Oral pharmaceutical formulation comprising GLP-1 agonist, and preparation method therefor

Abstract

The present invention relates to an oral pharmaceutical formulation and a preparation method therefor, the oral pharmaceutical formulation comprising: a GLP-1 agonist; an absorption promoter of a medium-chain fatty acid salt having 8 to 10 carbon atoms; and a magnesium-based antacid.

Description

Oral pharmaceutical preparations containing a GLP-1 agonist and methods for manufacturing the same

[0001] The present invention relates to an oral pharmaceutical formulation comprising a GLP-1 agonist and a method for manufacturing the same.

[0002] Human glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino acid polypeptide produced by intestinal endocrine L cells and central nervous system neurons. GLP-1 agonists act by binding to GLP-1 receptors, promoting insulin secretion and neuroprotection, and reducing appetite by inhibiting gastric emptying, acid secretion, and motility. GLP-1 agonists are used in the treatment of diabetes and obesity.

[0003] As a GLP-1 agonist, semaglutide is an oral hypoglycemic agent used for the treatment of type 2 diabetes and an anti-obesity agent used for long-term weight management. It was developed by Novo Nordisk in 2012 and approved for use in the United States in 2017. Semaglutide is a peptide modified with a side chain similar to GLP-1 and can be administered by subcutaneous injection or orally.

[0004] In particular, Rybelsus is sold as an oral semaglutide medication and utilizes SNAC (Salcaprozate sodium) as an absorption enhancer for semaglutide. Research is being conducted to replace SNAC, used as an absorption enhancer in Rybelsus, with naturally derived substances, and medium-chain fatty acids (MCFAs) can serve as alternatives. At this time, there is a need for formulation research to apply optimal medium-chain fatty acids and optimally control pH in the gastric environment.

[0005] The present invention aims to provide an oral pharmaceutical formulation, etc., comprising a GLP-1 agonist; a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; and a magnesium-based antacid.

[0006] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0007] The present invention provides an oral pharmaceutical formulation comprising a GLP-1 agonist; a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; and a magnesium-based antacid.

[0008] The above GLP-1 agonist may be semaglutide, exendin-4, CA-exendin-4 (Imidazoacetyl-exendin-4), DA-exendin-4 (Desamino-histidyl-exendin-4), HY-exendin-4 (beta-hydroxy imidazopropoinyl-exendin-4), CX-exendin-4 (beta-carboxyimidazopropionyl-exendin-4), DM-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, or albiglutide.

[0009] The above absorption promoter may be one or more selected from the group consisting of sodium caprate (C10), sodium caprylate (C8), and combinations thereof.

[0010] The weight ratio of the above GLP-1 agent and the above absorption promoter may be 1:1 to 1:70.

[0011] The above magnesium-based antacid may be one or more selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium carbonate, and combinations thereof.

[0012] The weight ratio of the above GLP-1 agonist to the above magnesium-based antacid may be 1:0.5 to 1:20.

[0013] Based on 100 parts by weight of the above oral pharmaceutical formulation, the magnesium-based antacid may be in an amount of 1 to 50 parts by weight.

[0014] The above oral pharmaceutical formulation may further include one or more alkalizing agents selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, and combinations thereof.

[0015] The weight ratio of the magnesium-based antacid to the alkalizing agent may be 1:1 to 1:25.

[0016] Based on 100 parts by weight of the above oral pharmaceutical formulation, the alkalizing agent may be in an amount of more than 0 parts by weight to 90 parts by weight.

[0017] The above oral pharmaceutical formulation may further include one or more disintegrants selected from the group consisting of starch-based disintegrants, non-starch-based disintegrants, and combinations thereof.

[0018] The above oral pharmaceutical formulation may further include one or more lubricants selected from the group consisting of fatty acid-based lubricants, inorganic lubricants, and combinations thereof.

[0019] The above oral pharmaceutical preparation may be intended to prevent or treat any one or more metabolic diseases selected from the group consisting of obesity, diabetes, non-alcoholic fatty liver, hepatic steatosis, dyslipidemia, arteriosclerosis, insulin resistance syndrome, cardiovascular disease, alcoholism, chronic kidney disease, Alzheimer's disease and complications thereof.

[0020] The above oral pharmaceutical preparation may have the effect of reducing weight or food intake.

[0021] In one embodiment of the present invention, a method for manufacturing an oral pharmaceutical formulation is provided, comprising: (a) a step of preparing granules containing a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; (b) a step of administering a magnesium-based antacid; and (c) a step of tableting, wherein a GLP-1 agonist is administered during step (a), between step (a) and step (b), or during step (b).

[0022] In step (a) above, the granules can be produced by a wet or dry granulation method.

[0023] The above dry granulation method can be performed through one or more selected from the group consisting of slugging, roller compacting, high pressure extruding, and spheronizing.

[0024] In step (b) above, one or more alkalizing agents selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, and combinations thereof may be added.

[0025] The oral pharmaceutical formulation according to the present invention comprises a GLP-1 agonist; an absorption promoter of a medium-chain fatty acid salt having 8 to 10 carbon atoms; and a magnesium-based antacid. By the optimal combination of the absorption promoter and the magnesium-based antacid, an environment can be provided in which the GLP-1 agonist can be sufficiently dissolved in the stomach, and accordingly, the absorption of the GLP-1 agonist into the body can be effectively promoted.

[0026] Accordingly, the oral pharmaceutical formulation according to the present invention is manufactured without tablet compression issues, and can improve the sustained release of the GLP-1 agonist while maintaining the excellent efficacy of the GLP-1 agonist, and has the advantage of having effects of weight loss and reduced food intake.

[0027] In particular, in the oral pharmaceutical formulation according to the present invention, when an alkalizing agent is additionally included, the efficacy of the GLP-1 agonist can be significantly improved, and in addition to the effects of weight loss and reduced food intake, it can prevent the increase in blood glucose in a type 2 diabetes model or maintain glycated hemoglobin levels within a certain range over the long term, thereby preventing the development of severe diabetes.

[0028] Figure 1 is a graph comparing the change in pH increase according to the amount of 11 types of antacids added and dissolved in artificial gastric juice (pH 1.5-1.6).

[0029] Figure 2 is a graph showing the change in plasma concentration of semaglutide over time as a result of performing pharmacokinetic (PK) evaluation after orally administering the semaglutide preparations prepared in Example 7 and Comparative Example 1 and the control (2) [Rybelsus] to beagle dogs.

[0030] FIG. 3(a) is a graph comparing the dissolution rate of semaglutide prepared in Example 8 with that of the control group (3) [Rybelsus], and FIG. 3(b) is a graph showing the change in plasma concentration of semaglutide over time as a result of performing pharmacokinetic (PK) evaluation after orally administering the semaglutide prepared in Example 8 and the control group (2) [Rybelsus] to beagle dogs.

[0031] Figure 4 is a graph comparing the dissolution rate of semaglutide prepared in Examples 9-10 with that of the control group (3) [Rybelsus].

[0032] Figure 5 is a graph comparing the dissolution rate of semaglutide prepared in Example 11 with that of a control group (3) [Rybelsus].

[0033] Figure 6 is a graph comparing the dissolution rate of semaglutide prepared in Example 12 with that of a control group (3) [Rybelsus].

[0034] Figure 7 is a graph showing the results of an initial efficacy test by measuring changes in body weight, feed intake, and blood glucose levels for 4 weeks after orally administering semaglutide compositions according to Examples 13-14 and Comparative Examples 2-3 to db / db mice.

[0035] Figure 8 is a graph showing the results of a long-term deepening efficacy test in which semaglutide compositions according to Example 13 and Comparative Examples 3-4 were administered orally or subcutaneously to db / db mice, changes in body weight and feed intake were measured after 8 weeks, and glycated hemoglobin was measured at week 8.

[0036] The inventors of the present invention completed the invention by researching to replace SNAC as an absorption enhancer with a naturally derived substance in an oral pharmaceutical formulation containing a GLP-1 analog (in particular, semaglutide), and by applying sodium caprate (C10) or sodium caprylate (C8) among medium-chain fatty acids (MCFAs) alone or in combination thereof, and by applying a magnesium-based antacid to optimally control the pH in the gastric environment.

[0037]

[0038] The present invention will be described in detail below.

[0039]

[0040] Oral pharmaceutical preparations containing GLP-1 analogs

[0041]

[0042] The present invention provides an oral pharmaceutical formulation comprising a GLP-1 agonist; a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; and a magnesium-based antacid.

[0043]

[0044] The oral pharmaceutical formulation according to the present invention is characterized by comprising a GLP-1 agonist.

[0045] The above-mentioned GLP-1 agonist can be used for the prevention or treatment of one or more metabolic diseases selected from the group consisting of obesity, diabetes, non-alcoholic fatty liver, hepatic steatosis, dyslipidemia, arteriosclerosis, insulin resistance syndrome, cardiovascular disease, alcoholism, chronic kidney disease, Alzheimer's disease, and complications thereof. In order to administer such a GLP-1 agonist orally, it is necessary to dissolve it sufficiently in the stomach and also effectively promote absorption into the body without breakdown in the stomach.

[0046] Specifically, the GLP-1 agonist may be semaglutide, exendin-4, CA-exendin-4 (Imidazoacetyl-exendin-4), DA-exendin-4 (Desamino-histidyl-exendin-4), HY-exendin-4 (beta-hydroxy imidazopropoinyl-exendin-4), CX-exendin-4 (beta-carboxyimidazopropionyl-exendin-4), DM-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, or albiglutide, and is preferably semaglutide, but is not limited thereto.

[0047] At this time, among the above GLP-1 agonists, semaglutide exhibits a significant absorption rate in the body due to its structural characteristics, depending on the optimal combination of the absorption enhancer and magnesium-based antacid described below.

[0048] More specifically, the semaglutide is a peptide modified with a side chain similar to Human glucagon-like peptide-1 (GLP-1). The semaglutide is represented by the following structure, and its CAS number is 910463-68-2:

[0049] .

[0050] Based on 100 parts by weight of an oral pharmaceutical formulation according to the present invention, the GLP-1 agonist may be in an amount of 0.1 to 20 parts by weight, preferably 0.2 to 12 parts by weight, and more preferably 1 to 5 parts by weight, but is not limited thereto.

[0051] Meanwhile, the above GLP-1 agonist may be administered orally at a dose of 7 mg / kg to 56 mg / kg once a day.

[0052]

[0053] In conventional oral pharmaceutical formulations containing GLP-1 agonists, SNAC (Salcaprozate sodium) was used as an absorption enhancer, but since it contains a salicylamide group at the terminal end, it had the limitation of only temporarily enhancing the absorption of semaglutide by increasing only the local pH of the stomach.

[0054] Accordingly, the inventors conducted research to replace SNAC as an absorption promoter for conventional GLP-1 agonists with a naturally derived substance and to enhance the absorption rate in the body. As a result, the oral pharmaceutical formulation according to the present invention is characterized by comprising a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms (also referred to as 'C8 to C10') and a magnesium-based antacid.

[0055] The above-mentioned medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms is intended to effectively absorb the above-mentioned GLP-1 agonist into the body without degradation in the stomach when administered orally. However, if the above-mentioned medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms is used alone, there is a limitation in that it does not provide an environment in the stomach where the above-mentioned GLP-1 agonist can be sufficiently dissolved. Accordingly, it is essential to combine the above-mentioned medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms with the above-mentioned magnesium-based antacid.

[0056] Specifically, the absorption promoter may be one or more selected from the group consisting of sodium caprate (C10), sodium caprylate (C8), and combinations thereof. More specifically, sodium caprate (C10) alone, sodium caprylate (C8) alone, or a combination of sodium caprate (C10) and sodium caprylate (C8) may be used as the absorption promoter. In this case, when sodium caprate (C10) and sodium caprylate (C8) are combined as the absorption promoter, the weight ratio may be 1:9 to 9:1.

[0057] More specifically, the sodium caprate (C10) has the following structure, and its CAS number is 1002-62-6:

[0058] .

[0059] In addition, the above sodium caprylate (C8) is represented by the following structure, and its CAS number is 1984-06-1:

[0060] .

[0061] The weight ratio of the above GLP-1 agonist to the above absorption promoter may be 1:5 to 1:70, and more preferably 1:5 to 1:30, but is not limited thereto.

[0062] Based on 100 parts by weight of an oral pharmaceutical formulation according to the present invention, the absorption promoter may be 10 to 90 parts by weight (preferably 10 to 85 parts by weight, most preferably 10 to 80 parts by weight).

[0063]

[0064] Meanwhile, the magnesium-based antacid is intended to provide an environment in which the GLP-1 agonist can be sufficiently dissolved in the stomach, thereby maintaining the excellent efficacy of the GLP-1 agonist while improving the sustained release of the GLP-1 agonist, and accordingly, increasing the bioavailability of the GLP-1 agonist.

[0065] Specifically, the magnesium-based antacid may be one or more selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium carbonate, and combinations thereof, and is preferably magnesium oxide, but is not limited thereto.

[0066] In particular, when magnesium oxide is used as the magnesium-based antacid, there is an advantage that the pH of the stomach can be effectively neutralized with a small amount compared to when other antacids are used. Accordingly, when the magnesium-based antacid is magnesium oxide, the weight ratio of the GLP-1 agent to the magnesium oxide may be 1:0.5 to 1:20, preferably 1:0.5 to 1:10, and more preferably 1:0.5 to 1:5, but is not limited thereto.

[0067] Based on 100 parts by weight of an oral pharmaceutical formulation according to the present invention, the magnesium-based antacid may be in an amount of 1 to 50 parts by weight (preferably 3 to 50 parts by weight, more preferably 5 to 20 parts by weight). At this time, if the content of the magnesium-based antacid is too low, there is a limitation in that the bioavailability of the GLP-1 agonist cannot be sufficiently increased. On the other hand, if the content of the magnesium-based antacid is excessively high, there is a problem in that tablet compressibility is reduced or disintegration is delayed.

[0068]

[0069] In particular, the oral pharmaceutical formulation according to the present invention may further include one or more alkalizing agents selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, and combinations thereof. Phosphate alkalizing agents such as trisodium phosphate, disodium hydrogen phosphate, calcium hydrogen phosphate hydrate, and anhydrous calcium hydrogen phosphate; hydroxide alkalizing agents such as sodium hydroxide and calcium hydroxide; silicate alkalizing agents such as calcium silicate, aluminum silicate, and magnesium aluminum metasilicate; aluminum alkalizing agents such as aluminum hydroxide, aluminum phosphate, and magaldrate; or amino-based alkalizing agents such as meglumine, tromethamine [tris(hydroxymethyl)aminomethane], L-arginine, and L-lysine may be used.

[0070] The above alkalizing agent is intended to finely adjust the pH of the above GLP-1 agonist to more effectively promote its absorption into the body, thereby significantly improving the efficacy of the GLP-1 agonist, and accordingly, it can have effects of weight loss and reduced food intake, as well as an effect of preventing blood sugar increase.

[0071] Specifically, the alkalizing agent is preferably one or more selected from the group consisting of sodium bicarbonate, calcium carbonate, and combinations thereof, and is more preferably sodium bicarbonate, but is not limited thereto.

[0072] The weight ratio of the magnesium-based antacid to the alkalizing agent may be 1:1 to 1:25, preferably 1:1 to 1:20, and more preferably 1:1 to 1:5, but is not limited thereto.

[0073] Based on 100 parts by weight of an oral pharmaceutical formulation according to the present invention, the alkalizing agent may be greater than 0 parts by weight to 90 parts by weight (preferably greater than 0 parts by weight to 70 parts by weight, more preferably greater than 0 parts by weight to 50 parts by weight).

[0074]

[0075] If necessary, the oral pharmaceutical formulation according to the present invention may additionally include one or more disintegrants selected from the group consisting of starch-based disintegrants, non-starch-based disintegrants, and combinations thereof, and it is preferable to additionally include a starch-based disintegrant, but is not limited thereto. In this case, starch-based disintegrants include starch, pregelatinized starch, sodium starch glycolate, etc., and non-starch-based disintegrants include sodium croscarmellose, crospovidone, alginate / sodium alginate, microcrystalline cellulose, etc.

[0076] Based on 100 parts by weight of an oral pharmaceutical formulation according to the present invention, the disintegrant may be in an amount of 0.1 to 10 parts by weight, and preferably in an amount of 0.1 to 7 parts by weight, but is not limited thereto.

[0077] In addition, the oral pharmaceutical formulation according to the present invention may further include one or more lubricants selected from the group consisting of fatty acid-based lubricants, inorganic lubricants, and combinations thereof, and it is preferable to further include a combination of fatty acid-based lubricants and inorganic lubricants, but is not limited thereto. In this case, fatty acid-based lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, etc., and inorganic lubricants include talc, colloidal silicon dioxide, anhydrous silicic acid (hard), etc.

[0078] Based on 100 parts by weight of an oral pharmaceutical formulation according to the present invention, the lubricant may be in an amount of 0.1 to 10 parts by weight, and preferably in an amount of 0.1 to 7 parts by weight, but is not limited thereto.

[0079]

[0080] Thus, the oral pharmaceutical formulation according to the present invention may be intended to prevent or treat any one or more metabolic diseases selected from the group consisting of obesity, diabetes, non-alcoholic fatty liver, hepatic steatosis, dyslipidemia, arteriosclerosis, insulin resistance syndrome, cardiovascular disease, alcoholism, chronic kidney disease, Alzheimer's disease and complications thereof, and is preferably intended to prevent or treat obesity or diabetes (particularly severe diabetes), but is not limited thereto.

[0081] To this end, the oral pharmaceutical formulation according to the present invention may have the effect of reducing weight or food intake. In particular, in the oral pharmaceutical formulation according to the present invention, when the alkalizing agent is additionally included, in addition to the effects of reducing weight and food intake, it may have the effect of preventing the development of severe diabetes by preventing an increase in blood glucose in a type 2 diabetes model or maintaining glycated hemoglobin levels within a certain range over the long term.

[0082]

[0083] Method for manufacturing an oral pharmaceutical preparation containing a GLP-1 agonist

[0084]

[0085] The present invention provides a method for manufacturing an oral pharmaceutical formulation comprising: (a) a step of preparing granules containing a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; (b) a step of administering a magnesium-based antacid; and (c) a step of tableting, wherein a GLP-1 agonist is administered during step (a), between step (a) and step (b), or during step (b).

[0086]

[0087] First, the method for manufacturing an oral pharmaceutical formulation according to the present invention comprises the step of manufacturing granules containing a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms [step (a)].

[0088] The above-mentioned medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms is intended to promote the absorption of the above-mentioned GLP-1 agonist into the body, and since the specific details have been described above, a redundant explanation will be omitted.

[0089] The above granules may be manufactured by a wet or dry granulation method. Specifically, when the above granules are manufactured by a wet granulation method, they may be manufactured by combining the C8 to C10 medium-chain fatty acid salt absorption promoter with water, and subsequently dried and granulated. At this time, drying may be performed at 40°C to 60°C and may be performed so that the loss on drying (LOD) is 3% or less (preferably 2% or less). Meanwhile, when the above granules are manufactured by a dry granulation method, they may be manufactured by performing one or more selected from the group consisting of slugging, roller compacting, high pressure extruding, and spheronizing on the C8 to C10 medium-chain fatty acid salt absorption promoter, and subsequently granulated.

[0090]

[0091] Next, the method for manufacturing an oral pharmaceutical formulation according to the present invention includes the step of administering a magnesium-based antacid [step (b)].

[0092] The above magnesium antacid is intended to provide an environment in which the GLP-1 agonist can be sufficiently dissolved in the stomach by combining it with the above medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; since specific details have been described above, a redundant explanation will be omitted. At this time, the above addition may be performed through post-mixing for 1 to 10 minutes.

[0093] One or more alkalizing agents selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, and combinations thereof may be added, and accordingly, the efficacy of the GLP-1 agonist can be significantly improved. Since specific details have been described above, a redundant explanation will be omitted.

[0094]

[0095] Meanwhile, the method for manufacturing an oral pharmaceutical formulation according to the present invention is characterized by administering a GLP-1 agonist during step (a), between step (a) and step (b), or during step (b).

[0096] As the specific details of the above GLP-1 agonist have been described above, a redundant explanation will be omitted. The above GLP-1 agonist may be added during the preparation of the granules in step (a), added separately between step (a) and step (b), or added during post-mixing in step (c). In this case, if the above GLP-1 agonist is added separately between step (a) and step (b), the separate addition may be performed through separate post-mixing for 5 to 20 minutes.

[0097]

[0098] If necessary, the method for preparing an oral pharmaceutical formulation according to the present invention may subsequently mix magnesium stearate or talc. At this time, the subsequent mixing may also be performed for 1 to 10 minutes.

[0099]

[0100] Next, the method for manufacturing an oral pharmaceutical formulation according to the present invention includes a step of tableting [step (c)].

[0101]

[0102] Alternatively, the present invention provides a use for an oral pharmaceutical preparation comprising a GLP-1 agonist; a medium-chain fatty acid salt absorption enhancer having 8 to 10 carbon atoms; and a magnesium-based antacid to prevent, treat, or improve any one or more metabolic diseases selected from the group consisting of obesity, diabetes, non-alcoholic fatty liver, hepatic steatosis, dyslipidemia, arteriosclerosis, insulin resistance syndrome, cardiovascular disease, alcoholism, chronic kidney disease, Alzheimer's disease, and complications thereof.

[0103] Alternatively, the present invention provides a method for the prevention, treatment, or improvement of any one or more metabolic diseases selected from the group consisting of obesity, diabetes, non-alcoholic fatty liver, hepatic steatosis, dyslipidemia, arteriosclerosis, insulin resistance syndrome, cardiovascular disease, alcoholism, chronic kidney disease, Alzheimer's disease, and complications thereof, comprising the step of orally administering to an individual a pharmaceutical preparation comprising a GLP-1 agonist; a medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; and a magnesium-based antacid. In this case, "individual" refers to a subject requiring treatment for the disease, and more specifically, refers to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cattle.

[0104]

[0105] As reviewed above, the oral pharmaceutical formulation according to the present invention comprises a GLP-1 agonist; an absorption promoter of a medium-chain fatty acid salt having 8 to 10 carbon atoms; and a magnesium-based antacid. By the optimal combination of the absorption promoter and the magnesium-based antacid, an environment can be provided in which the GLP-1 agonist can be sufficiently dissolved in the stomach, and accordingly, the absorption of the GLP-1 agonist into the body can be effectively promoted.

[0106] Accordingly, the oral pharmaceutical formulation according to the present invention is manufactured without tablet compression issues, and can improve the sustained release of the GLP-1 agonist while maintaining the excellent efficacy of the GLP-1 agonist, and has the advantage of having effects of weight loss and reduced food intake.

[0107] In particular, in the oral pharmaceutical formulation according to the present invention, when an alkalizing agent is additionally included, the efficacy of the GLP-1 agonist can be significantly improved, and in addition to the effects of weight loss and reduced food intake, it can prevent the increase in blood glucose in a type 2 diabetes model or maintain glycated hemoglobin levels within a certain range over the long term, thereby preventing the development of severe diabetes.

[0108]

[0109] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention, and the scope of the invention is not limited by the following embodiments.

[0110]

[0111] [Example]

[0112] Preliminary Example: Antacid Screening Test

[0113] 50 mg each of 11 types of antacids were added to 50 mL of artificial gastric fluid (pH 1.5-1.6) and dissolved, and the final pH of the artificial gastric fluid was measured to determine the change in pH increase according to the amount of 11 types of antacids added (Fig. 1).

[0114] As shown in Figure 1, first, when a total of 500 mg of 11 types of antacids were added to artificial gastric juice, it was confirmed that aluminum-based antacids, such as aluminum silicate, aluminum hydroxide, and aluminum phosphate, did not raise the pH of the artificial gastric juice at all.

[0115] Subsequently, when the remaining eight types of antacids were added to the artificial gastric fluid in amounts up to a total of 1500 mg, it was confirmed that antacids such as calcium carbonate, sodium bicarbonate, calcium hydrogen phosphate hydrate, and anhydrous calcium hydrogen phosphate slightly increased the pH of the artificial gastric fluid but were not sufficient to dissolve GLP-1 agonists (especially semaglutide). However, magnesium-based antacids such as magnesium carbonate, magnesium hydroxide, and magnesium oxide (light / heavy) were found to sufficiently increase the pH of the artificial gastric fluid to effectively dissolve GLP-1 agonists (especially semaglutide). In particular, magnesium oxide (light / heavy) could be screened as the most desirable antacid because it could significantly increase the pH of the artificial gastric fluid even when administered in a relatively small amount (e.g., a total of 500 mg).

[0116]

[0117] Examples 1 to 4: Pharmacokinetic (PK) Evaluation According to Combinations of Magnesium-Based Antacids with Sodium Caprate (C10) Absorption Enhancer Doses

[0118] Semaglutide compositions [semaglutide 20 mg / kg, C10 37.5–300 mg / kg and magnesium oxide (hard) 20 mg / kg] according to Examples 1 to 4 were prepared and each was administered a single oral dose to SD rats (n=4). Meanwhile, a control group (1) [semaglutide 4 mg / kg, SNAC (Salcaprozate sodium) 300 mg / kg and magnesium oxide (hard) 20 mg / kg] was prepared and administered a single oral dose to SD rats (n=3). Pharmacokinetic (PK) evaluation of semaglutide was performed for these. Specifically, after orally administering the prepared solution to SD rats using a sonde, 0.3 mL of blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and the collected blood was immediately transferred to a tube treated with heparin sodium and stored under refrigeration. The refrigerated blood was immediately centrifuged at 3,000 rpm for 10 minutes to separate the plasma, and the concentration of semaglutide in the plasma was analyzed using LC-MS / MS, and the results were compared (Table 1).

[0119] Control group (1) Example 1 Example 2 Example 3 Example 4 Semaglutide (mg / kg) 420202020 Absorption promoter SNAC (mg / kg) 300----C10 (mg / kg) -37.575150300 Magnesium oxide (hard) (mg / kg) 2020202020AUC last ng / mL*hr266268308685883C max ng / mL 76.24 4.86 1.41 12.51 55.2T 1 / 2 hr3.35.03.96.35.7T max hr0.3750.70.50.30.6

[0120] As a result, as shown in Table 1, the semaglutide compositions according to Examples 1 to 4, in the case where C10 was applied as an absorption promoter and magnesium oxide (light) was applied as a magnesium-based antacid, showed that the AUC of semaglutide was dependent on the C10 dose. last and Cmax It is confirmed that the value is increasing.

[0121]

[0122] Examples 5 and 6: Pharmacokinetic (PK) Evaluation According to Combinations of Magnesium-Based Antacids with Sodium Caprylate (C8) Absorption Enhancer Doses

[0123] Semaglutide compositions [semaglutide 20 mg / kg, C8 150–300 mg / kg, and magnesium oxide (hard) 20 mg / kg] according to Examples 5 and 6 were prepared and administered as a single oral dose to SD rats (n=4). Meanwhile, a control group (1) [semaglutide 4 mg / kg, SNAC (Salcaprozate sodium) 300 mg / kg, and magnesium oxide (hard) 20 mg / kg] was prepared and administered as a single oral dose to SD rats (n=3). Pharmacokinetic (PK) evaluations were performed on these. Specifically, after orally administering the prepared solutions to SD rats using a sonde, 0.3 mL of blood was collected after 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and the obtained blood was immediately transferred to a tube treated with heparin sodium and stored under refrigeration. Refrigerated blood was immediately centrifuged at 3,000 rpm for 10 minutes to separate the plasma, and the concentration of semaglutide in the plasma was analyzed using LC-MS / MS, and the results were compared (Table 2).

[0124] Control group (1) Example 5 Example 6 Maglutide (mg / kg) 42020 Absorption promoter SNAC (mg / kg) 300--C8 (mg / kg) 150300 Magnesium oxide (hard) (mg / kg) 202020 AUC last ng / mL*hr266441646C max ng / mL 76.25 2.28 5.0T 1 / 2 hr3.37.88.2T max hr0.3751.31.8

[0125]

[0126] As a result, as shown in Table 2, the semaglutide compositions according to Examples 5 and 6, in which C8 was applied as an absorption enhancer and magnesium oxide (light) was applied as a magnesium-based antacid, showed that the AUC of semaglutide was likewise dependent on the C8 dose. last and C max It is confirmed that the value increases. Synthesizing the findings from Tables 1 and 2, when the semaglutide composition is combined with magnesium-based antacids as an absorption enhancer—not only for C10 but also for C8—the AUC of semaglutide is dose-dependent of the absorption enhancer. last Value and C max As the value was increased, the drug delivery rate could be improved.

[0127] In particular, when C10 and magnesium-based antacids are combined as absorption enhancers, compared to when C8 and magnesium-based antacids are combined as absorption enhancers, the AUC of semaglutide last Value and C max It is confirmed that the value can be further increased.

[0128]

[0129] Example 7 and Comparative Example 1: Pharmacokinetic (PK) evaluation according to the wet granulation method and the presence or absence of a magnesium-based antacid in a sodium caprate (C10) absorption enhancer

[0130] Referring to Table 3 below, a semaglutide formulation according to Example 7 was prepared as follows: Granules of 420 mg of C10 and 112 mg of purified water were dried at 50°C to a loss on drying (LOD) of 2% or less, and then granulated to a size of #35 mesh. Subsequently, 14 mg of semaglutide was separately mixed for 10 minutes, and then 63 mg of magnesium oxide (light) as a magnesium-based antacid was mixed for 5 minutes. Afterward, 5 mg of magnesium stearate and 25 mg of talc were subsequently mixed as a lubricant for 5 minutes, and then the formulation was prepared by compressing with a tablet press. Meanwhile, a semaglutide preparation according to Comparative Example 1 was prepared as follows: the preparation was prepared in the same manner as Example 7, except that 420 mg of C10 and 14 mg of semaglutide were used, the magnesium-based antacid was omitted, and the tablets were compressed using a nuclear tablet press.

[0131] Example 7 Comparative Example 1 Main ingredient Semaglutide 14 mg 14 mg Absorption enhancer C10 4 20 mg 420 mg Magnesium-based antacid Magnesium oxide 63 mg Lubricant Magnesium stearate 5 mg 5 mg Talc 25 mg 25 mg Solvent Purified water 112 mg 112 mg Total weight 527 mg 464 mg

[0132] Referring to Table 4 below, the semaglutide formulations prepared in Example 7 and Comparative Example 1 and the control group (2) [Rybelsus; semaglutide 14 mg and SNAC 300 mg] were prepared. Two tablets each of the control group and Example 7, and one tablet each of Comparative Example 1 were orally administered to Beagle dogs (n=5), and pharmacokinetic (PK) evaluations were performed. Specifically, after orally administering the prepared tablets to Beagles that had fasted for more than 16 hours using a sonde, 1 mL of blood was collected at 0.25, 0.5, 1, 2, 4, 8, 24, 32, 48, 56, 72, 80, and 96 hours, and the concentration of semaglutide in the plasma was analyzed and the results were compared (Table 4 and Fig. 2).

[0133] Control group (2) Example 7 Comparative Example 1 Maglutide (mg per animal) 282814 AUC last ng / mL*hr63015043930AUC inf ng / mL*hr62955162NAC max ng / mL 165.3144.128.4T 1 / 2 hr38.644.0NAT max hr1.52.01.0

[0134] As a result, as shown in Table 4 and Figure 2, the semaglutide preparation prepared in Example 7 has efficacy similar to the control group (2), and in particular, compared to the control group (2), T 1 / 2 and T max It is confirmed that extending the duration results in superior performance in terms of sustained blood drug concentration. Meanwhile, in the case of the semaglutide preparation prepared in Comparative Example 1, it is confirmed that the efficacy and sustained blood drug concentration are significantly reduced as the magnesium-based antacid is omitted.

[0135]

[0136] Example 8: Optimal combination of sodium caprate (C10) absorption enhancer and magnesium-based antacid / alkaliizing agent, dissolution test and pharmacokinetic (PK) evaluation according to wet granulation method

[0137] Referring to Table 5 below, a semaglutide formulation according to Example 8 was prepared as follows: Granules of 210 mg of C10 and 35 mg of purified water were dried at 50°C to a loss on drying (LOD) of 2% or less, and then granulated to a size of #35 mesh. Subsequently, 14 mg of semaglutide was separately mixed for 10 minutes, and then 60 mg of magnesium oxide (light) as a magnesium-based antacid, 180 mg of sodium bicarbonate as an alkalizing agent, and 15 mg of sodium starch glycolate as a disintegrant were mixed for 5 minutes. Subsequently, 6 mg of magnesium stearate and 15 mg of talc were subsequently mixed for 5 minutes, and then the formulation was prepared by compressing with a tablet press.

[0138] Example 8 Main ingredient: Semaglutide 14 mg Absorption enhancer: C102 10 mg Magnesium-based antacid: Magnesium oxide 60 mg Alkalinizing agent: Sodium bicarbonate 180 mg Disintegrant: Sodium starch glycolate 15 mg Lubricant: Magnesium stearate 6 mg Talc 15 mg Solvent: Purified water 35 mg Total weight: 500 mg

[0139] After preparing the semaglutide formulation prepared in Example 8 and a control group (3) [Rybelsus; semaglutide 14 mg and SNAC 300 mg], a dissolution test of semaglutide was performed under the following dissolution conditions, and the results were compared (Fig. 3(a)):

[0140] - Elution conditions: 0.05% brij pH 1.2 500 mL, 75 rpm.

[0141] As a result, as shown in Fig. 3(a), the semaglutide preparation prepared in Example 8 is confirmed to have an improved dissolution rate of semaglutide compared to the control group (3).

[0142] Subsequently, referring to Table 6 below, two tablets each of the control group (3) and Example 8 were orally administered to Beagle dogs (n=5), and pharmacokinetic (PK) evaluations were performed. Specifically, after orally administering the prepared tablets to Beagles that had fasted for more than 16 hours using a sonde, 1 mL of blood was collected at 0.25, 0.5, 1, 2, 4, 8, 24, 32, 48, 56, 72, 80, and 96 hours, and the concentration of semaglutide in the plasma was analyzed and the results were compared (Table 6 and Fig. 3(b)).

[0143] Control group (3) Example 8 Maglutide (mg per animal) 2828 AUC last ng / mL*hr213914467C max ng / mL 57.1303.6T 1 / 2 hrNANAT max hr1.54.0

[0144] As a result, as shown in Table 6 and Figure 3(b), the semaglutide formulation prepared in Example 8 has an AUC compared to the control group (3). last and C max It is confirmed that the levels are approximately 676% and 532%, respectively. In other words, it is confirmed that the semaglutide formulation prepared in Example 8 can significantly improve drug transfer even with a reduced dose of C10 as an absorption promoter by applying C10 as an absorption promoter, magnesium oxide (light) as a magnesium-based antacid, and sodium bicarbonate as an alkalizing agent. Furthermore, compared to the control group (3), T max It is confirmed to be particularly excellent in terms of release persistence as it significantly extends the duration.

[0145]

[0146] Examples 9 and 10: Optimal combination of sodium caprate (C10) absorption promoter and magnesium-based antacid / alkaliizing agent and dissolution test according to dry granulation method

[0147] Referring to Table 7 below, semaglutide formulations according to Examples 9 and 10 were prepared as follows: First, for Example 9, 210 mg of C10 was dry-granulated using a roller compactor and then granulated to a size of #30 mesh. Subsequently, 14 mg of semaglutide was separately mixed for 10 minutes, and then 60 mg of magnesium oxide (hard) as a magnesium-based antacid, 180 mg of sodium bicarbonate as an alkalizing agent, and 15 mg of sodium starch glycolate as a disintegrant were mixed for 5 minutes. Afterward, 6 mg of magnesium stearate and 15 mg of talc were subsequently mixed for 5 minutes, and then the formulation was prepared by compressing with a tablet press. Meanwhile, in Example 10, 210 mg of C10 sieved through #30 mesh and 14 mg of semaglutide were mixed for 5 minutes, dry granulated using a roller compactor, and then set to a size of #30 mesh. Subsequently, 60 mg of magnesium oxide (hard) as a magnesium-based antacid, 180 mg of sodium bicarbonate as an alkalizing agent, and 15 mg of sodium starch glycolate as a disintegrant were mixed for 5 minutes. Afterward, 6 mg of magnesium stearate and 15 mg of talc were mixed for 5 minutes as a lubricant, and then the formulation was prepared by compressing with a tablet press.

[0148] Example 9 Example 10 Main Components Semaglutide 14 mg 14 mg Absorption Enhancer C102 10 mg 210 mg Magnesium-based Antacid Magnesium Oxide 60 mg 60 mg Alkalinizing Agent Sodium Bicarbonate 180 mg 180 mg Disintegrant Sodium Starch Glycolate 15 mg 15 mg Llullator Magnesium Stearate 6 mg 6 mg Talc 15 mg 15 mg Total Weight 500 mg 500 mg

[0149] Semaglutide formulations prepared in Examples 9 and 10 and a control group (3) [Rybelsus; 14 mg of semaglutide and 300 mg of SNAC] were prepared, and then a dissolution test of semaglutide was performed under the following dissolution conditions, and the results were compared (Fig. 4):

[0150] - Elution conditions: 0.05% brij pH 1.2 500 mL, 75 rpm.

[0151] As a result, as shown in Figure 4, it is confirmed that the dissolution rate of semaglutide in both of the semaglutide preparations prepared in Examples 9 and 10 is significantly improved compared to the control group (3).

[0152] That is, in manufacturing the semaglutide formulation according to the present invention, it was confirmed that when the dry granulation method was applied, the dissolution rate of semaglutide was improved to an equivalent or higher level compared to when the wet granulation method was applied.

[0153]

[0154] Example 11: Optimal combination of sodium caprylate (C8) absorption promoter and magnesium-based antacid / alkaliizing agent and dissolution test according to wet granulation method

[0155] Referring to Table 8 below, a semaglutide formulation according to Example 11 was prepared as follows: Granules of 210 mg of C8 and 50 mg of purified water were dried at 50°C to a loss on drying (LOD) of 2% or less, and then granulated to a size of #35 mesh. Subsequently, 14 mg of semaglutide was separately mixed for 10 minutes, and then 60 mg of magnesium oxide (light) as a magnesium-based antacid, 180 mg of sodium bicarbonate as an alkalizing agent, and 15 mg of sodium starch glycolate as a disintegrant were mixed for 5 minutes. Subsequently, 6 mg of magnesium stearate and 15 mg of talc were subsequently mixed for 5 minutes, and then the formulation was prepared by compressing with a tablet press.

[0156] Example 11 Main ingredient: Semaglutide 14 mg Absorption enhancer: C82 10 mg Magnesium-based antacid: Magnesium oxide 60 mg Alkalinizing agent: Sodium bicarbonate 180 mg Disintegrant: Sodium starch glycolate 15 mg Lubricant: Magnesium stearate 6 mg Talc 15 mg Solvent: Purified water 50 mg Total weight: 500 mg

[0157] After preparing the semaglutide formulation prepared in Example 11 and a control group (3) [Rybelsus; semaglutide 14 mg and SNAC 300 mg], a dissolution test of semaglutide was performed under the following dissolution conditions, and the results were compared (Fig. 5):

[0158] - Elution conditions: 0.05% brij pH 1.2 500 mL, 75 rpm.

[0159] As a result, as shown in Fig. 5, the semaglutide preparation prepared in Example 11 is confirmed to have a significantly improved semaglutide dissolution rate compared to the control group (3).

[0160] That is, in preparing the semaglutide formulation according to the present invention, it was confirmed that when C8 was applied alone as an absorption promoter, the dissolution rate of semaglutide was improved to an equivalent or higher level compared to when C10 was applied alone.

[0161]

[0162] Example 12: Optimal combination of sodium caprate (C10) / sodium caprylate (C8) absorption promoter and magnesium-based antacid / alkaliizing agent and dissolution test according to wet granulation method

[0163] Referring to Table 9 below, a semaglutide formulation according to Example 12 was prepared as follows: a combination of 105 mg of C8 and 105 mg of C10 was combined with 40 mg of purified water, dried at 50°C to a loss on drying (LOD) of 2% or less, and then granulated to a size of #35 mesh. Subsequently, 14 mg of semaglutide was separately mixed for 10 minutes, followed by 60 mg of magnesium oxide (light) as a magnesium-based antacid and 15 mg of sodium starch glycolate as a disintegrant, followed by 5 minutes. Then, 6 mg of magnesium stearate and 15 mg of talc were subsequently mixed as a lubricant for 5 minutes, and the formulation was prepared by compressing with a tablet press.

[0164] Example 12 Main Ingredients: Semaglutide 14 mg, Absorption Enhancer C10 105 mg, C8 105 mg, Magnesium-based Antacid: Magnesium Oxide 60 mg, Alkalinizing Agent: Sodium Bicarbonate 180 mg, Disintegrant: Sodium Starch Glycol 15 mg, Lubricant: Magnesium Stearate 6 mg, Talc 15 mg, Solvent: Purified Water 50 mg, Total Weight 500 mg

[0165] After preparing the semaglutide formulation prepared in Example 12 and a control group (3) [Rybelsus; semaglutide 14 mg and SNAC 300 mg], a dissolution test of semaglutide was performed under the following dissolution conditions, and the results were compared (Fig. 6):

[0166] - Elution conditions: 0.05% brij pH 1.2 500 mL, 75 rpm.

[0167] As a result, as shown in Fig. 6, the semaglutide preparation prepared in Example 12 is confirmed to have a significantly improved semaglutide dissolution rate compared to the control group (3).

[0168] That is, in preparing the semaglutide formulation according to the present invention, it was confirmed that when C10 and C8 were applied in combination as absorption promoters, the dissolution rate of semaglutide was improved to an equivalent or higher level compared to when C10 was applied alone.

[0169]

[0170] Experimental Example 1: Initial efficacy test according to the optimal combination of sodium caprate (C10) absorption enhancer and magnesium-based antacid / alkaliizing agent (based on 4 weeks)

[0171] A semaglutide composition [semaglutide 20 mg / kg, C10 300 mg / kg, magnesium oxide (light) 4 mg / mL, and sodium bicarbonate 12 mg / mL] was prepared according to Example 13. A semaglutide composition [semaglutide 20 mg / kg, C10 300 mg / kg, and magnesium oxide (light) 4 mg / mL] was prepared according to Example 14, with the same composition as in Example 13 except for sodium bicarbonate.

[0172] Meanwhile, as a composition using SNAC as an absorption promoter, a semaglutide composition [semaglutide 20 mg / kg and SNAC 300 mg / kg] according to Comparative Example 2 was prepared. In addition, as a composition omitting the absorption promoter, a semaglutide composition [semaglutide 20 mg / kg] according to Comparative Example 3 was prepared.

[0173] Subsequently, antacids and alkalizing agents were orally administered at 5 mL / kg, and the other components (semaglutide and absorption enhancer) were administered at 10 mL / kg to db / db mice (n=6) once daily. Changes in body weight, feed intake, and blood glucose levels were measured over a period of 4 weeks. Specifically, body weight was measured once a week for each individual before the administration of the test substance and until the end of the study. Feed intake was calculated by measuring the remaining amount on the day following a quantitative feed intake, on a per-bed basis, before the administration of the test substance and until the end of the study. Blood glucose levels were measured once a week for each individual in a non-fasting state using a GDoctor®c (AGM-4000, All MEDICUS Co., LTD, Korea), and the results were compared (Table 10 and Fig. 7).

[0174] Negative Control Group (Excipient Group) Example 13 Example 14 Comparative Example 2 Comparative Example 3 Maglutide (mg / kg)-20202020 Absorption Enhancer SNAC (mg / kg)---300-C10 (mg / kg)-300300--Magnesium-based Antacid Magnesium Oxide (Hard) (mg / mL)-44--Alkalinizing Agent Sodium Bicarbonate (mg / mL)-12---Change in body weight (%) from Week 0 to Week 4 (%)-0.9-4.6-4.2-4.1-1.5 Change in feed intake (%) from Week 0 to Week 4 (%)-14.9-41.5-34.8-32.5-18.5 Change in blood glucose (%) from Week 0 to Week 4 (%)5.60.511.06.617.9

[0175] As shown in Table 10 and Figure 7, when examining the changes in body weight, the semaglutide compositions according to Examples 13 and 14, which use C10 as an absorption promoter and magnesium oxide (light) as a magnesium-based antacid, show that changes in body weight begin to occur from the beginning (especially after 1-2 weeks) and distinct changes in body weight are confirmed after 4 weeks. However, the semaglutide composition according to Comparative Example 2, which uses SNAC as an absorption promoter, shows no significant changes in body weight after 1-2 weeks. Furthermore, the semaglutide composition according to Comparative Example 3, which omits the absorption promoter, does not show any significant changes in body weight over 4 weeks.

[0176] In addition, when examining changes in feed intake, it was confirmed that the semaglutide compositions according to Examples 13 and 14 showed a rapid decrease in feed intake after 4 weeks. In particular, when C10 was applied as an absorption promoter, as in the semaglutide composition according to Example 13, and both magnesium oxide (light) as a magnesium-based antacid and sodium bicarbonate as an alkalizing agent were applied, it can be seen that the feed intake decreased particularly rapidly starting from 3-4 weeks, even compared to the case where the application of the alkalizing agent was omitted, as in Example 14.

[0177] Meanwhile, as a result of examining changes in blood glucose levels, it was confirmed that when C10 was applied as an absorption promoter, particularly as in the semaglutide composition according to Example 13, and magnesium oxide (light) as a magnesium-based antacid and sodium bicarbonate as an alkalizing agent were all applied, blood glucose levels were maintained at a constant level without a significant increase in blood glucose levels for 4 weeks in a type 2 diabetes model, which can be considered the most desirable combination.

[0178]

[0179] Experimental Example 2: Long-term intensive efficacy test based on the optimal combination of sodium caprate (C10) absorption enhancer and magnesium-based antacid / alkaliizing agent (based on 8 weeks)

[0180] A semaglutide composition [semaglutide 20 mg / kg, C10 300 mg / kg, magnesium oxide (light) 4 mg / mL and sodium bicarbonate 12 mg / mL] was prepared according to Example 13 (oral).

[0181] Meanwhile, as a composition omitting the absorption promoter, a semaglutide composition [semaglutide 20 mg / kg] according to Comparative Example 3 (oral) was prepared.

[0182] Subsequently, the antacid and alkalizing agent were orally administered to db / db mice (n=6) once a day at 5 mL / kg, and the other composition (semaglutide and absorption enhancer) at 10 mL / kg.

[0183] Meanwhile, a semaglutide composition [semaglutide 0.02 mg / kg] according to Comparative Example 4 (subcutaneous) was prepared and administered subcutaneously to db / db mice (n=6).

[0184] Changes in body weight and feed intake were measured after 8 weeks, and glycated hemoglobin was measured at week 8. Specifically, body weight was measured once a week for each individual before the administration of the test substance and thereafter until the end of the experiment. Feed intake was calculated by measuring the remaining amount on the day following a quantitative feed intake given once a week before the administration of the test substance and thereafter until the end of the experiment, and then calculating the difference. Glycated hemoglobin was measured at the end of the experiment using a DCA Vantage analyzer (SIEMENS, Germany) under non-fasting conditions, and the results were compared (Table 11 and Fig. 8).

[0185] Example 13 (Oral) Comparative Example 3 (Oral) Comparative Example 4 (Subcutaneous) Semaglutide (mg / kg) 20 20 0.02 Absorption enhancer SNAC (mg / kg) --- C10 (mg / kg) 300 -- Magnesium-based antacid Magnesium oxide (hard) (mg / mL) 4 -- Alkalinizing agent Sodium bicarbonate (mg / mL) 12 -- Change in body weight (%) from Week 0 to Week 8 - 13.6 - 11.2 - 8.1 Change in feed intake (%) from Week 8 to Week 10 - 48.6 - 29.6 - 42.8 Week 8 Glycated hemoglobin (%) 8.2 10.8 7.6

[0186] As shown in Table 11 and Figure 8, when examining changes in body weight, it was confirmed that when the semaglutide / C10 / magnesium-based antacid / alkaliizing agent composition according to Example 13 (oral) was administered orally, body weight decreased rapidly after 8 weeks. This can be seen as more effective compared to when the semaglutide-only composition according to Comparative Example 3 (oral) was administered orally or when the semaglutide-only composition according to Comparative Example 4 (subcutaneous) was administered subcutaneously. At this time, as the amount of weight loss after 8 weeks of oral administration of Example 13 (oral) increased by approximately 3 times compared to the amount of weight loss after 4 weeks, it can be seen that the efficacy is intensified and sustained over the long term.

[0187] In addition, when examining changes in feed intake, it was confirmed that feed intake decreased rapidly after 8 weeks when the semaglutide / C10 / magnesium-based antacid / alkaliizing agent composition according to Example 13 (oral) was administered orally. This can be seen as more effective compared to the oral administration of the semaglutide-only composition according to Comparative Example 3 (oral) or the subcutaneous administration of the semaglutide-only composition according to Comparative Example 4 (subcutaneous). At this time, it was found that the decrease in feed intake after 8 weeks in Example 13 (oral) was even greater than the decrease in feed intake after 4 weeks.

[0188] Meanwhile, as a result of examining changes in blood glucose levels, oral administration of the semaglutide / C10 / magnesium-based antacid / alkaliizing agent composition according to Example 13 (oral) is desirable in that it prevents the worsening of blood glucose levels in a type 2 diabetes model and thus prevents the development of severe diabetes, as it maintains glycated hemoglobin within 9% at week 8. On the other hand, it is confirmed that oral administration of the semaglutide-only composition according to Example 13 (oral) causes a problem of worsening blood glucose levels in a type 2 diabetes model and leading to the development of severe diabetes.

[0189]

[0190] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. GLP-1 agonists; A medium-chain fatty acid salt absorption promoter having 8 to 10 carbon atoms; and Oral pharmaceutical preparations containing magnesium-based antacids.

2. In Paragraph 1, An oral pharmaceutical preparation characterized in that the above-mentioned GLP-1 agonist is semaglutide, exendin-4, CA-exendin-4 (Imidazoacetyl-exendin-4), DA-exendin-4 (Desamino-histidyl-exendin-4), HY-exendin-4 (beta-hydroxy imidazopropoinyl-exendin-4), CX-exendin-4 (beta-carboxyimidazopropionyl-exendin-4), DM-exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, dulaglutide, or albiglutide.

3. In Paragraph 1, An oral pharmaceutical preparation characterized in that the absorption promoter is one or more selected from the group consisting of sodium caprate (C10), sodium caprylate (C8), and combinations thereof.

4. In Paragraph 1, An oral pharmaceutical preparation characterized in that the weight ratio of the above GLP-1 agonist to the above absorption promoter is 1:1 to 1:

70.

5. In Paragraph 1, An oral pharmaceutical preparation characterized in that the magnesium-based antacid is one or more selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium carbonate, and combinations thereof.

6. In Paragraph 1, An oral pharmaceutical preparation characterized in that the weight ratio of the above GLP-1 agonist to the above magnesium-based antacid is 1:0.5 to 1:

20.

7. In Paragraph 1, An oral pharmaceutical preparation characterized in that, based on 100 parts by weight of the above oral pharmaceutical preparation, the magnesium-based antacid is in an amount of 1 to 50 parts by weight.

8. In Paragraph 1, An oral pharmaceutical formulation characterized by further comprising one or more alkalizing agents selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, and combinations thereof.

9. In Paragraph 8, An oral pharmaceutical preparation characterized in that the weight ratio of the magnesium-based antacid to the alkalizing agent is 1:1 to 1:

25.

10. In Paragraph 8, An oral pharmaceutical preparation characterized in that, based on 100 parts by weight of the above oral pharmaceutical preparation, the alkalizing agent is in an amount greater than 0 parts by weight and up to 90 parts by weight.

11. In Paragraph 1, The above oral pharmaceutical preparation is characterized by further comprising one or more disintegrants selected from the group consisting of starch-based disintegrants, non-starch-based disintegrants, and combinations thereof.

12. In Paragraph 1, The above oral pharmaceutical preparation is characterized by further comprising one or more lubricants selected from the group consisting of fatty acid-based lubricants, inorganic lubricants, and combinations thereof.

13. In Paragraph 1, The above oral pharmaceutical preparation is characterized by being intended to prevent or treat one or more metabolic diseases selected from the group consisting of obesity, diabetes, non-alcoholic fatty liver, hepatic steatosis, dyslipidemia, arteriosclerosis, insulin resistance syndrome, cardiovascular disease, alcoholism, chronic kidney disease, Alzheimer's disease, and complications thereof.

14. In Paragraph 1, The above oral pharmaceutical preparation is characterized by having the effect of reducing weight or food intake.

15. (a) A step of preparing granules comprising an absorption promoter of a medium-chain fatty acid salt having 8 to 10 carbon atoms; (b) a step of administering a magnesium-based antacid; and (c) includes a step of compressing tablets, and A method for preparing an oral pharmaceutical formulation, characterized by administering a GLP-1 agonist during step (a), between step (a) and step (b), or during step (b).

16. In Paragraph 15, A method for manufacturing an oral pharmaceutical preparation, characterized in that, in step (a) above, the granules are manufactured by a wet or dry granulation method.

17. In Paragraph 16, A method for manufacturing an oral pharmaceutical formulation, characterized in that the above dry granulation method is performed through one or more selected from the group consisting of slugging, roller compacting, high pressure extruding, and spheronizing.

18. In Paragraph 15, A method for preparing an oral pharmaceutical formulation, characterized by adding one or more alkalizing agents selected from the group consisting of sodium bicarbonate, calcium carbonate, sodium carbonate, potassium carbonate, and combinations thereof in step (b) above.

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