Process for producing tablets containing GLP-1 peptides

Abstract

The present invention relates to a process for producing tablets comprising a GLP-1 peptide, the GLP-1 peptide being obtained by spray drying a feed solution comprising the GLP-1 peptide and a feed solution solvent, the pH of the feed solution being higher than the pI of the GLP-1 peptide or the pH of the feed solution being in the range of about 5 to about 10. The present invention also relates to tablets obtained by the process and to the use of the tablets in pharmaceutical preparations.

Description

[Technical Field]

[0001] The present invention relates to a process for producing tablets comprising a GLP-1 peptide, wherein the GLP-1 peptide in the tablet is obtained by spray drying of a feed solution comprising the GLP-1 peptide and a feed solution solvent, wherein the pH of the feed solution is in the range of about 5 to about 10, or the pH of the feed solution is higher than the pI of the GLP-1 peptide. More specifically, the present invention relates to a process for producing tablets comprising a GLP-1 peptide, wherein the dissolution rate of the resulting tablets is increased, to tablets obtained by said process, and to their use in pharmaceuticals. [Background technology]

[0002] A convenient and frequent method of administering medications is via the oral route. Generally, dosage forms contain an active pharmaceutical ingredient (API) and excipients that help ensure the medication reaches its site of action, prevent unwanted degradation, and in some cases, control release. To exert a therapeutic effect, a medication must dissolve in the aqueous environment of the gastrointestinal tract.

[0003] The effectiveness of oral dosage forms often depends on the intrinsic ability of a drug to dissolve in the gastrointestinal tract before being absorbed into the circulation. Drug solubility and dissolution are important parameters that affect bioavailability. Dissolution refers to the dynamic process involved in the kinetics of a material dissolving in a given medium (e.g., solvent). From the perspective of the resulting solution, dissolution can be characterized by the time rate of change of the sample material concentration in solution over the dissolution period. In contrast, "solubility" generally refers to an equilibrium state (e.g., thermodynamic value), specifically, how much sample material will dissolve in a given medium under conditions where thermodynamic equilibrium is achieved. In general, highly soluble materials will generally exhibit faster dissolution than less soluble materials. However, dissolution characteristics do not directly and specifically correlate to solubility, and valuable information can be obtained by examining dissolution profiles (e.g., in addition to overall solubility data).

[0004] Human GLP-1 and GLP-1 peptides generally have low bioavailability, and their exposure after oral administration is low.In order to increase bioavailability, certain absorption enhancers have been used (Am J Clin Nutr;Oct 2010;92;810-817, WO2010 / 020978, WO2012 / 080471, WO2013 / 189988, WO2013 / 139695).However, to ensure that the active ingredient is absorbed, such oral formulations of GLP-1 peptides still need to be taken some time before eating or taking other oral medications.For example, oral GLP-1 peptide semaglutide should be taken 30 minutes before eating to ensure maximum effect.Therefore, there is still a need to improve the absorption and bioavailability of such tablets containing GLP-1 peptides. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2010 / 020978 [Patent Document 2] International Publication No. 2012 / 080471 [Patent Document 3] International Publication No. 2013 / 189988 [Patent Document 4] International Publication No. 2013 / 139695 [Non-patent literature]

[0006] [Non-Patent Document 1] Am J Clin Nutr;Oct 2010;92;810-817 Summary of the Invention

[0007] In some embodiments, the present invention relates to a process for producing tablets comprising a GLP-1 peptide, the method comprising: a) spray-drying a feed solution comprising a GLP-1 peptide and a feed solvent, wherein the pH of the feed solution is in the range of about 5 to about 10, or the pH of the feed solution is higher than the pI of the GLP-1 peptide; and b) compressing the resulting powder of the GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into a tablet.

[0008] In some embodiments, the present invention relates to a tablet comprising a GLP-1 peptide, wherein the GLP-1 peptide is obtained by the process defined herein.

[0009] In some embodiments, the present invention relates to an oral dosage form, such as a tablet, obtained by the processes described herein for use in medicine, such as for the treatment of diabetes or obesity. In some embodiments, the present invention relates to a method for treating diabetes or obesity comprising administering to a subject an oral dosage form, such as a tablet, obtained by the processes defined herein. [Brief explanation of the drawings]

[0010] [Figure 1] Figure 1 shows the results of intrinsic dissolution tests of tablets containing semaglutide obtained from spray drying at given pH values. [Figure 2] Figure 2 shows the results of intrinsic dissolution testing of tablets containing Compound A obtained from spray drying at given pH values. * contains NaCl, # larger particles, ## smaller particles. DETAILED DESCRIPTION OF THE INVENTION

[0011] Many pharmaceutical and surgical support products contain dry drug substances, which are dried from their liquid phase to a dry phase, usually by lyophilization.

[0012] Spray drying involves atomizing a liquid feed into very small droplets in a hot drying gas, causing the droplets to rapidly dry into solid particles. The particles are then separated from the drying gas as the final spray-dried product, for example, using a cyclone and / or a filter bag. The feed may be a solution, suspension, or emulsion, and the resulting product may be classified as a powder. Such powders may be defined as containing solid, discrete particles, and powders may be further defined by a given size, shape, and morphology. Granules are a subclass of powder and may be defined as particles consisting of smaller, discrete primary particles that have been aggregated together to form new secondary particles or larger agglomerates. Thus, in a single, continuous process, spray drying converts the liquid feed into a powder. When a liquid is spray-dried, the resulting powder becomes compatible with many of the components that would otherwise have broken down into a matrix during spray drying.

[0013] The advantage of spray drying is that it allows for low temperature processability if necessary, and allows other process modifications to be made to further improve powder properties. The spray-dried powder can also be further formulated if necessary. In particular, the spray-dried powder may be formulated into capsules, tablets, or any other solid dosage form. Properties such as the moisture or residual solvent level in the spray-dried powder, particle morphology or particle size, and powder density can be significantly manipulated to target levels. More specifically, the selection of suitable spray-drying conditions can affect the product properties, i.e., residual moisture content, T g , have a significant impact on particle size and morphology, and the degree of protein aggregation and / or activation. Important process variables to consider when optimizing the spray drying process are inlet and outlet temperatures, feed rate, and atomization gas flow rate.

[0014] Other techniques similar to spray drying include freeze-drying and vacuum drying. To freeze-dry a composition, it is cooled until solidified and placed under reduced pressure to sublimate most of the volatile components in the composition. The solid residue may form a single mass that must be broken down to form a fine powder. Typical freeze-dried powders contain porous, irregularly shaped particles that are easily hydrated. The process of producing freeze-dried drug substances is a batch process that usually lasts several days and is limited by the capacity of the freeze-dryer size. This puts the entire drying batch at risk for a significant amount of time until the process is complete. Furthermore, the freeze-dried drug substance produced is in the form of a "cake," which requires further processing steps, including crushing, sieving, and / or milling, to obtain a powder. These steps can reduce the potency and mass yield of the dried product. The terms "cake" or "solid cake" may refer to the porous, sponge-like structure-like composition resulting from the freeze-drying process.

[0015] Advantageously, the use of a spray-drying process instead of freeze-drying provides a cost-effective, continuous, and large-volume process in which the dried product is readily obtained in the form of a dry powder rather than as a "cake." Compared to spray-drying, the powders produced by freeze-drying are often about twice as expensive due to the unnecessary complexity of the freeze-drying process (e.g., equipment for operating at reduced pressure). Furthermore, spray-dried materials generally take the form of a homogeneous powder that is less hygroscopic than that obtained by freeze-drying.

[0016] The dissolution rate of the active ingredient in a tablet is very important so that the active ingredient can be absorbed and thus exert its maximum effect. The dissolution rate can be controlled by various means, for example, by excipients that cause a controlled release of the active ingredient. Another technique utilizes pH dependency, where the active ingredient is retained at a certain pH value and released at another pH value. When the dissolution rate increases, the active ingredient is also absorbed faster in the body, which is beneficial for patients, for example, when oral dosage forms such as tablets need to be taken before meals. Achieving a faster dissolution rate leads to faster absorption, which can shorten the time between taking an oral dosage form such as a tablet and starting a meal, improving ease of use and compliance for patients.

[0017] Surprisingly, the inventors have observed that when a feed solution comprising a GLP-1 peptide and a feed solvent, wherein the feed solution has a pH greater than the pI of the GLP-1 peptide or has a pH in the range of about 5 to about 10, is spray dried, tablets made with the resulting GLP-1 peptide powder exhibit an increased dissolution rate when compared to tablets made from GLP-1 peptide spray dried from a feed solution having a pH below the pI of the GLP-1 peptide or from a feed solution having a pH below about 5.

[0018] Thus, in some embodiments, the present invention relates to a process for producing a GLP-1 peptide, such as semaglutide or Compound A, wherein the GLP-1 peptide is obtained by spray drying a feed solution comprising the GLP-1 peptide and a feed solution solvent, wherein the pH of the feed solution is higher than the pI of the GLP-1 peptide or wherein the pH of the feed solution is in the range of about 5 to about 10, and the resulting GLP-1 peptide powder has an improved dissolution rate.

[0019] Thus, in some embodiments, the present invention relates to a process for producing tablets comprising a GLP-1 peptide, wherein the GLP-1 peptide is obtained by spray drying a feed solution comprising the GLP-1 peptide and a feed solution solvent, wherein the feed solution has a pH higher than the pI of the GLP-1 peptide, wherein the feed solution has a pH in the range of about 5 to about 10, and wherein the resulting tablets have an improved dissolution rate.

[0020] Process for producing tablets In some embodiments, the present invention relates to a process for producing tablets comprising a GLP-1 peptide, the process comprising: a) spray-drying a feed solution comprising a GLP-1 peptide and a feed solution solvent, wherein the pH of the feed solution is higher than the pI of GLP-1 or the pH of the feed solution is in the range of about 5 to about 10; and b) compressing the resulting powder of the GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into tablets.

[0021] In some embodiments, a process for producing tablets comprises the steps of: a) providing a GLP-1 peptide in a feed solution; b) adjusting the pH of the feed solution to a pH above the pI of the GLP-1 peptide or to a pH in the range of about 5 to about 10 by adding a non-volatile base to the feed solution; c) introducing the feed solution into a spray dryer to dry the GLP-1 peptide; and d) compressing the resulting powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into tablets.

[0022] The "non-volatile" base referred to herein is a base that does not evaporate during the spray-drying process. Exemplary non-volatile bases are sodium hydroxide, potassium hydroxide, and buffers selected from, for example, phosphate buffer, TRIS buffer, and acetate buffer. As used herein, "pI" refers to the isoelectric point of the GLP-1 peptide, i.e., the pH value at which the peptide has no net charge.

[0023] In some embodiments, the feed solution containing the GLP-1 peptide is obtained by solubilizing a powder of the GLP-1 peptide in a feed solvent. Similarly, or alternatively, in some embodiments, the feed solution is obtained directly from a previous manufacturing step, e.g., the eluate of a final chromatographic purification, ultrafiltration, or diafiltration. In some embodiments, the feed solution from a previous manufacturing step contains the GLP-1 peptide as the primary solid component (80-100% (w / w) of the solid component), but may also contain small amounts of salts and impurities carried over from manufacturing.

[0024] In some embodiments, the pH of the GLP-1 peptide-containing feed solution is within a pH range of about 4 to about 12, e.g., about 5 to about 10, about 6 to about 9, or about 6 to about 8. In some embodiments, the pH of the GLP-1 peptide-containing feed solution is within a pH range of 4 to 12, e.g., about 5 to about 10, 6 to about 9, or about 6 to about 8. Similarly or alternatively, in some embodiments, the pH of the GLP-1 peptide-containing feed solution is higher than the pI of the GLP-1 peptide. In some embodiments, the pH of the GLP-1 peptide-containing feed solution is within a pH range of about 5 to about 10. In some embodiments, the pH of the GLP-1 peptide-containing feed solution is about 5 to about 9, e.g., about 6 to about 8, about 7 to about 9, or about 8 to about 10.

[0025] In some embodiments, the term "about" as used herein means ±10% of the referenced value, inclusive.

[0026] In some embodiments, the pH of the feed solution is adjusted by adding a non-volatile base, such as 1 M aqueous sodium hydroxide. The pH is measured at room temperature using either a probe or strip in the feed solution solvent, e.g., an aqueous alcoholic solvent such as aqueous ethanol.

[0027] In some embodiments, the feed solution comprises a GLP-1 peptide in a feed solution solvent. In some embodiments, the GLP-1 peptide is selected from semaglutide or Nε27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl], Nε36-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (compound A).

[0028] In some embodiments, the pH of the semaglutide-containing feed solution is greater than about 5.4. In some embodiments, the pH of the semaglutide-containing feed solution is greater than 5.4. In some embodiments, the pH of the semaglutide-containing feed solution is in the range of about 5 to about 12, for example, about 5.4 to about 12, about 6 to about 10, or about 6 to about 8. In some embodiments, the pH of the semaglutide-containing feed solution is in the range of 5 to 12, for example, 5.4 to 12, 6 to 10, or 6 to 8. In some embodiments,

[0029] In some embodiments, the pH of the feed solution containing compound A is greater than about 4.6. In some embodiments, the pH of the feed solution containing compound A is greater than 4.6. In some embodiments, the pH of the feed solution containing compound A is in the range of about 4.6 to about 12, e.g., about 6 to about 10, about 7 to about 10, or about 7 to about 9. In some embodiments, the pH of the feed solution containing compound A is in the range of 4.6 to 12, e.g., 6 to 10 or 7 to 9. In some embodiments, the pH of the feed solution containing compound A is in the range of about 8 to about 10, e.g., about 8.5 to about 9.5.

[0030] In some embodiments, the feed solvent used in spray drying is a mixture of a water-miscible organic solvent and water. As used herein, "water-miscible organic solvent" refers to an organic solvent that, when mixed with water, forms a homogeneous solution, e.g., an alcoholic solvent such as methanol, ethanol, isopropanol, acetone, or acetonitrile. In some embodiments, the feed solvent is an aqueous alcoholic solvent, such as aqueous ethanol, i.e., one comprising water and ethanol. In some embodiments, the feed consists essentially of a GLP-1 peptide in aqueous ethanol. In some embodiments, the aqueous ethanol is at a concentration of about 40 to about 70 percent (w / w), e.g., about 45 to about 65 percent (w / w), or about 50 to about 60 percent (w / w). In some embodiments, the aqueous ethanol is at a concentration of 40 to 70 percent (w / w), e.g., 45 to 65 percent (w / w), or 50 to 60 percent (w / w). The concentration of aqueous ethanol is defined in terms of ethanol content, i.e., about 70 percent (w / w) aqueous ethanol consists essentially of about 70 weight percent ethanol and about 30 weight percent water.The concentration of aqueous ethanol is defined in terms of ethanol content, i.e., about 70 percent (w / w) aqueous ethanol consists essentially of 70 weight percent ethanol and 30 weight percent water.

[0031] In some embodiments, the concentration of the GLP-1 peptide in the feed solution for spray drying is about 0.5 to about 10 percent (w / w), e.g., about 1 to about 7 percent (w / w), about 1 to about 5 percent (w / w), or about 1 to about 3 percent (w / w). In some embodiments, the concentration of the GLP-1 peptide in the feed solution for spray drying is 0.5 to 10 percent (w / w), e.g., 1 to 7 percent (w / w), 1 to 5 percent (w / w), or 1 to 3 percent (w / w). In certain embodiments, the concentration of the GLP-1 peptide in the feed solution is about 1.8 to about 2.1 percent (w / w) semaglutide in about 50 to about 55 percent (w / w) aqueous ethanol, e.g., about 1.8 to about 2.1 percent (w / w) semaglutide in about 50 to about 55 percent (w / w) aqueous ethanol. In certain embodiments, the concentration of the GLP-1 peptide in the feed solution is 1.8 to 2.1 percent (w / w) semaglutide in 50 to 55 percent (w / w) aqueous ethanol, e.g., 1.8 to 2.1 percent (w / w) in 50 to 55 percent (w / w) aqueous ethanol. Similarly or alternatively, in one embodiment, the concentration of the GLP-1 peptide in the feed solution is about 3 to about 5 percent (w / w) Compound A in about 50 to about 65 percent (w / w) aqueous ethanol, e.g., about 3 to about 5 percent (w / w) in about 50 to about 65 percent (w / w) aqueous ethanol. Similarly or alternatively, in one embodiment, the concentration of the GLP-1 peptide in the feed solution is 3 to 5 percent (w / w) Compound A in 50 to 65 percent (w / w) aqueous ethanol, e.g., 3 to 5 percent (w / w) in 50 to 65 percent (w / w) aqueous ethanol.

[0032] In some embodiments, the process includes a compression step, in which the GLP-1 peptide powder obtained from spray-drying step a) is compressed into a tablet, optionally further comprising at least one pharmaceutically acceptable excipient. In some embodiments, the tablet produced comprises a therapeutically effective amount of GLP-1 peptide. In some embodiments, the tablet produced comprises the GLP-1 peptide in an amount of about 0.01 to about 100 mg. In some embodiments, the tablet produced comprises the GLP-1 peptide in an amount of 0.01 to 100 mg. In some embodiments, the tablet produced comprises about 0.1 to about 80 mg or about 1 to about 30 mg of GLP-1 peptide. In some embodiments, the tablet produced comprises 0.1 to 80 mg or 1 to 30 mg of GLP-1 peptide.

[0033] Process for producing GLP-1 peptide powder In some embodiments, the invention relates to a process for producing a spray-dried powder of a GLP-1 peptide, wherein the GLP-1 peptide is semaglutide or Compound A, the process comprising spray-drying a feed solution comprising the GLP-1 peptide and a feed solution solvent, wherein the pH of the feed solution is greater than the pI of the GLP-1 peptide or the pH of the feed solution is in the range of about 5 to about 10. In some embodiments, the process for producing a spray-dried powder of a GLP-1 peptide, wherein the GLP-1 peptide is semaglutide or Compound A, comprises the steps of: a) providing the GLP-1 peptide in a feed solution; b) adjusting the pH of the feed solution to a pH greater than the pI of the GLP-1 peptide or to a pH in the range of about 5 to about 10 by adding a non-volatile base to the feed solution; and c) introducing the feed solution into a spray dryer and drying the GLP-1 peptide. In some embodiments, the feed solution comprising the GLP-1 peptide is obtained by solubilizing a powder of the GLP-1 peptide in a feed solution solvent. Similarly or alternatively, in some embodiments, the feed solution is obtained directly from a previous manufacturing step, e.g., the eluate of a final chromatographic purification, ultrafiltration, or diafiltration. In some embodiments, the feed solution from a previous manufacturing step contains the GLP-1 peptide as the primary solid component (80-100% (w / w) of the solid component), but may also contain small amounts of salts and impurities carried over from manufacturing.

[0034] In some embodiments, the pH of the GLP-1 peptide-containing feed solution is in the range of about 4 to about 12, e.g., about 5 to about 10, about 6 to about 9, or about 6 to about 8. Similarly or alternatively, in some embodiments, the pH of the GLP-1 peptide-containing feed solution is higher than the pI of the GLP-1 peptide. In some embodiments, the pH of the GLP-1 peptide-containing feed solution is in the range of about 5 to about 10. In some embodiments, the pH of the GLP-1 peptide-containing feed solution is about 5 to about 9, e.g., about 6 to about 8, about 7 to about 9, or about 8 to about 10. In some embodiments, the pH of the GLP-1 peptide-containing feed solution is in the range of about 8 to about 10.

[0035] In some embodiments, the pH of the feed solution is adjusted by adding a non-volatile base, such as 1 M aqueous sodium hydroxide. The pH is measured at room temperature using either a probe or strip in the feed solution solvent, e.g., an aqueous alcoholic solvent such as aqueous ethanol.

[0036] In some embodiments, the pH of the semaglutide-containing feed solution is above about 5.4. In some embodiments, the pH of the semaglutide-containing feed solution is in the range of about 5 to about 12, for example, about 5.4 to about 12, about 6 to about 10, or about 6 to about 8.

[0037] In some embodiments, the pH of the feed solution comprising Compound A is greater than about 4.6. In some embodiments, the pH of the feed solution comprising Compound A is in the range of about 4.6 to about 12, for example, about 6 to about 10 or about 7 to about 9. In some embodiments, the pH of the feed solution comprising semaglutide is in the range of about 8 to about 10, for example, about 8.5 to about 9.5.

[0038] In some embodiments, the feed solvent used in spray drying is a mixture of a water-miscible organic solvent and water. In some embodiments, the feed solvent is an aqueous alcoholic solvent, such as aqueous ethanol, i.e., comprising water and ethanol. In some embodiments, the feed consists essentially of a GLP-1 peptide in aqueous ethanol. In some embodiments, the aqueous ethanol is at a concentration of about 40 to 70 percent (w / w), e.g., about 45 to about 65 percent (w / w) or about 50 to about 60 percent (w / w). The concentration of aqueous ethanol is defined by the ethanol content; i.e., about 70 percent (w / w) aqueous ethanol consists essentially of about 70 weight percent ethanol and about 30 weight percent water.

[0039] In some embodiments, the concentration of the GLP-1 peptide in the feed solution for spray drying is about 0.5 to about 10 percent (w / w), e.g., about 1 to about 7 percent (w / w), about 1 to about 5 percent (w / w), or about 1 to about 3 percent (w / w). In particular embodiments, the concentration of the GLP-1 peptide in the feed solution is about 1.8 to about 2.1 percent (w / w) semaglutide in about 50 to about 55 percent (w / w) aqueous ethanol, e.g., about 1.8 to about 2.1 percent (w / w) semaglutide in about 50 to about 55 percent (w / w) aqueous ethanol. Similarly or alternatively, in one embodiment, the concentration of the GLP-1 peptide in the feed solution is about 3 to about 5 percent (w / w) Compound A in about 50 to about 65 percent (w / w) aqueous ethanol, e.g., 3 to 5 percent (w / w) in about 50 to about 65 percent (w / w) aqueous ethanol.

[0040] In some embodiments, the GLP-1 peptide powders described herein have an intrinsic dissolution rate at 25° C. of about 1 mg / (min*cm 2 ), e.g., 1.0 mg / (min*cm 2 ), or 1.1 mg / (min*cm 2 ), or 1.4 mg / (min*cm 2 ), or 1.5 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 25° C. of about 2 mg / (min*cm). 2 ), e.g., 2.6 mg / (min*cm 2 ) or 2.1 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 25° C. of about 4 mg / (min*cm). 2 ), e.g., 4.2 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 25° C. of about 6 mg / (min*cm). 2 ), e.g., 6.4 mg / (min*cm 2In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 30° C. of about 1 mg / (min*cm). 2 ), e.g., 1.0 mg / (min*cm 2 ), or 1.1 mg / (min*cm 2 ), or 1.4 mg / (min*cm 2 ), or 1.5 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 30° C. of about 2 mg / (min*cm). 2 ), e.g., 2.6 mg / (min*cm 2 ) or 2.1 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 30° C. of about 4 mg / (min*cm). 2 ), e.g., 4.2 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powders described herein may have an intrinsic dissolution rate at 30° C. of about 6 mg / (min*cm). 2 ), e.g., 6.4 mg / (min*cm 2 In some embodiments, the GLP-1 peptide powder is semaglutide powder or Compound A powder. In some embodiments, the semaglutide powder has an intrinsic dissolution rate at 25°C of about 1 mg / (min*cm 2 ), e.g., 1.0 mg / (min*cm 2 ), or 1.1 mg / (min*cm 2 ), or 1.4 mg / (min*cm 2 ), or 1.5 mg / (min*cm 2 In some embodiments, Compound A powder may have an intrinsic dissolution rate of 2 mg / (min*cm) at 25° C. 2 In some embodiments, the Compound A powder has an intrinsic dissolution rate at 30° C. of 2 to 7 mg / (min*cm). 2 ), e.g., 2.1-7, 2.6-7, 4.2, or 6.4 mg / (min*cm 2 ) Intrinsic dissolution rate [mg / (min*cm 2) is defined as the rate of dissolution of a pharmaceutical active substance formulated in a compact when the total exposed surface area of ​​the compact and conditions such as temperature, agitation-stirring rate, pH, and ionic strength of the dissolution medium are held constant.

[0041] Pharmaceutical Composition In some embodiments, the present invention relates to a pharmaceutical composition comprising a GLP-1 peptide powder according to the present invention and, optionally, one or more pharmaceutically acceptable excipients. The term "excipient" as used herein broadly refers to any ingredient other than the active therapeutic ingredient. An excipient may be an inert, non-active, and / or pharmaceutically inactive substance. Excipients may serve various purposes, such as, for example, carriers, vehicles, fillers, binders, lubricants, glidants, disintegrants, flow control agents, crystallization retarders, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, and / or to improve the administration and / or absorption of an active substance, e.g., a delivery agent / absorption enhancer. One skilled in the art can select one or more of the aforementioned excipients with respect to the specific desired characteristics of the oral solid dosage form by routine experimentation and without undue burden. The amount of each excipient used may vary within ranges conventional in the art. Techniques and excipients that may be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2009), and Remington: the Science and Practice of Pharmacy, 21st edition, Gennaro, Ed., Lippincott Williams and Wilkins (2005).In some embodiments, the excipients include binders such as polyvinylpyrrolidone (povidone), fillers such as cellulose powder, microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, lubricants and / or glidants such as stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate, flow control agents such as colloidal silica, talc, and the like. crystallization retarders, for example, povidone, solubilizers, for example, pluronic, povidone, colorants, dyes and pigments, for example, red iron oxide or yellow iron oxide, titanium dioxide, talc, pH adjusters, for example, citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, surfactants and emulsifiers, for example, pluronic, polyethylene glycol, sodium carboxymethylcellulose, polyethoxylated and hydrogenated castor oil, and mixtures of two or more of these excipients and / or adjuvants.

[0042] In some embodiments, the pharmaceutical compositions described herein may include a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, and / or a lubricant such as magnesium stearate, and / or a filler such as microcrystalline cellulose, and / or a binder such as povidone.

[0043] In some embodiments, the pharmaceutical composition may comprise a first type of granules and a second type of granules, wherein the first type of granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, and the second type of granules comprises a GLP-1 peptide powder according to the present invention. In some embodiments, the first type of granules further comprises a lubricant such as magnesium stearate. In some embodiments, the first type of granules further comprises a filler such as microcrystalline cellulose. Thus, the first type of granules may further comprise a lubricant and, optionally, a filler. In some embodiments, the second type of granules further comprises a filler such as microcrystalline cellulose. In some embodiments, the second type of granules further comprises a binder such as povidone. Thus, the second type of granules may further comprise a filler and, optionally, a binder. In some embodiments, the composition further comprises an extragranular lubricant such as magnesium stearate.

[0044] In some embodiments, the composition is in the form of a solid dosage form. In some embodiments, the composition is in the form of a tablet. In some embodiments, the composition is in the form of a capsule. In some embodiments, the composition is in the form of a sachet.

[0045] For the avoidance of doubt, references herein to the GLP-1 peptide powders of the invention being for particular uses (and similarly to uses and methods of use relating to the compounds of the invention) may also apply to pharmaceutical compositions comprising the compounds of the invention, as described herein.

[0046] Oral dosage form In some embodiments, the present invention relates to an oral dosage form comprising a GLP-1 peptide powder obtainable by the process of the present invention. In some embodiments, the oral dosage form is a tablet, a capsule, or a sachet. In some embodiments, the oral dosage form is a sachet. In some embodiments, the oral dosage form is a capsule. In some embodiments, the oral dosage form is a tablet.

[0047] tablet In some embodiments, the present invention relates to tablets obtained by the process described in the paragraph "Process for Producing Tablets." In some embodiments, the present invention relates to tablets comprising a GLP-1 peptide, wherein the GLP-1 peptide is obtained by a spray-drying process, wherein a feed solution comprises the GLP-1 peptide and a feed solvent, and wherein the pH of the feed solution is greater than the pI of the GLP-1 peptide or the pH of the feed solution is in the range of about 5 to about 10. In some embodiments, the tablets comprising the GLP-1 peptide are obtained by a spray-drying process, which includes the steps of: a) providing the GLP-1 peptide in a feed solution; b) adjusting the pH of the feed solution to a pH greater than the pI of the GLP-1 peptide or to a pH in the range of about 5 to about 10 by adding a non-volatile base to the feed solution; and c) introducing the feed solution into a spray dryer and drying the GLP-1 peptide. The GLP-1 peptide obtained by the described spray-drying process is then compressed, optionally with at least one pharmaceutically acceptable excipient, into tablets.

[0048] In some embodiments, tablets of the invention comprising a GLP-1 peptide are obtained by spray drying using a feed solution, wherein the pH of the GLP-1 peptide-containing feed solution is in the range of about 5 to about 12, e.g., about 5 to about 10 or about 6 to about 8. In some embodiments, tablets of the invention comprising a GLP-1 peptide are obtained by spray drying using a feed solution, wherein the pH of the GLP-1 peptide-containing feed solution is in the range of 5 to 12, e.g., about 5 to 10 or about 6 to 8. Similarly or alternatively, in some embodiments, the GLP-1 peptide contained in the tablet is obtained by spray drying a feed solution, wherein the pH of the GLP-1 peptide-containing feed solution is higher than the pI of the GLP-1 peptide or in the range of about 5 to about 10. In some embodiments, the pH of the feed solution is adjusted by adding a non-volatile base, e.g., aqueous sodium hydroxide, at a concentration of, e.g., 1 M.

[0049] In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, the GLP-1 peptide powder having an intrinsic dissolution rate at 25° C. of about 1 mg / (min*cm 2 ), e.g., 1.0 mg / (min*cm 2 ), or 1.1 mg / (min*cm 2 ), or 1.4 mg / (min*cm 2 ), or 1.5 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 25° C. of about 2 mg / (min*cm 2 ), e.g., 2.6 mg / (min*cm 2 ), or 2.1 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 25° C. of about 4 mg / (min*cm 2 ), e.g., 4.2 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 25° C. of about 6 mg / (min*cm 2 ), e.g., 6.4 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 30° C. of about 1 mg / (min*cm 2 ), e.g., 1.0 mg / (min*cm 2 ), or 1.1 mg / (min*cm 2 ), or 1.4 mg / (min*cm 2 ), or 1.5 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 30° C. of about 2 mg / (min*cm 2 ), e.g., 2.6 mg / (min*cm 2), or 2.1 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 30° C. of about 4 mg / (min*cm 2 ), e.g., 4.2 mg / (min*cm 2 In some embodiments, the tablets of the present invention comprise a GLP-1 peptide powder obtained by the process of the present invention, wherein the GLP-1 peptide powder has an intrinsic dissolution rate at 30° C. of about 6 mg / (min*cm). 2 ), e.g., 6.4 mg / (min*cm 2 )

[0050] In some embodiments, the tablet contains semaglutide or Nε27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl], Nε36-[2-[2-[[2-[[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl] and a GLP-1 peptide selected from the group consisting of: carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (Compound A).

[0051] In some embodiments, the tablet comprises a therapeutically effective amount of GLP-1 peptide. In some embodiments, the tablet comprises the GLP-1 peptide in an amount of about 0.01 to about 100 mg. In some embodiments, the tablet comprises the GLP-1 peptide in an amount of 0.01 to 100 mg. In some embodiments, the tablet comprises about 0.2 to about 80 mg, about 0.5 to about 60 mg, or about 1 to about 30 mg of GLP-1 peptide. In some embodiments, the tablet comprises 0.2 to 80 mg, 0.5 to 60 mg, or 1 to 30 mg of GLP-1 peptide.

[0052] In some embodiments, a tablet is a solid composition compressed into a tablet and intended for oral administration.

[0053] The tablet may comprise at least one pharmaceutically acceptable excipient.

[0054] In some embodiments, the tablet comprises at least about 60 percent (w / w), such as at least about 70 percent (w / w) or at least about 75 percent (w / w), of a delivery agent. In some embodiments, the tablet comprises at least 60 percent (w / w), such as at least 70 percent (w / w) or at least 75 percent (w / w), of a delivery agent. In some embodiments, the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as sodium N-(8-(2-hydroxybenzoyl)aminocaprylate. In some embodiments, the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, e.g., sodium N-(8-(2-hydroxybenzoyl)aminocaprylate, and comprises at least about 90 percent (w / w) of the total amount of excipients in the tablet. In some embodiments, the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, e.g., sodium N-(8-(2-hydroxybenzoyl)aminocaprylate, and comprises at least 90 percent (w / w) of the total amount of excipients in the tablet.

[0055] In some embodiments, the tablet contains about 0.1 to about 10 percent (w / w), or about 0.5 to about 5 percent (w / w), e.g., about 1 to about 3.5 percent (w / w) or about 1 percent (w / w), of a lubricant and / or glidant. In some embodiments, the tablet contains 0.1 to about 10 percent (w / w), or 0.5 to 5 percent (w / w), e.g., 1 to 3.5 percent (w / w) or 1 percent (w / w), of a lubricant and / or glidant. In some embodiments, the tablet contains about 2 to about 2.5 percent (w / w). In some embodiments, the tablet contains a lubricant and / or glidant, such as a salt of stearic acid. In some embodiments, the tablet contains magnesium stearate as a lubricant. In some embodiments, the lubricant is magnesium stearate, and comprises about 10 percent (w / w) or less of the total amount of excipients in the tablet. In some embodiments, the tablet contains magnesium stearate as a lubricant. In some embodiments, the lubricant is magnesium stearate, which comprises 10 percent (w / w) or less of the total excipients of the tablet.

[0056] Still further, tablets may be formulated as known in the art for oral formulations of insulinotropic compounds, for example, using any one or more of the formulations described in WO2008 / 145728 and WO / 2019 / 149880.

[0057] Tablets may also be used in the formulation of site-specific, controlled, sustained, extended, extended, delayed, pulsed, retarded, and / or sustained release drug delivery systems.

[0058] Tablets obtained by the process of the present invention may be prepared as known in the art. A tablet press may be used to compress a "compacted material" or "tabletting material." "Compacted material" refers to the GLP-1 peptide obtained by spray drying as described herein. "Tabletting material" refers to the GLP-1 peptide obtained by spray drying as described herein and at least one pharmaceutically acceptable excipient. In some embodiments, the ingredients are granulated before being compressed or compacted into a tablet. In some embodiments, the tablet is compacted using a tablet press. In a tableting press, the tableting material is loaded (e.g., force-fed or gravity-fed) into the cavities of a die. The tableting material is then compacted by punches using pressure. The resulting compact, i.e., tablet, is then ejected from the tableting press. The compaction process described above is hereinafter referred to as a "compacting process." Suitable tablet presses include, but are not limited to, rotary tablet presses and eccentric tablet presses. Examples of tablet presses include, but are not limited to, the Fette 102i (Fette GmbH), Korsch XL100, Korsch PH106 rotary tablet press (Korsch AG, Germany), Korsch EK-0 eccentric tablet press (Korsch AG, Germany), and Manesty F-Press (Manesty Machines Ltd., United Kingdom).

[0059] In some embodiments, the GLP-1 peptide powder described herein may be further granulated. In some embodiments, the term "granule" may refer to particles that are aggregated into larger particles. A "granule" may also be formed by combining smaller particles into larger agglomerates. The term "granulation" refers to several granules, such as two or more granules. When the GLP-1 peptide powder described herein is made into granules and such granules are used as a tableting compound, the granules may be produced in a manner known to those skilled in the art, for example, by dry granulation techniques, in which the pharmaceutically active agent and / or delivery agent are compacted with excipients to form relatively large bodies, such as slugs or ribbons, which are then broken down by grinding, and the ground material serves as the tableting compound that is subsequently compressed into tablets. Suitable equipment for dry granulation includes, but is not limited to, roller compaction equipment manufactured by Gerteis, such as the Gerteis MINI-PACTOR.

[0060] Tablets may be administered in several dosage forms, for example, as uncoated or coated tablets.

[0061] Tablet may comprise at least one pharmaceutically acceptable excipient.Those skilled in the art can select one or more of the above-mentioned excipients according to the specific desired properties of oral solid dosage form through routine experimentation and without undue burden.The amount of each excipient used can vary within the range that is customary in the art.

[0062] The tablet may be of any suitable weight. In some embodiments, the weight of the tablet is within the range of about 100 mg to about 1000 mg, for example, about 175 mg to about 1000 mg, or for example, about 100 mg. In some embodiments, the weight of the tablet is within the range of about 175 mg to about 250 mg, about 300 mg to about 500 mg, or about 500 mg to about 900 mg. In some embodiments, the weight of the tablet is within the range of 175 mg to 1000 mg, for example, 175 mg to 250 mg, 300 mg to 500 mg, or 500 mg to 900 mg, or for example, about 200 mg, about 400 mg, or about 700 mg. In some embodiments, the weight of the tablet is within the range of about 200 mg to about 1000 mg, for example, about 500 mg to about 700 mg or about 600 mg to about 1000 mg. In some embodiments, the tablet weight is in the range of 200 mg to 1000 mg, e.g., 500 to 700 mg or 600 to 1000 mg, or, for example, in the range of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.

[0063] GLP-1 peptides The tablets obtained by the process of the present invention contain a GLP-1 peptide. As used herein, the term "GLP-1 peptide" refers to a compound that fully or partially activates the human GLP-1 receptor.

[0064] In some embodiments, the GLP-1 peptide may be semaglutide. Semaglutide may be prepared as described in Example 4 of WO2006 / 097537. Semaglutide may also be used in combination with 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). See WHO Drug Information Vol. 24, No. 1, 2010. The pI of semaglutide is approximately 5.4. Semaglutide has the following structure: [ka]

[0065] In some embodiments, the GLP-1 peptide is one of those found in WO2012 / 140117, such as Nε27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl], Nε36-[2-[2-[[2-[[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl], Nε36-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl], Nε46-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl], Nε56-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl], Nε66-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl], Nε76-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl], Nε86-[2-[2 The compound may be hydroxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (Compound A), which may be prepared as described in Example 31 of WO 2012 / 140117. The pI of Compound A is about 4.6. Compound A has the following structure: [ka]

[0066] In some embodiments, the GLP-1 peptide may be present in its fully or partially ionized form, e.g., one or more carboxylic acid groups (—COOH) may be deprotonated to form carboxylate groups (—COO - ) and / or deprotonating one or more amino groups (-NH2) to give -NH3 + In some embodiments, the GLP-1 peptide is in the form of a salt.

[0067] Drug indications The present invention relates to oral dosage forms such as the tablet of the present invention or the pharmaceutical composition of the present invention for use as a medicine. In certain embodiments, the tablet may be used for the following medical treatments, all preferably related to diabetes: (i) prevention and / or treatment of all forms of diabetes, including hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (maturity-onset diabetes of the young), and gestational diabetes, and / or reduction of HbA1C; (ii) delaying or preventing the progression of diabetic disease, such as the progression of type 2 diabetes, delaying the progression from impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delaying the progression from insulin-nonrequiring type 2 diabetes to insulin-requiring type 2 diabetes; (iii) improved beta cell function, such as reduced beta cell apoptosis, increased beta cell function and / or beta cell mass, and / or restored glucose sensitivity to beta cells; (iv) prevention and / or treatment of cognitive impairment; (v) prevention and / or treatment of eating disorders such as obesity (e.g., by reducing food intake, weight loss, suppressing appetite, inducing satiety), treatment or prevention of antipsychotic or steroid-induced binge eating disorder, bulimia nervosa, and / or obesity, reducing gastric motility and / or delaying gastric emptying; (vi) prevention and / or treatment of diabetic complications such as neuropathy, including peripheral neuropathy, nephropathy, or retinopathy; (vii) improvement of lipid parameters (such as prevention and / or treatment of dyslipidemia, reduction of total serum lipids, reduction of HDL, reduction of small dense LDL, reduction of VLDL, reduction of triglycerides, reduction of cholesterol, increase of HDL, reduction of plasma levels of lipoprotein a (Lp(a)) in humans, or inhibition of apolipoprotein a (apo(a)) production in vitro and / or in vitro); (viii) prevention and / or treatment of cardiovascular diseases, e.g., syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, stroke, cerebral ischemia, premature heart or premature cardiovascular disease, e.g., left ventricular hypertrophy, ischemic heart disease, essential hypertension, acute hypertensive attack, cardiomyopathy, cardiac dysfunction, exercise tolerance, chronic heart failure, arrhythmias, cardiac dysrhythmias, syncope, atherosclerosis, mild chronic heart failure, angina pectoris, cardiac bypass reocclusion, intermittent claudication (arteriosclerosis obliterans), diastolic dysfunction, and / or systolic dysfunction; (ix) prevention and / or treatment of gastrointestinal disorders such as inflammatory bowel syndrome, small bowel syndrome, Crohn's disease, dyspepsia, and / or gastric ulcers; (x) preventing and / or treating critical illness, e.g., treating critically ill patients, critical illness polyneuropathy (CIPNP) patients, and / or potential CIPNP patients, preventing the onset of critical illness or CIPNP, preventing, treating, and / or curing systemic inflammatory response syndrome (SIRS) in patients, and / or preventing or reducing the likelihood that a patient will suffer from bacteremia, sepsis, and / or septic shock during hospitalization; and / or (xi) prevention and / or treatment of polycystic ovary syndrome (PCOS).

[0068] In certain embodiments, the indication is selected from the group consisting of (i)-(iii) and (v)-(viii), such as indication (i), (ii), and / or (iii), or indication (v), indication (vi), indication (vii), and / or indication (viii). In another particular embodiment, the indication is (i). In a further particular embodiment, the indication is (v). In yet a further particular embodiment, the indication is (viii). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0069] Unless otherwise indicated herein, terms provided in the singular also include the plural.

[0070] In some embodiments, as used herein, a particular value given in connection with a number or interval may be understood as the particular value or as approximately the particular value (e.g., plus or minus 10 percent of the particular value).

[0071] Embodiment The following are non-limiting embodiments of the present invention. 1. A process for producing a tablet comprising a GLP-1 peptide, the process comprising: a. spray drying a feed solution comprising a GLP-1 peptide and a feed solvent, wherein the pH of the feed solution is higher than the pI of the GLP-1 peptide; b. compressing the obtained powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into tablets. 2. a. dissolving the GLP-1 peptide in a feed solvent or obtaining the GLP-1 peptide in solution directly from a purification process; b. adjusting the pH of the feed solution to a pH above the pI of the GLP-1 peptide by adding a non-volatile base to the feed solution; c. introducing the feed solution into a spray dryer and drying the GLP-1 peptide; d. Compressing the resulting powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into tablets. 3. A process for producing a tablet containing a GLP-1 peptide, the process comprising: a. spray drying a feed solution comprising a GLP-1 peptide and a feed solvent, wherein the pH of the feed solution is in the range of 5 to 12; b. compressing the obtained powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into tablets. 4. a. dissolving the GLP-1 peptide in a feed solvent or obtaining the GLP-1 peptide in solution directly from a purification process; b. adjusting the pH of the feed solution to a pH of 5 to 12 by adding a non-volatile base to the feed solution; c. introducing the feed solution into a spray dryer and drying the GLP-1 peptide; d. Compressing the obtained powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into tablets. 5. A process for producing a spray-dried powder of a GLP-1 peptide powder, wherein the GLP-1 peptide is semaglutide or Compound A, the process comprising spray-drying a feed solution comprising the GLP-1 peptide and a feed solution solvent, wherein the pH of the feed solution is in the range of about 5 to about 10. 6. a. dissolving the GLP-1 peptide in a feed solvent or obtaining the GLP-1 peptide in solution directly from a purification process; b. adjusting the pH of the feed solution to a pH of about 5 to about 10 by adding a non-volatile base to the feed solution; c. introducing the feed solution into a spray dryer and drying the GLP-1 peptide. 7. The process of any one of embodiments 1 to 4, wherein the pH of the feed solution is adjusted to a pH of 5 to 12. 8. The process of any one of embodiments 1 to 7, wherein the pH of the feed solution is adjusted to pH 5 to 10. 9. The process of any one of embodiments 1 to 8, wherein the pH of the feed solution is adjusted to pH 6 to 9. 10. The process of any one of embodiments 1-9, wherein the pH of the feed solution is adjusted to pH 6-8. 11. The process of any one of embodiments 1 to 10, wherein the feed pH is adjusted to a given pH interval using a non-volatile base. 12. The process of embodiment 11, wherein the non-volatile base is selected from alkali hydroxides such as sodium hydroxide or potassium hydroxide, buffers such as phosphate buffer, TRIS, acetate buffer, and the like. 13. The process of embodiment 11 or 12, wherein the fixed base is sodium hydroxide, for example, 1 M aqueous sodium hydroxide. 14. The GLP-1 peptide is semaglutide or Nε27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl], Nε36-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[ 14. The process of any one of embodiments 1 to 13, wherein the compound is selected from: 10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (Compound A). 15. The process of any one of embodiments 1-14, wherein the feed solvent comprises a water-miscible organic solvent. 16. The process of any one of embodiments 1-15, wherein the feed solvent comprises an organic alcohol solvent. 17. The process of any one of embodiments 1-16, wherein the feed solvent comprises ethanol. 18. The process of any one of embodiments 1-17, wherein the feed solvent is aqueous ethanol. 19. The process of any one of embodiments 1-18, wherein the feed solvent is 40 to 70 percent (w / w) aqueous ethanol. 20. The process of any one of embodiments 1-19, wherein the feed solvent is 45 to 65 percent (w / w) aqueous ethanol. 21. The process of any one of embodiments 1 to 20, wherein the feed solvent is 50 to 60 percent (w / w) aqueous ethanol. 22. The process of any one of embodiments 1-21, wherein the feed solution comprises 0.5 to 10 percent (w / w) of the GLP-1 peptide. 23. The process of any one of embodiments 1-22, wherein the feed solution comprises 1 to 7 percent (w / w) of GLP-1 peptide. 24. The process of any one of embodiments 1-23, wherein the feed solution comprises 1.8 to 5 percent (w / w) of GLP-1 peptide. 25. The process of any one of embodiments 1-24, wherein the feed solution comprises 1 to 3 percent (w / w) semaglutide. 26. The process of any one of embodiments 1-25, wherein the feed solution comprises 1.8 to 2.1 percent (w / w) semaglutide. 27. The process of any one of embodiments 1-26, wherein the feed solution comprises 1 to 3 percent (w / w) semaglutide in 50 to 55 percent (w / w) aqueous ethanol. 28. The process of any one of embodiments 1-27, wherein the feed solution comprises 1.8 to 2.1 percent (w / w) semaglutide in 50 to 55 percent (w / w) ethanol. 29. The process of any one of embodiments 1-24, wherein the feed solution comprises 3 to 5 percent (w / w) of Compound A. 30. The process of any one of embodiments 1-24 or 29, wherein the feed solution comprises 3 to 5 percent (w / w) Compound A in 50 to 65 percent (w / w) aqueous ethanol. 31. The process of any one of embodiments 1-30, wherein the produced tablet comprises a therapeutically effective amount of a GLP-1 peptide. 32. The process of any one of embodiments 1-31, wherein the produced tablet comprises the GLP-1 peptide in an amount of 0.01 to 100 mg. 33. The process of any one of embodiments 1-32, wherein the produced tablet comprises the GLP-1 peptide in an amount of 0.1 to 50 mg. 34. The process of any one of embodiments 1-33, wherein the produced tablet comprises at least one pharmaceutically acceptable excipient. 35. The process of any one of embodiments 1-34, wherein the produced tablet comprises one or more excipients selected from the group consisting of binders, fillers, disintegrants, lubricants, delivery agents, and / or glidants. 36. The process of embodiment 35, wherein the lubricant is magnesium stearate. 37. The process of any one of embodiments 1-36, wherein the produced tablet comprises a delivery agent. 38. The process of embodiment 37, wherein the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. 39. The process of embodiment 37 or 38, wherein the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate. 40. The process of any one of embodiments 37-39, wherein the delivery agent is present in an amount of at least 0.05 mmol. 41. The process of any one of embodiments 37 to 40, wherein the delivery agent is present in an amount of 0.05 to 3 mmol. 42. The process of any one of embodiments 1-41, wherein the produced tablet has a weight in the range of 150 to 1000 mg. 43. The process of any one of embodiments 1-42, wherein the produced tablet has a weight in the range of 200 to 800 mg. 44. The process of any one of embodiments 1-43, wherein the produced tablet has a weight in the range of 300-700 mg, such as 400 mg, 500 mg, 600 mg. 45. The process of any one of embodiments 1-44, wherein the tablet produced is for oral administration. 46. ​​A tablet obtainable by the process according to any one of embodiments 1 to 45. 47. The tablet of embodiment 46, which provides an improved intrinsic dissolution rate, e.g., as measured by the methods of Examples 1 and 2 herein. 48. The tablet of embodiment 46 or 47, wherein the tablet comprises a delivery agent. 49. A tablet according to any one of embodiments 48, wherein the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate. 50. A tablet according to any one of embodiments 46 to 49 for use in medicine. 51. A tablet according to any one of embodiments 46 to 50 for use in treating type 2 diabetes or obesity. 52. A method for treating type 2 diabetes, comprising administering to a subject a tablet according to any one of embodiments 46 to 49. 53. A method for treating obesity, comprising administering to a subject a tablet according to any one of embodiments 46 to 49. 54. Use of a tablet according to any one of embodiments 46 to 49 in the manufacture of a medicament for the treatment of type 2 diabetes. 55. Use of a tablet according to any one of embodiments 46-49 in the manufacture of a medicament for the treatment of obesity. [Example]

[0072] Abbreviation MCC: Microcrystalline cellulose MgSt: Magnesium stearate PVP: Povidone K90

[0073] General method Common methods of spray drying: A feed solution of GLP-1 peptide in aqueous ethanol solvent was used for all experiments. Concentration details are given for each example. The pH of the feed solution was adjusted to the given pH value using 1 M NaOH or 1 M HCl.

[0074] Spray drying was carried out in a Buchi B-290 laboratory-scale spray dryer connected to an inert loop B-295 for recirculation of the drying gas and, optionally, to a dehumidifier B-296. Nitrogen gas was used as the drying and atomizing gas. A two-fluid nozzle with an inner diameter of 0.7 mm and a cap diameter of 1.5 mm was used for atomization.

[0075] The condenser temperature set point was below 0° C. for all experiments, and the solvent used for stabilization was aqueous ethanol at a concentration corresponding to the ethanol concentration of the feed.

[0076] The aspirator was turned on at 100%, followed by nitrogen gas at a level of 23-30 mm Hg on the built-in rotameter, corresponding to 0.35-0.50 kg / hr of atomizing gas. When a sufficiently low oxygen level (<6% by volume) was reached within the spray dryer, the heater was turned on at a set point of approximately 90°C to heat the spray dryer (gas stabilization). When the intended outlet temperature was reached (70-73°C), the inlet temperature was increased to 110-136°C. Once the target feed flow rate was reached (0.32-0.41 kg / hr), the inlet temperature was fine-tuned to achieve the target outlet temperature. All parameters were verified as necessary.

[0077] Once a stable temperature profile was reached, the actual spray drying process was initiated by transferring the feed line of the spray dryer from the stabilizing solvent to the actual feed solution containing the GLP-1 peptide as described above. The product was collected for 2–56 min by a high-efficiency cyclone connected to the drying chamber.

[0078] Preparation of compacted material Compacts (also referred to herein as compacted tablets) were made by compressing the GLP-1 peptide powder obtained from the general method of spray drying described above into compacted tablets. More specifically, spray-dried GLP-1 peptide compositions (20-50 mg) were compressed into compacts in a mold (4-7 mm) using pressure (0.5-1 metric tons) for 1 minute.

[0079] Tablet preparation Tablets were prepared using two types of granules: SNAC / MCC / MgSt granules and MCC / PVP granules, as described in WO 2013 / 139695. SNAC / MCC / MgSt granules and MCC / PVP granules were prepared and mixed with extragranular semaglutide. The amount of MgSt included in Table 7 includes the total amount and extragranular material in parentheses. Similarly, the total amount of MCC includes the amount of MCC in the SNAC / MCC / MgSt and MCC / PVP granules, respectively, in parentheses (Table 7).

[0080] A blend of 9.4 g of MCC / PVP granules and 0.6 g of MgSt was prepared in a 100 mL container by blending in a Pharmatech MB mixer at 25 rpm for 30 minutes. One tablet of SNAC / MCC / MgSt granules was weighed onto a weighing pan. One tablet of the MCC / PVP granule and MgSt blend was weighed on top of it. One tablet of semaglutide was then weighed on top of the other ingredients in the weighing pan. The ingredients were then mixed by hand and transferred directly to the tablet die cavities of an instrumented rotary tablet press (Fette 102i). The mixture in the die cavities was compressed into oval, convex tablets measuring 7.5 x 13 mm at a die table rotation speed of 20 rpm and a compression force of approximately 9.5 kN.

[0081] General method for intrinsic dissolution experiments (compacted tablets) and dissolution experiments (tablets): Intrinsic dissolution experiments (compressed tablets) Intrinsic dissolution was used to analyze the variation of powder properties after spray drying. A rotating disk apparatus (Woods apparatus) was used. Compacted tablets were fitted into a tablet holder with one side exposed to the dissolution medium so that the solid / liquid surface remained constant over the analysis period. The compacted tablets were then rotated at a constant speed, and samples for concentration determination were taken from the dissolution medium at predefined intervals. The amount of GLP-1 peptide dissolved in each sample was quantified by standard UPLC using UV detection at 215 nm or by UV spectroscopy using a Shimadzu UV spectrometer (215 nm). Intrinsic dissolution was determined according to Pharmacopoeia guides (e.g., Ph.Eur 2.9.29; USP <1087> ) was measured.

[0082] Dissolution experiment (tablets) Dissolution tests were performed using Apparatus 2 in accordance with United States Pharmacopoeia 35, using a paddle rotation speed of 50 rpm. 500 mL of dissolution medium was used: 0.05 M phosphate buffer (pH 6.8) at a temperature of 37°C. All dissolution media contained 0.05% polyoxyethylene lauryl ether. Sample aliquots were removed at appropriate intervals over 1 hour, and sample content was determined using an RP-UHPLC method for dual detection of SNAC and GLP-1. The UHPLC method was based on gradient elution on a C18 column. The eluent system was 0.09 M (NH4)2HPO4 in water (pH 3.6), acetonitrile, and 2-propanol, with UV detection at 210 and 335 nm. Sample content was calculated based on the major peak areas of SNAC and semaglutide in the chromatogram relative to the major peak areas of the SNAC and semaglutide references, respectively. The released amounts of SNAC and semaglutide were calculated as a percentage of the actual content in the tablets by extracting all SNAC and semaglutide at 250 rpm for 10 minutes after a 1-hour dissolution test.

[0083] Example 1: Intrinsic dissolution of semaglutide at different pH values A feed solution containing 2 percent (w / w) semaglutide in 53 percent (w / w) aqueous ethanol was prepared as described in the General Methods for Spray Drying. From this stock solution, feed solutions of various pH values ​​were prepared by adjusting the pH using 1 M HCl or 1 M NaOH to obtain a pH range of 3 to 10 as measured using pH strips at room temperature, as shown in Table 1. Spray drying was carried out using a Buchi B-290 spray dryer with the following parameters: feed flow rate: 0.38-0.41 kg / hr, atomization gas flow rate: 0.50 kg / hr, outlet temperature: 73°C, inlet temperature: 110-114°C. [Table 1]

[0084] From each of Experiments 1-6, 20 mg of the resulting spray-dried semaglutide powder was compressed into a compacted tablet using a pressure of 0.5 metric tons in a 4 mm die for 1 minute. Each compacted tablet was tested for intrinsic dissolution using the general method for intrinsic dissolution testing described above. The dissolution medium was 500 ml of 50 mM phosphate buffer at pH 6.8 containing 0.2 percent Brij 35®. The test conditions used were a temperature of 25°C and a rotation speed of 75 rpm. 1 ml samples were taken from each dissolution vessel every 5 minutes, and the dissolved semaglutide content in the samples was subsequently quantified using UPLC analysis. The results are presented in Table 2 and Figure 1. [Table 2]

[0085] The intrinsic dissolution rate of semaglutide is shown in Table 3 and was calculated based on the data in Table 2. The slope from the linear regression of the release of semaglutide for the linear part of the intrinsic dissolution and the mean value of 0.1257 cm 2 The release area was used to calculate the intrinsic dissolution rate. Linear regression was based on all time points for experiments 1-4 and 6, whereas for experiment 5, the first three time points at 5, 10, and 15 min of intrinsic dissolution were excluded due to nonlinearity. [Table 3]

[0086] The data in Table 3 and Figure 1 show that when semaglutide is obtained by spray drying from a feed solution with a pH above 3.5, the intrinsic dissolution rate of semaglutide is higher (Experiments 3-6) than when the feed solution has a pH of 3.5 or less (Experiments 1-2). Furthermore, the intrinsic dissolution rates in Table 1 show that the intrinsic dissolution rate of semaglutide is highest when the feed solution has a pH of about 5.

[0087] Example 2: Intrinsic dissolution of Compound A at various pH values 30-40 mg / ml of Nε27-[2-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl], Nε36-[2-[2-[[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10 -(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (Compound A) was prepared as described in General Methods and had a pH of 5 as measured with pH strips at room temperature. From this stock solution, various pH working solutions were made by adjusting the pH with 1 M HCl or 1 M NaOH to give a pH range of 3.6 to 7 as measured with pH strips at room temperature, as shown in Table 1. Optionally, NaCl was added at a concentration of 5 mg / ml according to Table 4. Spray drying parameters used on a Buchi B-290: Feed flow rate: 6 ml / min (equivalent to 0.32-0.33 kg / hr), atomization gas flow rate: 0.35-0.50 kg / hr, outlet temperature: 70°C, inlet temperature: 120-136°C [Table 4]

[0088] From each of Experiments 7-10, 50 mg of the resulting spray-dried powder of Compound A was compressed into a compacted tablet in a 7 mm die using 1 metric ton of pressure for 1 minute. Each compacted tablet was tested for intrinsic dissolution using the General Method for Intrinsic Dissolution Test. The dissolution medium was 500 ml of 50 mM dibasic sodium phosphate buffer at pH 6.8 containing 0.05 percent Brij 35®. The test conditions used were a temperature of 30°C and a rotation speed of 50 rpm. 1 ml samples were taken from each dissolution vessel every 2.5 minutes for 10 minutes, then every 5 minutes for an additional 20 minutes. The dissolved Compound A content in the samples was then quantified by UV spectroscopy (215 nm). The results are presented in Table 5 and Figure 2. For comparison, compacted tablets were also prepared directly from the initial Compound A powder used to prepare the stock solution. The powder was obtained by a different spray drying method that produced smaller particles, and these particles were included in the intrinsic dissolution experiment to assess whether dissolution was dependent on particle size. The feed solution for spray drying had a pH of 5 (experiment no. 11).

[0089] The results are presented in Table 5 and Figure 2. [Table 5]

[0090] The intrinsic dissolution rate of Compound A is shown in Table 6 and was calculated based on the data in Table 5. The slope from the linear regression of the release of Compound A for the linear portion of the intrinsic dissolution and the mean value of 0.3848 cm 2 The release area was used to calculate the intrinsic dissolution rate. The linear regression was based on all time points for Experiment 7, whereas for Experiments 8 and 11, and for Experiments 9–10, the last two time points at 25 and 30 min of intrinsic dissolution and the last three time points at 20, 25, and 30 min, respectively, were excluded due to nonlinearity. [Table 6]

[0091] The data in Table 6 and Figure 2 show that spray-dried Compound A obtained by a process according to the present invention, i.e., spray drying a feed solution comprising a GLP-1 peptide and a feed solvent, wherein the pH of the feed solution was in the range of about 5 to about 10 (Runs 8-11), exhibited increased intrinsic dissolution rates compared to spray-dried Compound A obtained by spray-drying a feed solution comprising a GLP-1 peptide and a feed solvent, wherein the pH of the feed solution was in the range below 5 (Run 7).

[0092] Example 3: Dissolution testing of tablets containing spray-dried semaglutide Different samples of spray-dried semaglutide powder were produced by spray drying as described in Example 1. The spray-dried semaglutide powder thus obtained was compressed into tablets according to the procedure described in "Tablet preparation". The tablet compositions are shown in Table 7. Each experiment is the average of 6 individual tablets. [Table 7]

[0093] Dissolution tests were performed on tablets I to V as described in "Dissolution Experiments." The results are shown in Table 8. [Table 8]

[0094] The semaglutide dissolution results (Tablets I-V, Table 8) show that the lower the pH during spray drying of semaglutide, the slower the dissolution and release of semaglutide from the tablets. Specifically, the results in Table 8 show that when semaglutide tablets are obtained by spray drying from a feed solution with a pH of 5 or above (Tablets III-V), the dissolution rate of the resulting tablets is increased compared to tablets with a pH below 5 (Tablets I-II). As Tablets I-V are so-called normal dissolution immediate-release tablets, the 30 and 45 minute time points for Tablets I-V are suitable for use in comparing dissolution results between these tablets (this is in accordance with, for example, the US Pharmacopoeia guidelines, which state that immediate-release tablets typically reach 85-100% release within 30-45 minutes). <1092> This is consistent with section 2.4.1 in "The dissolution procedure: Development and validation"; the "Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action" published by the European Medicines Agency (EMA / CHMP / CVMP / QWP / 336031 / 2017), which states that immediate-release tablets should be able to release 75% or more within 45 minutes; and ICH guideline Q6A (decision tree #7-1), which defines "rapid dissolution" as greater than 80% within 15 minutes for immediate-release tablets, whereas "normal dissolution" for immediate-release tablets is greater than 80% dissolution after 15 minutes. As can be seen in Table 8, the amount of dissolved semaglutide at 30 and 45 minutes is higher for tablets III-V than for tablets I and II.

[0095] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. 1. A process for producing a tablet comprising a GLP-1 peptide, said process comprising: a. spray drying a feed solution comprising the GLP-1 peptide and a feed solvent, wherein the pH of the feed solution is in the range of 5 to 10; b. compressing the resulting powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into a tablet; The process wherein the GLP-1 peptide is semaglutide and the feed solvent is 40 to 70 percent (w / w) aqueous ethanol.

2. a. dissolving the GLP-1 peptide in the feed solvent or obtaining the GLP-1 peptide in solution directly from a purification process; b. adjusting the pH of the feed solution to a pH of 5 to 10 by adding a fixed base to the feed solution; c. introducing the feed solution into a spray dryer and drying the GLP-1 peptide; and (d) compressing the resulting powder of GLP-1 peptide, and optionally at least one pharmaceutically acceptable excipient, into a tablet.

3. 3. The process of claim 1 or 2, wherein the pH of the feed solution is adjusted to a pH above the pI of the GLP-1 peptide or in the range of pH 5-10 using a non-volatile base.

4. 4. The process of claim 3, wherein the fixed base is selected from alkali hydroxides.

5. A process described in any one of claims 1 to 4, wherein the pH of the feed solution containing semaglutide is in the range of 6 to 10, or 6 to 8, or 8.5 to 9.

5.

6. 6. The process of any one of claims 1 to 5, wherein the feed solution comprises 0.5 to 10 percent (w / w) of the GLP-1 peptide.

7. A tablet obtainable by the process according to any one of claims 1 to 6.

8. 8. The tablet of claim 7, wherein the tablet comprises a delivery agent.

9. 9. The tablet of claim 8, wherein the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.

10. A tablet described in any one of claims 7 to 9, wherein the weight of the tablet is in the range of 100 mg to 1000 mg.

11. The tablet of claim 7, wherein the tablet contains 0.2 to 80 mg of GLP-1 peptide.

12. The tablet according to any one of claims 7 to 11 for use in medicine.

13. The tablet according to any one of claims 7 to 12 for the treatment of type II diabetes or obesity.

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