖症的方法，包括施用有效量的本发明如上所述的药物组合物。
附图说明
图1a示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对KM小鼠的降糖效果。
图1b与图1a相对应地示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对KM小鼠的降糖效果的AUC。
图1c示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对KM小鼠的食物摄入量的控制效果。
图2a示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对db/db小鼠的降糖效果。
图2b与图2a相对应地示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对db/db小鼠的降糖效果的AUC。
图3a示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对SD大鼠的降糖效果。
图3b与图3a相对应地示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对SD大鼠的降糖效果的AUC。
图4a示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对ICR小鼠的降糖效果。
图4b与图4a相对应地示出了包含化合物5和SNAC的药物组合物、包含索马鲁肽和SNAC的药物组合物、和溶媒对ICR小鼠的降糖效果的AUC。
图5a示出了本发明实施例5的标题化合物、实施例2的标题化合物和溶媒对Kkay小鼠的降糖效果。
图5b与图5a相对应地示出了本发明实施例5的标题化合物、实施例2的标题化合物和溶媒对Kkay小鼠的降糖效果的AUC。
图5c示出了本发明实施例5的标题化合物、实施例2的标题化合物和溶媒对Kkay小鼠的降HbA1c效果。
图6a示出了包含化合物5和SNAC的药物组合物、和溶媒对db/db小鼠或正常小鼠的降糖效果。
图6b与图6a相应地示出了包含化合物5和SNAC的药物组合物、和溶媒对db/db小鼠或正常小鼠的降糖效果的AUC。
图7a示出了包含化合物5和SNAC的药物组合物、和溶媒对db/db小鼠的降糖效果。
图7b与图7a相应地示出了包含化合物5和SNAC的药物组合物、和溶媒对db/db小鼠的降糖效果的AUC。
图7c示出了包含化合物5和SNAC的药物组合物、和溶媒对db/db小鼠的降体重效果。
图7d示出了包含化合物5和SNAC的药物组合物、和溶媒对db/db小鼠的摄食抑制效果。
图8示出了包含化合物5和SNAC的药物组合物、和溶媒对SD大鼠的体重控制效果。
具体实施方法
定义
GLP-1类似物、和GLP-1衍生物
本文所用的术语“GLP-1类似物”或“GLP-1的类似物”是指作为人胰高血糖素样肽-1(GLP-1(7-37))变体的肽或化合物，其中GLP-1(7-37)的一个或多个氨基酸残基被替换、和/或其中一个或多个氨基酸残基被缺失、和/或其中增加了一个或多个氨基酸残基。具体地，GLP-1(7-37)的序列如序列表中的SEQ ID NO：1所示。具有SEQ ID NO：1所示序列的肽也可称为“天然”GLP-1或“天然”GLP-1(7-37)。
在序列表中，SEQ ID NO：1的第一个氨基酸残基(组氨酸)编号为1。然而，在下文中，依据本领域已建立的习惯，该组氨酸残基编号定为7，并且其后的氨基酸残基也随之编号，结尾是37号甘氨酸。因此，通常，本文所涉及到的GLP-1(7-37)序列的氨基酸残基编号或位置编号是开始于位置7的His和结束于位置37的Gly的序列。
[Gly8，Arg34]GLP-1-(7-37)肽，是在对应于GLP-1(7-37)(SEQ ID NO：1)位置8和位置34的位置处分别具有Gly和Arg的GLP-1类似物，[Arg34]GLP-1-(7-37)肽，是在对应于GLP-1(7-37)(SEQ ID NO：1)位置34 的位置处具有Arg的GLP-1类似物。具体地，[Gly8，Arg34]GLP-1-(7-37)肽和[Arg34]GLP-1-(7-37)肽的氨基酸序列分别如序列表中的SEQ ID NO：2和SEQ ID NO：3所示。
在GLP-1肽或其类似物的情况下，本文所用的术语“衍生物”是指经化学修饰的GLP-1肽或类似物，其中一个或多个取代基已与所述肽共价连接。取代基也可称为侧链。
除非另有说明，否则当提及与赖氨酸残基酰化时，理解为与其ε-氨基进行。
本发明的式(B)的GLP-1衍生物可存在不同的立体异构体形式，其具有相同分子式和所连接的原子序列，但仅在其原子空间的三维方向上不同。除非另有说明，否则本发明涉及要求保护的衍生物的所有立体异构体形式。
术语“肽”当用于例如本发明的GLP-1类似物时，是指包含通过酰胺(或肽)键相互连接的一系列氨基酸的化合物。
在一个具体的实施方案中，肽很大程度上或主要由通过酰胺键相互连接的氨基酸组成(例如摩尔质量的至少50％、60％、70％、80％或至少90％)。在另一个具体的实施方案中，肽由通过肽键相互连接的氨基酸组成。
氨基酸是含有氨基和羧酸基的分子，任选含有一个或多个额外基团，通常称为侧链。
术语“氨基酸”包含蛋白质性的氨基酸(由遗传密码所编码，包括天然氨基酸和标准氨基酸)、以及非蛋白质性(在蛋白质中未发现，和/或在标准遗传密码中未编码)、和合成氨基酸。非蛋白质源性氨基酸是可以通过肽键整合进肽的部分，但不是蛋白质源性氨基酸。合成的非蛋白质源性氨基酸包括通过化学合成产生的氨基酸，即通过遗传密码编码的氨基酸的D-异构体例如D-丙氨酸和D-亮氨酸、Aib(α-氨基异丁酸)、Abu(α-氨基丁酸)、3-氨甲基苯甲酸、邻氨基苯甲酸、脱氨基-组氨酸、氨基酸的β类似物例如β-丙氨酸等、D-组氨酸、脱氨基-组氨酸、2-氨基-组氨酸、β-羟基-组氨酸、和高组氨酸(homohistidine)等。
不由遗传密码所编码的氨基酸的非限制性实例是γ-羧基谷氨酸、鸟氨酸、D-丙氨酸、D-谷氨酰胺和磷酸丝氨酸。合成氨基酸的非限制性实例是氨基酸的D-异构体，例如D-丙氨酸和D-亮氨酸、Aib(α-氨基异丁酸)、β-丙氨酸和des-氨基-组氨酸(desH，替代名称咪唑丙酸，缩写Imp)。
在下文中，并未标明旋光异构体的所有氨基酸都理解为是指L-异构体(除非另有说明)。
药学上可接受的盐、酰胺或酯
本发明的GLP-1衍生物、类似物和中间产物可以呈药学上可接受的盐、酰胺或酯的形式。盐可以是碱式盐、酸式盐，或者中性盐。在水中碱式盐产生氢氧离子，酸式盐产生水合氢离子。本发明衍生物的盐可以用分别与阴离子基团或阳离子基团反应的添加的阳离子或阴离子来形成。这些基团可位于肽部分内和/或在本发明衍生物的侧链内。
本发明衍生物的阴离子基团的非限制性实例包括侧链(如果有的话)以及肽部分中的游离羧基。肽部分通常包括C-端的游离羧酸，并且它也可包括在内部酸性氨基酸残基例如Asp和Glu上的游离羧基。
肽部分的阳离子基团的非限制性实例包括N-端的游离氨基(如果有的话)以及在内部碱性氨基酸残基例如His、Arg和Lys上的任何游离氨基。
本发明衍生物的酯可以是例如通过游离羧酸基团与醇或酚反应而形成，其导致至少一个羟基被烷氧基或芳氧基取代。酯的形成可涉及肽的C-端的游离羧基，和/或侧链的任何游离羧基。
本发明衍生物的酰胺可以是例如通过游离羧酸基团与胺或取代胺反应，或通过游离或取代氨基与羧酸反应而生成。酰胺的形成可涉及肽的C-端的游离羧基、侧链的任何游离羧基、肽的N-端的游离氨基、和/或在肽和/或侧链中的任何游离或取代的肽氨基。
在一个具体的实施方案中，本发明的GLP-1化合物或GLP-1衍生物呈药学上可接受的盐的形式。在另一个具体的实施方案中，呈药学上可接受的酰胺的形式，优选在肽的C-端具有酰胺基。在再进一步的具体的实施方案中，肽或衍生物呈药学上可接受的酯的形式。
术语“氨基酸残基”包含从其中氢原子已从氨基中去除和/或羟基已从羧基中去除和/或氢原子已从巯基中去除的氨基酸。不精确地，氨基酸残基可以叫做氨基酸。
除非另有说明，本文提及的氨基酸都是L-氨基酸。
此处，术语亚烷基二醇包含寡和聚亚烷基二醇部分以及单亚烷基二醇部分。单亚烷基二醇和聚亚烷基二醇包括例如基于单和聚乙二醇、基于单和聚丙二醇、和基于单和聚丁二醇的链，即基于重复单位-CH 2CH 2O-、-CH 2CH 2CH 2O-或-CH 2CH 2CH 2CH 2O-的链。亚烷基二醇部分可以是单分散(具有定义明确的长度/分子量)以及多分散(具有定义较不明确的长度/平均分子量)。单亚烷基二醇部分包括在每个末端处包含不同基团的-OCH 2CH 2O-、-OCH 2CH 2CH 2O-或-OCH 2CH 2CH 2CH 2O-。
术语“脂肪酸”包括直链或支链脂族羧酸，其具有至少两个碳原子并为饱和或不饱和的。脂肪酸的非限定实例为例如肉豆蔻酸、棕榈酸、硬脂酸和二十烷酸。
此处，术语“脂肪族二酸”包括直链或支链脂族二羧酸，其具有至少两个碳原子并为饱和或不饱和的。脂肪族二酸的非限定实例为己二酸、辛二酸、癸二酸、十二烷二酸、十四烷二酸、十六烷二酸、十七烷二酸、十八烷二酸、二十烷二酸、二十二烷二酸和二十四烷二酸。
在本文中，GLP-1化合物的命名按照以下原则进行：按相对于天然GLP-1(7-37)的突变和修饰(例如酰化)给予名称。对于酰基部分的命名，按照IUPAC命名法和在其它情况下按肽命名法进行命名。例如，命名下述酰基部分：
可例如命名为“二十烷二酰基-γGlu-OEG-OEG”、“二十烷二酰基-γGlu-2xOEG”或“二十烷二酰基-gGlu-2xOEG”、“19-羧基十九烷酰基-γGlu-2xOEG”或“19-羧基十九烷酰基-γGlu-OEG-OEG”，其中OEG表示基团-NH(CH 2) 2O(CH 2) 2OCH 2CO-(即，2-[2-(2-氨基乙氧基)乙氧基]乙酰基)的简写，γGlu(以及gGlu)是呈L构型的氨基酸γ谷氨酸的简写表示。或者，酰基部分可按照IUPAC命名法(OpenEye，IUPAC格式)命名。根据该命名法，本发明的上述酰基部分被称为以下名称：“[2-[2-[2-[2-[2-[2-[(4S)-4-羧基-4-(19-羧基十九烷酰基氨基)丁酰基]-氨基]-乙氧基]-乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]”或“[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基]”。
在本文中，术语“递送剂或N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐”是指能够增加GLP-1化合物的口服暴露的辅料。
在一个具体的实施方案中，N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐含有阴离子N-(8-(2-羟基苯甲酰基)氨基)辛酸根。N-(8-(2-羟基苯甲酰基)氨基)辛酸根的结构式在式(I)中示出。
Figure PCTCN2022101272-appb-000001
在另一个具体的实施方案中，N-(8-(2-羟基苯甲酰基)氨基)辛酸的盐选自钠盐。N-(8-(2-羟基苯甲酰基)氨基)辛酸的盐可以使用例如 WO96/030036、WO00/046182、WO01/092206或WO2008/028859中所述的方法来制备。
在一个具体的实施方案中，所述药物组合物包含至少一种药学上可接受的赋形剂。如本文所用的术语“赋形剂”广义上是指除了活性治疗成分之外的任何成分。赋形剂可以是惰性物质、无活性物质和/或并非药物活性物质。赋形剂可用于多种目的，例如作为载体、溶媒、粘合剂、润滑剂、助流剂、稀释剂、和/或用于改善给药、和/或活性物质的吸收。药物活性成分与不同赋形剂的配制是本领域已知的，参见例如Remington：The Science and Practice ofPharmacy(例如第19版(1995)，和任何更新版本)。
在一些实施方案中，本文提到的并且关于数字或间隔给出的具体值可以被理解为该具体值或大约该具体值。在一些实施方案中，术语“约”是指所提及的值±10％，因此约100mM包括100mM±10mM，10％包括10％±1％，等等。
在一些实施方案中，药物组合物中各成分的浓度表述成％(w/w)，是指该成分的质量百分比，如20％(w/w)的聚维酮，即表示聚维酮的质量比上药物组合物的总质量为20％。
本发明的GLP-1衍生物和类似物具有GLP-1活性。具有GLP-1活性是指与GLP-1受体结合并引发信号转导途径而产生促胰岛素作用或其它生理效应的能力。
术语“生物利用度”是指制剂中活性药物(API)，例如本文的GLP-1化合物，在未经改变地到达体循环时占给药剂量的分数。根据定义，当静脉给药API时，其生物利用度为100％。然而，当其以其它途径(例如口服)给药时，其生物利用度会降低(由于不完全吸收和首过代谢)。当计算用于非静脉内给药途径的剂量时，了解生物利用度是重要的。
本文中，“药效”或“效力”是指药物组合物产生某种作用或效果(例如降低血糖)的能力。
缩略语
Na 2HPO 4是磷酸氢二钠；
NaOH是氢氧化钠；
OEG是氨基酸残基-NH(CH 2) 2O(CH 2) 2OCH 2CO-；
OSu是琥珀酰亚胺基-1-基氧基-2，5-二氧代-吡咯烷-1-基氧基；
OtBu是氧叔丁基；
HCl是氯化氢；
γGlu或gGlu是γL-谷氨酰基；
NHS是N-羟基琥珀酰亚胺；
DCC是二环己基碳二亚胺；
AEEA是2-(2-(2-氨基乙氧基)乙氧基)乙酸；
OH是氢氧根；
Gly是甘氨酸；
Arg是精氨酸；
TFA是三氟乙酸；
HbA1c是糖化血红蛋白；
RD％是相对偏差。
实施例1
标题化合物：N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽(化合物1)
Figure PCTCN2022101272-appb-000002
1、N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基 氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8， Arg34]GLP-1-(7-37)肽的制备
通过一般的蛋白质重组表达方法制备[Gly8，Arg34]GLP-1-(7-37)肽(具体方法参见Molecular Cloning：A Laboratory Manual(Fourth Edition)，Michael R.Green，Cold Spring Harbor Press，2012)。使[Gly8，Arg34]GLP-1-(7-37)肽(5g，1.48mmol)溶解于100mM Na 2HPO 4水溶液(150mL)中，并且加入乙腈(100mL)，并用1N NaOH将pH调整至pH10-12.5。使叔丁基二十烷二酰-γGlu(2xOEG-OSu)-OtBu(1.59g，1.63mmol)溶解于乙腈(50mL)中，并且缓慢加入[Gly8，Arg34]GLP-1-(7-37)肽溶液中。使pH维持在10-12.5。在120分钟后，将反应混合物加入水(150mL)中，并且用1N HCl水溶液将pH调整至5.0。通过离心分离沉淀，并且冻干。将粗产物加入三氟乙酸(60mL)与二氯甲烷(60ml)混合溶液中，并且在室温下搅拌30分钟。将混合物浓缩至约30ml，倾注到冰冷的正庚烷(300mL) 中，通过过滤分离沉淀的产物，并用正庚烷洗涤2次。真空干燥后，真空干燥后，产物通过离子交换层析(Ressource Q，在42.5％乙醇中的0.25％-1.25％乙酸铵梯度，pH7.5)、反相层析(乙腈，水，TFA)纯化，将纯化的级分合并，用1N HCl将pH调整至5.2，分离沉淀物，并冻干得到标题化合物。
LC-MS(电喷雾)：m/z＝1028.79[M+4H] 4+
2、中间体叔丁基二十烷二酰-γ Glu-(2xOEG-OSu)-OtBu的制备
2.1叔丁基二十烷二酰-OSu
氮气保护条件下，将二十烷二酸单叔丁酯(20g，50.17mmol)和NHS(5.77g，50.17mmol)在二氯甲烷(400mL)中混合，加入三乙胺(13.95mL)，将得到的浑浊混合物在室温下搅拌，然后加入DCC(11.39g，55.19mmol)，将其进一步搅拌过夜。过滤，将得到的滤液浓缩至几乎干燥，将残余物与冷的水和乙酸乙酯混合，搅拌20分钟，分液，上层有机相加入饱和食盐水进行水洗，分液后上层有机相用无水硫酸钠干燥，过滤后将滤液减压浓缩至几乎干燥，真空干燥过夜，得到24.12g(收率97％)的叔丁基二十烷二酰-OSu。
LC-MS(Scie×100API)：m/z＝496.36(M+1) +
2.2叔丁基二十烷二酰-γGlu-OtBu
将叔丁基二十烷二酰-OSu(24.12g，48.66mmol)溶于二氯甲烷(250mL)搅拌，依次加入H-Glu-OtBu(10.88g，53.53mmol)，三乙胺(12.49mL)，水(25mL)，将其加热得到澄清溶液，将该溶液在室温下搅拌4小时。然后加入10％柠檬酸水溶液(200mL)，分液，下层有机相加入饱和盐水进行水洗，分液后下层有机相用无水硫酸钠干燥，过滤后将滤液减压浓缩至几乎干燥，真空干燥过夜。得到27.27g(收率96％)的叔丁基二十烷二酰-γGlu-OtBu。
LC-MS(Scie×100API)：m/z＝584.44(M+1) +
2.3叔丁基二十烷二酰-γGlu(OSu)-OtBu。
氮气保护条件下，将叔丁基二十烷二酰-γGlu-OtBu(27.27g，46.71mmol)溶于二氯甲烷(300mL)，加入三乙胺(11.99mL)搅拌10分钟，再加入NHS(5.38g，50.17mmol)，接着加入DCC(10.60g，51.38mmol)。在室温下搅拌混合物过夜。过滤，将得到的滤液浓缩至几乎干燥，将残余物与冷的水和乙酸乙酯混合，搅拌20分钟，分液，上层有机相加入饱和食盐水进行水洗，分液后上层有机相用无水硫酸钠干燥，过滤后将滤液减压浓缩至几乎干燥，加入甲基叔丁基醚，搅拌30分钟，抽滤，滤饼真空干燥过夜，得到25.76g(收率81％)的叔丁基二十烷二酰-γGlu-(OSu)-OtBu。
LC-MS(Scie×100API)：m/z＝681.46(M+1) +
2.4叔丁基二十烷二酰-γGlu-(2xOEG-OH)-OtBu
将叔丁基二十烷二酰-γGlu-(OSu)-OtBu(25.76g，37.83mmol)溶于二氯甲烷(250mL)搅拌，依次加入2xAEEA(11.66g，37.83mmol)，三乙胺(9.71mL)，水(25mL)，将其加热得到澄清溶液，将该溶液在室温下搅拌4小时。然后加入10％柠檬酸水溶液(200mL)分液，下层有机相加入饱和盐水进行水洗，分液后下层有机相用无水硫酸钠干燥，过滤后将滤液减压浓缩至几乎干燥，真空干燥过夜。得到30.75g(收率93％)的叔丁基二十烷二酰-γGlu-(2xOEG-OH)-OtBu。
LC-MS(Scie×100API)：m/z＝874.59(M+1) +
2.5叔丁基二十烷二酰-γGlu-(2xOEG-OSu)-OtBu。
氮气保护条件下，将叔丁基二十烷二酰-γGlu-(2xOEG-OH)-OtBu(30.75g，35.18mmol)溶于二氯甲烷(300mL)，加入三乙胺(9.03mL)搅拌10分钟，再加入NHS(4.05g，35.18mmol)，接着加入DCC(7.98g，38.70mmol)。在室温下搅拌混合物过夜。过滤，将得到的滤液浓缩至几乎干燥，将残余物与冷的水和乙酸乙酯混合，搅拌20分钟，分液，上层有机相加入饱和食盐水进行水洗，分液后上层有机相用无水硫酸钠干燥、过滤，将滤液减压浓缩至几乎干燥，真空干燥过夜，得到31.09g(收率91％)的叔丁基二十烷二酰-γGlu-(2xOEG-OSu)-OtBu。
LC-MS(Scie×100API)：m/z＝971.61(M+1) +
实施例2
标题化合物：N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽(化合物2)
Figure PCTCN2022101272-appb-000003
以与实施例1第1部分类似的步骤制备N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽
LC-MS(电喷雾)：m/z＝992.52[M+4H] 4+
中间体 叔丁基二十烷二酰-γGlu-(OEG-OSu)-OtBu以与实施例1第2部分类似的步骤进行制备。
LC-MS(Scie×100API)：m/z＝826.54(M+1) +
实施例3
标题化合物：N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽(化合物3)
Figure PCTCN2022101272-appb-000004
以与实施例1第1部分类似的步骤制备 N-ε 26-(19-羧基十九烷酰基氨 基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽
LC-MS(电喷雾)：m/z＝956.25[M+4H] 4+
中间体 叔丁基二十烷二酰-γGlu-(OSu)-OtBu以与实施例1第2部分类似的步骤进行制备。
LC-MS(Scie×100API)：m/z＝681.46(M+1) +
实施例4
标题化合物：N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽(化合物4)
Figure PCTCN2022101272-appb-000005
以与实施例1第1部分类似的步骤制备 N-ε 26-(19-羧基十九烷酰基氨 基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽
LC-MS(电喷雾)：m/z＝959.75[M+4H] 4+
中间体 叔丁基二十烷二酰-γGlu-(OSu)-OtBu以与实施例1第2部分类似的步骤进行制备。
LC-MS(Scie×100API)：m/z＝681.46(M+1) +
实施例5：
标题化合物：N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽(化合物5)
Figure PCTCN2022101272-appb-000006
以与实施例1第1部分类似的步骤制备N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽
LC-MS(电喷雾)：m/z＝1035.80[M+4H] 4+
中间体 叔丁基二十二烷二酰-γGlu-(2xOEG-OSu)-OtBu以与实施例1第2部分类似的步骤进行制备。
LC-MS(Scie×100API)：m/z＝999.64(M+1) +
实施例6
组合物的制备
根据表1中显示的各组分含量，制备含有SNAC和GLP-1化合物的片剂，以及仅包含SNAC而不包含GLP-1化合物的片剂。本实施例中的索马鲁肽化合物购于固拓生物科技有限公司。
表1.片剂组成，以“每片”表示
组分/组合物 A B C D E F G H J
化合物5(mg) 7 10 7 7 7 20 0.7 - -
索马鲁肽(mg) - - - - - - - 0.7 -
SNAC(mg) 350 350 300 150 400 350 30 30 30
聚维酮K90(mg) 8 8 8 8 8 8 0.8 0.8 0.8
微晶纤维素(mg) 68 68 68 68 68 68 6.8 6.8 6.8
硬脂酸镁(mg) 14 14 14 14 14 14 1.4 1.4 1.4
二氧化硅(mg) 8 8 8 8 8 8 0.8 0.8 0.8
片重(mg) 455 458 405 255 505 468 40.5 40.5 39.8
根据表1中各成分的含量，按下述方法制备相应组合物：
(1)预混步骤1：将SNAC与胶态二氧化硅、部分硬脂酸镁共同过40目筛，而后加入料斗混合机中，20rpm转速下混合20分钟，得到预混粉1。
(2)预混步骤2：将GLP-1化合物与微晶纤维素、聚维酮K90共同过筛，加入上述预混粉1中，以20rpm转速混合20分钟，得到预混粉2。
(3)制粒：将预混粉2置于干法制粒机中进行一次性制粒，水平螺旋供料，辊轮转速2rpm，辊轮压力40bar，供料螺杆转速40rpm，辊轮间隙0.5-2mm，整粒筛网1.2mm。
(4)总混：将得到的颗粒与剩余的硬脂酸镁共同加入料斗混合机中，以10rpm的转速混合5分钟得到总混颗粒。
(5)压片：将总混颗粒进行压片，控制片剂硬度和片重，得到片剂产品。
根据表2中各组分含量，制备含有SNAC和GLP-1化合物的组合物，以及仅含有SNAC而不含有GLP-1化合物的组合物，各组合物溶剂均为纯化水。
表2.
组分/组合物 I II III IV V VI VII VIII IX X XI XII
化合物5(mg/ml) 3 3 3 3 - - 1 - - 2 - -
索马鲁肽(mg/ml) - - - - 3 - - 1 - - 2 -
SNAC(mg/ml) 64.3 128.5 149.9 171.4 128.5 171.4 42.8 42.8 42.8 85.7 85.7 85.7
对照例1
组合物的分开制粒工艺
表3.对照组合物A片剂组成，以“每片”表示
Figure PCTCN2022101272-appb-000007
根据表3中各成分的含量，按下述分开制粒的工艺制备对照组合物A：
按照颗粒1中各组分的量，称取SNAC、硬脂酸镁、胶态二氧化硅，置于混合机中，混合20min；再加入微晶纤维素置于混合机中，混合20min，取混粉用干法制粒机制粒后为颗粒1。
按照颗粒2中各组分的量，称取化合物5、微晶纤维素、聚维酮K90，置于混合机中，混合5min，取混粉用干法制粒机制粒后为颗粒2。
将颗粒1、颗粒2与硬脂酸镁，置于混合机中，混合5min，取总混粉 在旋转式压片机上压片。
实施例7 溶出实验
根据中国药典2020版四部通则0931法溶出度测定第二法(桨法)，对实施例6中的组合物B、组合物C、组合物F以及对照组索马鲁肽片(诺和诺德公司产品RYBELSUS)进行溶出度测定，分别使用900ml的含0.8％吐温80的盐酸加氯化钾缓冲溶液(pH2.0)、含1.0％吐温80的醋酸盐缓冲液(pH4.5)、含0.1％吐温80的磷酸盐缓冲液(pH6.8)和纯化水作为溶出介质，并在37℃，以50rpm的桨速进行溶出实验，结果如表4-11所示。
表4 索马鲁肽片中索马鲁肽在不同溶出介质中的溶出数据及索马鲁肽与SNAC溶出曲线相似度F2因子
溶出介质/时间(min) 0 15 30 45 60 F2因子
pH4.5+1.0％吐温 0.0％ 49.3％ 82.4％ 95.3％ 98.7％ 67
pH2.0+0.8％吐温 0.0％ 56.3％ 91.0％ 99.8％ 102.0％ 71
纯化水 0.0％ 47.1％ 79.1％ 88.4％ 86.0％ 65
表5 索马鲁肽片中的SNAC在不同溶出介质中的溶出数据
溶出介质/时间(min) 0 15 30 45 60
pH4.5+1.0％吐温 0.0％ 50.1％ 77.4％ 86.9％ 89.2％
pH2.0+0.8％吐温 0.0％ 57.6％ 84.8％ 90.3％ 92.5％
纯化水 0.0％ 50.4％ 73.8％ 81.2％ 84.5％
表6 组合物B中化合物5在不同溶出介质中的溶出数据及化合物5与SNAC溶出曲线相似度F2因子
Figure PCTCN2022101272-appb-000008
表7 组合物B中SNAC在不同溶出介质中的溶出数据
溶出介质/时间(min) 0 15 30 45 60
pH6.8+0.1％吐温 0.0％ 70.6％ 95.6％ 96.1％ 96.3％
pH2.0+0.8％吐温 0.0％ 70.3％ 96.0％ 96.1％ 96.4％
表8 组合物C中化合物5在不同溶出介质中的溶出数据及化合物5与SNAC溶出曲线相似度F2因子
Figure PCTCN2022101272-appb-000009
表9 组合物C中SNAC在不同溶出介质中的溶出数据
溶出介质/时间(min) 0 15 30 45 60
pH6.8+0.1％吐温 0.0％ 48.5％ 79.6％ 93.8％ 95.9％
pH4.5+1.0％吐温 0.0％ 51.9％ 78.1％ 90.3％ 91.7％
pH2.0+0.8％吐温 0.0％ 59.5％ 84.4％ 93.1％ 95.4％
纯化水 0.0％ 54.0％ 78.9％ 88.8％ 91.0％
表10 组合物F中化合物5在不同溶出介质中的溶出数据及化合物5与SNAC溶出曲线相似度F2因子
Figure PCTCN2022101272-appb-000010
表11 组合物F中SNAC在不同溶出介质中的溶出数据
溶出介质/时间(min) 0 15 30 45 60
pH6.8+0.1％吐温 0.0％ 70.9％ 96.2％ 96.6％ 96.6％
pH2.0+0.8％吐温 0.0％ 70.2％ 95.0％ 95.3％ 94.9％
从上述实验结果可知，本发明的GLP-1药物组合物中活性物质与SNAC的溶出速率与索马鲁肽口服片相比相当甚至更接近，即具有相当或更高的F2因子，提示本发明的药物组合物具有更好的生物利用度。
实施例8
参考实施例7中的实验步骤，对实施例6中的组合物A以及对照组索马鲁肽片(诺和诺德公司产品)在500ml的溶出介质中进行溶出度测试，结果如表12-15所示。
表12 索马鲁肽片中索马鲁肽在不同溶出介质中的溶出数据及索马鲁肽与SNAC溶出曲线相似度F2因子
溶出介质/时间(min) 0min 15min 30min 45min 60min F2因子
pH2.0+0.8％吐温 0.0％ 56.3％ 91.0％ 99.8％ 102.0％ 69
pH4.5+1％吐温 0.0％ 49.3％ 82.4％ 95.3％ 98.7％ 64
pH6.8+0.1％吐温 0.0％ 48.7％ 76.1％ 87.8％ 90.0％ 66
表13 索马鲁肽片中的SNAC在不同溶出介质中的溶出数据
溶出介质/时间(min) 0min 15min 30min 45min 60min
pH2.0+0.8％吐温 0.0％ 57.6％ 84.8％ 90.3％ 92.5％
pH4.5+1.0％吐温 0.0％ 50.1％ 77.4％ 86.9％ 89.2％
pH6.8+0.1％吐温 0.0％ 49.0％ 71.9％ 80.0％ 83.5％
表14 组合物A中化合物5在不同溶出介质中的溶出数据及化合物5与SNAC溶出曲线相似度F2因子
溶出介质/时间(min) 0min 15min 30min 45min 60min F2因子
pH2.0+0.8％吐温 0.0％ 63.0％ 88.5％ 99.3％ 101.4％ 72
pH4.5+1.0％吐温 0.0％ 52.4％ 79.7％ 93.2％ 95.3％ 85
pH6.8+0.1％吐温 0.0％ 48.6％ 73.6％ 86.7％ 93.1％ 69
表15 组合物A中SNAC在不同溶出介质中的溶出数据
溶出介质/时间(min) 0min 15min 30min 45min 60min
pH2.0+0.8％吐温 0.0％ 59.5％ 84.4％ 93.1％ 95.4％
pH4.5+1％吐温 0.0％ 51.9％ 78.1％ 90.3％ 91.7％
pH6.8+0.1％吐温 0.0％ 45.0％ 69.7％ 82.3％ 88.5％
从上述实验结果可知，本发明的GLP-1药物组合物中活性物质与SNAC的溶出速率更接近，即具有相当或更高的F2因子，提示本发明的药物组合物具有更好的生物利用度。
实施例9
本实验的目的在于测试本发明的具有不同硬度的GLP-1药物组合物的溶出性能
按照与实施例7中类似的步骤，对具有不同硬度的实施例6中的组合物B进行溶出度测定，使用500ml的含0.8％吐温80的盐酸加氯化钾缓冲液(pH2.0)作为溶出介质，并在37℃以50rpm的桨速进行溶出实验，结果如表16-17所示。
表16 组合物B中化合物5在不同溶出介质中的溶出数据
硬度 0min 15min 30min 45min 60min
110N 0.0％ 67.0％ 92.8％ 95.1％ 95.8％
120N 0.0％ 74.3％ 97.9％ 99.8％ 102.9％
130N 0.0％ 47.6％ 79.4％ 92.4％ 94.9％
表17 组合物B中SNAC在不同溶出介质中的溶出数据
硬度 0min 15min 30min 45min 60min
110N 0.0％ 69.3％ 93.4％ 95.1％ 95.9％
120N 0.0％ 72.1％ 94.8％ 96.3％ 96.5％
130N 0.0％ 51.8％ 82.4％ 94.0％ 95.3％
从上述实验结果可知，本发明的GLP-1药物组合物在硬度低于130N时，均有较好的溶出性能。
实施例10
本实验的目的在于测试本发明的活性物质起始物料具有不同粒径D90的GLP-1药物组合物的溶出性能
按照实施例7中类似的步骤，对活性物质起始物料具有不同粒径D90的实施例6中的组合物B进行溶出度测定，使用500ml的含0.8％吐温80的盐酸加氯化钾缓冲液(pH2.0)作为溶出介质，并在37℃以50rpm的桨速进行溶出实验，结果如表18-19所示。
表18 组合物B中化合物5在不同溶出介质中的溶出数据
粒径D90(μm) 0min 15min 30min 45min 60min
15 0.0％ 71.6％ 95.2％ 95.5％ 95.5％
75 0.0％ 68.6％ 94.4％ 97.1％ 97.5％
130 0.0％ 67.0％ 92.8％ 95.1％ 95.8％
表19 组合物B中SNAC在不同溶出介质中的溶出数据
粒径D90(μm) 0min 15min 30min 45min 60min
15 0.0％ 75.0％ 98.4％ 98.7％ 98.7％
75 0.0％ 70.0％ 95.6％ 98.2％ 98.6％
130 0.0％ 69.3％ 93.4％ 95.1％ 95.9％
从上述实验结果可知，本发明的GLP-1药物组合物所用活性物质起始物料的粒径D90处于15-130μm之间时，均有较好的溶出性能。
实施例11 在正常小鼠昆明(KM)小鼠中的药效学研究
本研究的目的在于证实本发明GLP-1药物组合物对血糖和摄食量的控制。
将雄性KM小鼠(购自维通利华)于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在在相对湿度40％-60％，温度为22℃-26℃。1-2周的适应期后，开始用于实验。
于实验当日前一天禁食，实验开始前，评估基础血糖，并对小鼠称重。根据随机血糖和体重将小鼠匹配分配到治疗组、对照组或溶媒组(SNAC组)，共6组，每组6只，各组分别接受如下处理：灌胃混悬液给药(10ml/kg)，向治疗组分别施用组合物I、组合物II、组合物III和组合物IV，向对照组施用组合物V，向溶媒组施用组合物VI。
采用灌胃给药方式(10ml/kg体重)，在给药1.5小时时测定血糖(设置为0时血糖)，于给药2小时时进行腹腔糖耐量实验(ipGTT实验)，步骤如下：于指定时间点尾尖采血测定空腹血糖，之后腹腔给予葡萄糖溶液(20％葡萄糖，10mL/kg)，监测给糖后0.5小时、1小时、2小时后小鼠血糖值，连续开展ipGTT实验两次。用酒精棉球清洁鼠尾部，使用一次性采血针从尾巴采集血滴，用血糖仪(罗氏)及配套试纸进行测定。ipGTT实验结束后给食，分别于当日下午9时和第二日早上9时监测小鼠摄食量。
绘制给药后血糖对时间的剂量响应曲线，为了更直观及定量说明本发明的GLP-1组合物对血糖的影响，对于每个单独的剂量响应曲线，计算从0至监测终点的血糖-时间曲线下面积(AUC)。其中，AUC值越小，表明降糖效果越好，药效越好。
图1a-图1c显示了本发明的GLP-1组合物在灌胃给药后具有降糖和抑制摄食的效果。图1a和图1b显示，本发明的包含化合物5与SNAC的组合物对KM小鼠具有降糖效果，当化合物5与SNAC的质量比为7∶350或7∶400时，其降糖效果与包含索马鲁肽的组合物相当或更优。图1c显示，当化合物5与SNAC的质量比为7∶350时，其抑制小鼠摄食的效果与同剂量的索马鲁肽相当。
实施例12 在II型糖尿病db/db小鼠中的药效学研究
本研究的目的在于证实本发明GLP-1药物组合物对db/db小鼠的血糖控制。
将雄性db/db小鼠(卡文斯)于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在相对湿度40％-60％，温度为22℃-26℃。1-2周的适应期后，开始用于实验。
于实验当日前一天禁食，实验开始前，评估基础血糖，并对小鼠称重。根据随机血糖和体重将糖尿病小鼠匹配分配到治疗组、对照组或溶媒组 (SNAC组)，共3组，每组6只，各组分别接受如下处理：灌胃混悬液给药(10ml/kg)，向治疗组施用组合物VII，向对照组施用组合物VIII，向溶媒组施用组合物IX。
采用灌胃给药方式(10ml/kg体重)，在给药0.5小时后测定0时血糖，给药后1小时参照实施例11进行ipGTT实验(10％葡萄糖，10mL/kg)，监测给糖后0.5小时、1小时、2小时后小鼠血糖值，连续开展两次ipGTT实验。
用酒精棉球清洁鼠尾部，使用一次性采血针从尾巴采集血滴，用血糖仪(罗氏)及配套试纸进行测定。
绘制给药后血糖对时间的剂量响应曲线，为了更直观及定量说明本发明的GLP-1组合物对血糖的影响，对于每个单独的剂量响应曲线，计算从0至监测终点的血糖-时间曲线下面积(AUC)。其中，AUC值越小，表明降糖效果越好，药效越好。
如图2a-图2b所示，本发明的GLP-1组合物在给药后具有预料不到的增加的降糖药效。这进一步证明了本发明的包含化合物5与SNAC的组合物在给药后对db/db小鼠的降糖效果与同剂量下索马鲁肽灌胃后的降糖效果基本一致。
实施例13 在SD大鼠中的药效学研究
本研究的目的在于证实本发明GLP-1药物组合物对血糖的控制。
雄性SD大鼠(维通利华)于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在在相对湿度40％-60％，温度为22℃-26℃。1-2周的适应期后，开始用于实验。
于实验当日前一天禁食16小时，实验开始前评估基础血糖，并对大鼠称重。根据随机血糖和体重将SD大鼠匹配分配到治疗组、对照组或溶媒组(SNAC组)，共3组，每组6只，各组分别接受如下处理：灌胃片剂给药(3片/只，给水3ml)，向治疗组施用组合物G，向对照组包施用组合物H，向溶媒组施用组合物J。
采用灌胃片剂给药方式，3片/只，在给药后2小时参照实施例11进行ipGTT(20％葡萄糖，10mL/kg)，监测给糖后0.5小时、1小时、2小时后小鼠血糖值。
用酒精棉球清洁鼠尾部，使用一次性采血针从尾巴采集血滴，用血糖仪(罗氏)及配套试纸进行测定。
绘制给药后血糖对时间的剂量响应曲线，为了更直观及定量说明本发明的GLP-1组合物对血糖的影响，对于每个单独的剂量响应曲线，计算从0至 监测终点的血糖-时间曲线下面积(AUC)。其中，AUC值越小，表明降糖效果越好，药效越好。
图3a-图3b显示了本发明的GLP-1组合物在灌胃给药后，相对于索马鲁肽组合物，在SD大鼠中有预料不到的更加优异的降糖效果。
实施例14 在ICR小鼠中的药效学研究
本研究的目的在于证实本发明GLP-1药物组合物对血糖的控制。
将ICR小鼠于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在在相对湿度40％-60％，温度为22℃-26℃。1-2周的适应期后，开始用于实验。
于实验当日前禁食16小时，实验开始前评估基础血糖，并对小鼠称重。根据随机血糖和体重将ICR小鼠匹配分配到治疗组、对照组或溶媒组(SNAC组)，共3组，每组6只，各组分别接受如下处理：灌胃混悬液给药(10ml/kg)，向治疗组施用组合物X，向对照组施用组合物XI，向溶媒组施用组合物XII。
采用灌胃给药方式，在给药1.5小时后测定0时血糖，在给药后2小时参照实施例11进行ipGTT(10％葡萄糖，10mL/kg)，监测给糖前、糖后0.5小时、1小时、2小时后小鼠血糖值。用酒精棉球清洁鼠尾部，使用一次性采血针从尾巴采集血滴，用血糖仪(罗氏)及配套试纸进行测定。第二天及第三天分别再进行ipGTT。
绘制给药后血糖对时间的剂量响应曲线，为了更直观及定量说明本发明的GLP-1组合物对血糖的影响，对于每个单独的剂量响应曲线，计算从0至监测终点的血糖-时间曲线下面积(AUC)。其中，AUC值越小，表明降糖效果越好，药效越好。
图4a-图4b显示，本发明的包含化合物5与SNAC的组合物对ICR小鼠具有降糖效果，其降糖效果与包含索马鲁肽的组合物相当。
实施例15 药代动力学
本实施例的目的在于说明本发明药物组合物的体内药代动力学性质。
SD大鼠的药代动力学
SD大鼠25只，每组5只(雄性)，分为组合物B低剂量组(10mg/kg)、组合物B中剂量组(15mg/kg)、和组合物B高剂量组(20mg/kg)，经口灌胃单次给药。给药前禁食约16小时，分别于给药前(0min)、给药后15min、30min、1hr，2hr，3hr，5hr，8hr，12hr，24hr，48hr，72hr采 血测定血药浓度。使用WinNonLin v6.4软件的非房室模型计算药代参数C max、T max、T 1/2、AUC 0-t、MRT，试验结果示出在表20中。
表20：向SD大鼠灌胃给药组合物B后的药代动力学参数
Figure PCTCN2022101272-appb-000011
C max＝最大实测血浆浓度，T max＝最大实测血药浓度对应的时间，T 1/2＝末端消除半衰期，AUC 0-t＝0-t时间-血糖浓度时间曲线下面积，MRT＝平均驻留时间
由上述实验结果可知，在SD大鼠体内，本发明的化合物5与SNAC的组合物具有较长的半衰期，以及较长的平均驻留时间。
实施例16 颗粒均匀度实验
本实施例的目的在于说明不同制备方法得到的本发明组合物的均匀度。
按照实施例6中的一次性制粒工艺制备组合物C，对照例1中的分开制粒工艺制备对照组合物A，待各自混合机停止转动后，打开混合机盖，在物料上、中、下三个水平位置进行多点取样，取样数量不少于6个点，每点取样量为1-3倍单个片剂重量，取样后通过高效液相色谱法(HPLC)进行含量检测，检测步骤如下：
在Phenomenex Luna C8(4.6*50mm)柱上，在柱温为35℃、样品池温度为5℃时，用洗脱相以1.0ml/min的流速进行测试。洗脱用由以下组成的流动相进行：
A相为0.1％三氟乙酸水溶液；
B相为0.1％三氟乙酸乙腈溶液。
梯度：0-8min的70％/30％A/B至35％/65％A/B的线性变化，8-8.01min至70％/30％A/B的线性变化，8.01-13min的70％/30％A/B的等度梯度。
检测波长为214nm/235nm，流速为1.0ml/min，进样量为10μl。表21示出了分开制粒与一次制粒得到样品的总混颗粒均匀度。
表21
样品 化合物5纯度均值％ RSD％
对照组合物A 95.70 8.01
组合物C 101.4 2.82
从上述实验结果可知，通过一次制粒工艺得到的组合物C的样品颗粒均匀度比分开制粒得到的对照组合物A更高。
实施例17
本实施例中制剂的化学稳定性能够用在30℃/65RH条件下存储1个月和2个月后测得的有关物质的量的变化来表示。
有关物质的量的测定
通过高效液相色谱法(HPLC)测定有关杂质的含量，在Waters Kromasil 100-3.5-C8(4.6*250mm)柱上，在柱温为35℃、样品池温度为5℃时，用洗脱相以1.0ml/min的流速进行测试。洗脱用由以下组成的流动相进行：
A相包含90mM磷酸二氢钾和10％乙腈(v/v)，pH2.4
B相为75％(v/v)乙腈。
梯度：0-5min的75％/25％A/B至55％/45％A/B的线性变化，5-12min至50％/50％A/B的线性变化，12-42min至40％/60％A/B的线性变化，42-60min的10％/90％A/B的线性变化，60-61min至75％/25％A/B的线性变化，61-70min的75％/25％A/B的等度梯度。
检测波长为214nm，流速为1.0ml/min，进样量为15μl。表22示出了，在30℃存储1个月和2个月相对于第0天时有关物质的量的变化。
表22
Figure PCTCN2022101272-appb-000012
由上表可知，本发明的GLP-1药物组合物中有关物质的量随着时间的变化增加非常缓慢，表明上述药物组合物具有优异的化学稳定性。
实施例18
在II型糖尿病Kkay小鼠中的长期药效学研究
本研究的目的在于证实本发明GLP-1药物组合物中的GLP-1化合物对II型糖尿病Kkay小鼠的降糖效果
在II型糖尿病Kkay小鼠上测试实施例5的化合物5和实施例2的化合物2。化合物5和化合物2以100和300μg/kg的不同剂量给予小鼠，测定本发明GLP-1药物组合物中的GLP-1化合物降低血糖效果和HbA1c的效果。
12-14周龄雄性Kkay小鼠于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在在相对湿度40％-60％，温度为22℃-24℃。1-2周的适应期后，开始用于实验。
于当日实验开始前评估基础血糖，并对小鼠称重。根据随机血糖和体重将糖尿病小鼠匹配分配到溶媒组或治疗组，接受如下处理：皮下注射溶媒，或皮下注射本发明的GLP-1药物组合物中的GLP-1化合物100和300μg/kg。其中溶媒包含：丙二醇14mg/ml，苯酚5.5mg/ml，磷酸氢二钠1.133mg/ml，pH7.4。
采用皮下给药方式(50μl/10g体重)，颈背部皮下注射给药，在大约上午10：00(时间0)给予本发明的GLP-1药物组合物中的GLP-1化合物或溶媒，每2天给药1次，连续给药16次，在首次给药后3h、6h，1天和2天评估小鼠血糖，末次给药48h后取EDTA抗凝检测HbA1c。
图5a-5b显示了本发明的药物组合物中使用的GLP-1衍生物具有预料不到的增加的降糖药效，实施例5和实施例2的标题化合物对Kkay小鼠有明显的降糖效果。图5c显示本发明实施例5和实施例2的标题化合物对II型糖尿病Kkay小鼠有明显的降低HbA1c的效果。
实施例19
组合物的制备
根据表23中显示的各组分含量，参考实施例6中的制备方法，制备含有SNAC和本发明GLP-1化合物的片剂。
表23 片剂组成，以“每片”表示
组分 K L M N O P Q R S
化合物5(mg) 15 80 10 20 - 3 - 40 60
索马鲁肽(mg) - - - - 7 - - - -
SNAC(mg) 300 300 300 300 300 18 18 300 300
聚维酮K90(mg) 8 8 8 8 8 0.5 0.5 8 8
微晶纤维素(mg) 68 68 68 68 68 0.8 0.8 68 68
硬脂酸镁(mg) 14 14 14 14 14 4.1 4.1 14 14
二氧化硅(mg) 8 8 8 8 8 0.5 0.5 8 8
片重(mg) 413 478 408 418 405 26.9 23.9 438 458
根据表24中各组分含量，制备含有SNAC和本发明的GLP-1化合物的组合物，以及仅含有SNAC而不含有GLP-1化合物的组合物，各组合物溶剂均为纯化水，均为混悬液的形式。
表24
组分/组合物 XIII XIV XV XVI
化合物5(mg/ml) 0.5 1.5 4.5 0
SNAC(mg/ml) 30 30 30 30
实施例20
参考实施例7中的实验步骤，对实施例19中的组合物K和L进行溶出度测定，使用含0.1％吐温介质的磷酸盐缓冲液(pH6.8)作为溶出介质，并在37℃，以70rpm的桨速进行溶出实验，结果如表25-26所示。
表25 组合物K和L中化合物5的溶出数据
样品 0min 10min 15min 20min 30min
组合物L 0.0％ 46.7％ 64.7％ 78.9％ 93.7％
组合物K 0.0％ 48.3％ 67.3％ 82.1％ 96.5％
表26 组合物K和L中SNAC的溶出数据及SNAC与化合物5的溶出曲线相似度F2因子
样品 0min 10min 15min 20min 30min F2
组合物L 0.0％ 49.3％ 67.2％ 80.8％ 94.3％ 82.0
组合物K 0.0％ 48.1％ 65.8％ 79.1％ 91.2％ 74.1
从上述实验结果可知，本发明的GLP-1药物组合物中活性物质与SNAC的溶出速率接近，即具有较高的F2因子，提示本发明的药物组合物具有较好的生物利用度。
实施例21
在II型糖尿病db/db小鼠中的药效学研究
本研究的目的在于证实本发明GLP-1药物组合物对db/db小鼠的血糖控制。
将db/db小鼠(雌雄各半)和m/m小鼠(雌雄各半)于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在相对湿度40％-60％，温度为22℃-26℃。1-2周的适应期后，开始用于实验。
于实验当日前一天禁食，实验开始前评估基础血糖，并对小鼠称重。m/m小鼠作为正常对照组，db/db小鼠根据随机血糖和体重被分配到治疗组、或溶媒组(SNAC组)，共5组，每组8只，治疗组和溶媒组分别接受如下处理：灌胃混悬液给药(10ml/kg)，向治疗组分别施用组合物VIII、组合物XIV、和组合物XV，向溶媒组施用组合物XVI。
采用灌胃给药方式(10ml/kg体重)，在给药0.5小时后测定0时血糖，给药后1小时参照实施例11进行ipGTT实验(10％葡萄糖，1g/kg)，监测给糖后15min、30min、60min、75min、90min、120min、150min、210min、240min、360min小鼠血糖值。
用酒精棉球清洁鼠尾部，使用一次性采血针从尾巴采集血滴，用血糖仪(罗氏)及配套试纸进行测定。
绘制给药后血糖对时间的剂量响应曲线，为了更直观及定量说明本发明的GLP-1组合物对血糖的影响，对于每个单独的剂量响应曲线，计算从0至监测终点的血糖-时间曲线下面积(AUC)。其中，AUC值越小，表明降糖效果越好，药效越好。
如图6a-图6b所示，本发明的GLP-1组合物在给药后具有预料不到的降糖药效，本发明实施例5的标题化合物和SNAC的组合物对db/db小鼠有明显的降糖效果，改善db/db小鼠的糖耐量，且呈现剂量依赖性。
实施例22
在II型糖尿病db/db小鼠中的药效学研究
本研究的目的在于证实本发明GLP-1药物组合物对db/db小鼠的血糖和摄食量的控制。
参照实施例21类似的实验步骤，在II型糖尿病db/db小鼠中进行药效学研究。根据随机血糖和体重将糖尿病小鼠分配到治疗组、或溶媒组(SNAC组)，共3组，每组8只，治疗组和溶媒组分别接受如下处理：灌胃混悬液给药(10ml/kg)，向治疗组分别施用组合物XIV、和组合物XV，向溶媒组施用组合物XVI。
采用灌胃给药方式(10ml/kg体重)，监测给药后1h、2h、4h、6h、12h、24h、48h小鼠血糖值。同时，给药后即刻恢复饮食，并记录施用组合物XV和组合物XVI小鼠在给药前(0min)的体重，和给药后12h、24h、48h、72h的体重和摄食量。
用酒精棉球清洁鼠尾部，使用一次性采血针从尾巴采集血滴，用血糖仪(罗氏)及配套试纸进行测定。
如图7a-图7d所示，本发明的GLP-1组合物在给药后具有预料不到的降糖药效、体重减轻效果、及抑制摄食的效果。如图7a和7b显示，本发明实施例5的标题化合物和SNAC的组合物对db/db小鼠有明显的降糖效果，图7c和图7d分别显示了本发明实施例5的标题化合物和SNAC的组合物对db/db小鼠有降体重和控制摄食的效果。
实施例23
本实施例的目的在于说明本发明组合物的体内药代动力学性质。
食蟹猴中的药代动力学
食蟹猴9只，每组3只(2只雄性，1只雌性)，分为化合物5低剂量组(组合物M)、化合物5高剂量组(组合物N)，和索马鲁肽组(对照组，组合物O)，连续7天经口灌胃给药，每天一次，每次一片。第七天分别于给药前(0min)、给药后15min、30min、1hr，2hr，4hr，8hr，12hr，24hr采血测定血药浓度。使用WinNonLin v6.4软件的非房室模型计算药代参数C max、T max、T 1/2、AUC 0-t、MRT，试验结果示出在表27中。
表27 向食蟹猴灌胃给药后的药代动力学参数
Figure PCTCN2022101272-appb-000013
由上述实验结果可知，在食蟹猴体内，本发明的化合物5口服制剂表现与对照组索马鲁肽口服制剂相当甚至更长的半衰期，以及具有相当的平均驻留时间。
实施例24 在SD大鼠中的药效学及药代学研究
本研究的目的在于证实本发明GLP-1药物组合物体重的控制及在SD大鼠体内的药代动力学性质。
雄性SD大鼠(维通利华)于屏障环境内饲养于合适规格的饲养盒中，自由获取标准食物和纯化水，环境条件控制在在相对湿度40％-60％，温度为22℃-26℃。1-2周的适应期后，开始用于实验。
于实验当日前一天禁食，实验开始前评估基础血糖，并对大鼠称重。根 据随机血糖和体重将SD大鼠匹配分配到治疗组、或溶媒组(SNAC组)，共4组，每组8只，各组分别接受如下处理：灌胃片剂给药(3片/只，给水3m1)，向治疗组施用粒径分别为15.7μm(小粒径组)、51.6μm(中粒径组)、和134μm(大粒径组)的组合物P，向溶媒组施用组合物Q。
采用灌胃片剂给药方式，3片/只，在给药前(day0)，给药后12、24、和48小时检测体重，并在给药前(day-1)、给药后15min、30min、1hr，2hr，3hr，8hr，24hr、48hr采血测定血药浓度。使用WinNonLin v6.4软件的非房室模型计算药代参数C max、T max、T 1/2、AUC 0-t、MRT，试验结果示出在表28中。
表28：向SD大鼠灌胃给药后的药代动力学参数
Figure PCTCN2022101272-appb-000014
如图8所示，本发明的化合物5口服制剂在上述粒径范围内均有预料不到的体重减轻效果。
且在SD大鼠体内，本发明的化合物5口服制剂在上述粒径范围内均较长的半衰期、较高的体内暴露量，以及较长的平均驻留时间。
序列表
Figure PCTCN2022101272-appb-000015

Claims (25)

  1. 药物组合物，其包含GLP-1化合物和N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐，其中所述GLP-1化合物为式B的化合物，或其药学上可接受的盐、酰胺或酯：
    [Acy-(L1) r-(L2) q]-G1  (B)，
    其中G1为在对应于GLP-1(7-37)(SEQ ID NO：1)的位置34处具有Arg及位置8处具有Ala或Gly的GLP-1类似物，[Acy-(L1) r-(L2) q]是连接至所述GLP-1类似物的位置26的Lys残基的ε氨基上的取代基，其中
    r为1-10的整数，q为0或1-10的整数；
    Acy是包含20-24个碳原子的脂肪族二酸，其中在形式上羟基已从所述脂肪族二酸的羧基之一中去除；
    L1是选自下述的氨基酸残基：γGlu、αGlu、βAsp、αAsp、γ-D-Glu、α-D-Glu、β-D-Asp或α-D-Asp；
    L2是中性的、包含亚烷基二醇的氨基酸残基；
    Acy、L1、和L2之间以酰胺键连接；和
    L1和L2在式(B)中出现的顺序可以独立地互换。
  2. 如权利要求1所述的药物组合物，其中，
    G1为[Gly8，Arg34]GLP-1-(7-37)肽(SEQ ID NO：2)或[Arg34]GLP-1-(7-37)肽(SEQ ID NO：3)，优选为[Gly8，Arg34]GLP-1-(7-37)肽；和/或
    r为1、2、3、4、5或6，优选地，r为1、2、3或4，优选地，r为1或2，优选地，r为1；和/或
    q为0、1、2、3、4、5、6、7或8，优选地，q为0、1、2、3或4，更优选，q为0、1、或2；和/或
    Acy是包含20-23个碳原子的脂肪族二酸，优选Acy是包含20、21、或22个碳原子的脂肪族二酸。
  3. 如权利要求1-2任一项所述的药物组合物，其中，
    L2是：-HN-(CH 2) 2-O-(CH 2) 2-O-CH 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-CO-、-HN-(CH 2) 3-O-(CH 2) 4-O-(CH 2) 3-NH-CO-、 -HN-(CH 2) 3-O-(CH 2) 4-O-(CH 2) 3-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 4-O-(CH 2) 3-NH-CO-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-CH 2-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-NH-CO-(CH 2) 2-CO-、-HN-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-NH-CO-(CH 2) 2-CO-、-HN-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 2-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-NH-CO-CH 2-O-CH 2-CO-、-HN-(CH 2) 3-O-(CH 2) 3-O-CH 2-CO-、或-HN-(CH 2) 4-O-(CH 2) 4-O-CH 2-CO-；优选L2是-HN-(CH 2) 2-O-(CH 2) 2-O-CH 2-CO-；和/或
    L1选自γGlu或βAsp，优选L1为γGlu；和/或
    Acy是HOOC-(CH 2) 18-CO-、HOOC-(CH 2) 19-CO-、HOOC-(CH 2) 20-CO-、HOOC-(CH 2) 21-CO-或HOOC-(CH 2) 22-CO-，优选地，Acy是HOOC-(CH 2) 18-CO-、HOOC-(CH 2) 20-CO-或HOOC-(CH 2) 22-CO-。
  4. 如权利要求1-3任一项所述的药物组合物，其中，式(B)中Acy、L1、和L2之间依次以酰胺键连接，L2的C末端连接至所述GLP-1类似物的位置26的Lys残基的ε氨基上。
  5. 如权利要求1-4任一项所述的药物组合物，所述GLP-1化合物选自下述化合物：
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8， Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37) 肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、或
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽；
    优选，所述化合物选自下述化合物：
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、或
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽。
  6. 如权利要求1-5任一项所述的药物组合物，其中所述N-(8-(2-羟基苯甲酰基)氨基)辛酸(NAC)的盐为N-(8-(2-羟基苯甲酰基)氨基)辛酸钠盐(SNAC)。
  7. 如权利要求1-6任一项所述的药物组合物，其中所述组合物进一步包含一种或多种可药用赋形剂。
  8. 如权利要求1-7任一项所述的药物组合物，其中所述可药用赋形剂选自助流剂、粘合剂、填充剂、崩解剂和润滑剂中的一种或多种。
  9. 如权利要求1-8任一项所述的药物组合物，其中所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅；和/或
    所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90；和/或
    所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素或无水乳糖，更优选为微晶纤维素；和/或
    所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁。
  10. 如权利要求1-9任一项所述的药物组合物，其包含：
    至少约50％(w/w)、优选至少约55％(w/w)、优选至少约60％(w/w)、优选约50％-90％(w/w)、优选约55％-85％(w/w)、优选约60％-80％(w/w)、优选约61％(w/w)、约62％(w/w)、约63％(w/w)、约64％(w/w)、约65％(w/w)、约66％(w/w)、约67％(w/w)、约68％(w/w)、约69％(w/w)、约70％(w/w)、约71％(w/w)、约72％(w/w)、约73％(w/w)、约74％(w/w)、 约75％(w/w)、约76％(w/w)、约77％(w/w)、约78％(w/w)或约79％(w/w)的NAC的盐，优选，所述NAC的盐为SNAC；和/或
    不超过25％，优选不超过20％(w/w)、优选不超过17％(w/w)、优选不超过15％(w/w)、优选约0.5％-20％(w/w)、优选约0.5％-18.5％(w/w)、优选约0.5％-16.5％(w/w)、优选约0.5％-15％(w/w)、优选约0.5％-13％(w/w)、优选约0.5％-12％(w/w)、优选约0.5％-11％(w/w)、优选约0.6％-11％(w/w)、优选约0.6％-10％(w/w)、优选约0.6％-9％(w/w)、优选约0.6％-8％(w/w)、优选约0.6％-7％(w/w)、优选约0.6％-6％(w/w)、优选约0.7％-5％(w/w)、优选约1.2％-11％(w/w)、优选约1.2％-10％(w/w)、优选约1.2％-9％(w/w)、优选约1.2％-8％(w/w)、优选约1.2％-7％(w/w)、优选约1.2％-6％(w/w)、优选约1.2％-5％(w/w)、优选约1.2％-4.5％(w/w)、优选约1.4％-4％(w/w)、优选约1.4％-3.5％(w/w)、优选约1.4％-3％(w/w)，优选约1.5％(w/w)、约1.7％(w/w)、约2％(w/w)、约2.5％(w/w)、或约2.8％(w/w)的所述GLP-1化合物，优选，所述GLP-1化合物选自N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8， Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、和
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽。
  11. 如权利要求1-10任一项所述的药物组合物，其还包含：
    约0.1％-20％(w/w)、优选约0.2％-10％(w/w)、优选约0.3％-5％(w/w)、优选约0.5％-3％(w/w)、优选约0.7％-2％(w/w)、优选约1％-2％(w/w)、优选约1.6％(w/w)、约2.0％(w/w)、优选约1.6％(w/w)、约1.7％(w/w)、约1.8％(w/w)、约1.9％(w/w)、或约2.0％(w/w)的粘合剂，优选所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90；和/或
    约5％-40％(w/w)、优选约10％-35％(w/w)、优选约10％-30％(w/w)、优选约10％-25％(w/w)、优选约13％-17％(w/w)、优选约13％(w/w)、约14％(w/w)、约15％(w/w)、约16％(w/w)、约17％(w/w)、或约20％(w/w)的填充剂，所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和 糊精中的一种或多种，优选为微晶纤维素或无水乳糖，更优选为微晶纤维素；和/或
    约0.1％-10％(w/w)、优选约0.5％-10％(w/w)、优选约0.5％-5％(w/w)、优选约0.5％-3.5％(w/w)、优选约2.8％(w/w)、约2.9％(w/w)、约3％(w/w)、约3.1％(w/w)、约3.2％(w/w)、约3.3％(w/w)、约3.4％(w/w)、或约3.5％(w/w)的润滑剂，所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁；和/或
    约0.1％-20％(w/w)、优选约0.2％-10％(w/w)、优选约0.3％-5％(w/w)、优选约0.5％-3％(w/w)、优选约0.7％-2％(w/w)、优选约1％-2％(w/w)、优选约1.6％-2％(w/w)、优选约1.6％(w/w)、约1.7％(w/w)、约1.8％(w/w)、约1.9％(w/w)、或约2％(w/w)的助流剂，所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
  12. 如权利要求1-11任一项所述的药物组合物，其包含：
    约1-100mg，优选约2-90mg，优选约3-80mg，优选约4-60mg，优选约5-55mg，优选约5-50mg，优选约5-45mg，优选约5-40mg，优选约5-35mg，优选约5-30mg，优选约5-25mg，优选约5-20mg，优选约5-15mg，优选约5-10mg，优选约7-50mg，优选约7-30mg，优选约7-25mg，优选约7-20mg，优选约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约14mg、约25mg、或约50mg的所述GLP-1化合物，优选，所述GLP-1化合物选自N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8， Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37) 肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、和
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽；和/或
    至少约50mg、优选至少约100mg、优选至少约150mg、优选约50-600mg、优选约100-500mg、优选约150-450mg、优选175-425mg、优选约200-400mg、优选约250-400mg、更优选约300mg、350mg、400mg的NAC的盐，所述NAC的盐是SNAC；和/或
    约0.5-50mg，优选约1-40mg，优选约1-30mg，优选约1-25mg，优选约1-20mg，优选约1-15mg，优选约2-14mg，优选约3-13mg，优选约4-12mg， 优选约5-11mg，优选约6-10mg，优选约7-9mg，优选约8mg的粘合剂，所述粘合剂选自聚维酮、共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90；和/或
    约10-150mg，优选约20-140mg，优选约30-130mg，优选约40-120mg，优选约50-110mg，优选约50-100mg，优选约60-90mg，优选约60-80mg，优选约60-70mg，优选约68mg的填充剂，所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素、或无水乳糖，更优选为微晶纤维素；和/或
    约1-50mg，优选约1-40mg，优选约1-30mg，优选约2-20mg，优选约3-20mg，优选约5-20mg，优选约5-15mg，优选约10-15mg，优选约14mg的润滑剂，所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁；和/或
    约1-50mg，优选约1-40mg，优选约1-30mg，优选约2-20mg，优选约3-20mg，优选约5-15mg，优选约5-10mg，优选约8mg的助流剂，所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
  13. 如权利要求1-12任一项所述的药物组合物，所述药物组合物为片剂、颗粒剂或胶囊剂形式，优选，所述药物组合物为片剂形式。
  14. 如权利要求1-13任一项所述的药物组合物，其硬度低于约130N，优选约80-130N，优选约90-130N，优选约100-125N，更优选约110-120N。
  15. 如权利要求1-14任一项所述的药物组合物，其中，所述GLP-1化合物粒径D90优选不超过约200μm，优选不超过约130μm，优选约15-130μm，更优选为约15-50μm。
  16. 药物组合物，含有如下成分：
    约5、10、15、20、25、30、35、40、45、50、55、60、70、80、90、或100mg、优选约7-10mg的N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽；
    约300、350或400mg的SNAC；
    约8mg的聚维酮K90；
    约68mg的微晶纤维素；
    约14mg的硬脂酸镁；和
    约8mg的胶态二氧化硅。
  17. 如权利要求1-16任一项所述的药物组合物，其中，所述药物组合物的总重为约150-1000mg、优选为约175-1000mg、优选为约200-800mg、优选为约400mg-500mg、优选为约400mg、约403mg、约405mg、约408mg、约413mg、约418mg、约423mg、约428mg、约433mg、约438mg、约443mg、约448mg、约455mg、约500mg、约600mg、或约800mg。
  18. 权利要求1-17任一项所述的药物组合物的制备方法，包括将所述GLP-1化合物与NAC的盐混合后进行一次性制粒的步骤。
  19. 如权利要求18所述的方法，其中在将所述NAC的盐与所述GLP-1化合物混合之前，先将所述NAC的盐与润滑剂和/或助流剂混合。
  20. 权利要求1-17任一项所述的药物组合物的制备方法，包括：
    (1)将所述NAC的盐、助流剂和部分润滑剂混合，得到预混粉A；
    (2)将所述GLP-1化合物、粘合剂和填充剂与所述预混粉A混合，得到预混粉B；
    (3)将预混粉B制粒，优选采用干法制粒；
    (4)将得到的颗粒与剩余润滑剂混合，得到总混颗粒；
    (5)将总混颗粒进行压片。
  21. 权利要求18-20任一项所述的药物组合物的制备方法，其中
    所述GLP-1化合物选自N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8， Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[19-羧基十九烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[21-羧基二十一烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[23-羧基二十三烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(23-羧基二十三烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(19-羧基十九烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-(21-羧基二十一烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37) 肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Gly8，Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[20-羧基二十烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(2-[2-(2-[4-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-[2-(2-[2-(4-[22-羧基二十二烷酰基氨基]-4(S)-羧基丁酰基氨基)乙氧基]乙氧基)乙酰基][Arg34]GLP-1-(7-37)肽、
    N-ε 26-(20-羧基二十烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽、和
    N-ε 26-(22-羧基二十二烷酰基氨基)-4(S)-羧基丁酰基-[Arg34]GLP-1-(7-37)肽；和/或
    所述NAC的盐是SNAC；和/或
    所述粘合剂选自聚维酮共聚维酮和羟丙基纤维素，优选为聚维酮，更优选为聚维酮K90；和/或
    所述填充剂选自微晶纤维素、纤维素粉、磷酸氢钙、玉米淀粉、预胶化淀粉、无水乳糖、甘露醇、赤藓糖醇、蔗糖、山梨糖醇、磷酸钙、和糊精中的一种或多种，优选为微晶纤维素、或无水乳糖，更优选为微晶纤维素；和/ 或
    所述润滑剂选自硬脂酸镁、月桂醇硫酸镁、硬脂酸、十八烷基富马酸钠、三山嵛酸甘油酯中的一种或多种，优选为硬脂酸镁；和/或
    所述助流剂选自滑石粉、和胶态二氧化硅，优选为胶态二氧化硅。
  22. 权利要求1-17任一项所述的药物组合物，其用作药物。
  23. 权利要求1-17任一项所述的药物组合物，其用于治疗或预防高血糖症、糖尿病、和/或肥胖症。
  24. 权利要求1-17任一项所述的药物组合物，在制备用于治疗或预防高血糖症、糖尿病、和/或肥胖症的药物中的用途。
  25. 治疗或预防高血糖、糖尿病、和/或肥胖症的方法，包括施用有效量的权利要求1-17任一项所述的药物组合物。
PCT/CN2022/101272 2021-06-25 2022-06-24 含glp-1化合物的药物组合物 WO2022268213A1 (zh)

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