COMPOSITIONS OF GLP-1 PEPTIDES AND PREPARATION THEREOF

Abstract

The invention relates to pharmaceutical compositions comprising a first type of granules and a second type of granules, wherein said first type of granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and no GLP-1 peptide, and wherein said second type of granules comprises a GLP-1 peptide and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as the intermediate granules, processes for the preparation of the granules and compositions, and use thereof in medicine.

Claims

1. A solid dosage pharmaceutical composition comprising (1) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (salt of NAC) and (2) a granule; wherein the granule comprises semaglutide, a binder, a filler, and no salt of NAC; wherein the filler is at least 15% (w/w) of the granule; and wherein the binder is less than 40% (w/w) of the granule.

2. The composition according to claim 1, wherein the salt of NAC is sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC).

3. The composition according to claim 1, wherein the filler is microcrystalline cellulose.

4. The composition according to claim 1, wherein the filler is 50-75% (w/w) of the granule.

5. The composition according to claim 4, wherein the filler is microcrystalline cellulose.

6. The composition according to claim 1, wherein the binder is povidone.

7. The composition according to claim 1, wherein the binder is 15-25% (w/w) of the granule.

8. The composition according to claim 7, wherein the binder is povidone.

9. The composition according to claim 1, further comprising a lubricant that is not in the granule.

10. The composition according to claim 9, wherein the lubricant is magnesium stearate.

11. The composition according to claim 1, wherein the weight of the composition is in the range of 150 mg to 1000 mg.

12. The composition according to claim 11, wherein the weight of the composition is in the range of 300 mg to 600 mg.

13. The composition according to claim 12, wherein the weight of the composition is in the range of 350 mg to 450 g.

14. The composition according to claim 1, wherein the salt of NAC is sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC), the filler is microcrystalline cellulose, and the binder is povidone.

15. The composition according to claim 1, wherein the filler is 50-75% (w/w) of the granule, and wherein the binder is 15-25% (w/w) of the granule.

16. The composition according to claim 15, wherein the salt of NAC is sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC), the filler is microcrystalline cellulose, and the binder is povidone.

17. The composition according to claim 14, further comprising magnesium stearate that is not in the granule.

18. (canceled)

19. The composition according to claim 15, further comprising magnesium stearate that is not in the granule.

20. (canceled)

21. The composition according to claim 16, further comprising magnesium stearate that is not in the granule.

22. (canceled)

23. (canceled)

24. The composition according to claim 14, wherein the weight of the composition is in the range of 300 mg to 600 mg.

25. (canceled)

26. The composition according to claim 15, wherein the weight of the composition is in the range of 300 mg to 600 mg.

27. (canceled)

28. The composition according to claim 16, wherein the weight of the composition is in the range of 300 mg to 600 mg.

29. The composition according to claim 1, wherein the composition comprises at least 60% (w/w) of the salt of NAC.

30. The composition according to claim 29, wherein the salt of NAC is sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC).

31. The composition according to claim 29, wherein the composition comprises at least 70% (w/w) of the salt of NAC.

32. The composition according to claim 31, wherein the salt of NAC is sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC).

33. The composition according to claim 16, wherein the composition comprises at least 60% (w/w) of the SNAC.

34. The composition according to claim 33, wherein the composition comprises at least 70% (w/w) of the SNAC.

Description

EXAMPLES

Materials and Methods

General Methods of Preparation

Dry Granulation

[0273] Dry granulation was carried out by roller compaction on a Gerteis MINI-PACTOR using smooth rolls and the settings listed in Table 1.

TABLE-US-00002 TABLE 1 Settings for dry granulation on the roller compactor Parameter Setting Agitator speed 5.0 rpm Roll speed 1.5 or 3.0 rpm Gap 1.0 mm Force 5.0 or 6.0 kN/cm Granulator screen 0.63 mm wire screen Granulator speed 60 rpm

[0274] Roller compaction force, i.e. the force between the rolls of the roller compactor when compacting materials into a continuous strip of compressed material, was determined by a pressure transducer that converts the hydraulic pressure into electrical signal; the roller compaction force may be measured in kiloNewton (kN) or in kiloNewton per roll width (kN/cm).

[0275] Subsequent to dry granulation comminution of the moldings into granules was carried out.

Tablet Preparation

[0276] Tablets were produced on a Korsch PH106 or a Fette 102i mounted with a gravity feeder and a single set of punches resulting in 13 mm×7.5 mm convex oval tablets having no score. The press speed of the Korsch PH106 was set around 25 rpm and the counter pressure was adjusted to 40 kN. The press speed of the Fette 102i was set around 20 rpm. The fill volume was adjusted to obtain tablets having a target weight 407.7 mg. The compression force was set to obtain tablets with a crushing strength of around 180±20 N for the Korsch PH106 and of around 128 N for the Fette 102i.

Resistance to Crushing of Tablets

[0277] Resistance to crushing of tablets was determined according to section 2.9.8 in the European Pharmacopoeia 7.5, 7th edition 2012 and at a jaw speed of 20 N/s.

General Methods of Detection and Characterisation

Assay (I): Dissolution Testing

[0278] The dissolution test was conducted with apparatus 2 in accordance with United States Pharmacopoeia 35 using a paddle rotation speed of 50 rpm. For testing at pH 1.0, 2.5 or 6.8, the 500 mL dissolution medium of 0.1 N hydrochloric acid (pH 1.0), 0.05 M phthalate buffer (pH 2.5), or 0.05 M phosphate buffer (pH 6.8), respectively, was used at a temperature of 37° C. All dissolution media had a content of 0.1% Tween80. Sample aliquots were removed at appropriate intervals and samples with acidic medium were neutralized with tribasic sodium phosphate to prevent precipitation. Sample contents were determined using a RP-HPLC method for dual detection of SNAC and GLP-1 (e.g. semaglutide) The HPLC method was based on gradient elution on a C8 column. The solvent system was trifluoroacetic acid and acetonitrile with UV detection at 210 and 335 nm. The sample contents were calculated based on the peak area of the SNAC and GLP-1 (e.g. semaglutide) peaks in the chromatogram relative to the peak areas of the SNAC and GLP-1 (e.g. semaglutide) references, respectively. The released amounts of SNAC and GLP-1 (e.g. semaglutide) were calculated as percentages of the nominal contents in the tablet i.e. 300 mg/tablet SNAC and 10 mg/tablet GLP-1 (e.g. semaglutide) and then optionally corrected for the actual contents in the tablets. The actual contents in the tablets were determined using Assay (III).

Assay (II): Bioavailability in Dogs

[0279] Animals, Dosing and Blood Sampling: Male and female beagle dogs, weighing approx. 6-22 kg during the study period, were included in the study. The dogs were dosed in fasting state and the dogs were fed approx. 4 hours post dosing. The formulations were administered by oral administration to the dogs in groups of typically 8 (such as 4 male and 4 females).

[0280] The bioavailability studies were conducted either as single dose (SD) studies or multiple dose (MD) studies. In the MD studies the formulation was administered with five consecutive dosing occasions in each study (once a day dosing).

[0281] Blood samples were taken to cover the pharmacokinetic profile. An example of a SD blood sampling regimen could be the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours post dosing. An example of a MD blood sampling regimen could be the following time points: pre-dose, 0.5, 1.5 and 3 hr post dosing after each dosing occasion and a blood sampling regimen equivalent to a SD blood sampling regimen following the last dosing occasion.

[0282] Preparation of Plasma: All blood samples were collected into test tubes containing EDTA for stabilisation and kept on ice until centrifugation. Plasma was separated from whole blood by centrifugation and the plasma was stored at −20° C. or lower until analysis.

[0283] Analysis of Plasma Samples: The plasma was analysed for semaglutide using a Luminescence Oxygen Channeling Immunoassay (LOCI). The LOCI assay employs donor beads coated with streptavidin and acceptor beads conjugated with a monoclonal antibody binding to a mid-molecular region of GLP-1 (e.g. semaglutide). The other monoclonal antibody, specific for an N-terminal epitope, was biotinylated. In the assay the three reactants were combined with the GLP-1 (e.g. semaglutide) which form a two-sited immuno-complex. Illumination of the complex releases singlet oxygen atoms from the donor beads which channels into the acceptor beads and trigger chemiluminescence which was measured in the EnVision plate reader. The amount of light was proportional to the concentration of semaglutide and the lower limit of quantification (LLOQ) in plasma was 100 pM.

[0284] Pharmacokinetic Calculations: GLP-1 (e.g. semaglutide) plasma concentration data were subjected to non-compartmental pharmacokinetic analysis using the PC based software WinNonlin, v. 5.2 or later (Pharsight, Mountain View, Calif. 94041, USA). For each individual dog the following pharmacokinetic parameters were estimated: Area Under the Curve (AUC), and dose normalized AUC (AUC/D). Bioavailability (F) was calculated as the fraction absorbed (in %) based on the dose normalised AUC (AUCinf./D) following oral and intravenous administration. Summary statistics of pharmacokinetic results were presented as arithmetic mean.

Assay (III): Analysis of Amount of GLP-1 and SNAC

[0285] For assay analysis tablets were dissolved using 0.05 M Na.sub.2HPO.sub.4 with 0.01% Tween20 as extraction buffer. Sample content was determined using a RP-HPLC method for dual detection of SNAC and GLP-1 (e.g. semaglutide). The HPLC method was based on gradient elution on a C8 column. The solvent system was trifluoroacetic acid and acetonitrile with UV detection at 210 and 335 nm. The sample contents were calculated based on the peak area of the SNAC and GLP-1 (e.g. semaglutide) peaks in the chromatogram relative to the peak areas of the SNAC and GLP-1 (e.g. semaglutide) references, respectively. The content was reported as average of 10 tablets.

Example 1

Preparation of Tablet Compositions Comprising GLP-1 and SNAC

[0286] Tablet compositions comprising GLP-1 and SNAC were prepared with the components shown in Table 2. Compound A is N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy) decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy) ethoxy]acetyl}, N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy) decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy) ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH.

TABLE-US-00003 TABLE 2 Composition of the tablet compositions Component Amount (mg/tablet) Function Semaglutide or Compound A 10 Active ingredient SNAC 300 Delivery agent Microcrystalline cellulose 80 Filler (Avicel PH 101) Povidone K 90 (Kollidon 90F) 8 Binder Magnesium stearate 9.7 Lubricant Total amount 407.7

[0287] Tablet compositions were prepared by mixing the components listed in Table 2 in different ways. The tablet compositions consisted of a first type of granules, in some cases a second type of granules, as well as extragranular ingredients mixed with the first type of granules and, if present, the second type of granules. Preparation of granules by roller compaction and preparation of tablets from the tablet compositions were as described in the section General Methods of Preparation. The design of the tablet compositions is shown in Table 3.

TABLE-US-00004 TABLE 3 Design of tablet compositions (the amount of each component in mg/tablet is shown in brackets) Composition of Composition of Tablet first type of second type of Extragranular compo- granules granules ingredients sition (mg/tablet) (mg/tablet) (mg/tablet) B SNAC (300), semaglutide (10), magnesium magnesium microcrystalline stearate (2) stearate (7.7) cellulose (80), povidone (8) C SNAC (300), — microcrystalline semaglutide (10), cellulose (80), magnesium povidone (8), stearate (7.7) magnesium stearate (2) D SNAC (300), — microcrystalline semaglutide (10), cellulose (80), povidone (8), magnesium magnesium stearate (2) stearate (7.7) E SNAC (300), — magnesium semaglutide (10), stearate (2) microcrystalline cellulose (80), povidone (8), magnesium stearate (7.7) F SNAC (300), semaglutide (10), magnesium microcrystalline microcrystalline stearate (2) cellulose (57), cellulose (23), magnesium povidone (8) stearate (7.7) G SNAC (300), Compound A (10), magnesium magnesium microcrystalline stearate (2) stearate (7.7) cellulose (80), povidone (8) H SNAC (300), Compound A (10), magnesium microcrystalline microcrystalline stearate (2) cellulose (57), cellulose (23), magnesium povidone (8) stearate (7.7)
Further details of the preparation of the tablet compositions are provided below.

Tablet Composition B

[0288] Magnesium stearate for the first granule fraction was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a stainless steel bowl in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s until the blend was visually homogenous. The remaining quantity of SNAC was transferred to a blender and was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearate pre-mix was added to the blender and mixing was performed for 20 min at 25 rpm. The blend was roller compacted. The granules were sieved through a 180 μm mesh.

[0289] Semaglutide, microcrystalline cellulose and povidone for the second granule fraction were weighed directly into a stainless steel bowl in the order of decreasing amounts and mixed manually for at least 3 min until visually homogenous before transferring the pre-mix to a 1000 mL Duma bottle. The Duma bottle was closed with a lid and tumbled manually in a Turbula-like movement for 1 min. The blend was roller compacted.

[0290] The two types of granules were added to a blending container in order of decreasing content and mixed for 5 minutes at 32 rpm. Extragranular magnesium stearate was mixed with the granule blend by manual mixing using volume-doubling followed by 30 s mixing in the Turbula mixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition C

[0291] Magnesium stearate for the granule fraction was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a stainless steel bowl in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s until the blend was visually homogenous. The remaining quantity of SNAC was transferred to a blender and was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearate pre-mix was added to the blender and mixing was performed for 20 min at 25 rpm. Semaglutide was geometrically diluted using the mixed SNAC and magnesium stearate from the blender by mixing it manually for at least 60 s until visually homogenous. The pre-mix was then added to the mixed SNAC and magnesium stearate. The mixing step was finalized by mixing in the blender for 10 min at 25 rpm. The blend was roller compacted.

[0292] The granules and all other constituents except extragranular magnesium stearate were added to a blending container in order of decreasing content and mixed for 5 minutes at 32 rpm. Extragranular magnesium stearate was mixed with the granule blend by manual mixing using volume-doubling followed by 30 s mixing in the Turbula mixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition D

[0293] Magnesium stearate for the granule fraction was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a stainless steel bowl in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s until the blend was visually homogenous. The remaining quantity of SNAC was transferred to a blender and was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearate pre-mix was added to the blender and mixing was performed for 20 min at 25 rpm. Semaglutide and povidone were weighed into a stainless steel bowl in the order of decreasing amounts and the components were mixed manually until visually homogenous. A geometric dilution was then performed using the mixed SNAC and magnesium stearate from the blender by mixing it manually for at least 60 s until visually homogenous. The pre-mix was then added to the mixed SNAC and magnesium stearate. The mixing step was finalized in the blender by mixing for 10 min at 25 rpm. The blend was roller compacted.

[0294] The granules and microcrystalline cellulose were added to a blending container in order of decreasing content and mixed for 5 minutes at 32 rpm. Extragranular magnesium stearate was mixed with the granule blend by manual mixing using volume-doubling followed by 30 s mixing in the Turbula mixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition E

[0295] Magnesium stearate for the granule fraction was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a stainless steel bowl in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s until the blend was visually homogenous. The remaining quantity of SNAC was transferred to a blender and was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearate pre-mix was added to the blender and mixing was performed for 20 min at 25 rpm. Semaglutide, microcrystalline cellulose and povidone were weighed into a stainless steel bowl in the order of decreasing amounts and the components were mixed manually until visually homogenous. A geometric dilution was then performed using the mixed SNAC and magnesium stearate from the blender by mixing it manually for at least 60 s until visually homogenous. The pre-mix was then added to the mixed SNAC and magnesium stearate. The mixing step was finalized in the blender by mixing for 10 min at 25 rpm. The blend was roller compacted.

[0296] Extragranular magnesium stearate was mixed with the granules by manual mixing using volume-doubling followed by 30 s mixing in the Turbula mixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition F

[0297] Magnesium stearate for granule fraction one was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a stainless steel bowl in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s until the blend was visually homogenous. The remaining quantity of SNAC was transferred to a blender and was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearate pre-mix was added to the blender and mixing was performed for 20 min at 25 rpm. Microcrystalline cellulose was geometrically diluted using the mixed SNAC and magnesium stearate from the blender by mixing it manually for at least 60 s until visually homogenous. The pre-mix was then added to the mixed SNAC and magnesium stearate. The mixing step was finalized by mixing in the blender for 10 min at 25 rpm. The blend was roller compacted.

[0298] Semaglutide, microcrystalline cellulose (Avicel PH 101, FMC Biopolymer) and povidone (Kollidon 90F, BASF) for granule fraction two were weighed directly into a stainless steel bowl in the order of decreasing amounts and mixed manually for at least 3 min until visually homogenous before transferring the pre-mix to a 500 mL Duma bottle. The Duma bottle was closed with a lid and tumbled manually in a Turbula-like movement for 1 min. The blend was roller compacted.

[0299] The two types of granules were added to a blending container in order of decreasing content and mixed for 5 minutes at 32 rpm. Extragranular magnesium stearate was mixed with the granule blend by manual mixing using volume-doubling followed by 30 s mixing in the Turbula mixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition G

[0300] Magnesium stearate for the first granule fraction was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a plastic bag in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s. The SNAC and magnesium stearate pre-mix was added to the blender followed by the addition of the remaining SNAC and mixing was performed for 50 min at 25 rpm. The blend was roller compacted. The granules were sieved through a 1000 and 90 μm mesh.

[0301] Compound A, microcrystalline cellulose and povidone for the second granule fraction were weighed directly into a stainless steel bowl in the order of decreasing amounts and mixed manually for at least 3 min until visually homogenous before transferring the pre-mix to a 500 mL Duma bottle. The Duma bottle was closed with a lid and tumbled manually in a Turbula-like movement for 3 min. The blend was roller compacted.

[0302] The two types of granules were added to a blending container and mixed for 20 minutes at 25 rpm. Extragranular magnesium stearate was passed through a 355 μm sieve and mixed with the granule blend by manual mixing using volume-doubling followed by 2 min mixing in the Turbula mixer at 25 rpm. Tablets were prepared from this composition.

Tablet Composition H

[0303] Magnesium stearate for granule fraction one was passed through a 355 μm sieve. Magnesium stearate was manually mixed with SNAC in a plastic bag in corresponding volumes. Two cycles of geometric dilution was applied by mixing for around 60 s. The SNAC and magnesium stearate pre-mix was added to the blender followed by the addition of the remaining SNAC and mixing was performed for 50 min at 25 rpm. Microcrystalline cellulose was then added to the mixed SNAC and magnesium stearate and the mixing step was finalized by mixing in the blender for 20 min at 25 rpm. The blend was roller compacted.

[0304] Compound A, microcrystalline cellulose (Avicel PH 101, FMC Biopolymer) and povidone (Kollidon 90F, BASF) for granule fraction two were weighed directly into a stainless steel bowl in the order of decreasing amounts and mixed manually for at least 3 min until visually homogenous before transferring the pre-mix to a 500 mL Duma bottle. The Duma bottle was closed with a lid and tumbled manually in a Turbula-like movement for at least 3 min. The blend was roller compacted.

[0305] The two types of granules were added to a blending container and mixed for 20 minutes at 25 rpm. Extragranular magnesium stearate was passed through a 355 μm sieve and mixed with the granule blend by manual mixing using volume-doubling followed by 2 minutes mixing in the Turbula mixer at 25 rpm. Tablets were prepared from this composition.

Example 2

Dissolution of GLP-1 and SNAC from Tablet Composition B

[0306] The dissolution of semaglutide and SNAC from tablet composition B was determined using Assay (I) described herein. The results are shown in Table 4. Corrected results are adjusted for the content of semaglutide or SNAC determined by analysis using Assay (III) described herein. The corrected results show that SNAC is released faster than semaglutide during the initial 20 min of dissolution. Furthermore, it shows that the difference between the faster release of SNAC compared to semaglutide is the largest in the dissolution medium with the pH-value of 2.5. Lastly, the data shows that in dissolution media with pH-values of 1.0 and 2.5 the amount of dissolved SNAC peaks within the initial 45 and 30 min, respectively.

TABLE-US-00005 TABLE 4 Dissolution of semaglutide and SNAC from tablet composition B pH of dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNAC Semaglutide SNAC Semaglutide SNAC time released released released released released released (min) (% of total) (% of total) (% of total) (% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  0 5 — — — — 8 9 19 19 — — — — 10  9 10 13 13 17 18 28 28 — — — — 15 — — — — 22 24 32 32 45 49 53 52 20 17 18 19 19 27 29 34 34 — — — — 30 20 22 20 20 35 38 33 33 74 81 81 80 45 23 25 20 20 42 46 30 30 86 94 92 91 60 24 26 19 19 46 50 28 28 92 100  96 95 Corrected Yes No Yes No Yes No Yes No Yes No Yes No for actual content

Example 3

Dissolution of GLP-1 and SNAC from Tablet Composition C

[0307] The dissolution of semaglutide and SNAC from tablet composition C was determined using Assay (I) described herein. The results are shown in Table 5. The results show that SNAC is released slower than semaglutide after the initial 5 min of dissolution in the dissolution media with low pH-values of 1.0 and 2.5. Corrected results are adjusted for the content of semaglutide or SNAC determined by analysis using Assay (III) described herein. During the initial 5 min of corrected dissolution in the dissolution medium with the pH-value of 2.5 SNAC is released equally fast as semaglutide. Furthermore, the corrected dissolution values show that SNAC is released faster than semaglutide in the dissolution medium with the pH-value of 6.8.

TABLE-US-00006 TABLE 5 Dissolution of semaglutide and SNAC from tablet composition C pH of dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNAC Semaglutide SNAC Semaglutide SNAC time released released released released released released (min) (% of total) (% of total) (% of total) (% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  0 5 — — — — 11 12 11 11 — — — — 10 14 16 11 11 20 22 19 19 — — — — 15 — — — — 24 27 23 23 45 50 48 47 20 23 25 16 16 28 31 25 25 — — — — 30 27 30 18 18 34 38 28 28 77 85 80 79 45 30 33 19 19 41 46 29 29 88 98 93 91 60 31 34 18 18 46 51 27 27 94 104  99 97 Corrected Yes No Yes No Yes No Yes No Yes No Yes No for actual content

Example 4

Dissolution of GLP-1 and SNAC from Tablet Composition D

[0308] The dissolution of semaglutide and SNAC from tablet composition D was determined using Assay (I) described herein. The results are shown in Table 6. The results show that SNAC is released slower than semaglutide after the initial 5 min of dissolution in the dissolution media with low pH-values of 1.0 and 2.5. Corrected results are adjusted for the content of semaglutide or SNAC determined by analysis using Assay (III) described herein. During the initial 5 min of corrected dissolution in the dissolution medium with the pH-value of 2.5 SNAC is released equally fast with semaglutide. Furthermore, the corrected dissolution values show that SNAC is released faster than semaglutide in the dissolution medium with the pH-value of 6.8.

TABLE-US-00007 TABLE 6 Dissolution of semaglutide and SNAC from tablet composition D pH of dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNAC Semaglutide SNAC Semaglutide SNAC time released released released released released released (min) (% of total) (% of total) (% of total) (% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  0 5 — — — — 11 12 11 11 — — — — 10 10 11  8  8 17 19 16 16 — — — — 15 — — — — 21 23 19 19 33 37 35 35 20 17 19 12 12 23 26 20 20 — — — — 30 23 26 15 15 28 31 22 22 59 66 62 62 45 26 29 16 16 33 37 24 24 75 83 77 77 60 27 30 15 15 38 42 25 25 82 91 84 84 Corrected Yes No Yes No Yes No Yes No Yes No Yes No for actual content

Example 5

Dissolution of GLP-1 and SNAC from Tablet Composition E

[0309] The dissolution of semaglutide and SNAC from tablet composition E was determined using Assay (I) described herein. The results are shown in Table 7. Corrected results are adjusted for the content of semaglutide or SNAC determined by analysis using Assay (III) described herein. The results show that SNAC is released slower than semaglutide during the entire dissolution time in a dissolution medium with a pH-value of 1.0. In a dissolution media with a pH-value of 2.5 the results show that SNAC initially is released faster than semaglutide during the initial 10 to 15 min of dissolution before becoming slower. Furthermore, the data shows that in dissolution medium with a pH-value of 2.5 the amount of dissolved SNAC peaks within the initial 20 min. Lastly, the corrected dissolution values show that SNAC is released faster than semaglutide in the dissolution medium with the pH-value of 6.8.

TABLE-US-00008 TABLE 7 Dissolution of semaglutide and SNAC from tablet composition E pH of dissolution media 1.0 2.5 6.8 SNAC SNAC SNAC Dissolution Semaglutide released Semaglutide released Semaglutide released time released (% of released (% of released (% of (min) (% of total) total) (% of total) total) (% of total) total) 0  0  0  0  0 0 0 0 0  0  0  0 5 — — — — 21 23 22 22 — — — — 10 15 17 12 12 38 42 40 40 — — — — 15 — — — — 50 56 46 46 47 53 51 51 20 23 26 16 16 57 64 43 43 — — — — 30 28 31 16 16 63 71 37 37 76 85 79 79 45 32 36 17 17 68 76 31 31 86 96 89 89 60 36 40 17 17 70 78 28 28 90 101 93 93 Corrected Yes No Yes No Yes No Yes No Yes No Yes No for actual content

Example 6

Dissolution of GLP-1 and SNAC from Tablet Composition F

[0310] The dissolution of semaglutide and SNAC from tablet composition F was determined using Assay (I) described herein. The results are shown in Table 8. Corrected results are adjusted for the content of semaglutide or SNAC determined by analysis using Assay (III) described herein. The corrected results show that SNAC is released faster than semaglutide during the initial 20 to 30 min of dissolution. Furthermore, it shows that the difference between the faster release of SNAC compared to semaglutide is the largest in the dissolution medium with the pH-value of 2.5. Lastly, the data shows that in a dissolution medium with a pH-value of 2.5 the amount of dissolved SNAC peaks within the initial 30 min.

TABLE-US-00009 TABLE 8 Dissolution of semaglutide and SNAC from tablet composition F pH of dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNAC Semaglutide SNAC Semaglutide SNAC time released released released released released released (min) (% of total) (% of total) (% of total) (% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  0 5 — — — — 9 10 17 17 — — — — 10  8  9 10 10 20 22 31 31 — — — — 15 — — — — 28 31 40 40 51 56 56 56 20 12 13 13 13 33 36 43 43 — — — — 30 15 17 15 15 38 42 42 42 75 82 79 79 45 19 21 16 16 43 47 39 39 85 93 88 88 60 21 23 16 16 48 53 38 38 89 98 93 93 Corrected Yes No Yes No Yes No Yes No Yes No Yes No for actual content

Example 7

Bioavailability of GLP-1 in Dogs from Tablet Compositions B-F

[0311] Bioavailability of GLP-1 from tablet compositions B-F was determined in dogs according to Assay (II) described herein. The results are shown in Table 9.

TABLE-US-00010 TABLE 9 Bioavailability of GLP-1 in dogs from tablet compositions B-F Bioavailability of GLP-1 in dogs Tablet composition (% F) B 0.7 C 0.5 D 0.3 E 0.4 F 1.0

[0312] The results show that tablet composition F provided a bioavailability of 1.0%. The results show that tablet composition B provided a bioavailability of 0.7%. The results show that tablet composition C provided a bioavailability of 0.5%. The results show that tablet composition E provided a bioavailability of 0.4%. The results show that tablet composition D provided a bioavailability of 0.3%.

Example 8

Dissolution of GLP-1 and SNAC from Tablet Composition G

[0313] The dissolution of Compound A and SNAC from tablet composition G was determined using Assay (I) described herein. The results are shown in Table 10. The results show that SNAC is released faster than Compound A during the initial 20 min of dissolution. Furthermore, it shows that the difference between the faster release of SNAC compared to Compound A is the largest in the dissolution medium with the pH-value of 2.5. Lastly, the data shows that in dissolution media with pH-value of 2.5 the amount of dissolved SNAC peaks within the initial 45 min, respectively.

TABLE-US-00011 TABLE 10 Dissolution of Compound A and SNAC from tablet composition G pH of dissolution media Disso- 2.5 6.8 lution Compound A SNAC Compound A SNAC time released released released released (min) (% of total) (% of total) (% of total) (% of total) 0 0 0  0  0 5 9 17 — — 10 16 24 — — 15 21 26 38 49 20 25 28 — — 30 32 28 70 79 45 39 28 85 92 60 43 26 91 96 120 — — 95 101 

Example 9

Dissolution of GLP-1 and SNAC from Tablet Composition H

[0314] The dissolution of Compound A and SNAC from tablet composition H was determined using Assay (I) described herein. The results are shown in Table 11. The results show that SNAC is released faster than Compound A during the initial 20 min of dissolution. Furthermore, it shows that the difference between the faster release of SNAC compared to Compound A is the largest in the dissolution medium with the pH-value of 2.5. Lastly, the data shows that in a dissolution medium with a pH-value of 2.5 the amount of dissolved SNAC peaks within the initial 30 min.

TABLE-US-00012 TABLE 11 Dissolution of Compound A and SNAC from tablet composition H pH of dissolution media 2.5 6.8 Disso- Compound A SNAC Compound A SNAC lution released released released released time (% of total) (% of total) (% of total) (% of total) 0 0 0  0  0 5 10 19 — — 10 19 31 — — 15 26 37 37 47 20 31 38 — — 30 36 34 63 75 45 42 29 74 83 60 46 27 79 87 120 — — 89 97

Example 10

Bioavailability of GLP-1 in Dogs from Tablet Compositions G-H

[0315] Bioavailability of GLP-1 from tablet compositions G-H was determined in dogs according to Assay (II) described herein. The results are shown in Table 12.

TABLE-US-00013 TABLE 12 Bioavailability of GLP-1 in dogs from tablet compositions G-H Bioavailability of GLP-1 in dogs Tablet composition (% F) G 2.1 H 2.5

[0316] The results show that tablet composition G provided a bioavailability of 2.1%. The results show that tablet composition H provided a bioavailability of 2.5%.

[0317] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.