A pharmaceutical composition comprising a peptide drug active molecule and uses thereof

Abstract

The application relates to the technical field of biological medicine, and particularly provides a pharmaceutical composition containing a peptide drug active molecule and an application thereof. The pharmaceutical composition comprises a peptide drug active molecule and a drug delivery molecule, and the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(1-500); the drug delivery molecule is selected from a structure as shown in formula (I) or a pharmaceutically acceptable salt thereof. The application provides an application of the pharmaceutical composition in preparing an oral dosage form drug. The peptide drug active molecule is significantly improved in stability and permeability in a gastrointestinal fluid by being compounded with the drug delivery molecule, so that gastrointestinal absorption of the peptide drug active molecule is increased and oral bioavailability of the peptide drug active molecule is improved.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a pharmaceutical composition comprising peptide drug active molecules and its uses. Background Technology

[0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone that binds to the GLP-1 receptor expressed on pancreatic β-cells, thereby increasing the expression of glucose transporter 2 and insulin secretion in response to increased blood glucose levels. In addition, GLP-1 reduces the secretion of some pro-inflammatory cytokines. GLP-1 receptor agonists are commonly used to treat type 2 diabetes.

[0003] Currently, GLP-1 receptor agonists on the market are mainly available in injectable form; however, the administration method of injectable formulations is invasive, leading to low patient compliance. This is because GLP-1 receptor agonists have a complex peptide drug active macromolecular structure, and peptides are easily inactivated by digestive enzymes and gastric acid, making it difficult for the active macromolecular structure of peptide drugs to penetrate the gastrointestinal mucosa, resulting in low oral bioavailability. Summary of the Invention

[0004] In view of this, this application provides a pharmaceutical composition comprising a peptide drug active molecule and its use.

[0005] In a first aspect, this application provides a pharmaceutical composition comprising a peptide, the pharmaceutical composition comprising a peptide drug active molecule and a drug delivery molecule, wherein the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(1-500) (e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:13 ...100, 1:110, 1:120, 1:130, 1:100, 1:120, 1:130, 1:100, 1:100, 1:120, 1:130, 1:100, 1:100, 1:120, 1:130, 1:100, 1:100, 1:120, 1:130, 1:100, 1:100, 1:100, 1:120, 1:130, 1:100, 1:100, 1:100, 1:120, 1:1 :140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400, 1:410, 1:420, 1:430, 1:440, 1:450, 1:460, 1:470, 1:480, 1:490, 1:500 (or any range of two values).

[0006] The drug delivery molecule is selected from the structure shown in formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Where j1, j2, and j3 are each independently selected from integers from 0 to 3 (e.g., 0, 1, 2, or 3); and at least one of j1, j2, and j3 is not 0, and j1 + j2 + j3 ≤ 3;

[0009] X is selected from -NHC(O)-, -C(O)O-, or -OC(O)O-;

[0010] R 1a and R 1b Each is independently selected from H, halogens, or C1-C3 alkyl groups;

[0011] L2 exists or does not exist; if L2 exists, L2 is selected from... Among them, R L2a and R L2b Each is independently selected from H, halogen or C1-C3 alkyl, k1 is selected from an integer from 1 to 3 (e.g. 0, 1, 2 or 3), and k2 is selected from an integer from 1 to 5 (e.g. 0, 1, 2, 3, 4 or 5).

[0012] L1 is selected from substituted or unsubstituted C7-C30 hydrocarbon groups (e.g., C7-C30 alkane group, C7-C30 enynyl group, or C7-C30 alkyne group).

[0013] In some alternative implementations, L2 is absent; or L2 is present, and L2 is selected from... ; where k2 is selected from integers from 1 to 5 (e.g., 0, 1, 2, 3, 4 or 5).

[0014] In some specific implementations, L2 is not present.

[0015] In some alternative implementations, L2 is present, and L2 is selected from... ; where k2 is selected from integers from 1 to 5 (e.g., 0, 1, 2, 3, 4 or 5).

[0016] In some specific implementations, X is selected from -C(O)O-.

[0017] In some alternative embodiments, the drug delivery molecule is selected from the structure shown in formula (II) or a pharmaceutically acceptable salt thereof:

[0018]

[0019] Among them, j1, j2, j3, R 1a R 1b L1 is defined as in equation (I).

[0020] In some alternative implementations, j2 = 0; j1 and j3 are each independently selected from integers from 0 to 3 (e.g., 0, 1, 2, or 3); and at least one of j1 and j3 is not 0, j1 + j2 + j3 ≤ 3. In other alternative implementations, j2 = 0; j1 and j3 are each independently selected from integers from 0 to 3; and at least one of j1 and j3 is not 0, j1 + j2 + j3 ≤ 3. In still other alternative implementations, j2 = 0; j1 and j3 are each independently selected from integers from 0 to 2; and at least one of j1 and j3 is not 0, j1 + j2 + j3 ≤ 3. In still other alternative implementations, j2 = 0; j1 and j3 are each independently selected from 0 or 1; and at least one of j1 and j3 is not 0 (e.g., j1 = 1 and j2 = 0 and j3 = 0, or j1 = 0 and j2 = 0 and j3 = 1, or j1 = 1 and j2 = 0 and j3 = 1). In some alternative implementations, j2 = 0; j1 and j3 are each independently selected from 0 or 1, and j1 ≠ j3; in some specific implementations, j1 = 1, j2 = 0, and j3 = 0. In other specific implementations, j1 = 0, j2 = 0, and j3 = 1.

[0021] In some alternative embodiments, the drug delivery molecule is selected from the structure shown in formula (III) or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Where j1 and j3 are each independently selected from integers between 0 and 3 (e.g., 0, 1, 2, or 3); and at least one of j1 and j3 is not 0, and j1 + j3 ≤ 3; R 1a R 1b L1 is defined as in equation (I). In some alternative embodiments, j1 and j3 are each independently selected from integers between 0 and 2; and at least one of j1 and j3 is not 0, j1 + j3 ≤ 3. In some alternative embodiments, j1 and j3 are each independently selected from 0 or 1; and at least one of j1 and j3 is not 0. In some alternative embodiments, j1 and j3 are each independently selected from 0 or 1; and j1 ≠ j3 (e.g., j1 = 0 and j3 = 1, or j1 = 1 and j3 = 0).

[0024] In some alternative embodiments, the drug delivery molecule is selected from the structure shown in formula (IIIA) or a pharmaceutically acceptable salt thereof:

[0025]

[0026] Where j1 is selected from integers between 0 and 3 (e.g., 0, 1, 2, or 3); R 1a R 1b L1 is defined as in equation (I).

[0027] In some alternative embodiments, the drug delivery molecule is selected from the structure shown in formula (IIIB) or a pharmaceutically acceptable salt thereof:

[0028]

[0029] Where j3 is selected from integers between 0 and 3 (e.g., 0, 1, 2, or 3); R 1a R 1b L1 is defined as in equation (I).

[0030] In some alternative implementations, j1, j2, and j3 are each independently selected from 0 or 1; and at least one of j1, j2, and j3 is not 0. For example, j1=1 and j2=0 and j3=0, or j1=0 and j2=1 and j3=0, or j1=0 and j2=0 and j3=1, or j1=1 and j2=1 and j3=0, or j1=1 and j2=0 and j3=1, or j1=0 and j2=1 and j3=1, or j1=1 and j2=1 and j3=1.

[0031] In some alternative implementations, j2 is selected from 0; j1 and j3 are each independently selected from 0 or 1, and at least one of j1 and j3 is not 0. For example, j1=1 and j2=0 and j3=0, or j1=0 and j2=0 and j3=1, or j1=1 and j2=0 and j3=1.

[0032] In some implementations, j1=1, j2=0, and j3=0. In other implementations, j1=0, j2=0, and j3=1.

[0033] In some alternative embodiments, L1 is selected from substituted or unsubstituted C7-C30 alkane groups (e.g., C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, or C30 alkane groups). In other alternative embodiments, L1 is selected from substituted or unsubstituted C7-C19 alkane groups.

[0034] In some alternative implementations, L1 is selected from , , , , , , , , , , , or .

[0035] In some specific implementations, L1 is selected from .

[0036] In some specific implementations, L1 is selected from .

[0037] In some specific implementations, L1 is selected from .

[0038] In some specific implementations, L1 is selected from .

[0039] In some specific implementations, L1 is selected from .

[0040] In some specific implementations, L1 is selected from .

[0041] In some specific implementations, L1 is selected from .

[0042] In some alternative embodiments, L1 is selected from substituted or unsubstituted C7-C30 olefins (e.g., C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, or C30 olefins). In other alternative embodiments, L1 is selected from substituted or unsubstituted C7-C30 olefins, and L1 contains 1-3 carbon-carbon double bonds (e.g., 1, 2, or 3).

[0043] In some alternative embodiments, L1 is selected from substituted or unsubstituted C7-C30 alkynyl groups (e.g., C7-alkynyl, C8-alkynyl, C9-alkynyl, C10-alkynyl, C11-alkynyl, C12-alkynyl, C13-alkynyl, C14-alkynyl, C15-alkynyl, C16-alkynyl, C17-alkynyl, C18-alkynyl, C19-alkynyl, C20-alkynyl, C21-alkynyl, C22-alkynyl, C23-alkynyl, C24-alkynyl, C25-alkynyl, C26-alkynyl, C27-alkynyl, C28-alkynyl, C29-alkynyl, or C30-alkynyl). In other alternative embodiments, L1 is selected from substituted or unsubstituted C7-C30 olefinic groups, and L1 contains 1-3 carbon-carbon triple bonds (e.g., 1, 2, or 3).

[0044] In some alternative embodiments, the drug delivery molecule comprises any of the structures shown below, or a pharmaceutically acceptable salt thereof:

[0045] , ,

[0046] , ,

[0047] , ,

[0048] , ,

[0049] , ,

[0050] , ,

[0051] , ,

[0052] , ,

[0053] , ,

[0054] , ,

[0055] , ,

[0056] , ,

[0057] or .

[0058] In some specific embodiments, the drug delivery molecule is selected from any of the structures shown below or pharmaceutically acceptable salts thereof:

[0059] , , ,or , , , or .

[0060] In some alternative embodiments, the drug delivery molecule comprises any of the structures shown below, or a pharmaceutically acceptable salt thereof:

[0061] , In some alternative embodiments, the drug delivery molecule includes at least one of disodium dodecyl sulfosuccinate (CAS No. 13192-12-6) or disodium dodecyl sulfosuccinate (CAS No. 19040-44-9).

[0062] In some specific embodiments, the drug delivery molecule is selected from... Or, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the drug delivery molecule is selected from disodium dodecyl sulfosuccinate (CAS No. 13192-12-6).

[0063] In some specific embodiments, the drug delivery molecule is selected from... Or, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the drug delivery molecule is selected from disodium dodecyl sulfosuccinate (CAS No. 19040-44-9).

[0064] In some optional embodiments, the molecular weight of the peptide drug active molecule is 300-63000 Da. In some optional embodiments, the molecular weight of the peptide drug active molecule is 300-10000 Da. In some optional embodiments, the molecular weight of the peptide drug active molecule is 300-5000 Da. In some optional embodiments, the molecular weight of the peptide drug active molecule is 1000-6000 Da (e.g., 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, 2000 Da, 2100 Da, 2200 Da, 2300 Da, 2400 Da, 2500 Da, 2600 Da, 2700 Da, 2800 Da, 2900 Da, 3000 Da, 3100 Da, 3200 Da, 3300 Da). The range is 3400Da, 3500Da, 3600Da, 3700Da, 3800Da, 3900Da, 4000Da, 4100Da, 4200Da, 4300Da, 4400Da, 4500Da, 4600Da, 4700Da, 4800Da, 4900Da, 5000Da, 5100Da, 5200Da, 5300Da, 5400Da, 5500Da, 5600Da, 5700Da, 5800Da, 5900Da, 6000Da, or any two values ​​within a range.

[0065] In some optional embodiments, the peptide drug active molecule includes at least one selected from oligopeptide drug active molecules, polypeptide drug active molecules, or protein drug active molecules. In some specific embodiments, the peptide drug active molecule is selected from oligopeptide drug active molecules (e.g., glutathione or thymopentin). In some specific embodiments, the peptide drug active molecule is selected from polypeptide drug active molecules (e.g., liraglutide, smegglutide, exenatide, lixisenatide, benaglutide, or telpoxetine). In some specific embodiments, the peptide drug active molecule is selected from protein drug active molecules (e.g., insulin or dulaglutide).

[0066] In some alternative embodiments, the active peptide drug molecule includes at least one of insulin and its analogues (e.g., insulin aspart, insulin glargine, insulin detemir, etc.), glucagon and its derivatives, glucagon-like peptide-1 receptor agonists, glucagon-like peptide-2 receptor agonists, calcitonin and its derivatives (e.g., calcitonin), growth hormone and its derivatives, somatostatin and its derivatives, thyrotropin-releasing hormone and its derivatives, parathyroid hormone and its derivatives, gonadotropin-releasing hormone and its derivatives, granulocyte colony-stimulating factor and its derivatives, cyclosporine and its derivatives, interferon and its derivatives, angiotensin and its derivatives, erythropoietin and its derivatives, glutathione and its derivatives, or thymosin (e.g., thymosin α1, thymosin β4, thymosin β9, thymosin β10, thymosin β15, or thymopentin, etc.).

[0067] In some specific embodiments, the active peptide drug molecule is selected from glucagon-like peptide-1 receptor agonists.

[0068] In some optional embodiments, the glucagon-like peptide-1 receptor agonist includes at least one of liraglutide (CAS No. 204656-20-2), smegglutide (CAS No. 910463-68-2), dulaglutide (CAS No. 923950-08-7), exenatide (CAS No. 141758-74-9), lixisenatide (CAS No. 320367-13-3), benaglutide (CAS No. 123475-27-4), loxenatide, polyethylene glycol loxenatide (CAS No. 2420483-82-3), or telpolide (CAS No. 2023788-19-2). In some optional embodiments, the glucagon-like peptide-1 receptor agonist includes at least one of exenatide or smegglutide. In some specific embodiments, the active peptide molecule is selected from exenatide. In some other embodiments, the active peptide drug molecule is selected from smeglucopyranoside.

[0069] In some optional embodiments, the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(5-100) (e.g., 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:4 ... 1:48, 1:49, 1:50, 1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, 1:60, 1:61, 1:62, 1:63, 1:64, 1:65, 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, 1:95, 1:96, 1:97, 1:98, 1:99, 1:100, or any range of two values.

[0070] In some alternative embodiments, the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(10-100). In some alternative embodiments, the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(10-50).

[0071] In some embodiments, the weight ratio of the active peptide drug molecule to the drug delivery molecule is 1:5. In some embodiments, the weight ratio is 1:10. In some embodiments, the weight ratio is 1:50. In some embodiments, the weight ratio is 1:100. In some preferred embodiments, the weight ratio is 1:10.

[0072] Secondly, this application provides the use of the pharmaceutical composition described in the first aspect in the preparation of an oral dosage form of medicine.

[0073] In some alternative embodiments, the dosage form of the oral dosage form is selected from tablets, capsules, granules, suspensions, dry suspensions, oral solutions, oral emulsions, oral powders, or granules.

[0074] In some specific embodiments, the dosage form of the oral dosage form is selected from tablets (e.g., regular tablets, sustained-release tablets, enteric-coated tablets, etc.). In some more specific embodiments, the dosage form of the oral dosage form is selected from regular tablets.

[0075] In some other embodiments, the dosage form of the oral dosage form is selected from capsules (e.g., hard capsules, soft capsules, etc.). In some more specific embodiments, the dosage form of the oral dosage form is selected from hard capsules.

[0076] Thirdly, this application provides a medicament comprising the pharmaceutical composition described in the first aspect, and one or more pharmaceutically acceptable excipients.

[0077] In some alternative embodiments, the amount of the pharmaceutical composition based on the medicament is selected from (1-50) wt% (e.g., 1 wt%, 1.25 wt%, 1.5 wt%, 1.75 wt%, 2 wt%, 2.25 wt%, 2.5 wt%, 2.75 wt%, 3 wt%, 3.25 wt%, 3.5 wt%, 3.75 wt%, 4 wt%, 4.25 wt%, 4.5 wt%, 4.75 wt%, 5 wt%, 5.25 wt%, 5.5 wt%, 5.75 wt%, 6 wt%, 6.25 wt%, 6.5 wt%, 6.75 wt%, 7 wt%, 7 wt%). 25wt%, 7.5wt%, 7.75wt%, 8wt%, 8.25wt%, 8.5wt%, 8.75wt%, 9wt%, 9.25wt%, 9.5wt%, 9.75wt%, 10wt%, 10.5wt%, 11wt%, 11.5wt%, 12wt %, 12.5wt%, 13wt%, 13.5wt%, 14wt%, 14.5wt%, 15wt%, 15.5wt%, 16wt%, 16.5wt%, 17wt%, 17.5wt%, 18wt%, 18.5wt%, 19wt%, 19.5wt%, 20 wt%, 20.5wt%, 21wt%, 21.5wt%, 22wt%, 22.5wt%, 23wt%, 23.5wt%, 24wt%, 24.5wt%, 25wt%, 25.5wt%, 26wt%, 26.5wt%, 27wt%, 27.5wt% , 28wt%, 28.5wt%, 29wt%, 29.5wt%, 30wt%, 30.5wt%, 31wt%, 31.5wt%, 32wt%, 32.5wt%, 33wt%, 33.5wt%, 34wt%, 34.5wt%, 35wt%, 35.5w t%, 36wt%, 36.5wt%, 37wt%, 37.5wt%, 38wt%, 38.5wt%, 39wt%, 39.5wt%, 40wt%, 40.5wt%, 41wt%, 41.5wt%, 42wt%, 42.5wt%, 43wt%, 43.5wt%, 44wt%, 44.5wt%, 45wt%, 45.5wt%, 46wt%, 46.5wt%, 47wt%, 47.5wt%, 48wt%, 48.5wt%, 49wt%, 49.5wt%, 50wt% or any range of two values).

[0078] In some alternative embodiments, the pharmaceutically acceptable excipients include at least one of fillers, binders, lubricants, disintegrants, flow aids, flavoring agents, or slow-release modifiers.

[0079] In some alternative embodiments, the filler comprises at least one of microcrystalline cellulose, sorbitol, mannitol, pregelatinized starch, lactose, dicalcium phosphate, or polyvinylpyrrolidone. In other alternative embodiments, the amount of the filler (e.g., microcrystalline cellulose) is selected from (60-90) wt% (e.g., 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 71.25 wt%, 71.5 wt%, 71.75 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 76.5 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, or any range of two values) based on the drug.

[0080] In some alternative embodiments, the gliding agent comprises colloidal silica. In other alternative embodiments, the amount of the gliding agent (e.g., colloidal silica) is selected from (0.1-3.0) wt% (e.g., 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, or any range of two values) based on the drug. In some alternative embodiments, the amount of the gliding agent (e.g., colloidal silica) is selected from (0.1-2.0) wt%, based on the drug.

[0081] In some alternative embodiments, the lubricant comprises at least one of magnesium stearate or talc. In other alternative embodiments, the amount of the lubricant (e.g., magnesium stearate) is selected from (0.1-1.5) wt% (e.g., 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, or any range of two values) based on the drug.

[0082] In some alternative embodiments, the adhesive comprises at least one of povidone, polyvinylpyrrolidone, starch paste, hydroxypropyl methylcellulose (specifically, low-viscosity hydroxypropyl methylcellulose, such as E3, E5, or E15), hydroxypropyl cellulose, or methylcellulose. In other alternative embodiments, the amount of the adhesive, based on the drug, is (2-10) wt% (e.g., 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%, or any range of two values).

[0083] In some alternative embodiments, the disintegrant includes at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, or low-substituted hydroxypropyl cellulose. In other alternative embodiments, the amount of the disintegrant based on the drug is (3-15) wt% (e.g., 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%, 10.5 wt%, 11 wt%, 11.5 wt%, 12 wt%, 12.5 wt%, 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, 15 wt%, or any range of two values).

[0084] In some alternative embodiments, the flavoring agent includes at least one selected from sorbitol, mannitol, aspartame, sucrose, peppermint flavoring, or fruit flavoring. In other alternative embodiments, the amount of the flavoring agent based on the drug is (0.5-3) wt% (e.g., 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%, or any range of two values).

[0085] In some alternative embodiments, the release modifier includes hydroxypropyl methylcellulose (specifically, high-viscosity hydroxypropyl methylcellulose, such as K4M, K15M, or K100M). In other alternative embodiments, the amount of the release modifier (e.g., hydroxypropyl methylcellulose) is selected from (10-80) wt% (e.g., 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, or any range of two values) based on the drug.

[0086] In some optional embodiments, based on the drug, the drug comprises 0.5-3 wt% peptide drug active molecules, 5-30 wt% drug delivery molecules, 60-90 wt% filler, 0-2 wt% flow aid, 0-30 wt% release regulator, and 0.1-1 wt% lubricant. In other optional embodiments, based on the drug, the drug comprises 0.75-3 wt% peptide drug active molecules, 7.5-30 wt% drug delivery molecules, 69.15-85 wt% filler, 0-2 wt% flow aid, 0-22.5 wt% release regulator, and 0.1-1 wt% lubricant. In still other optional embodiments, based on the drug, the drug comprises 0.75-2 wt% peptide drug active molecules, 7.5-20 wt% drug delivery molecules, 70-85 wt% filler, 0-2 wt% flow aid, 0-21.65 wt% release regulator, and 0.1-1 wt% lubricant. In some embodiments, the active peptide drug molecule is selected from exenatide or smegglutinide. In some embodiments, the drug delivery molecule is selected from disodium dodecyl sulfosuccinate. In some embodiments, the filler is selected from microcrystalline cellulose. In some embodiments, the flow aid is selected from colloidal silica. In some optional embodiments, the release regulator is selected from hydroxypropyl methylcellulose. In some embodiments, the lubricant is selected from magnesium stearate.

[0087] In some specific embodiments, based on the drug, the drug comprises 2 wt% peptide drug active molecules, 20 wt% drug delivery molecules, 76.83 wt% microcrystalline cellulose, 0.67 wt% colloidal silica, and 0.5 wt% magnesium stearate.

[0088] In some other embodiments, based on the drug, the drug comprises 1.2 wt% peptide drug active molecules, 12 wt% drug delivery molecules, 85.9 wt% microcrystalline cellulose, 0.5 wt% colloidal silica, and 0.4 wt% magnesium stearate.

[0089] In some alternative embodiments, the drug is based on 1.5 wt% peptide drug active molecules, 15 wt% drug delivery molecules, 82 wt% microcrystalline cellulose, 1 wt% colloidal silica, and 0.5 wt% magnesium stearate.

[0090] In some alternative embodiments, the drug is based on 0.75 wt% peptide drug active molecule, 7.5 wt% drug delivery molecule, 71.25 wt% microcrystalline cellulose, 20 wt% hydroxypropyl methylcellulose, and 0.5 wt% magnesium stearate.

[0091] This application has the following beneficial effects:

[0092] By combining the active peptide drug molecule with the drug delivery molecule of this application, the stability and permeability of the active peptide drug molecule in gastrointestinal fluid are significantly improved, thereby increasing its absorption in the gastrointestinal tract and improving its oral bioavailability. Attached Figure Description

[0093] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0094] Figure 1 These are the dissolution profiles for the capsules and tablets in this application. Detailed Implementation

[0095] This application discloses "a pharmaceutical composition comprising a peptide drug active molecule and its use." Those skilled in the art can refer to the content herein and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this application. The methods and applications of this application have been described through preferred preparation examples. Those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this application to realize and apply the technology of this application.

[0096] General definitions and terminology:

[0097] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this application, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0098] In this article, "halogen" or "halogenated" refers to any of the radioactive-stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0099] In this document, "alkyl" refers to a fully saturated (i.e., free of carbon-carbon double or triple bonds) straight-chain or branched alkane chain. Alkyl groups can have 1 to 6 carbon atoms (wherein the text, numerical ranges such as "1 to 6" refer to each integer within a given range; for example, "1 to 6 carbon atoms" means that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the term "alkyl" where no numerical range is specified). By way of example only, "C1-C3 alkyl" indicates an alkyl chain having one to three carbon atoms, i.e., the C1-C3 alkyl group is selected from methyl, ethyl, propyl, and isopropyl. Alkyl groups can be substituted or unsubstituted.

[0100] In the text, "unsubstituted" means that the specified group does not have substituents.

[0101] In this text, “substituted,” “substituted,” and “replaced” are used interchangeably to indicate that any one or more hydrogen atoms in the given structure are replaced by a specific substituent (e.g., a C1-3 alkyl, C1-3 alkoxy, or halogen) provided that the substitution does not exceed the normal valence of the specified atom and yields a stable compound. Unless otherwise indicated, a substituted group may have one substituent at each substituted position of the group. When more than one position in the given structural formula can be replaced by one or more substituents selected from a specific group, the substituents may be substituted at the substituted positions in the same or different manner.

[0102] In the text, "optionally substituted" is used to define a variable, which can be either unsubstituted or substituted.

[0103] In this document, "includes" or "includes" is an open-ended expression, meaning it includes the contents specified in this disclosure but does not exclude other contents.

[0104] In this document, “optionally,” “optionally,” or “optionally” generally means that the event or condition described below may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0105] In this article, “each… is independently selected”, “…each independently selected”, and “…is independently selected” can be used interchangeably and should be interpreted broadly. They can mean that the specific options expressed by the same symbol in different groups do not affect each other, or that the specific options expressed by the same symbol in the same group do not affect each other.

[0106] In this document, "pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutical acceptable" as described in this disclosure means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0107] In this article, "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0108] In this article, "pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecenoate, glycolate, gluconate, lactate, sebate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylic acid, and naphthalenedisulfonate. These salts can be prepared by methods known in the art.

[0109] In this article, "pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that maintain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts, with sodium salts being the most preferred. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0110] In this text, "pharmaceutical composition" or "composition" may refer to something used for the treatment of a disease or for use in in vitro cell culture experiments. When used for the treatment of a disease, the term "pharmaceutical composition" usually refers to a unit dose form and can be prepared by any method well known in the pharmaceutical industry. All methods involve the step of combining the active ingredient with excipients that constitute one or more adjunct components.

[0111] The term "pharmaceutically acceptable carrier or excipient" as used herein may include any solvent, solid excipient, diluent, or other liquid excipient, etc., suitable for the specific target dosage form. The use of any conventional excipients that are incompatible with the active peptide molecule described herein, such as for any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this disclosure.

[0112] Unless otherwise stated, the structural formula of "compound S1-C12" in this article is: The CAS number is 13192-12-6; it is named disodium dodecyl sulfosuccinate, disodium lauryl sulfosuccinate, disodium 4-dodecyl-3-sulfonate succinate, and disodium 4-(dodecyloxy)-4-oxo-2-sulfobutyrate.

[0113] Unless otherwise stated, the structural formula of "compound S2-C12" in this article is: CAS No. 19040-44-9; named as disodium dodecyl sulfosuccinate, disodium 4-dodecyl-2-sulfonate succinate, disodium 4-(dodecyloxy)-4-oxo-3-sulfobutyrate.

[0114] Unless otherwise stated, the structural formula of "compound S2-C8" in this article is: The CAS number is 18299-70-2; it is named disodium 4-(octyloxy)-4-oxo-3-sulfobutyrate.

[0115] Unless otherwise stated, the structural formula of "compound S2-C10" in this article is: The CAS number is 18278-69-8; it is named disodium 4-(decakoxy)-4-oxo-3-sulfobutyrate.

[0116] Unless otherwise stated, the structural formula of "compound S2-C16" in this article is: The CAS number is 42160-83-8; it is named disodium 4-(hexadecyloxy)-4-oxo-3-sulfobutyrate.

[0117] Unless otherwise stated, the structural formula of "compound S2-C18" in this article is: The CAS number is 65277-59-0; it is named disodium 4-(octadecyloxy)-4-oxo-3-sulfobutyrate.

[0118] Unless otherwise stated, the structural formula of "compound S2-C20" in this article is: The CAS number is 85455-64-7; it is named disodium 4-(eicosyloxy)-4-oxo-3-sulfobutyrate.

[0119] Unless otherwise stated, the structural formula of "sodium dodecyl sulfate (CAS No. 151-21-3, also known as SDS)" in this article is: .

[0120] Unless otherwise stated, the structural formula of “octylphenol polyoxyethylene (9) ether (CAS No. 9002-93-1)” in this article is: .

[0121] Unless otherwise stated, the structural formula of "nonylphenol polyoxyethylene (9) ether (CAS No. 14409-72-4)" in this article is: .

[0122] Unless otherwise stated, the structural formula of "dodecylphenol polyoxyethylene (9) ether (CAS No. 2201101-54-2)" in this document is: .

[0123] Unless otherwise stated, the structural formula of "dodecyl alcohol polyoxyethylene (4) ether (CAS No. 5274-68-0, also known as lauryl alcohol polyoxyethylene ether-4, polyoxyethylene (4) lauryl ether)" in this article is: .

[0124] Unless otherwise stated, the structural formula of "dodecyl alcohol polyoxyethylene (9) ether (CAS No. 3055-99-0, also known as lauryl alcohol polyoxyethylene ether-9, polyoxyethylene (9) lauryl ether)" in this article is: .

[0125] Unless otherwise stated, the structural formula of "dodecyl alcohol polyoxyethylene (23) ether (CAS No. 9002-92-0, also known as polyoxyethylene (23) lauryl ether, lauryl alcohol polyoxyethylene ether-23, Brij35)" in this article is: .

[0126] Unless otherwise stated, all experimental methods described in this article are conventional methods.

[0127] Unless otherwise stated, all reagents used in this paper are commercially available and are of analytical grade; the water used in this paper should meet the requirements of Grade I water in GB / T6682.

[0128] Unless otherwise stated, “RSD” in this article represents relative standard deviation.

[0129] To make the objectives, technical solutions, and advantages of this application clearer, the implementation schemes of this application will be further described in detail below with reference to the embodiments.

[0130] Preparation of pharmaceutical compositions

[0131] Table 1. Ingredients of the Pharmaceutical Composition:

[0132]

[0133] Stability test of the drug composition in simulated gastrointestinal fluid

[0134] Test Methods: The methods described in the Chinese Pharmacopoeia were followed. The drug composition was incubated at 37°C with simulated gastric juice (pH=1.2, containing pepsin) and simulated intestinal juice (pH=6.8, containing pancreatin), as specified in the Chinese Pharmacopoeia. The initial concentration of the active pharmaceutical ingredient (API) in both simulated gastric and intestinal juices was 0.652 mg / ml. Samples were taken at predetermined time points (10 min, 30 min, 1 h, and 2 h), and the API content in the simulated gastric and intestinal juices was determined by high-performance liquid chromatography (HPLC). The residual API content in the simulated gastric and intestinal juices was calculated.

[0135] Table 2. Results of the simulated gastrointestinal fluid stability test:

[0136]

[0137] As can be seen from Table 2, compounds (S1-C12, S2-C8, S2-C10, S2-C12, S2-C16, S2-C18, S2-C20), sodium dodecyl sulfate, dodecyl alcohol polyoxyethylene (23) ether, and dodecyl alcohol polyoxyethylene (4) ether can give peptide drug active molecules better gastric juice stability; in particular, compounds (S1-C12, S2-C8, S2-C10, S2-C12, S2-C16, S2-C18, S2-C20) and sodium dodecyl sulfate can give peptide drug active molecules better gastrointestinal juice stability. It is predicted that compounds (S1-C12, S2-C8, S2-C10, S2-C12, S2-C16, S2-C18, S2-C20), sodium dodecyl sulfate, dodecyl alcohol polyoxyethylene (23) ether, and dodecyl alcohol polyoxyethylene (4) ether can potentially improve the oral bioavailability of active peptide drug molecules.

[0138] Drug preparation:

[0139] Table 3. Dosage Forms and Prescription Composition of Drugs:

[0140]

[0141] The tablet preparation process is as follows:

[0142] Premix: Weigh the prescribed amounts of drug delivery molecules, microcrystalline cellulose, and peptide drug active molecules, and premix for 10 min;

[0143] Total mixture: Add the prescribed amounts of colloidal silica and magnesium stearate, and mix for 5 minutes;

[0144] Tableting: Tableting is performed using a φ9 shallow concave die, with a theoretical tablet weight of 250mg and a hardness of 50~100N.

[0145] The preparation process of capsules is as follows:

[0146] Premix: Weigh the prescribed amounts of drug delivery molecules, microcrystalline cellulose, peptide drug active molecules, and colloidal silica, and mix for 10 min;

[0147] Total mixture: Add magnesium stearate and mix for 5 minutes;

[0148] Filling: No. 2 capsule shells are used for filling, with a content of 150mg and a content variation of ±5.0%.

[0149] Pharmacokinetic Study 1:

[0150] Test drugs: Examples 4-6, 11-13 and 15-19 of the drug compositions, Comparative Examples 2, 9-10 and 13-14, Application Examples 1-2 of the drug, exenatide solution (50 μg / mL), exenatide. The solvent for the exenatide solution was phosphate buffer solution at pH 7.4.

[0151] Preparation of test substances: Pharmaceutical compositions Examples 4-6, 11-13 and 15-19, Comparative Examples 2, 9-10 and 13-14, Drug Application Examples 1-2, and exenatide were prepared into suspensions with an API concentration of 100 μg / mL using 1% sodium carboxymethyl cellulose (CMC-Na). Each animal was vortexed before administration and then aspirated.

[0152] Experimental animals: SPF-grade SD rats (male, 200-250g / rat) were randomly divided into 20 groups, with 3 rats in each group.

[0153] Administration methods: For the pharmaceutical compositions described in Examples 4-6, 11-13, and 15-19, Comparative Examples 2, 9-10, and 13-14, Application Examples 1-2, and exenatide, a single oral gavage administration was administered at a dose of 200 μg (as exenatide) / kg (as a rat), with an administration volume of 2 mL / kg (as a rat). For exenatide solution, a single subcutaneous injection was administered at a dose of 20 μg / kg (as a rat), with an administration volume of 0.4 mL / kg (as a rat). Patients were fasted for at least 2 hours prior to administration and resumed feeding 4 hours after administration.

[0154] Blood collection points: before administration (0h) and 0.25h, 0.5h, 1h, 2h, 3h, 4h, 8h, and 12h after administration (a total of 9 blood collection points).

[0155] Anticoagulant: Dipotassium ethylenediaminetetraacetate (molecular formula EDTA•2K•2H2O, abbreviated as EDTA-K2).

[0156] Sample collection: Collect 0.3 mL of whole blood via the jugular vein and place it in an EDTA-K2 anticoagulant tube. Gently invert the tube completely to mix with the anticoagulant. Centrifuge at 1700 g for 10 min at 4°C to separate the plasma. The test tube should contain at least 150 μL of plasma, and the remainder should be placed in a backup tube. Store the plasma at -60°C to -90°C until testing.

[0157] Sample analysis: The concentration of exenatide in rat plasma was determined by LC-MS / MS. The AUC, the main pharmacokinetic parameter, was calculated using the Winnolin non-compartmental model. 0~t and AUC 0~∞ .

[0158] Table 4 Results of Pharmacokinetic Study 1:

[0159]

[0160] As can be seen from Table 4, compared with other drug delivery molecules, the oral bioavailability of peptide drug active molecules is significantly improved by combining them with the drug delivery molecules of this application (S1-C12, S2-C8, S2-C10, S2-C12, S2-C16, S2-C18, S2-C20).

[0161] Comparative studies of Examples 4-6 show that a weight ratio of the active peptide molecule to the drug delivery molecule in the range of 1:(10-50) can improve the AUC. 0~t and AUC 0~∞ All aspects are improved, especially for peptide drugs where the weight ratio of active molecule to drug delivery molecule is 1:10, which can improve AUC. 0~t and AUC 0~∞ All showed significant improvement. Similarly, the same conclusion was reached by comparing Examples 11-13.

[0162] Comparison of Examples 4, 11, and 15-19 shows that as the length of the L1 alkyl carbon chain in the drug delivery molecule of this application increases, the oral bioavailability of the peptide drug exhibits an increasing trend of "first increasing, then decreasing". Specifically, the oral bioavailability of the peptide drug molecule reaches its optimal level when L1 is a C11 straight-chain alkane group.

[0163] Pharmacokinetic Study 2:

[0164] Test drug: Example 21 of the drug composition, original drug (Smegglutide tablets, 0.0075 mg / mg, Novo Nordisk).

[0165] Preparation of the test substance: A suspension with an API concentration of 0.5 mg / mL was prepared using 1% sodium carboxymethyl cellulose (CMC-Na). The suspension was vortexed thoroughly before administration to each animal.

[0166] Experimental animals: SPF-grade SD rats (male, 200-250g / rat) were randomly divided into 2 groups of 3 rats each.

[0167] Administration method: Single oral gavage, dose is 5 mg (as API) / kg (as rat), volume is 10 mL / kg (as rat); fasting for at least 10 hours before administration, feeding resumes 4 hours after administration.

[0168] Blood collection points: before administration (0h) and 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, and 48h after administration (a total of 10 blood collection points).

[0169] Anticoagulant: Dipotassium ethylenediaminetetraacetate (molecular formula EDTA•2K•2H2O, abbreviated as EDTA-K2).

[0170] Sample collection: Collect 0.3 mL of whole blood via the jugular vein and place it in an EDTA-K2 anticoagulant tube. Gently invert the tube completely to mix with the anticoagulant. Centrifuge at 1700 g for 10 min at 4°C to separate the plasma. The test tube should contain at least 150 μL of plasma, and the remainder should be placed in a backup tube. Store the plasma at -60°C to -90°C until testing.

[0171] Sample analysis: The concentration of API in rat plasma was determined by LC-MS / MS, and the AUC, the main pharmacokinetic parameter, was calculated using the Winnolin non-compartmental model. 0~t and AUC 0~∞ .

[0172] Table 5 Results of Pharmacokinetic Study 2:

[0173]

[0174] As can be seen from Table 5, the oral bioavailability of peptide drug active molecules is significantly improved by combining them with the drug delivery molecules of this application.

[0175] In summary, the combination of peptide drug active molecules with the drug delivery molecules of this application significantly improves the stability and permeability of peptide drug active molecules in gastrointestinal fluid, thereby increasing their absorption in the gastrointestinal tract and improving their oral bioavailability.

[0176] Drug dissolution determination:

[0177] The dissolution rate of exenatide capsules and tablets was determined. The detection method was as follows: Following Method II of Dissolution and Release Determination in Chapter 0931 of the 2025 edition of the Chinese Pharmacopoeia, Part IV, the paddle method was used at 70 rpm. A phosphate buffer solution (pH 6.8) with a volume of 500 ml was used as the dissolution medium. High-performance liquid chromatography (HPLC) was employed to determine the API content in the dissolution medium of a group of parallel samples (n=6) at five time points: 10 min, 15 min, 20 min, 30 min, and 45 min. Based on the measured API content, the cumulative dissolution amount Q per capsule (tablet) was first calculated, then the arithmetic mean of the cumulative dissolution amounts Q (denoted as Q-mean) was calculated, and finally, a dissolution curve was plotted.

[0178] Table 6. Results of the determination of the cumulative dissolution of the drug:

[0179]

[0180] Combined with Table 6 and Figure 1 It can be seen that tablets dissolve more slowly than capsules. Capsules dissolve more than 80% in 10 minutes, while tablets dissolve more than 80% in 30 minutes.

[0181] The foregoing has provided a detailed description of this application, "A pharmaceutical composition comprising a peptide drug active molecule and its use therein." Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are merely for the purpose of helping to understand the method and core ideas of this application. It should be noted that those skilled in the art can make various improvements and modifications to this application without departing from its principles, and these improvements and modifications also fall within the protection scope of the claims of this application.

Claims

1. A pharmaceutical composition comprising a peptide drug active molecule, characterized in that, The pharmaceutical composition comprises a peptide drug active molecule and a drug delivery molecule, wherein the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(10-500); The drug delivery molecule is selected from the structure shown in formula (I) or a pharmaceutically acceptable salt thereof: Where j2=0; j1 and j3 are each independently selected from 0 or 1, and j1≠j3; X is selected from -C(O)O-; R 1a and R 1b All selected from H; L2 does not exist; L1 is selected from unsubstituted C11 alkane groups; The active molecule of the peptide drug is selected from glucagon-like peptide-1 receptor agonists, which include at least one of smegglutide or exenatide.

2. The pharmaceutical composition according to claim 1, characterized in that, The drug delivery molecule is selected from the structure shown in formula (II) or a pharmaceutically acceptable salt thereof: Among them, j1, j2, j3, R 1a R 1b L1 is defined as in formula (I) of claim 1.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, L1 is selected from .

4. The pharmaceutical composition according to claim 1, characterized in that, The drug delivery molecule includes any of the structures shown below, or pharmaceutically acceptable salts thereof: 、 。 5. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(10-100); Alternatively, the weight ratio of the peptide drug active molecule to the drug delivery molecule is 1:(10-50); Alternatively, the weight ratio of the active peptide drug molecule to the drug delivery molecule is 1:

10.

6. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of an oral dosage form of medicine.

7. A drug, characterized in that, The drug comprises the pharmaceutical composition according to any one of claims 1 to 5, and one or more pharmaceutically acceptable excipients.

8. The medicament according to claim 7, characterized in that, Based on the drug, the amount of the pharmaceutical composition is selected from (1-50) wt%.

9. The drug according to claim 7, characterized in that, Based on the drug, the drug comprises 0.5-3 wt% peptide drug active molecules, 5-30 wt% drug delivery molecules, 60-90 wt% filler, 0-2 wt% flow aid, 0-30 wt% slow-release regulator and 0.1-1 wt% lubricant.

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