Use of disulfide fatty acids and salts thereof for oral delivery of protein or polypeptide drugs

Abstract

The application belongs to the field of pharmaceutical preparations, and particularly discloses application of a dithio fatty acid and a salt thereof in oral delivery of a protein or polypeptide drug, and particularly relates to a GLP-1 analogue polypeptide oral drug composition. The protein or polypeptide oral drug composition disclosed by the application comprises a protein or polypeptide drug, a dithio fatty acid and / or a salt thereof, the dithio fatty acid is preferably lipoic acid and / or thioctoic acid, and the protein or polypeptide drug is preferably a GLP-1 analogue polypeptide drug. The dithio fatty acid and the salt thereof can improve intestinal permeability of the protein and polypeptide drug, improve bioavailability thereof, and promote oral absorption of the macromolecular drug. When lipoic acid or a lipoic acid salt is used to prepare the GLP-1 analogue polypeptide drug composition, the lipoic acid or the lipoic acid salt can also synergistically reduce blood sugar together with the GLP-1 analogue polypeptide drug, and an unexpected therapeutic effect can be achieved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulations and relates to the application of disulfide fatty acids and their salts in the oral delivery of protein or polypeptide drugs, as well as oral protein or polypeptide drug compositions, particularly GLP-1 analog polypeptide oral drug compositions. Background Technology

[0002] The main obstacle to oral delivery of protein and peptide drugs is their low intestinal permeability and poor absorption. This deficiency means that the vast majority of protein and peptide drugs can only be administered parenterally, especially by injection, causing significant discomfort to patients. Currently, the FDA has approved Novo Nordisk's semaglutide oral tablets (FDA, NDA: 213182) and Chiasma's octreotide oral capsules (FDA, NDA: 208232), successfully avoiding the pain of injection and greatly improving drug compliance.

[0003] However, the bioavailability of semaglutide oral tablets is only 0.4% to 1.0%, and the bioavailability of octreotide oral capsules prepared by Chiasma using transient permeability enhancer (TPE) technology is also less than 1%. The extremely poor bioavailability remains the biggest obstacle to its oral administration. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention proposes the application of disulfide fatty acids and their salts in the oral delivery of protein or polypeptide drugs.

[0005] Disulfide fatty acids and their salts are natural compounds widely found in plants and animals. Common disulfide fatty acids include lipoic acid, thiodecanoic acid, and their salts. Lipoic acid is a drug approved in the 1990s for the treatment of diabetic polyneuropathy, which can lower blood sugar. In the health food market of Europe and America, lipoic acid is a very common nutritional supplement. Lipoic acid can improve pancreatic function and glucose metabolism, reduce AGE formation and weaken oxidative stress, help prevent heart disease and stroke, and prevent diabetic complications. This invention discovers that disulfide fatty acids and their salts can increase the intestinal permeability of protein and peptide drugs, promote the oral absorption of macromolecular drugs, especially promote the oral absorption of GLP-1 (glucagon-like peptide-1) agonist peptides (such as liraglutide, semaglutide, etc.). Moreover, due to the function of lipoic acid in improving pancreatic function and glucose metabolism, it can synergistically lower blood sugar in the type II diabetes model Bama miniature pigs with GLP-1 peptide drugs, achieving unexpected effects. The specific scheme is as follows:

[0006] The first aspect of this invention provides the use of disulfide fatty acids and their salts as oral delivery agents for protein or polypeptide drugs.

[0007] Furthermore, the disulfide fatty acid is lipoic acid and / or thiodecanoic acid;

[0008] Preferably, the protein or polypeptide drug is a GLP-1 analog polypeptide drug;

[0009] Preferably, the GLP-1 analog peptide drug is liraglutide or semaglutide.

[0010] A second aspect of the present invention provides an oral pharmaceutical composition of a protein or polypeptide, comprising a protein or polypeptide drug, a disulfide fatty acid and / or its salt.

[0011] Furthermore, the disulfide fatty acid is lipoic acid and / or thiodecanoic acid;

[0012] The protein or polypeptide drug is a GLP-1 analog polypeptide drug;

[0013] Preferably, the GLP-1 analog peptide drug is liraglutide or semaglutide.

[0014] Furthermore, the mass ratio of the protein or polypeptide drug to disulfide fatty acids and / or their salts is 1:40 to 1:100.

[0015] Furthermore, the oral pharmaceutical composition of the protein or polypeptide may also include pharmaceutically acceptable excipients and / or enteric materials.

[0016] Furthermore, the excipient is selected from one or more of fatty acids and their salts, polyol fatty acid esters, phospholipids, sterols, Tween compounds, poloxamer, and bile salts;

[0017] The enteric material is acrylic resin;

[0018] Preferably, the excipient is selected from one or more of Tween 80, glyceryl monocaprylate, polyvinylpyrrolidone, and phospholipids;

[0019] Preferably, the enteric material is methacrylic resin.

[0020] Further, based on the weight of the pharmaceutical composition, the protein or polypeptide drug accounts for 0.1% to 20%, the disulfide fatty acid and / or its salt accounts for 10% to 90%, the pharmaceutically acceptable excipient accounts for 0% to 60%, and the enteric material accounts for 1% to 20%.

[0021] Furthermore, the dosage form of the protein or polypeptide oral pharmaceutical composition is a tablet or a capsule.

[0022] Furthermore, the tablet preparation method is as follows: the components of the protein or polypeptide oral drug composition are wet granulated, dry granulated or spray dried and then compressed into tablets, or the powder is directly compressed into tablets, and the resulting tablet core is coated to prepare tablets;

[0023] The capsule preparation method is as follows: after wet granulation or dry granulation of each component of the protein or polypeptide oral drug composition, the granules are filled into enteric-coated capsules to prepare the capsule.

[0024] The beneficial effects of this invention are as follows:

[0025] 1. This invention discovers that disulfide fatty acids and their salts can improve the intestinal permeability of protein and polypeptide drugs, enhance their bioavailability, and promote the oral absorption of macromolecular drugs, especially promoting the oral absorption of GLP-1 (glucagon-like peptide-1) agonist polypeptides (such as liraglutide, semaglutide, etc.).

[0026] 2. This invention utilizes lipoic acid or lipoate to prepare a GLP-1 analog peptide drug composition for oral delivery of GLP-1 analog peptide drugs. Simultaneously, lipoic acid improves pancreatic function and glucose metabolism, synergistically reducing blood glucose and weight in patients with type II diabetes, resulting in more significant hypoglycemic and weight-reducing effects, achieving unexpected therapeutic effects and demonstrating significant clinical advantages. Detailed Implementation

[0027] This article uses the typical GLP-1 analog peptide drug semaglutide as an example to illustrate the formulation, preparation process, and efficacy of the GLP-1 analog peptide drug composition of the present invention, demonstrating that the GLP-1 analog peptide drug composition of the present invention has significant clinical advantages over existing commercially available drugs. The method of the present invention has been described through preferred embodiments. Those skilled in the art will clearly be able to modify or appropriately alter and combine the formulation or process described herein without departing from the content, spirit, and scope of the present invention to realize and apply the technology of the present invention.

[0028] Example 1

[0029] Weigh 0.7g of semaglutide and 50g of sodium thiocate, granulate them by wet granulation, compress them into 100 tablets, and then coat them with 12g of methacrylate to make tablets.

[0030] Example 2

[0031] Weigh out 0.7g of semaglutide, 40g of thioctic acid, and 10g of polyvinylpyrrolidone. After wet granulation, compress into 100 tablets, and then coat with 7g of methacrylate to form tablets.

[0032] Example 3

[0033] Weigh out 0.7g of semaglutide, 40g of sodium thiodecanoate, 1g of Tween 80, 10g of phospholipid, and 20g of polyvinylpyrrolidone. After wet granulation, compress into 100 tablets, and then coat with 4g of methacrylate to form tablets.

[0034] Example 4

[0035] Weigh out 0.7g of semaglutide, 30g of lipoic acid, 2g of Tween 80, 10g of glyceryl monooctanoate, and 20g of polyvinylpyrrolidone. After granulation, fill the mixture into enteric-coated capsules. In this example, the enteric-coated capsules are gelatin capsules.

[0036] Experimental Example 1: In vitro disintegration test

[0037] The oral formulations of semaglutide from Examples 1-4 were subjected to in vitro disintegration time studies using simulated gastric and intestinal fluids. The results are shown in Table 1.

[0038] Table 1. Disintegration time data of the compositions in Examples 1-4

[0039]

[0040] As shown in Table 1, the pharmaceutical compositions of Examples 1-4 showed no change in artificial gastric fluid and disintegrated in artificial intestinal fluid within 30 minutes, meeting the requirements for enteric-coated preparations.

[0041] Experimental Example 2: Pharmacokinetic Study

[0042] Animal experiments were conducted using samples from Example 1 to determine the blood concentration of semaglutide after oral absorption. Six Bama miniature pigs with type II diabetes were administered OZEMPIC semaglutide injection, RYBELSUS semaglutide oral tablets, and the oral tablets from Example 1, respectively, at doses of 0.0035 mg / kg / 7 days, 0.05 mg / kg / day, and 0.05 mg / kg / day, for one month. Pharmacokinetic parameters, fasting blood glucose concentration, and weight changes in the Bama miniature pigs were compared. The results are shown in Table 2.

[0043] Table 2 Pharmacokinetic parameters after administration

[0044]

[0045] As shown in Table 2, the average steady-state plasma concentration of the oral tablets in Example 1 was significantly higher than that of OZEMPIC semaglutide injection and RYBELSUS semaglutide oral tablets. At the same dosage, the bioavailability of RYBELSUS semaglutide oral tablets was only 0.8%, while the bioavailability of the oral tablets in Example 1 of this invention reached 1.21%, which was 51% higher (approximately 1.51 times) than that of semaglutide oral tablets. This indicates that the pharmaceutical composition of this invention can significantly improve the oral absorption of GLP-1 analog peptides.

[0046] Experimental Example 3: Pharmacodynamic Test

[0047] To eliminate the influence of inconsistent blood drug concentrations on the experimental results, the dosage was readjusted to ensure consistent steady-state blood drug concentrations, and the hypoglycemic and weight control effects of the composition of the present invention on Bama miniature pigs with type II diabetes were investigated.

[0048] The dosages of OZEMPIC semaglutide injection, RYBELSUS semaglutide oral tablets, and the oral tablets from Example 1 were adjusted to 0.005 mg / kg / 7 days, 0.08 mg / kg / day, and 0.05 mg / kg / day, respectively, to maintain steady-state blood drug concentrations in type II diabetic Bama miniature pigs within the range of 10 nmol / L ± 1 nmol / L after administration of these three drugs for 6 consecutive months. Changes in fasting blood glucose and body weight in type II diabetic Bama miniature pigs were compared. The results are shown in Tables 3 and 4.

[0049] Table 3 Fasting blood glucose concentrations in whole blood of animals after drug administration

[0050]

[0051] Table 4. Data on changes in animal body weight after drug administration.

[0052]

[0053] As shown in Tables 3 and 4, when the dosage of the oral tablets of Example 1 was reduced to maintain the same average steady-state blood drug concentration, compared with OZEMPIC semaglutide injection and RYBELSUS semaglutide oral tablets, the fasting blood glucose control of Bama miniature pigs administered the oral tablets of Example 1 was lower and closer to the normal blood glucose range. Simultaneously, the weight loss of Bama miniature pigs administered the oral tablets of Example 1 was greater, indicating that the drug combination of the present invention has significant advantages in lowering blood glucose and controlling weight. The reason for this result may be that sodium lipoate is neutralized to lipoic acid in the body. Lipoic acid is a coenzyme present in mitochondria that can improve pancreatic function and glucose metabolism, thus having a hypoglycemic effect. This hypoglycemic effect, together with semaglutide, synergistically lowers blood glucose and reduces weight in type II diabetic animals, achieving unexpected efficacy.

[0054] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. The application of disulfide fatty acid salts as oral delivery agents for protein or polypeptide drugs in improving the intestinal permeability of protein and polypeptide drugs, enhancing their bioavailability, and promoting the oral absorption of macromolecular drugs. The dithiocarboxylic acid salt is sodium lipoate; The protein or polypeptide drug in question is semaglutide.

2. A protein or polypeptide oral pharmaceutical composition, characterized in that, The oral pharmaceutical composition of the protein or polypeptide is made of a protein or polypeptide drug, a disulfide fatty acid salt, and an enteric material; The dithiocarboxylic acid salt is sodium lipoate; The protein or polypeptide drug is semaglutide; The enteric material is methacrylic resin; The mass ratio of the protein or polypeptide drug to the disulfide fatty acid salt is 1:40 to 1:100; Based on the weight of the pharmaceutical composition, the protein or polypeptide drug accounts for 0.1% to 20%, the disulfide fatty acid salt accounts for 10% to 90%, and the enteric material accounts for 1% to 20%.

3. The oral pharmaceutical composition of protein or polypeptide according to claim 2, characterized in that, The dosage form of the protein or polypeptide oral pharmaceutical composition is tablets or capsules.

4. The oral pharmaceutical composition of protein or polypeptide according to claim 2, characterized in that, The tablet preparation method is as follows: the components of the protein or polypeptide oral drug composition are wet granulated, dry granulated or spray dried and then compressed into tablets, or the powder is directly compressed into tablets, and the resulting tablet core is coated to prepare tablets. The capsule preparation method is as follows: after wet granulation or dry granulation of each component of the protein or polypeptide oral drug composition, the granules are filled into enteric-coated capsules to prepare the capsule.

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