Tablets with specific surface area

Abstract

The present invention relates to characterization of tablet surface area wherein tablet compositions comprising semaglutide and one or more pharmaceutically acceptable excipients. Particularly, present invention relates to a tablet composition comprises semaglutide, SNAC (Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) and one or more pharmaceutically acceptable excipients wherein semaglutide has a specific surface area.

Description

[0001] DESCRIPTION

[0002] TABLETS WITH SPECIFIC SURFACE AREA

[0003] Field of Invention

[0004] The present invention relates to characterization of tablet surface area wherein tablet compositions comprising semaglutide and one or more pharmaceutically acceptable excipients. Particularly, present invention relates to a tablet composition comprises semaglutide, SNAC (Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate,) and one or more pharmaceutically acceptable excipients wherein the tablet has a specific surface area.

[0005] Background of the Invention

[0006] The development of oral formulations for peptide-based drugs has long presented significant challenges due to the inherent instability of peptides in the gastrointestinal (Gl) tract and their poor permeability across the intestinal epithelium. Various strategies have been employed to overcome these barriers, including the use of enzyme inhibitors, absorption enhancers, and advanced delivery systems.

[0007] Semaglutide, a glucagon-like peptide- 1 (GLP-1) receptor agonist, has been primarily administered via subcutaneous injection due to its susceptibility to degradation by proteolytic enzymes and its limited permeability through the intestinal mucosa. The advancement of oral formulations for such peptides aims to improve patient compliance and broaden the therapeutic use of these compounds.

[0008] Tablet surface area refers to the total exterior surface of a tablet, which plays a crucial role in drug dissolution, coating efficiency, and mechanical properties. It is influenced by the tablet’s shape, size, and geometry. For standard shapes like cylindrical or biconvex tablets, surface area can be estimated using mathematical formulas based on dimensions such as diameter, height, and radius of curvature. In irregular or complex shapes, computational methods like digital imaging or 3D scanning may be used for more accurate measurement.

[0009] Measurement of tablet surface area can be performed using direct and indirect methods. Direct methods involve 3D scanning or laser profilometry, capturing precise topographical data. Indirect methods rely on mathematical approximations derived fromtablet dimensions obtained via calipers or micrometers. Advanced techniques such as image analysis and computational modeling can also provide highly accurate surface area estimations, which are crucial for optimizing coating processes, dissolution rates, and bioavailability.

[0010] One of the key strategies in the development of an oral semaglutide formulation has been optimizing the tablet's surface area to enhance gastric absorption. A larger surface area allows for better interaction between the drug and absorption enhancers, such as sodium N-[8-(2-hydroxybenzoyl)-amino]-caprylate (SNAC). SNAC facilitates the transcellular absorption of semaglutide by transiently increasing the permeability of the epithelial cell membrane. By maximizing the exposure of semaglutide to SNAC and the gastric mucosa, an increased tablet surface area can further improve the peptide’s bioavailability and efficient entry into the bloodstream.

[0011] In view of the foregoing, there is a need to enhance bioavailability, stability, and dissolution in oral compositions comprising semaglutide, SNAC and one or more pharmaceutically acceptable excipients. The present invention addresses these challenges by optimizing the tablet’s surface area, thereby improving drug release and absorption. Increasing the surface area facilitates better interaction between semaglutide, absorption enhancers, and the gastric mucosa, leading to improved bioavailability. Additionally, a well-optimized surface area contributes to enhanced stability by reducing drug degradation and ensures efficient dissolution, promoting consistent therapeutic effects. These advancements represent a significant step forward in the development of patient-friendly oral peptide formulations and will be described in detail.

[0012] Summary of the Invention

[0013] The present invention provides a tablet composition comprising semaglutide and one or more pharmaceutically acceptable excipients where in the tablet surface area is between 70 mm2and 220 mm2.

[0014] The oral pharmaceutical composition in present invention comprises SNAC in an amount of between 30.00 - 90.00% (w / w).The tablet composition in present invention comprises SNAC in an amount of between 40.00 - 85.00% (w / w).

[0015] In further embodiment, tablet composition of present invention can be comprised of additional absorption enhancer.

[0016] In one embodiment, additional absorption enhancer can be sodium caprate.

[0017] The tablet composition in present invention comprises sodium caprate in an amount of between 20.00 - 40.00% (w / w).

[0018] The tablet composition in present invention comprises sodium caprate in an amount of between 25.00 - 35.00% (w / w).

[0019] The tablet surface area in present invention can be between 80 mm2and 180 mm2, more preferably can be 90 mm2and 150 mm2.

[0020] In other aspect of the present invention a process for preparing tablet compositions comprising the steps of

[0021] a. Mixing semaglutide, sodium a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid and one or more diluents,

[0022] b. Lubricating with lubricants,

[0023] c. Compressing into tablets.

[0024] In preferred aspect of the present invention a process for preparing tablet compositions comprising the steps of

[0025] a. Mixing semaglutide, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), sodium caprate and microcrystalline cellulose,

[0026] b. Lubricating with lubricant,

[0027] c. Compressing into tablets.

[0028] In one embodiment lubricant in present invention compositions can be magnesium stearate.

[0029] In preferred aspect of the present invention a process for preparing tablet compositions comprising the steps ofa. Mixing semaglutide, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), sodium caprate and microcrystalline cellulose,

[0030] b. Lubricating with magnesium stearate,

[0031] c. Compressing into tablets.

[0032] A tablet composition of the present invention can be use in the treatment of type II diabetes and / obesity.

[0033] Detailed Description of the Invention

[0034] The present invention relates to preparation of pharmaceutical compositions comprising semaglutide in the treatment of type 2 diabetes and / or obesity.

[0035] The present invention relates to preparation of pharmaceutical compositions comprising semaglutide, and one or more pharmaceutically acceptable carriers or excipients.

[0036] In one embodiment tablet surface area is the total external surface of a tablet, which plays a critical role in various pharmaceutical processes such as coating, dissolution, and drug release. It is influenced by the tablet’s shape, size, and geometry. The surface area determines the amount of coating material required, affects the dissolution rate, and influences the mechanical properties of the tablet.

[0037] In general pharmaceutical practice, tablet surface area is used for several key purposes, including:

[0038] 1. Coating Applications - Surface area determines the amount of coating material needed for film- or sugar-coated tablets. Larger surface areas require more coating, impacting formulation costs and process efficiency.

[0039] 2. Dissolution and Bioavailability - Surface area affects drug release rates. Higher surface areas generally lead to faster dissolution, which is critical for immediate- release tablets.

[0040] 3. Compression and Mechanical Properties - Surface area influences tablet hardness and friability, affecting the manufacturing process and tablet stability.4. Mathematical Estimations - Standard equations, such as for cylindrical or biconvex tablets, are commonly used to approximate surface area. For round, flat tablets, the surface area is calculated as:

[0041] A=2m’h+2m’2

[0042] where r is the radius and h is the height.

[0043] In one embodiment present invention a tablet composition comprising semaglutide and one or more pharmaceutically acceptable excipients wherein tablet surface area is between 70 mm2and 220 mm2. Preferably, tablet surface area can be 80 mm2-180 mm2, more preferably, the tablet surface area can be 90 mm2-150 mm2.

[0044] Tablet surface area is primarily measured using geometric calculations for regular shapes, such as flat-faced or cylindrical tablets, based on dimensions like diameter and thickness. For more complex or irregular shapes, methods like 3D scanning, laser profilometry, or image analysis are used for precise surface area measurement. Additionally, the BET (Brunauer-Emmett-Teller) method is used for measuring surface areas of powders or porous materials, though it is not typically applied to solid tablets. This method involves nitrogen gas adsorption and is valuable for analyzing excipients that can impact drug dissolution and bioavailability.

[0045] The tablet composition in present invention comprises SNAC in an amount of between 30.00 - 90.00% (w / w).

[0046] The tablet composition in present invention comprises SNAC in an amount of between 40.00 - 85.00% (w / w).

[0047] In further embodiment, tablet composition of present invention can be comprised of additional absorption enhancer.

[0048] In one embodiment, additional absorption enhancer can be sodium caprate.

[0049] The tablet composition in present invention comprises sodium caprate in an amount of between 20.00 - 40.00% (w / w).

[0050] The tablet composition in present invention comprises sodium caprate in an amount of between 25.00 - 35.00% (w / w).The tablet surface area in present invention can be between 80 mm2and 180 mm2, more preferably can be 90 mm2and 150 mm2.

[0051] Excipients used in a tablet composition may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0052] Preferably, the present invention relates to a tablet composition comprising semaglutide, SNAC and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to diluents, lubricants, glidants, binders, disintegrants, antioxidants, absorption enhancer, solubility increasing agents, preservatives, buffering agents, solvents, flavoring agent, stabilizers, sweetening agent, mixtures thereof, and other materials known to one of ordinary skill in the art and the mixtures thereof.

[0053] Diluents are essential components in tablet compositions, serving to increase the volume of the formulation, ensuring uniform distribution of the active pharmaceutical ingredient (API), and enhancing the stability and manufacturability of the product. They help achieve consistent dosing, improve the flow properties of powders, and ensure that tablets and capsules reach a practical size for handling and administration. Diluents also contribute to the appearance and taste of the final product, thereby enhancing patient compliance and acceptability. In tablet formulations, they provide the necessary bulk for compression, while in capsules, they fill the dosage unit to the desired weight and volume. For injectable formulations, diluents help maintain isotonicity and stability.

[0054] Commonly used diluents in tablet compositions include lactose, which is valued for its compressibility and compatibility with most APIs; microcrystalline cellulose (MCC), known for its excellent binding properties; and dicalcium phosphate (DCP), which offers good flowability. Starch is used for its binding and disintegration properties, while mannitol and sorbitol are favored for their pleasant mouthfeel and sweet taste, respectively. Calcium carbonate is commonly used in antacid formulations, sodium chloride is used in small amounts in injectable formulations, and sucrose is used in chewable tablets and lozenges for its sweetness. Microcrystalline cellulose (MCC) is highlyregarded for its exceptional binding properties and ability to enhance the hardness and stability of tablets. It also improves the flow properties of powder blends, making it a versatile diluent in various solid dosage forms. In preferred embodiment in the present invention the amount of diluent can be at 3.00 to 25.00% (w / w).

[0055] In preferred embodiment in present invention diluent can be microcrystalline cellulose. In preferred embodiment in the present invention amount of micro crystalline cellulose can be at 3.00 to 25.00% (w / w).

[0056] Lubricants are crucial excipients in tablet compositions, primarily used to reduce friction during the tablet manufacturing process. They help prevent the tablet blend from sticking to the equipment, ensuring a smooth and efficient production process. Lubricants improve the flow of the tablet mixture through the machinery, enhancing the uniformity and consistency of the final product. Additionally, they aid in the ejection of tablets from the die cavity, preventing damage and ensuring the integrity of the tablets.

[0057] Commonly used lubricants in tablet compositions include magnesium stearate, stearic acid, talc, sodium stearyl fumarate, colloidal silicon dioxide, and polyethylene glycol (PEG). In preferred embodiment in the present invention amount of lubricant can be at 1.0 to 2.0% (w / w).

[0058] In preferred embodiment in present invention lubricant can be magnesium stearate. In preferred embodiment present invention amount of lubricant can be at 1.0 to 2.0% (w / w).

[0059] In one embodiment in the present invention, SNAC is used as absorption enhancer. Absorption enhancers are agents used in pharmaceutical formulations to improve the absorption of drugs, especially those that are poorly absorbed through the gastrointestinal (Gl) tract. They work by various mechanisms to increase the permeability of the epithelial cells lining the G1 tract, thereby facilitating the drug's entry into the systemic circulation.

[0060] In other embodiment in the present invention, SNAC and sodium caprate are used as absorption enhancers. Absorption enhancers are agents used in pharmaceutical formulations to improve the absorption of drugs, especially those that are poorlyabsorbed through the gastrointestinal (GI) tract. They work by various mechanisms to increase the permeability of the epithelial cells lining the GI tract, thereby facilitating the drug's entry into the systemic circulation.

[0061] The inventors surprisingly have found that SNAC with semaglutide tablet composition wherein the tablet surface area is between 70 mm2and 220 mm2represents a significant advancement in drug delivery, providing a viable alternative to injectable formulations, enhances the bioavailability of semaglutide and develops patient-friendly oral peptide therapies.

[0062] In present invention water or ethanol can be used as solvent. More preferably water can be selected as a solvent.

[0063] The inventors surprisingly have found that SNAC with semaglutide tablet composition wherein the tablet surface area is between 80 mm2and 180 mm2represents a significant advancement in drug delivery, providing a viable alternative to injectable formulations, enhances the bioavailability of semaglutide and develops patient-friendly oral peptide therapies.

[0064] The inventors surprisingly have found that SNAC with semaglutide tablet composition wherein the tablet surface area is between 90 mm2and 150 mm2represents a significant advancement in drug delivery, providing a viable alternative to injectable formulations, enhances the bioavailability of semaglutide, stability and develops patient-friendly oral peptide therapies.

[0065] The tablet composition of the present invention comprises below:

[0066] • 1.00% - 8.00% by weight semaglutide,

[0067] • 50.00%-85.00% weight a salt of N-[8-(2-hydroxybenzoyl]amino]caprylic acid, • 3.00%-25.00% by weight diluent, and

[0068] • 1.00%-2.00% by weight lubricant, and

[0069] • Solvent.

[0070] In other aspect of the present invention a process for preparing tablet compositions comprising the steps ofd. Mixing semaglutide, sodium a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid and one or more diluents,

[0071] e. Lubricating with lubricants,

[0072] f. Compressing into tablets.

[0073] The tablet composition of the present invention comprises below:

[0074] • 1.00% - 8.00% by weight semaglutide,

[0075] • 50.00%-85.00% weight a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid, • 3.00%-25.00% by weight microcrystalline cellulose, and

[0076] • 1.00%-2.00% by weight magnesium stearate, and

[0077] • Solvent.

[0078] In other aspect of the present invention a process for preparing tablet compositions comprising the steps of

[0079] a. Mixing semaglutide, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) and microcrystalline cellulose,,

[0080] b. Lubricating with lubricant,

[0081] c. Compressing into tablets.

[0082] The tablet composition of the present invention comprises below:

[0083] • 1.00% - 8.00% by weight semaglutide,

[0084] • 50.00%-85.00% weight a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid, • 20.00%-40.00% by weight sodium caprate

[0085] • 3.00%-25.00% by weight microcrystalline cellulose, and

[0086] • 1.00%-2.00% by weight magnesium stearate, and

[0087] • Solvent.

[0088] In preferred aspect of the present invention a process for preparing tablet compositions comprising the steps of

[0089] a. Mixing semaglutide, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), sodium caprate and microcrystalline cellulose,

[0090] b. Lubricating with lubricant,

[0091] c. Compressing into tablets.In other aspect of a pharmaceutical composition of the present invention for use adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

[0092] In other aspect of a tablet composition of the present invention can be use in the treatment of type II diabetes and / obesity.

[0093] The term "(w / w)" as used herein, refers to a percentage by weight compared to the total weight of the composition considered.

[0094] A pharmaceutical composition according to the invention is considered "stable", if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of semaglutide, is maintained over said period of time.

[0095] Experiments

[0096] Stability Results

[0097] The stability of the product was monitored under the following three conditions. During the stability period, the product was found to meet the specifications.

[0098] 25°C ± 2°C / %60 RH ± %5 RH

[0099] 30°C ± 2°C / %65 RH ± %5 RH

[0100] 40°C ± 2°C / %75 RH ± %5 RH

[0101] Result of the stability study indicates that present semaglutide composition in accordance with the present invention exhibits excellent storage stability.

[0102] During the stability period, the product was found to comply with specifications.

[0103] Examples

[0104] Example 1

[0105] In another preferred embodiment, the pharmaceutical composition according to invention:

[0106] Table 1: Pharmaceutical composition comprising semaglutide and relevant excipients Ingredients Amount (% w / w) Semaglutide 1.00%-8.00% a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid 50.00%-85.00%

[0107]

[0108] One or more diluents 3.00%-25.00%

[0109] One or more lubricants 1.00%-2.00%

[0110] Total 100.00%

[0111]

[0112] A process of preparing tablet composition of Example 1:

[0113] g. Mixing semaglutide, sodium a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid and one or more diluents,

[0114] h. Lubricating with lubricants,

[0115] i. Compressing into tablets.

[0116] Example 2:

[0117] In another preferred embodiment, the pharmaceutical composition according to invention:

[0118] Table 2: Pharmaceutical composition comprising semaglutide and relevant excipients Amount Ingredients

[0119] (% w / w) Semaglutide 1.00%-8.00%

[0120] SNAC 50.00%-85.00%

[0121] Sodium Caprate 20.00%-40.00% Microcrystalline Cellulose 3.00%-25.00% Magnesium Stearate 1.00%-2.00%

[0122] Total 100.00%

[0123]

[0124] A process of preparing tablet composition of Example 2:

[0125] a. Mixing semaglutide, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), sodium caprate and microcrystalline cellulose,

[0126] b. Lubricating with lubricant,

[0127] c. Compressing into tablets.

Claims

CLAIMS1. A tablet composition comprising:a] semaglutide,b] salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid at 50.0% (w / w) to 85.0% (w / w) of the composition;c] one or more pharmaceutically acceptable excipients;wherein tablet surface area is between 70 mm2and 220 mm2.

2. The tablet composition according to claim 1, wherein tablet surface area is between 80 mm2and 180 mm2.

3. The tablet composition according to claim 1, wherein tablet surface area is between 90 mm2and 150 mm2.

4. The tablet composition according to claim 1, wherein the said salt of N-[8-(2- hydroxybenzoyl)amino] caprylic acid is sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC).

5. A process for preparing tablet compositions according to claim 1, comprising the steps of:a. Mixing semaglutide, sodium a salt of N-[8-(2-hydroxybenzoyl)amino]caprylic acid and one or more diluents,b. Lubricating with lubricants,c. Compressing into tablets.

6. The process for preparing tablet composition according to claim 4, lubricant is magnesium stearate.

7. A tablet composition obtained with the process defined in claim 5.

8. The tablet composition according to any one of the proceeding claims for use in the treatment of type II diabetes and / or obesity.

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