Formulation for oral administration comprising semaglutide and absorption promoter as active ingredients and preparation method therefor

Abstract

The present invention relates to: a formulation for oral administration, comprising semaglutide and an absorption promoter as active ingredients and optionally further comprising an alkalizing agent; and a preparation method for the formulation. It has been confirmed that sodium caprate exhibits an excellent effect as an absorption promoter for the oral administration of semaglutide, which is a drug, and when the two substances are combined in the form of a single-layer tablet, a bilayer tablet, or a cored tablet, the stability of the formulation, the bioavailability of semaglutide, and the like are significantly increased, and thus it is possible to provide a formulation for oral administration with increased bioavailability and a preparation method for the formulation.

Description

Oral formulation containing semaglutide and an absorption enhancer as active ingredients and a method for manufacturing the same

[0001] The present invention relates to an oral formulation comprising semaglutide and an absorption promoter as active ingredients, and a method for manufacturing the same.

[0002] Semaglutide is a human glucagon-like peptide receptor agonist (GLP-1 RA) drug used for the management of diabetes and obesity. GLP-1 is a naturally occurring hormone in humans that plays a crucial role in blood sugar regulation; semaglutide acts as a GLP-1 receptor agonist in place of the rapidly disappearing GLP-1, helping to manage diabetes by lowering blood sugar levels, stimulating insulin secretion, and suppressing glucagon secretion. In addition, it is used as an obesity treatment drug because it also plays a role in reducing glucose production in the liver or slowing down digestion by suppressing appetite.

[0003] Oral administration of semaglutide has limitations due to low oral bioavailability caused by various barriers, such as enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption from the intestinal mucosa, and first-pass metabolism in the liver.

[0004] To date, oral delivery of GLP-1 derivatives has been studied in the form of once-daily tablets containing salcaprozate sodium (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate; Salcaprozate sodium; SNAC), an absorption enhancer, to improve the very low absorption and bioavailability of GLP-1 derivatives after oral administration, but it still shows low bioavailability, so research is needed to increase the bioavailability of semaglutide.

[0005] The object of the present invention is to provide an oral formulation comprising semaglutide and an absorption enhancer as active ingredients.

[0006] Another objective of the present invention is to provide an oral formulation comprising semaglutide, an absorption promoter, and an alkalizing agent as active ingredients.

[0007] Another objective of the present invention is to provide a method for manufacturing the above-mentioned oral administration formulation.

[0008] Another objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of obesity or diabetes comprising the above-mentioned oral formulation as an active ingredient.

[0009] To achieve the above objective, the present invention relates to an oral formulation comprising semaglutide or a pharmaceutically acceptable salt thereof; and an absorption enhancer as an active ingredient, wherein

[0010] The present invention provides an oral formulation characterized by the absorption promoter being one or more selected from the group consisting of sodium caprate, sodium laurate, docosahexaenoic acid-cysteine-capric acid (DOCA-Cys-C10), or pharmaceutically acceptable salts thereof.

[0011] The present invention provides an oral formulation comprising semaglutide or a pharmaceutically acceptable salt thereof; sodium caprate; and an alkalizing agent as active ingredients.

[0012] In addition, the present invention provides a method for manufacturing an oral formulation comprising the step of manufacturing a single-layer tablet, a bilayer tablet, and a core tablet comprising semaglutide and an absorption promoter as active ingredients.

[0013] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of obesity or diabetes comprising the above-mentioned oral formulation as an active ingredient.

[0014] According to the present invention, sodium caprate exhibits excellent effects as an oral absorption enhancer for the drug semaglutide, and by confirming that the stability of the formulation and the bioavailability of semaglutide are significantly increased when the two substances are combined in the form of a single-layer tablet, a bilayer tablet, or a core tablet, an oral formulation with increased bioavailability and a method for manufacturing the same can be provided.

[0015] Figure 1 shows an oral formulation prepared according to Experimental Example 1 below. The left side of the figure is a single-layer tablet formulation, the center is a bilayer tablet formulation, and the right side is a core tablet formulation.

[0016] Figure 2 shows the results of analyzing the in vitro dissolution rate of the active ingredient (semaglutide) over time in the oral administration formulation prepared in Experimental Example 1 below.

[0017] Figure 3 shows the results of analyzing absorption permeability in in vitro cells according to Table 16 below.

[0018] Figure 4 shows the results of analyzing the plasma absorption permeability of the orally administered formulation in in vivo rat pK according to Table 19 below.

[0019] Figure 5 shows the results of analyzing the plasma absorption permeability of oral administration formulations (Examples 11 and 12 of Table 3 below) in in vivo beagle pK.

[0020] The terms used in this specification have been selected based on currently widely used general terms whenever possible, taking into account their functions in the present invention; however, these terms may vary depending on the intent of those skilled in the art, case law, the emergence of new technologies, etc. Additionally, in specific cases, terms have been arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the relevant description of the invention. Therefore, the terms used in this invention should be defined not merely by their names, but based on their meanings and the overall content of the invention.

[0021] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0022]

[0023] The present invention will be described in more detail below.

[0024]

[0025] The present invention relates to an oral formulation comprising semaglutide or a pharmaceutically acceptable salt thereof; and an absorption promoter as an active ingredient, wherein

[0026] The present invention provides an oral formulation characterized by the absorption promoter being one or more selected from the group consisting of sodium caprate, sodium laurate, docosahexaenoic acid-cysteine-capric acid (DOCA-Cys-C10), or pharmaceutically acceptable salts thereof.

[0027] The above semaglutide is a compound represented by the following chemical formula 1, and its chemical name is N 6.26 -{18-[N-(17-carboxyheptadecanoyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1(7-37).

[0028] [Chemical Formula 1]

[0029]

[0030] In addition, the semaglutide is a human glucagon-like peptide receptor agonist (GLP-1 RA), and GLP-1 is a naturally occurring hormone important for blood sugar regulation in humans. Semaglutide acts as a GLP-1 receptor agonist in place of GLP-1, which disappears quickly, thereby helping to manage diabetes by lowering blood sugar levels, promoting insulin secretion, and suppressing glucagon secretion. Furthermore, it also plays a role in reducing glucose production in the liver or slowing down digestion by suppressing appetite, and is therefore used as an obesity treatment.

[0031] The above pharmaceutically acceptable salts may be one or more selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, and rifium, but are not limited thereto.

[0032] The above oral formulation may contain 0.1 to 10 parts by weight of semaglutide per 100 parts by weight of sodium caprate.

[0033]

[0034] The present invention provides an oral formulation comprising semaglutide or a pharmaceutically acceptable salt thereof; sodium caprate; and an alkalizing agent as active ingredients.

[0035] The above alkalizing agent may be one or more selected from sodium bicarbonate, sodium carbonate, calcium carbonate, or magnesium oxide.

[0036] The above oral formulation may contain 0.1 to 10 parts by weight of semaglutide per 100 parts by weight of sodium bicarbonate.

[0037] Specifically, sodium caprate (a C10 fatty acid) is one of the most studied absorption promoters for improving the oral absorption of low-penetration compounds (e.g., peptide and nucleotide-based drugs) and is a substance utilized to improve drug absorption through the gastrointestinal epithelium. When administered orally, sodium caprate raises the local pH of the gastric mucosa and accelerates the absorption of semaglutide within 15 to 30 minutes after administration, thereby increasing the bioavailability of semaglutide in the gastrointestinal tract.

[0038] The above-mentioned oral formulation may be any one form selected from the group consisting of single-layer tablets, bilayer tablets, and core tablets.

[0039] The above monolayer tablet form may comprise semaglutide or a pharmaceutically acceptable salt thereof, sodium caprate, and an alkalizing agent.

[0040] The above bilayer tablet form may consist of an upper layer comprising semaglutide or a pharmaceutically acceptable salt thereof; and a lower layer comprising sodium caprate.

[0041] The upper layer further comprises one or more additives selected from the group consisting of alkalizing agents, excipients, disintegrants, binders, and lubricants, and the alkalizing agent may be sodium bicarbonate or calcium carbonate.

[0042] The above lower layer may additionally include one or more additives selected from the group consisting of disintegrants, binders, and lubricants, but is not limited thereto.

[0043] The above-mentioned core form may consist of an inner core comprising semaglutide or a pharmaceutically acceptable salt thereof; and an outer layer comprising sodium caprate.

[0044] The above inner core may additionally include one or more additives selected from the group consisting of excipients, disintegrants, binders, and lubricants, but is not limited thereto.

[0045] The above outer layer further comprises one or more additives selected from the group consisting of alkalizing agents, disintegrants, binders, and lubricants, and the alkalizing agent may be sodium bicarbonate or calcium carbonate.

[0046] The above-mentioned oral formulation may include an absorption promoter of semiglutide, and the absorption promoter comprises a medium-chain fatty acid (caprylic acid, capric acid, lauric acid), a medium-chain fatty acid salt (sodium caprylate, potassium caprylate, sodium caprate, potassium capricate, potassium laurate, sodium laurate), a long-chain fatty acid (palmitic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, docohexaenoic acid) and a long-chain fatty acid salt (potassium palmitate, sodium palmitate, potassium stearate, sodium stearate, potassium oleate, sodium oleate, potassium linoleate, sodium linoleic acid, potassium alpha-linolenic acid, sodium alpha-linolenic acid, potassium arachidonic acid, sodium arachidonic acid, It may be one or more selected from the group consisting of potassium eicosapentaenoate, sodium eicosapentaenoate, potassium docosahexaenoate, and sodium docosahexaenoate, but is not limited thereto, and preferably may be a medium-chain fatty acid salt, more preferably sodium caprate. In addition, the absorption promoter may be included in an amount of 10 to 800 parts by weight per 100 parts by weight of the oral administration preparation.

[0047] The above excipient may be one or more selected from the group consisting of lactose (spray-dried lactose, α-lactose, β-lactose, Tabletose®, Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (Avicel®, Elcema®, Vivapur®, Ming Tai®, Heweten® or Solka-Floc®), other cellulose derivatives, corn starch, potato starch, wheat starch, sorbitol, mannitol, dextrin, dextran, maltodextrin, kaolin, sucrose, glucose, dicalcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate, calcium sulfate, calcium carbonate and sodium alginate, but is not limited thereto, and preferably may be microcrystalline cellulose (Heweten® 102). In addition, the above excipient may be included in an amount of 10 to 90 parts by weight per 100 parts by weight of the oral formulation.

[0048] The above binder may be one or more selected from the group consisting of lactose (spray-dried lactose, α-lactose, β-lactose, Tabletose®, Pharmatose®, Microtose®, or Fast-FloC®), microcrystalline cellulose (Avicel®, Elcema®, Vivapur®, Ming Tai®, Heweten®, or Solka-Floc®), hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hypromellose, methylcellulose polymer (Methocel A, Methocel A4C, or Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, calcium lactate, calcium carbonate, acacia, sodium alginate, gelatin, guar gum, pectin, PEG, povidone, and copovidone, but is not limited thereto, preferably povidone, more preferably It may be Copovidone VA64. In addition, the binder may be included in an amount of 2 to 40 parts by weight per 100 parts by weight of the oral formulation.

[0049] The above disintegrant may be one or more selected from the group consisting of sodium starch glycolate, crospovidone, sodium croscarmellose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, and calcium carboxymethylcellulose, but is not limited thereto, and preferably may be crospovidone, more preferably crospovidone CL. In addition, the above disintegrant may be included in an amount of 0.1 to 32 parts by weight per 100 parts by weight of the oral administration preparation.

[0050] The above alkalizing agent (antacid, gastric acid neutralizing agent) may be one or more selected from the group consisting of magnesium-based alkalizing agents (antacids), sodium-based alkalizing agents (antacids), calcium-based alkalizing agents (antacids), and aluminum-based alkalizing agents (antacids), but is not limited thereto; preferably, it may be a sodium-based alkalizing agent (antacid), and more preferably, sodium carbonate, calcium carbonate, magnesium oxide, or sodium bicarbonate. In addition, the alkalizing agent may be included in an amount of 5 to 80 parts by weight per 100 parts by weight of the oral administration preparation.

[0051] The above lubricant may be one or more selected from the group consisting of magnesium stearate, talc, stearic acid, and anhydrous hard silica, but is not limited thereto. The above lubricant may be included in an amount of 0.1 to 20 parts by weight per 100 parts by weight of the oral administration preparation.

[0052] The size of the entire formulation of the above-mentioned core-shaped oral preparation may be determined according to the size of the inner core. The total weight of the above-mentioned core-shaped oral preparation may be 600 mg or more for tablet stability and 1200 mg or less for patient convenience. Additionally, the total weight of the above-mentioned inner core may be 250 mg or less for patient convenience, preferably 90 mg or more to maintain tablet stability of the inner core, and more preferably 100 mg to 150 mg.

[0053]

[0054] The present invention comprises (1) a step of preparing a mixture comprising semaglutide or a pharmaceutically acceptable salt thereof and sodium caprate; and

[0055] (2) A method for manufacturing an oral formulation is provided, comprising the step of manufacturing a single-layer tablet by compressing the mixture of step (1) above.

[0056] The mixture of step (1) above may additionally include an alkalizing agent selected from sodium bicarbonate or calcium carbonate.

[0057]

[0058] The present invention comprises (1) a step of preparing an upper layer comprising semaglutide or a pharmaceutically acceptable salt thereof;

[0059] (2) A step of manufacturing a lower layer containing sodium caprate;

[0060] (3) A step of mixing and granulating the upper layer of step (1) and the lower layer of step (2), and then mixing a lubricant to produce a mixture; and

[0061] (4) A method for manufacturing an oral formulation is provided, comprising the step of compressing the mixture of step (3) into a bilayer tablet to produce a bilayer tablet.

[0062] The upper layer of the above step (1) may additionally include an alkalizing agent selected from sodium bicarbonate or calcium carbonate.

[0063]

[0064] The present invention comprises the step of (1) preparing an inner core comprising semaglutide or a pharmaceutically acceptable salt thereof;

[0065] (2) A step of manufacturing an outer layer containing sodium caprate;

[0066] (3) A step of sequentially injecting the outer layer of step (2) and the inner core of step (1) into the tablet punch die;

[0067] (4) A step of applying pre-pressure to the punch die of step (3) above;

[0068] (5) A step of injecting the outer layer of step (2) into the punch die to which preload was applied in step (4); and

[0069] (6) A method for manufacturing an oral formulation is provided, comprising the step of applying main pressure to a punch die into which the outer layer was injected in step (5) above to compress the tablet to produce a core tablet.

[0070] The outer layer of step (2) above may additionally include an alkalizing agent selected from sodium bicarbonate or calcium carbonate.

[0071] In step (4) above, the pre-pressure may be 1 to 10 kN, and in step (6) above, the main pressure may be 5 to 30 kN.

[0072]

[0073] The present invention provides a pharmaceutical composition for the prevention or treatment of obesity or diabetes comprising the above-mentioned oral formulation as an active ingredient.

[0074] The pharmaceutical composition of the present invention may be manufactured in a unit dose form or contained in a multi-dose container by formulation using a pharmaceutically acceptable carrier according to a method that can be easily carried out by a person skilled in the art to which the invention belongs.

[0075] The above-mentioned pharmaceutically acceptable carriers are those commonly used in formulations and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc. In addition to the above components, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

[0076] In the present invention, the content of the additive included in the pharmaceutical composition is not particularly limited and can be appropriately adjusted within the content range used in conventional formulations.

[0077] The above pharmaceutical composition may be formulated in the form of one or more external skin preparations selected from the group consisting of injectable formulations such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, tablets, creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastes, and cataplasms, but is not limited thereto.

[0078] The pharmaceutical composition of the present invention may further include pharmaceutically acceptable carriers and diluents for formulation. The pharmaceutically acceptable carriers and diluents include, but are not limited to, excipients such as starch, sugars, and mannitol; fillers and extenders such as calcium phosphate; cellulose derivatives such as carboxymethylcellulose and hydroxypropylcellulose; binders such as gelatin, alginates, and polyvinylpyrrolidone; lubricants such as talc, calcium stearate, hydrogenated castor oil, and polyethylene glycol; disintegrants such as povidone and crospovidone; and surfactants such as polysorbate, cetyl alcohol, and glycerol. The pharmaceutically acceptable carriers and diluents may be biologically and physiologically affinities for the target. Examples of diluents include, but are not limited to, saline solution, aqueous buffer solution, solvent, and / or dispersion media.

[0079] The pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. In the case of oral administration, it may be formulated into tablets, troches, lozenges, water-soluble suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. In the case of parenteral administration, it may be formulated into injectable solutions, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for topical application, oils, creams, etc.

[0080] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition, weight, age, gender, health status, dietary constitutional specificity, properties of the formulation, degree of disease, time of administration of the composition, method of administration, duration or interval of administration, excretion rate, and form of the drug, and may be appropriately selected by a person skilled in the art. For example, it may be in the range of about 0.1 to 10,000 mg / kg, but is not limited thereto, and may be administered once or several times a day.

[0081] The above pharmaceutical composition may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. The pharmaceutical effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, method of administration, time of administration, route of administration, etc., and a person skilled in the art can easily determine and prescribe a dosage effective for the intended treatment. The pharmaceutical composition of the present invention may be administered once a day or divided into several doses.

[0082] Hereinafter, the present invention will be described in detail with reference to examples to aid in understanding. However, the following examples are merely illustrative of the content of the present invention and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

[0083]

[0084] [Experimental Example 1] Preparation of an Oral Administration Formulation

[0085] Oral formulations were prepared containing semaglutide, a drug used as an obesity treatment; and sodium caprate, an oral permeability absorption enhancer, and were prepared in the form of monolayer tablets (Tables 1–2, Comparative Example 1 and Examples 1–10) (Fig. 1), bilayer tablets (Table 3, Examples 11–16) (Fig. 1), and core tablets (Tables 4–6, Examples 17–32) (Fig. 1). The control group (Comparative Example 1) used sodium caprate and salcaprozate sodium (hereinafter referred to as SNAC), an oral permeability absorption enhancer of a different type.

[0086] Specifically, monolayer tablets were prepared by dry granulating a mixture of semaglutide, an alkalizing agent (sodium bicarbonate or calcium carbonate), an absorption promoter (sodium caprate), an excipient (microcrystalline cellulose, lactose monohydrate), a disintegrant (crospovidone, sodium starch glycolate), and a binder (povidone K90), and then passing the mixture through a 3.0 mm mesh to produce granules. Subsequently, a lubricant (magnesium stearate) was added to prepare the final mixture. Then, monolayer tablets were manufactured by compressing (tablet-pressing) the mixture using a rotary tablet press.

[0087] A bilayer tablet was prepared by mixing and granulating semaglutide, an alkalizing agent (sodium bicarbonate or calcium carbonate), an excipient (microcrystalline cellulose), a disintegrant (crospovidone), and a binder (povidone K90), and then sifting the mixture using a #12 mesh to produce a granulated product. Subsequently, a lubricant (magnesium stearate) was mixed into the granulated product to produce an upper layer (granulated product). Then, an absorption promoter (sodium caprate), a disintegrant (crospovidone), and a binder (povidone K90) were mixed and granulated, and then sifting the mixture using a #12 mesh to produce a granulated product. Subsequently, a lubricant (magnesium stearate) was mixed into the mixture to produce a lower layer (granulated product). Finally, the upper and lower layers were compressed (tablet-pressed) using a bilayer tablet press to produce a bilayer tablet.

[0088] In addition, the inner core tablet (mixture) was prepared by mixing and granulating semaglutide, an excipient (microcrystalline cellulose 102 or / and lactose monohydrate 200), and a binder (povidone K90), and then sifting the mixture using a #12 mesh to produce a granulated product, after which a lubricant (magnesium stearate) was subsequently mixed into the granulated product. Then, an alkalizing agent (sodium bicarbonate or calcium carbonate), an absorption promoter (sodium caprate), a disintegrant (crospovidone, low-substituted hydroxypropylcellulose or sodium starch glycolate), and a binder (copovidone VA64) were mixed and granulated, and then sifting the mixture using a #12 mesh to produce a granulated product, after which a lubricant (magnesium stearate) was subsequently mixed into the granulated product to produce an outer layer (mixture). After that, the outer layer and the inner core were sequentially injected into the punch die of the tablet press, and a pre-pressure of 5.9 kN was applied to the punch die. Then, the outer layer was injected again into the punch die, and a main pressure of 15.5 kN was applied to produce a core tablet.

[0089] Comparison of Main Functional Ingredients Example 1 Example 1 Example 2 Example 3 Example 4 Example 5mg / Tmg / Tmg / Tmg / Tmg / Tmg / T Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 14.00 Excipient Microcrystalline Cellulose 1027 3.00 80.00 80.00 80.00 80.00 80.00 Alkalinizing Agent Sodium Bicarbonate ---- 100.00 200.00 Absorption Enhancer SNAC 300.00 ----- Absorption Enhancer Sodium Caprate 300.00 400.00 500.00 500.00 500.00 Disintegrant Crospovidone -- 2.00 5.00 5.00 5.00 Binder Povidone K9020.008.0010.0013.0013.0013.0013.00 Magnesium Stearate 4.009.009.0013.0011.0011.00 Total Tablet Weight 411.00411.00513.0620.0723.0823.0

[0090]

[0091] Main Functional Ingredients Example 6 Example 7 Example 8 Example 9 Example 10mg / Tmg / Tmg / Tmg / Tmg / T Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 Excipients Lactose Monohydrate 300.00 300.00 300.00 300.00 300.00 Alkalinizing Agent Sodium Bicarbonate 100.00 200.00 Absorption Enhancer Sodium Caprate 300.00 400.00 500.00 300.00 300.00 Disintegrant Sodium Starch Glycolate 32.00 32.00 32.00 32.00 32.00 Binder Povidone K9025.5625.5625.5625.5625.56 Activated Magnesium Stearate 9.009.009.009.009.00 Tablet Total Weight 680.56780.56880.56780.56880.566

[0092]

[0093] Main Functional Ingredients Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 mg / T mg / T mg / T mg / T mg / T mg Upper Layer Main Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 14.00 Alkalinizing Agent Sodium Bicarbonate-150.00 150.00 150.00 150.00 150.00 Excipient Microcrystalline Cellulose 1027 6.00 76.00 72.25 72.25 72.25 72.25 Crospovidone---3.75 2.50 3.50 Binder Povidone K905.05.08.755.006.255.25 Lubricant Magnesium stearate 5.05.05.005.005.005.005.00 Upper layer 250.00250.00250.00250.00250.00250.00 Lower layer Absorption promoter Sodium caprate 700.00700.00700.00700.00700.00700.00 Disintegrant Crospovidone 60.260.260.265.263.264.2 Binder Copovidone VA6413.013.012.09.010.09.0 Moisturizing Magnesium Stearate 6.86.85.85.86.86.8 Lower layer 680.00680.00680.00680.00680.00680.00 Bilayer tablet Total weight 780.00780.00780.0780.00780.00780.00

[0094]

[0095] Main Functional Ingredient Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 mg / T mg / T mg / T mg / T mg / T mg / T Intravenous Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 14.00 14.00 Excipient Microcrystalline Cellulose 10 2 8 2.00 4 1.00 -8 2.00 8 2.00 8 2.00 8 2.00 Lactose Monohydrate 20 0 -4 1.00 8 2.00 ---- Binding Agent Povidone K90 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Lubricant Magnesium Stearate 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Inner Core 100.00 100.00 100.00 100.00 100.00 100.00 Outer Layer Alkalinizing Agent Sodium Bicarbonate 2 11.00 311.00 311.00 200.00 202.80 200.00 200.00 Absorption Promoter Sodium Caprate 400.00300.00300.00400.00400.00400.00400.00400.00 Disintegrant Crospovidone 49.2049.2049.2060.2060.20--Low-substituted hydroxypropylcellulose----- 60.20-Sodium starch glycolate------60.20 Binder Copovidone VA 6413.0013.0013.0013.0010.2013.0013.00 Lubricant Magnesium stearate 6.806.806.806.806.806.806.806.80 Outer layer 680.00680.00680.00680.00680.00680.00680.00 Core tablet total Weight 780.00780.00780.0780.00780.00780.00780.00780.00

[0096]

[0097] Main Functional Ingredients Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 mg / T mg / T mg / T mg / T mg / T Inner Core Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 14.00 Excipient Microcrystalline Cellulose 102 82.00 80.00 77.00 72.00 82.00 82.00 Absorption Enhancer Sodium Caprate ---- 100.00 200.00 Disintegrant Crospovidone - 2.00 5.00 10.00 -- Binder Povidone K90 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Lubricant Magnesium Stearate 2.00 2.00 2.00 2.00 2.00 2.00 Inner Core 100.00 100.00 100.00 100.00 100.00 200.00 300.00 Outer Layer Alkalinizing Agent Sodium Bicarbonate 200.00 200.00 200.00 200.00 300.00 400.00 Absorption Enhancer Sodium Caprate 400.00 400.00 400.00 400.00 300.00 500.00 Disintegrant Crospovidon-60.20 60.20 60.20 60.20 60.20 Low Substitution Degree Hydroxypropylcellulose 60.20-----Binder Sodium starch glycolate 13.0013.0013.0013.0013.0013.00Llullator Copovidone VA 646.806.806.806.806.806.806.80 Outer layer 680.00680.00680.00680.00680.00980.00Core tablet Total weight 780.00780.00780.00780.00880.001280.00

[0098]

[0099] Main Functional Ingredients Example 30 Example 31 Example 32 mg / T mg / T mg / T Inner Core Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 Excipient Microcrystalline Cellulose 10 2 8 2.00 8 2.00 8 2.00 Absorption Enhancer Sodium Caprate- 100.00 200.00 Disintegrator Crospovidone- -- Binder Povidone K 90 2.00 2.00 2.00 Lubricant Magnesium Stearate 2.00 2.00 2.00 Inner Core Tablet 100.00 200.00 300.00 Outer Layer Alkalinizing Agent Sodium Bicarbonate--- Absorption Enhancer Sodium Caprate 400.00 300.00 500.00 Disintegrator Crospovidone- 60.20 60.20 Low Substitution Degree Hydroxypropylcellulose 60.20 -- Binder Sodium starch glycolate 13.00 13.00 13.00 Lubricant Copovidone VA 646.80 6.80 6.80 Outer layer 480.00 480.00 580.00 Core tablet Total weight 580.00 680.00 880.00

[0100]

[0101] [Experimental Example 2] Stability Analysis

[0102] To confirm the stability of the oral formulation prepared above, the content of semaglutide (drug) was measured for 6 months at 25 ℃ / 60% relative humidity (accelerated conditions). The conditions for measuring the content were set as follows, and commercially available Rybelsus tablets (NoVo Nordisk, Denmark) (single-layer tablet formulation) were used as the control group for the examples and comparative examples.

[0103] * Measurement conditions

[0104] 1) Detector: Ultraviolet absorption spectrophotometer (Measurement wavelength: 220 nm)

[0105] 2) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm is used, packed with 5 μm octadecyl silylated silica gel for liquid chromatography.

[0106] 3) A: 0.05% TFA (Trifluoroacetic acid) in distilled water (DW), B: 0.05% TFA in ACN (acetonitrile)

[0107] 4) Flow rate: 1.0 mL / min

[0108] 5) Temperature: 30℃

[0109] 6) Analysis (Measurement) Time: 18 minutes

[0110] As a result, as shown in Tables 7 to 11, under accelerated conditions, the decrease in content (%) and the generation of unknown impurities (%) of the single-layer tablets (Examples 1 to 11), bilayer tablets (Examples 12 to 16), and nucleated tablets (Examples 17 to 32) compared to the single-layer tablet (control group, Comparative Example 1) were significantly lower, confirming that the stability was superior.

[0111] Unit (%) Accelerated Conditions (25℃ / 60% Relative Humidity) Libelsus Maintenance Comparison Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 3 Months Decrease in Content Compared to Initial (%) 1.6 1.8 0.2 0.2 0.1 0.2 0.2 Amount of Unknown Irregular Substance Generated (%) 0.0 9 0.1 0.0 5 0.0 6 0.0 6 0.0 4 0.0 4 6 Months Decrease in Content Compared to Initial (%) 2.1 2.2 1.1 1.2 1.0 0.8 0.8 Amount of Unknown Irregular Substance Generated (%) 0.2 0.2 0.1 10.0 9 0.1 0 0.0 8 0.0 8

[0112]

[0113] Unit (%) Accelerated Conditions (25℃ / 60% Relative Humidity) Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 3 months Decrease in content compared to initial (%) 0.3 0.2 0.2 0.1 0.2 0.2 0.2 Amount of unknown impurity generated (%) 0.0 4 0.0 5 0.0 3 0.0 3 0.0 3 0.0 4 0.0 4 6 months Decrease in content compared to initial (%) 1.0 1.1 1.4 1.1 1.2 0.9 0.8 Amount of unknown impurity generated (%) 0.1 0.1 1 0.0 9 0.1 0 0.0 8 0.0 8 0.0 8

[0114]

[0115] Unit (%) Accelerated Conditions (25℃ / 60% Relative Humidity) Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 3 months Decrease in content compared to initial (%) 0.1 0.3 0.1 0.3 0.1 0.2 0.2 Amount of unknown impurity generated (%) 0.0 2 0.0 2 0.0 2 0.0 3 0.0 2 0.0 2 0.0 2 6 months Decrease in content compared to initial (%) 1.1 1.6 1.0 1.3 1.1 1.0 0.8 Amount of unknown impurity generated (%) 0.1 1 0.0 5 0.0 6 0.0 5 0.0 6 0.0 5 0.0 3

[0116]

[0117] Unit (%) Accelerated Conditions (25℃ / 60% Relative Humidity) Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 3 months Decrease in content compared to initial (%) 0.1 0.3 0.1 0.3 0.1 0.2 0.2 Amount of unknown impurity generated (%) 0.0 2 0.0 2 0.0 2 0.0 3 0.0 2 0.0 2 0.0 2 6 months Decrease in content compared to initial (%) 1.1 1.6 1.0 1.3 1.1 1.0 0.8 Amount of unknown impurity generated (%) 0.1 1 0.0 5 0.0 6 0.0 5 0.0 6 0.0 5 0.0 3

[0118]

[0119] Unit (%) Accelerated conditions (25℃ / 60% relative humidity) Example 27 Example 28 Example 29 Example 30 Example 31 Example 32 3 months Decrease in content compared to initial (%) 0.20.10.30.10.60.8 Amount of unknown impurities generated (%) 0.020.020.020.020.050.08 6 months Decrease in content compared to initial (%) 0.91.11.61.01.31.1 Amount of unknown impurities generated (%) 0.060.050.050.060.080.8

[0120]

[0121] [Experimental Example 3] Analysis of gastrointestinal stability

[0122] To confirm the stability of semaglutide in the in vivo gastrointestinal tract of the oral formulation prepared above, the semaglutide content was measured after stirring for 2 hours in a test solution simulating the human gastrointestinal tract. The conditions for measuring the content were set as follows, and the core tablets (Examples 24 and 28–32 of Tables 5–6) were set as the experimental group, and Ribelsus tablets (single-layer tablet formulation) were used as the control group.

[0123] * Measurement conditions

[0124] 1) Gastric juice simulation test solution: pH 1.2 solution specified by the Ministry of Food and Drug Safety (hydrochloric acid buffer) in the dissolution test method of the Korean Pharmacopoeia

[0125] 2) Test solution volume: 350ml

[0126] 3) Test temperature: 37±0.5℃

[0127] 4) Test method: Korean Pharmacopoeia Dissolution Test Method II (Paddle Method), 50 rotations per minute

[0128] 5) Sample Collection: After stirring for 2 hours, add 150 mL of *0.235 M disodium phosphate (hereinafter referred to as Na2HPO4) buffer (pH 10.4) to adjust the pH to 6.8, then filter through a 0.45 μm filter to obtain the test solution.

[0129] *Preparation method for 0.235M Na2HPO4 buffer (pH 10.4): Add 33.36g of anhydrous Na2HPO4 to 1L of distilled water, and adjust the pH to 10.4 by additionally adding 2N NaOH.

[0130] 6) Detector: Ultraviolet absorption spectrophotometer (Measurement wavelength: 220 nm)

[0131] 7) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm is used, packed with 5 μm octadecyl silylated silica gel for liquid chromatography.

[0132] 8) A: 0.05% TFA (Trifluoroacetic acid) in distilled water (DW), B: 0.05% TFA in ACN (acetonitrile)

[0133] 9) Flow rate: 1.0 mL / min

[0134] 10) Temperature: 30℃

[0135] 11) Analysis (Measurement) Time: 18 minutes

[0136] As a result, as shown in Table 12, under conditions simulating internal gastric juice, the semiglutide content (%) of Examples (24 and 28–32) was found to be significantly higher than that of the control group (Rybelsus tablet), confirming superior stability. In addition, the semiglutide content (%) of Examples 24, 28, and 29, which contain sodium bicarbonate, was found to be significantly higher than that of Examples 28–32, which do not contain sodium bicarbonate, confirming that sodium bicarbonate enhances the formulation stability of the oral administration preparation.

[0137] Unit (%) Gastrointestinal Stability Analysis Ribelsus Tablets Example 24 Example 28 Example 29 Example 30 Example 31 Example 32 Maglutide Content (%) 73.39 4.69 1.39 0.78 5.18 3.18 2.6

[0138]

[0139] [Experimental Example 4] Analysis of Dissolution Rate

[0140] To determine the in vitro dissolution rate of the drug (semaglutide) over time in the oral formulation prepared above, a dissolution experiment was performed according to the following conditions. The experimental groups were set as a control group (Rybelsus tablet, single-layer tablet formulation), a single-layer tablet (Example 4 in Table 1), a bilayer tablet (Example 13 in Table 3), and a core tablet (Example 17 in Table 5).

[0141] * Measurement conditions

[0142] 1) Dissolution test solutions: pH 1.2 solution (added 0.75% Brij), pH 4.0 solution (added 0.75% Brij), pH 6.8 solution (phosphate buffer) according to the dissolution test methods of the Korean Pharmacopoeia

[0143] 2) Volume of eluent: 900ml

[0144] 3) Test temperature: 37±0.5℃

[0145] 4) Test method: Korean Pharmacopoeia Dissolution Test Method II (Paddle Method), 50 rotations per minute

[0146] 5) Sampling: Take 4 mL of eluent at every sampling time, filter through a 0.45 μm filter, and prepare the test solution.

[0147] 6) Analytical Equipment: HPLC

[0148] As a result, as shown in Tables 13–15 and Figure 2, under pH 1.2 (with 0.75% Brij added), pH 4.0 (with 0.75% Brij added), and pH 6.8 conditions, all experimental groups exhibited immediate-release characteristics, showing a dissolution rate of over 80% within 45 minutes of administration, and dissolution behavior similar to that of the control drug was confirmed. In particular, due to the formulation characteristics of Example 17 (core tablet), full-scale dissolution proceeded only after the outer layer was completely disintegrated within the first 10 minutes, and subsequently showed a significant dissolution rate.

[0149] Classification Semaglutide Dissolution Rate (%) - pH 1.2 (0.75% Brij) 5 min 10 min 15 min 30 min 45 min 60 min 75 min 90 min 12 min Ribelsus Tablet 14 mg 16.0 29.3 43.1 69.0 80.0 85.7 85.7 85.7 101.5 Example 4 13.9 28.1 36.5 64.6 83.1 90.2 90.2 90.2 90.3 Example 13 15.8 29.0 46.3 66.5 89.1 90.8 90.8 90.8 88.1 Example 17 2.15.6 16.3 50.6 69.4 81.3 86.8 87.2 96.32

[0150]

[0151] Classification Semaglutide Dissolution Rate (%) - pH 4.0 (0.75% Brij) 5 min 10 min 15 min 30 min 45 min 60 min 75 min 90 min 120 min Ribelsus Tablet 14 mg 18.6 41.0 61.2 96.1 100.9 100.1 100.1 100.1 101.5 Example 4 25.0 43.2 60.2 90.7 96.0 98.2 98.2 98.2 90.3 Example 13 21.3 46.8 65.3 96.1 98.3 99.6 99.3 100.1 88.1 Example 1 72.2 4.0 17.3 73.6 94.6 96.8 96.2 96.2 96.3 2

[0152]

[0153] Classification Semaglutide Dissolution Rate (%) - pH 6.8 5 min 10 min 15 min 30 min 45 min 60 min 75 min 90 min 120 min Ribelsus Tablet 14 mg 33.26 2.98 3.6 100.2 100.4 100.2 100.8 101.8 101.5 Example 4 37.57 5.18 7.08 8.88 8.89 1.08 9.08 9.59 0.3 Example 13 32.36 8.78 3.38 6.08 6.68 6.88 7.68 8.08 8.1 Example 17 2.08.054 95.79 4.99 5.89 6.19 6.19 96.32

[0154]

[0155] [Experimental Example 5] Efficacy of Alkaline Agents by Type and Dosage

[0156] The bioavailability of the formulations was compared by adding an alkalizing agent to the oral tablets prepared above. As a result, it was confirmed that the oral absorption rate of semaglutide significantly increased with the addition of the alkalizing agent.

[0157] In this experiment, sodium bicarbonate, calcium carbonate, sodium carbonate, and magnesium oxide, which are representative alkalizing agents, were selected and added at three levels: low, medium, and high. A rat pharmacokinetic (PK) test was performed on the above preparations to calculate the AUC values.

[0158] Meanwhile, in the examples, 14 combinations including sodium bicarbonate, calcium carbonate, sodium carbonate, and magnesium oxide were presented as alkalizing agents to exemplify various applicability possibilities.

[0159] As a result, as shown in Table 19, it was confirmed that the bioavailability of semaglutide was differentially improved depending on the type and dosage of the alkalizing agent. In particular, the most excellent increase in AUC was observed when sodium bicarbonate and calcium carbonate were included, which is attributed to the alkalizing agent neutralizing the local environment within the stomach, thereby inhibiting drug degradation and improving permeability.

[0160] Main Functional Ingredients Example 33 Example 34 Example 35 Example 36 Example 37 mg / Tmg / Tmg / Tmg / Tmg / Tmg Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 Excipients Lactose Monohydrate 300.00 300.00 300.00 300.00 300.00 Alkalinizing Agent Sodium Bicarbonate 50.00 200.00 Calcium Carbonate 50.00 100.00 200.00 Absorption Enhancer Sodium Caprate 300.00 300.00 300.00 300.00 300.00 Disintegrant Sodium Starch Glycolate 32.00 32.00 32.00 32.00 32.00 Binder Povidone K9025.5625.5625.5625.5625.56 Activated Magnesium Stearate 9.009.009.009.009.00 Tablet Total Weight 780.56780.56780.56780.56780.56780.56

[0161]

[0162] Main Functional Ingredients Example 38 Example 39 Example 40 Example 41 Example 42 mg / T mg / T mg / T mg / T mg / T Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 14.00 14.00 Excipients Lactose Monohydrate 300.00 300.00 300.00 300.00 300.00 Alkalinizing Agent Sodium Carbonate 50.00 100.00 200.00 Magnesium Oxide 50.00 100.00 Absorption Enhancer Sodium Caprate 300.00 300.00 300.00 300.00 300.00 Disintegrant Sodium Starch Glycolate 32.00 32.00 32.00 32.00 32.00 Binder Povidone K9025.5625.5625.5625.5625.56 Activated Magnesium Stearate 9.009.009.009.009.00 Tablet Total Weight 780.56780.56780.56780.56780.56780.56

[0163]

[0164] Main Functional Ingredients Example 43 Example 44 Example 45 Example 46 mg / T mg / T mg / T mg / T Tablet Active Ingredient Semaglutide 14.00 14.00 14.00 14.00 Excipients Lactose Monohydrate 300.00 300.00 300.00 300.00 Alkalinizing Agent Magnesium Oxide 200.00 Magnesium Carbonate 100.00 Aluminum Hydroxide 100.00 Aluminum Phosphate 100.00 Absorption Enhancer Sodium Caprate 300.00 300.00 300.00 300.00 Disintegrant Sodium Starch Glycolate 32.00 32.00 32.00 32.00 Binder Povidone K9025.5625.5625.5625.56 Activated Magnesium Stearate 9.009.009.009.00 Tablet Total Weight 780.56780.56780.56780.56

[0165]

[0166] Alkalinizing Agent Classification Dosage Rat PK AUC (ng·h / mL) Increase Rate (%) Compared to Control Group - Distilled Water - Na - - Control Group - 40.63 ± 41.38 - Sodium Bicarbonate Example 33 Low 68.21 ± 56.19 67.88 Example 9 Medium 118.91 ± 102.61 192.67 Example 34 High 215.77 ± 199.98 431.06 Calcium Carbonate Example 35 Low 56.53 ± 55.94 39.13 Example 36 Medium 112.36 ± 81.73 176.77 Example 37 High 192.66 ± 199.98 374.18 Sodium Carbonate Example 38 Low 41.33 ± 40.19 1.72 Example 39 Medium 73.57 Example 40 High 154.06 ±160.18 279.15 Magnesium oxide Example 41 Low 43.75 ±43.6 07.68 Example 42 Medium 80.67 ±90.7 198.55 Example 43 High 166.13 ±161.65 294.12

[0167]

[0168] [Experimental Example 6] Improvement of Stability and In vitro Permeability Analysis of Low-Dose Sodium Bicarbonate at Different Concentrations

[0169] The stability and in vitro permeability of the oral monolayer, bilayer, and core tablet formulations prepared above were simultaneously confirmed when using a low dose of sodium bicarbonate. Table 20 below shows the bilayer tablets (Examples 47–49), and Table 21 below shows the core tablets (Examples 50–52). Stability tests for content and impurities under accelerated storage conditions were analyzed using the measurement method of Experimental Example 2.

[0170] As a result, as shown in Table 24 and Figure 3, it was confirmed that bilayer tablets and core tablets containing a low dose of sodium bicarbonate of 10% or less of the total weight had significantly higher stability compared to the control group (Rybelsus tablets) when stored under accelerated storage conditions for 8 weeks. In addition, it was confirmed that stability improved as the sodium bicarbonate concentration increased.

[0171]

[0172] Additionally, Table 23 (Experimental Examples 53–57) below describes an in vitro permeability assay performed to confirm the permeability of semaglutide, sodium caprate, and sodium bicarbonate. Sodium salcaprozate (SNAC), used as an absorption enhancer in Rybelsus tablets, was set as the control group. For the permeability experiment, the CacoReady Kit product (KRECE-CCR50, CacoReady 96 Transwell, Goma Biotech, Korea) was used, and the permeability of semaglutide was evaluated in solution form using only the kit without a separate cell culture process, based on the ingredients in Table 19 below. This permeability kit is an experiment that allows for the immediate verification of the permeability and characteristics of the in vivo intestinal barrier using Caco-2 cells derived from human colorectal carcinoma. For this test, the ingredients in Table 23 were diluted with distilled water to the concentrations listed in the table and administered into the CacoReady 96 Transwell to confirm the permeability.

[0173] As a result, as shown in Table 24, permeability was found to be equivalent to or significantly higher than that of the control group. It was confirmed that permeability in in vitro cells improved with increasing sodium bicarbonate concentration. Accordingly, an increase in permeability was confirmed when sodium bicarbonate was used in oral formulations.

[0174] Main Functional Ingredient Example 47 Example 48 Example 49 mg / T mg / T mg / T Upper Layer Main Ingredient Semaglutide 333 Excipient Microcrystalline Cellulose 102777777 Binder Povidone K 90555 Lubricant Magnesium Stearate 555 Upper Layer 909090 Lower Layer Excipient Microcrystalline Cellulose 102200159.5125 Alkalinizing Agent Sodium Bicarbonate-38.577 Absorption Enhancer Sodium Caprate 400400400 Disintegrant Crospovidone 60.260.260.2 Binder Copovidone VA 64131512 Lubricant Magnesium Stearate 6.86.85.8 Lower Layer 680680680 Bilayer Tablet Total Weight 770770770

[0175]

[0176] Main Functional Ingredient Example 50 Example 51 Example 52 mg / T mg / T mg / T Inner Core Injection Active Ingredient Semaglutide 333 Excipient Microcrystalline Cellulose 102838383 Binder Povidone K 90222 Lubricant Magnesium Stearate 222 Inner Core Tablet 909090 Outer Layer Excipient Microcrystalline Cellulose 102200159.5125 Alkalinizing Agent Sodium Bicarbonate-38.577 Absorption Enhancer Sodium Caprate 400400400 Disintegrant Crospovidone 60.260.260.2 Binder Copovidone VA 64131512 Lubricant Magnesium Stearate 6.86.85.8 Outer Layer 680680680 Inner Core Tablet Total Weight 770770770

[0177]

[0178] Unit (%) Accelerated conditions (25℃ / 60% relative humidity) Ribelsus Jeong Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 2. Decrease in content compared to initial (%) 0.5 0.2 0.1 0.3 0.3 0.1 0.2 Amount of unknown impurity generated (%) 0.07 0.0 2 0.0 2 0.0 2 0.0 2 0.0 2 0.0 2 4. Decrease in content compared to initial (%) 2.1 1.6 1.1 0.9 1.4 1.0 0.5 Amount of unknown impurity generated (%) 0.2 0.0 6 0.0 5 0.0 4 0.0 6 0.0 5 0.0 5 8. Decrease in content compared to initial (%) 3.3 2.5 2.2 1.9 1.9 1.6 0.8 Unknown impurity Occurrence Amount (%) 0.38 0.09 0.08 0.07 0.11 0.09 0.08

[0179]

[0180] Main Functional Ingredients Control Group Example 53 Example 54 Example 55 Example 56 Example 57 Main Ingredient Semaglutide 200μM 200μM 200μM 200μM 200μM Absorption Enhancer Salcaprozate Sodium 10 mM Absorption Enhancer Sodium Caprate 510 10 10 10 Alkalinizing Agent Sodium Bicarbonate 25 10

[0181]

[0182] Mean Papp (x10 -6 (cm / s) Distilled water control group Example 53 Example 54 Example 55 Example 56 Example 57 In vitro transmittance Papp (x10 -6cm / s)0.0000.4830.3050.6581.021.441.46

[0183]

[0184] [Experimental Example 7] Analysis of Absorption Permeability in Plasma

[0185] 7-1. Animal Experiment 1 (Quantitative Analysis of Semaglutide in Plasma of SD Rats)

[0186] Animal experiments were conducted to confirm the plasma absorption permeability of the oral formulation prepared above. The animal experiments were commissioned to the Animal Ethics Committee of Dongduk Womans University and NDIC Co., Ltd. (560, Dongtan-Giheung-ro, Hwaseong-si, Gyeonggi-do, 18469) (Experiment No.: NDIC Study No. P2024110, IRB Approval No.: 202407-01, Approval Date: July 18, 2024). The male Sprague-Dawley (SD) rats (7 weeks old, 230–270 g) used in the experiment were purchased from Young Bio (Gyeonggi-do, South Korea). All animals were housed according to a 12-hour day-dark cycle and fasted overnight. The mixture prepared under the conditions shown in Table 25 below was dissolved in distilled water and administered orally to the rats once, and the average maximum plasma concentration of the drug (semaglutide) was measured. SNAC (Comparative Example 2) was used as a control. This experiment was conducted to quantitatively analyze semaglutide in plasma samples (a total of 300) obtained from pharmacokinetic studies using SD rats to obtain the pharmacokinetic (PharmacoKinetics; hereinafter referred to as PK) profile of semaglutide in plasma, and to calculate PK parameters to analyze the pharmacokinetic characteristics of semaglutide for each experimental group. The quantitative range of the calibration curve for the quantitative analysis of semaglutide in rat plasma samples was 1 to 1000 ng / mL, and the correlation coefficient (r) of the calibration curve was 0.9900 or higher, satisfying all acceptance criteria and confirming linearity within the quantitative range.

[0187] As a result, as shown in Table 26 and Figure 4, semaglutide was not detected in the plasma of Group 1 (DW; distilled water administration group). Group 2 reached an average peak concentration (Cmax) at 3 hours after administration and subsequently decreased over time (n=3). In Group 2, the average values ​​of AUClast and AUCinf of semaglutide were 58.88±76.38 ng·hr / mL (n=3) and 211.58 ng·hr / mL (n=1), respectively, and the elimination half-life (T1 / 2) in one individual was 4.38 hours. Additionally, Group 3 (Example 58) reached an average peak concentration (Cmax) at 1.25 hours after administration and subsequently decreased over time (n=4). In group 3, the mean values ​​of AUClast and AUCinf of semaglutide were 230.46±431.57 ng·hr / mL (n=4) and 482.01±652.84 ng·hr / mL (n=2), respectively, and the elimination half-life (T1 / 2) was 4.70±2.31 hours (n=2). In addition, group 4 (Example 59) reached an average maximum concentration (Cmax) at 1.7 hours after administration and subsequently decreased over time. In group 4, the mean values ​​of AUClast and AUCinf of semaglutide were 1,966.51±2,507.23 ng·hr / mL and 2,266.95±2,882.10 ng·hr / mL, respectively, and the elimination half-life (T1 / 2) was 5.86±2.13 hours. In addition, Group 5 (Example 60) reached an average peak concentration (Cmax) at 1.8 hours after administration and subsequently decreased over time. In Group 5, the average values ​​of AUClast and AUCinf of semaglutide were 346.90±719.77 ng·hr / mL and 630.45±981.87 ng·hr / mL, respectively, and the elimination half-life (T1 / 2) was 4.07±2.17 hours. In addition, Group 6 (Example 61) was approximately 1.The average peak concentration (Cmax) was reached at 7 hours, and the average values ​​of AUClast and AUCinf of semaglutide were approximately 1,890.86 ng·hr / mL and 2,080.61 ng·hr / mL, respectively, and the elimination half-life (T1 / 2) was confirmed to be 6.96 ± 0.24 hours. Finally, Group 7 (Comparative Example 2) reached the average peak concentration (Cmax) at 1.5 hours after administration and subsequently decreased over time. In Group 7, the average values ​​of AUClast and AUCinf of semaglutide were 503.09 ± 586.33 ng·hr / mL and 939.60 ± 618.33 ng·hr / mL, respectively, and the elimination half-life (T1 / 2) was 7.23 ± 0.74 hours.

[0188] In summary, it was confirmed that co-administration with an absorption enhancer resulted in superior absorption enhancement efficiency compared to administering semaglutide alone, that the absorption enhancement efficiency of sodium caprate increased in a dose-dependent manner, and that sodium caprate showed superior absorption enhancement efficiency compared to SNAC at the same concentration. Furthermore, the average maximum plasma concentration of semaglutide increased sharply, particularly in Group 4 (Example 59) and Group 6 (Example 61), appearing to be approximately 4 to 5 times higher than in Group 5 (Example 60) and Group 7 (Comparative Example 2). From the above results, it was confirmed that the co-administration of sodium caprate and sodium bicarbonate exhibited drug absorption enhancement efficiency similar to or greater than that of SNAC.

[0189] Main Functional Ingredient DW Active Ingredient Single Example 58 Example 59 Example 60 Example 61 Comparative Example 21 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 mg / Tmg / Tmg / Tmg / Tmg / Tmg / Tmg / T Active Ingredient Semaglutide-333333 Absorption Enhancer SNAC------200 Sodium Caprate--100300200200- Alkalinizing Agent Sodium Bicarbonate-----200-

[0190]

[0191] Classification Plasma absorption permeability of rats (n=5 per group) Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 Average maximum plasma concentration Cmax (ng / kg) NA 9.92 ± 13.42 23.30 ± 39.08 17 1.15 ± 20 1.29 30.39 ± 5 3.15 15 2.15 ± 16 2.34 3.45 ± 4 4.41 Time to reach maximum blood concentration Tmax (hrs) NA 3.00 1.25 1.70 1.80 1.70 1.50

[0192]

[0193] 7-2. Animal Experiment 2 (Quantification of Semaglutide in Beagle Plasma and PK Profile)

[0194] Animal experiments were conducted to confirm the plasma absorption permeability of the above-mentioned oral formulations (bilayer tablets, Examples 11 and 12). The animals were 21 male Beagle dogs of the Canis familiaris, Ridglan Beagle breed (6–7 months old), obtained from Raon Bio Co., Ltd. (Rm. 1901, U-Tower, 120, Heungdeokjungang-ro, Giheung-gu, Yongin-si, Gyeonggi-do), and the experiment was commissioned to NDIC Co., Ltd. (560, Dongtan-Giheung-ro, Hwaseong-si, Gyeonggi-do, 18469) (Test No.: NDIC Study No. L2024086). At the start of the experiment, the Beagle dogs weighed 10–12 kg and were 24–36 months old. The rearing environment was maintained at a temperature of 21±2℃, relative humidity of 35–65%, a light-dark cycle of 12 hours / day (8 AM–8 PM), and a ventilation rate of 10–15 times / hour using a full exhaust method. Each Beagle was individually housed in a 600mm x 700mm x 800mm stainless steel box. After undergoing a quarantine and acclimatization process for approximately one week, their health status was checked, and individuals suitable for the experiment were selected. Animal identification was performed using individual identification cards on the cages. On the day of the experiment, groups were randomly separated based on body weight, and individual numbers and group information were marked on the cages for management. Solid food was provided daily.

[0195] Finally, 21 male Beagle dogs were selected as experimental animals, and 5 healthy dogs were ultimately selected based on clinical symptoms, feed intake, and body weight. These were divided into 3 groups of 7 dogs each to ensure an even average body weight and used in the experiment. The animals used in the experiment were fasted for at least 16 hours prior to sample administration and dehydrated for approximately 1 hour prior to sample administration. Rybelsus tablets were used as the control group, and one tablet of the Example 5 tablet (Table 2) was administered orally once with 20 mL of water as the sample. Blood collection was performed at a total of 12 time points (0 (pre-dosing), 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours). Blood was collected via jugular vein, and 3 mL of whole blood was collected at each time point. The blood collected at each time point was immediately stored in a container containing pre-prepared ice cubes (ice crush) and a Corning® CoolRack to maintain an ice-cold state until centrifugation. Once blood collection at each point was completed, the blood was centrifuged at 4,000 rpm for 10 minutes at 4°C within 30 minutes, and 500 μL of the separated supernatant was transferred into a 1.5 mL Protein LoBind tube. The samples were dispensed into one set. The remaining plasma was dispensed into another set to create a total of two sets per collection point, which were immediately stored in a container containing an ice crush and a Corning® CoolRack to maintain an ice-cold state and kept in a deep freezer at -70°C. Subsequently, to analyze semaglutide in the plasma, the blood concentrations of the collected samples were quantitatively analyzed using LC-MS / MS.

[0196] As a result, as shown in Table 27 and Figure 5, the average maximum plasma concentration (Cmax) of the control group (Rybelsus tablets, n=5) was 26.13±37.56 ng / kg, and Example 11 (n=4), containing semaglutide and sodium caprate, showed a level similar to the control group at 23.84±25.65 ng / kg. In contrast, Example 12 (n=7), containing semaglutide, sodium caprate and an alkalizing agent, showed an average Cmax of 120.85±30.51 ng / kg, which was approximately 4 to 5 times higher than the control group and Example 11. AUClast was also similar for Rybelsus tablets at 712.03±995.25 ng·hr / mL and for Example 11 at 619.96±697.68 ng·hr / mL, but for Example 12 it increased significantly to 3208.9±2566.7 ng·hr / mL. The half-life (t1 / 2) was similar for Rybelsus tablets at 42.32±24.82 hours and for Example 11 at 42.32±8.28 hours, while for Example 12 it showed a tendency to be slightly prolonged at 52.5±8.28 hours.

[0197]

[0198] Classification Plasma absorption permeability in Beagle dogs G1 G2 G3 Ribelsus Tablet (n=5) Example 11 (n=4) Example 12 (n=7) Time to reach maximum blood concentration Tmax (hrs) 3±1 2±0.8 22±1 Average maximum plasma concentration Cmax (ng / kg) 26.13±3 7.5 6 23.84±25.65 1 20.85±30.5 1 AUCA UClast (ng*hr / mL) to the last measurable blood concentration 7 12.03±9 95.25 6 19.96±6 97.68 320 8.9±25 66.7 Half-life t1 / 2 (hr) 4 2.32±24.8 24 2.32±8.28 52.5±8.28

[0199]

[0200] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. That is, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

1. An oral formulation comprising semaglutide or a pharmaceutically acceptable salt thereof; and an absorption enhancer as an active ingredient, An oral formulation characterized in that the absorption promoter is one or more selected from sodium caprate, sodium laurate, docosahexaenoic acid-cysteine-capric acid (DOCA-Cys-C10), or pharmaceutically acceptable salts thereof.

2. An oral formulation characterized by comprising semaglutide or a pharmaceutically acceptable salt thereof; sodium caprate; and an alkalizing agent as active ingredients.

3. An oral formulation according to claim 2, characterized in that the alkalizing agent is one or more selected from sodium bicarbonate, sodium carbonate, calcium carbonate, or magnesium oxide.

4. An oral administration formulation according to Claim 1 or Claim 2, wherein the oral administration formulation is in any one form selected from the group consisting of a single-layer tablet, a bilayer tablet, and a core tablet.

5. An oral formulation according to claim 4, wherein the monolayer tablet form comprises semaglutide or a pharmaceutically acceptable salt thereof, sodium caprate, and an alkalizing agent.

6. An oral formulation according to claim 4, wherein the bilayer tablet form comprises an upper layer comprising semaglutide or a pharmaceutically acceptable salt thereof; and a lower layer comprising sodium caprate.

7. An oral formulation according to claim 6, wherein the upper layer further comprises one or more additives selected from the group consisting of alkalizing agents, excipients, disintegrants, binders, and lubricants, and wherein the alkalizing agent is sodium bicarbonate or calcium carbonate.

8. An oral formulation according to claim 6, wherein the lower layer further comprises one or more additives selected from the group consisting of disintegrants, binders, and lubricants.

9. An oral formulation according to claim 4, wherein the core tablet form comprises an inner core comprising semaglutide or a pharmaceutically acceptable salt thereof; and an outer layer comprising sodium caprate.

10. An oral formulation according to claim 9, wherein the inner core further comprises one or more additives selected from the group consisting of excipients, disintegrants, binders, and lubricants.

11. An oral formulation according to claim 9, wherein the outer layer further comprises one or more additives selected from the group consisting of alkalizing agents, disintegrants, binders, and lubricants, and wherein the alkalizing agent is sodium bicarbonate or calcium carbonate.

12. (1) A step of preparing a mixture comprising semaglutide or a pharmaceutically acceptable salt thereof and sodium caprate; and (2) A method for manufacturing an oral formulation comprising the step of compressing the mixture of step (1) to produce a single-layer tablet.

13. A method of manufacturing according to claim 12, characterized in that the mixture of step (1) further comprises an alkalizing agent selected from sodium bicarbonate or calcium carbonate.

14. (1) A step of preparing an upper layer comprising semaglutide or a pharmaceutically acceptable salt thereof; (2) A step of manufacturing a lower layer containing sodium caprate; (3) A step of mixing and granulating the upper layer of step (1) and the lower layer of step (2), and then mixing a lubricant to produce a mixture; and (4) A method for manufacturing an oral formulation comprising the step of compressing the mixture of step (3) into a bilayer tablet to produce a bilayer tablet.

15. A manufacturing method according to claim 14, characterized in that the upper layer of step (1) further comprises an alkalizing agent selected from sodium bicarbonate or calcium carbonate. 16.(1) A step of preparing an inner core comprising semaglutide or a pharmaceutically acceptable salt thereof; (2) A step of manufacturing an outer layer containing sodium caprate; (3) A step of sequentially injecting the outer layer of step (2) and the inner core of step (1) into the tablet punch die; (4) A step of applying pre-pressure to the punch die of step (3) above; (5) A step of injecting the outer layer of step (2) into the punch die to which preload was applied in step (4); and (6) A method for manufacturing an oral formulation comprising the step of applying main pressure to a punch die into which the outer layer was injected in step (5) above to produce a core tablet.

17. A method of manufacturing according to claim 16, characterized in that the outer layer of step (2) further comprises an alkalizing agent selected from sodium bicarbonate or calcium carbonate.

18. A manufacturing method according to claim 16, characterized in that the pre-pressure in step (4) is 1 to 10 kN and the main pressure in step (6) is 5 to 30 kN.

19. A pharmaceutical composition for the prevention or treatment of obesity or diabetes comprising the orally administered formulation of Claim 1 or Claim 2 as an active ingredient.

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