Improved formulation for buccal mucosal drug delivery

Abstract

The invention relates to the field of therapeutic agent delivery using suction-cup orifice design (SCOD) as a vehicle. In particular, the invention provides new formulations for semaglutide delivery using SCOD that shows greater bioavailability across the buccal mucosa. This invention also provides methods of preparing these compositions.

Description

[0001] New PCT Patent Application Space Pharmaceuticals AG Vossius Ref.: AJ2733 PCT BS

[0002] Improved formulation for buccal mucosal drug delivery

[0003] The invention relates to the field of therapeutic agent delivery using suction-cup orifice design (SCOD) as a vehicle. In particular, the invention provides new formulations for semaglutide delivery using SCOD that shows greater bioavailability across the buccal mucosa. This invention also provides methods of preparing these compositions.

[0004] The development of new drugs, formulations, and other systems for administration of physiologically active peptides, proteins, organic drugs, other therapeutics, and materials is driven by the need to achieve the desirable physiological effects. In recent years, a growing number of peptides and proteins have been made available as therapeutic agents. However, while some oral formulations for delivering peptide- or protein-based pharmaceutical drugs exist, including tablets, capsules, lonzenges, powders, emulsions and liquids, the full potential of these biological drugs has often not been realized, because many of them have been observed to be unstable in the gastro-intestinal tract. Therefore, they may need to be stabilized or protected. Daily food consumption also affects the bioavailability of the active pharmaceutical ingredient, and the subject must have a good functioning digestive system to ensure proper absorption from the gastrointestinal tract.

[0005] To circumvent these problems associated with oral administration, many pharmaceutically active ingredients, e.g., insulin, are typically injected subcutaneously using needles and syringes, pens, jet injectors, and pumps. Using such devices can be uncomfortable, painful, and generally inconvenient, causing non-compliance of some patients. There is, thus, a strong need for simpler and less invasive methods of delivering compositions of biologies such as peptides and proteins while maintaining or improving the efficacy and the bioavailability of the active ingredient.

[0006] Significant efforts have, therefore, been devoted to developing novel non-parenteral drug delivery systems for these macromolecular drugs (M. Sam, D. Brayden. "Formulation strategies to improve the efficacy of intestinal permeation enhancers.” Adv. Drug Deliv. Rev (2021): 113925). However, success has been scarce. For example, in the case of peptides, only a few oral formulations for systemic delivery have entered clinical trials over the past 30 years, resulting in merely a few of them reaching the market. Meanwhile, the oral bioavailability of most of these drugs remains very low (generally < 1%). Consequently, non-parenteral drug administration systems for enhancing systemic delivery, particularly of macromolecular drugs are clearly needed.

[0007] In this context, a self-application suction cup orifice design (SCOD), more specifically, a polymer-based octopus-inspired suction patch currently under development by ETH Zurich, is disclosed in WO 2023 / 094971 A1. The formulation comprised in this type of transmucosal delivery system provides similar bioavailability as compared to the orally available Rybelsus semaglutide tablet, which has less than 1% bioavailability.

[0008] Semaglutide is a GLP-1 derivative for once weekly administration which has been developed by Novo Nordisk A / S. This compound is disclosed in WO 2006 / 097537 A2. Although Novo Nordisk's oral semaglutide product achieved the first oral administration of GLP-1 drugs on the market, its oral bioavailability remains limited (only 0.4% to 1%).

[0009] The present inventors hypothesized that changing the formulations for semaglutide delivery while employing a novel SCOD transmucosal delivery system could improve its bioavailability.

[0010] To address this issue, in the context of the present invention, formulations comprising at least one permeation enhancer, a water-soluble synthetic polymer to control the release of the drug, and the active ingredients in a buffer adjusted at physiological pH were tested and successfully administered using SCOD through buccal mucosa. Thus, the acidic environment of the stomach and enzymatic digestion in the gastrointestinal tract were bypassed and the skin damage caused by subcutaneous injection was avoided.

[0011] This resulted in a completely unexpected discovery: The formulation according to the invention containing a chemical permeation enhancer provides a 3% greater oral bioavailability of semaglutide across the buccal mucosa when applied using SCOD, whereas the control formulation with sodium taurocholate (NaTac) as a permeation enhancer only had a bioavailability of 1%. Previously, no formulations containing a permeation enhancer that showed improved bioavailability of semaglutide across the buccal mucosa were known. Similarly, no such formulations that showed improved bioavailability of semaglutide compared to the oral formulations with sodium salcaprozate (SNAC) alone (e.g., Rybelsus) were known.

[0012] These properties render the mucosal suction cups and the delivery methods using said mucosal suction cups of the present invention highly advantageous for the convenient delivery of semaglutide with improved bioavailability, thus overcoming the drawbacks of both oral and systemic delivery described hereinabove.

[0013] Accordingly, the present invention provides a mucosal suction cup comprising a composition comprising a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof.

[0014] The present invention also relates to the use of said mucosal suction cup for transmucosal administration of a composition comprising a therapeutic agent to a subject. The invention further relates to the use of said mucosal suction cup for the transmucosal delivery of a composition comprising a therapeutic agent to a subject, wherein the composition comprises a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof.

[0015] Moreover, the present invention relates to a method of treating or preventing a disease or disorder associated with GLP-1 comprising administering said mucosal suction cup.

[0016] In a first aspect, the invention provides new formulations for SOOD transmucosal delivery system for administrating at least one pharmaceutically active ingredient via buccal mucosa, wherein the system comprises at least one permeation enhancer, at least one water-soluble polymer, and at least one pharmaceutically active agent. Typically, the permeation enhancer comprises or consists of chemical permeation enhancers. The at least one permeation enhancer can be, for example, sodium glycocholate, sodium deoxycholate, sodium taurocholate (NaTac), sodium salcaprozate (SNAC), 5-amino caprilic acid (5-CNAC), salclobuzate sodium (4-CNAB), sodium caprylate (C8), Laurocapram (Azone), dodecyl-L-pyroglutamate, oleic acid, or propylene glycol.

[0017] Without being limited to these, other permeation enhancers can be used in the formulation, such as other fatty acids (e.g. sodium caprate, palmitoilycarnitine), other bile salts and steroidal compounds (e.g. saponin), natural and synthetic surfactants (e.g. phospholipids, sodium lauryl sulfate, dioctyl sodium sulfocuccinate), chelators (e.g. EDTA, citric acid / citrate, polyacrylates), positively charged polymers (e.g. chitosan), cylodextrins, thiomenthol, polysorbates and derivatives (e.g. tween-20, tween-80, np-40, tritonX-100).

[0018] The at least one water soluble polymer is included in this invention to control the release of the pharmaceutically active ingredients. These may be, for example, one or more of polyvinyl alcohol (PVA), Hypromellose (HPMC), Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose, Carboxymethylcellulose Sodium (CMC-Na), xanthan gum, Pectin, copovidone, povidone, guar gum, pullulan, polyethylene oxide, sodium alginate, and chitosan.

[0019] Typically, the at least one active agent is a hormone, hormone analogue, hormone mimetic, or a glucagon-like peptide-1 agonist.

[0020] The hormone, hormone analogue, or hormone mimetic can be a peptide-based hormone, peptide-based hormone analogue, or peptide-based hormone mimetic. In an exemplary embodiment, the peptide hormone, hormone analogue, hormone mimetic, or a glucagon- like peptide-1 agonist is a glucagon-like peptide-1 (GLP-1 ) agonist selected from Semaglutide, Liraglutide, and Tirzepatide.

[0021] In certain embodiments, the delivery system is absorbed on a solid carrier, such as SCOD.

[0022] In a second aspect of the present disclosure, this invention discloses a method for treating diabetes, controlling blood glucose, and / or preventing or treating hyperglycemia. The method comprises a delivery system across the buccal mucosa administering to a subject according to the aspect or the composition according to the first and second aspect.

[0023] The pharmaceutically active agent can be loaded in the SCOD patch with at least one or more permeation enhancers and / or at least a dispersion system, such as the water- soluble polymer PVA for controlling drug release. The combination of the chemical disruption produced by a permeation enhancer with the mechanical stretching, may cause a deformation of the mucosa that can further promote the diffusion of the pharmaceutically active agent.

[0024] The present disclosure beneficially ensures rapid delivery and absorption, avoids contact with the acidic environment of the stomach as well as the enzymatic digestion in the gastrointestinal tract, and considerably reduces skin damage, such as that caused by subcutaneous injections. The present disclosure provides greater bioavailability of the therapeutic agent through by administration via the buccal mucosa. The present delivery compositions of the present disclosure may be beneficial for the administration of any pharmaceutically active agent.

[0025] Without intending to be bound by the theory or mode of action, the formulations of the present inventions may provide greater absorption of the active drug, because of a better membrane permeability is provided by the chemical enhancers.

[0026] The present invention is also described by the appended figures:

[0027] Figure 1: A 3D model showing examples of the biological patch

[0028] Figure 2: Excellent blood drug solubility of Semaglutide was achieved with, e.g., the oral patch using formulation NO. 1. Formulations No. 1 to 5 show different levels of Semaglutide blood concentration (ng / mL) over time. The 0.1 mg IV dose is shown for comparison.

[0029] Figure 3: Excellent blood drug solubility of Semaglutide was achieved with the oral patch using formulations NO. 6 to 13. Formulations No. 6 to No. 13 show different levels of Semaglutide blood concentration (ng / mL) over time. The 0.1 mg IV dose is shown for comparison.

[0030] Figure 4. Standard curve of the compound CMS-D005 analyzed by MassLynxV4.2 software.

[0031] Figure 5. CMS-D005 concentration in plasma of beagle dogs after administration.

[0032] Figure 6. Standard curve of CMS-D005

[0033] Figure 7. CMS-D005 concentration in plasma of beagle dogs after administration.

[0034] Figure 8. CMS-D005 concentration in plasma of beagle dogs after administration.

[0035] Figure 9. Standard curve of CMS-D005.

[0036] Figure 10. CMS-D005 concentration in plasma of beagle dogs after administration.

[0037] The compounds of mucosal suction cup will be described in more detail in the following:

[0038] A mucosal suction cup comprising a composition comprising a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof. In a preferred embodiment, the one or more permeation enhancer is selected from a bile salt, a compound having a steroid skeleton and a surfactant. In a more preferred embodiment, the one or more permeation enhancer is selected from sodium glycocholate, sodium salcaprozate (SNAC), N-(5-chlorosalicyloyl)- 8-aminocaprylic acid (5-CNAC), and azone (1 -dodecylazepan-2-one). In an even more preferred embodiment, the one or more permeation enhancer is sodium glycocholate. In another preferred embodiment, the composition comprises exactly one permeation enhancer.

[0039] In certain embodiments, said composition comprises at least two permeation enhancers. In a preferred embodiment, the composition comprises exactly two permeation enhancers.

[0040] In certain embodiments, said composition comprises at least one permeation enhancer selected from sodium glycocholate, sodium salcaprozate (SNAC), sodium taurocholate, propylene glycol, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), sodium caprylate (C8), sodium 4-(2-hydroxy-4-chlorobenzamido)butyrate (4-CNAB), azone, tocofersolan (TPGS), ethylenediaminetetraacetic acid (EDTA), cholic acid, gentisic acid, gentisic acid ethanolamine, glycocholic acid, taurocholic acid, deoxycholic acid, sodium deoxycholate, sodium caprate, dodecyl pyroglutamate, sodium octanoate, acylcamitine, and alkyl maltoside. In a preferred embodiment, the one or more permeation enhancer is selected from sodium glycocholate, sodium salcaprozate (SNAC), sodium taurocholate, propylene glycol, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), sodium caprylate (C8), sodium 4-(2-hydroxy-4-chlorobenzamido)butyrate (4-CNAB), azone and tocofersolan (TPGS). In a more preferred embodiment, the one or more permeation enhancer is selected from sodium glycocholate, sodium taurocholate, sodium salcaprozate (SNAC) and propylene glycol. In an even more preferred embodiment, the one or more permeation enhancer is sodium glycocholate.

[0041] In preferred embodiments, the one or more permeation enhancer is selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium deoxycholate, sodium decanoate, sodium octanoate (C8), sodium glycocholate, sodium glycolate, sodium taurocholate, arginine (arg), and glycocholic acid. In preferred embodiments, the one or more permeation enhancer is selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium taurocholate, sodium glycocholate, sodium octanoate (C8), sodium deoxycholate, and glycocholic acid. In preferred embodiments, the one or more permeation enhancer is selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium taurocholate, sodium glycocholate, and sodium deoxycholate.

[0042] In certain embodiments, said composition comprises a therapeutic agent selected from a hormone, hormone analogue, and a hormone mimetic. In a preferred embodiment, the therapeutic agent is selected from a peptide-hormone, peptide-hormone analogue, peptide-hormone mimetic, and pharmaceutically acceptable salt thereof.

[0043] In certain embodiments, said composition comprises a therapeutic agent, wherein said therapeutic agent is a glucoagon-like peptide 1 agonist (GLP-1 agonist). In a preferred embodiment, the therapeutic agent is selected from semaglutide, Liraglutide, Tirzepatide, and a pharmaceutically acceptable salt thereof and / or a combination thereof. In certain embodiments, said composition further comprises a film-forming material. In a preferred embodiment, the film-forming material is selected from polyvinyl alcohol (PVA), Hypromellose (HPMC), Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose, Carboxymethylcellulose Sodium (CMC-Na), xanthan gum, Pectin, copovidone, povidone, guar gum, pullulan, polyethylene oxide, sodium alginate, and chitosan. In a more preferred embodiment, the film-forming material is selected from polyvinyl alcohol (PVA), Hypromellose (HPMC), and Hydroxypropyl Cellulose (HPC). In an even more preferred embodiment, the film-forming material is polyvinyl alcohol (PVA).

[0044] In certain embodiments, said composition further comprises a buffer. In a preferred embodiment, the buffer is selected from Tris-HCI, phosphate buffered saline (PBS), 3-(N- morpholino)propanesulfonic acid (TAPS), Tris buffer saline, sodium citrate (SSC), N- tris(hydroxymethyl)methylglycine, citric acid-disodium hydrogen phosphate buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) buffer, disodium hydrogen phosphate, sodium acetate / glacial acetic acid. In a more preferred embodiment, the buffer composition is selected Tris-HCI and phosphate buffered saline (PBS). In an even more preferred embodiment, the buffer is Tris-HCI.

[0045] In certain embodiments, the pH range of the buffer solution is between 6.0 and 8.0. In a preferred embodiment, the pH range of the buffer solution is between 6.5 and 7.4.

[0046] In certain embodiments, said composition comprises at least two permeation enhancers, which are sodium glycocholate and sodium salcaprozate (SNAC).

[0047] In certain embodiments, said composition comprises at least two permeation enhancers, which are sodium glycocholate and N-(5-chlorosalicyloyl)-8-aminocaprylicacid (5-CNAC).

[0048] In certain embodiments, said composition comprises at least two permeation enhancers, which are sodium taurocholate and propylene glycol. In certain embodiments, said composition comprises at least two permeation enhancers, which are SNAC and Sodium glycocholate, or Sodium decanoate and Sodium glycocholate, or Propylene glycol and Sodium taurocholate, or Sodium octanoate (C8) and Sodium glycocholate, or SNAC and sodium glycocholate, or SNAC, Sodium glycolate, or SNAC, Sodium glycocholate, and arginine (arg); or SNAC, Sodium glycocholate, propylene glycol and laurocapram; or SNAC, Sodium glycocholate, Propylene glycol, and Lauroamphetamine; or SNAC, Propylene glycol, and Sodium taurocholate; or SNAC, Propylene glycol, Sodium deoxycholate; or SNAC, Glycocholic acid, and Propylene glycol; or Sodium octanoate (C8) and Sodium glycolate, or Sodium decanoate and Sodium glycolate.

[0049] In certain embodiments, said composition comprises at least two permeation enhancers, which are Propylene glycol or sodium taurocholate, or SNAC, and sodium glycocholate, or SNAC, sodium glycocholate, propylene glycol, and Laurocapram, or SNAC, Sodium glycocholate, Propylene glycol, and Lauroamphetamine, or SNAC, Propylene glycol, and Sodium deoxycholate, or SNAC, Glycocholic acid, and Propylene glycol.

[0050] In certain embodiments, said composition comprises at least two permeation enhancers, wherein a first permeation enhancer is SNAC, wherein preferably the composition comprises about 2-5 wt%, preferably about 3-4 wt% SNAC, and a second permeation enhancer which is selected from the group consisting of Sodium glycocholate, Glycocholic acid, Sodium taurocholate, and Sodium deoxycholate, wherein preferably the composition comprises about 8-15 wt%, preferably about 9-14 wt%, more preferably about 10-13 wt% of the second enhancer.

[0051] In certain embodiments, said composition comprises at least two permeation enhancers, wherein a first permeation enhancer is SNAC, wherein preferably the composition comprises about 2-5 wt%, preferably about 3-4 wt% SNAC, and a second permeation enhancer which is selected from the group consisting of Sodium glycocholate, Glycocholic acid, Sodium taurocholate, and Sodium deoxycholate, wherein preferably the composition comprises about 8-15 wt%, preferably about 9-14 wt%, more preferably about 10-13 wt% of the second permeation enhancer, and a third enhancer, which is selected from the group consisting of Arginine, Propylene glycol, Laurocapram, and Lauroamphetamine, wherein preferably the composition comprises about 2-4 wt% of the third penneation enhancer.

[0052] In certain embodiments, said composition comprises at least two permeation enhancers, wherein a first permeation enhancer is SNAC, wherein preferably the composition comprises about 2-5 wt%, preferably about 3-4 wt% SNAC, and a second permeation enhancer which is selected from the group consisting of Sodium glycocholate, Glycocholic acid, Sodium taurocholate, and Sodium deoxycholate, wherein preferably the composition comprises about 8-15 wt%, preferably about 9-14 wt%, more preferably about 10-13 wt% of the second permeation enhancer, and a third enhancer, which is Propylene glycol, wherein preferably the composition comprises about 2-4 wt%, preferably about 2-3 wt% Propylene glycol. In certain embodiments, said composition comprises at least two permeation enhancers, wherein a first permeation enhancer is SNAC, wherein preferably the composition comprises about 2-5 wt%, preferably about 3-4 wt% SNAC, and a second permeation enhancer which is selected from the group consisting of Sodium glycocholate, Sodium taurocholate, and Sodium deoxycholate, wherein preferably the composition comprises about 8-15 wt%, preferably about 9-14 wt%, more preferably about 10-13 wt% of the second permeation enhancer, and a third enhancer, which is Propylene glycol, wherein preferably the composition comprises about 2-4 wt%, preferably about 2-3 wt% Propylene glycol.

[0053] In certain embodiments, said composition comprises at least two permeation enhancers, wherein one of the permeation enhancers is SNAC, wherein preferably the composition comprises about 2-5 wt%, preferably about 3-4 wt% SNAC.

[0054] In certain embodiments, said composition comprises at least two permeation enhancers, wherein the one of the permeation enhancer is Propylene glycol, wherein preferably the composition comprises about 2-4 wt%, preferably about 2-3 wt% Propylene glycol.

[0055] In certain embodiments, said composition comprises at least two permeation enhancers, wherein one of the permeation enhancers is selected from the group consisting of Sodium glycocholate, Glycocholic acid, Sodium taurocholate, and Sodium deoxycholate, wherein preferably the composition comprises about 8-15 wt%, preferably about 9-14 wt%, more preferably about 10-13 wt% of the permeation enhancer selected from the group consisting of Sodium glycocholate, Glycocholic acid, Sodium taurocholate, and Sodium deoxycholate. In certain embodiments, said composition comprises at least two permeation enhancers, wherein one of the permeation enhancers is selected from the group consisting of Sodium glycocholate, Sodium taurocholate, and Sodium deoxycholate, wherein preferably the composition comprises about 8-15 wt%, preferably about 9-14 wt%, more preferably about 10-13 wt% of the permeation enhancer selected from the group consisting of Sodium glycocholate, Sodium taurocholate, and Sodium deoxycholate.

[0056] In certain embodiments, said composition comprises at least two permeation enhancers, wherein one of the permeation enhancers is Laurocapram, or Lauroamphetamine, wherein preferably the composition comprises about 0,1 -0,3 wt% or about 0,1 -0,2 wt% Laurocapram, or Lauroamphetamine.

[0057] In certain embodiments, said composition comprises at least two permeation enhancers, wherein one of the permeation enhancers is Arginine, wherein preferably the composition comprises about 2-5 wt% or about 3-4 wt% Laurocapram, or Lauroamphetamine.

[0058] In certain embodiments, said composition comprises a film forming material which is preferably PVA or Sodium hyaluronate, preferably PVA. Preferably, the composition comprises about 0,5-2 wt% or 0,5-1 ,5% film forming material or PVA. Preferably, the composition comprises about 0,2-1 wt% or 0,4-0, 7% Sodium hyaluronate.

[0059] In certain embodiments, said composition comprises about 8-20 wt%, preferably about 10-18 wt% or about 10-17 wt% of at least two permeation enhancers. In certain embodiments, said composition comprises 2, 3, 4, 5, or 6 permeation enhancers.

[0060] In certain embodiments, said composition comprises about 5-20 wt%, preferably about 8- 15 wt% of the therapeutic agent.

[0061] In certain embodiments, said composition comprises between about 0.5 and 30 wt% of the at least one permeation enhancer, between about 0.5 and 10 wt% film-forming material, between about 0 and 2 wt% flavouring agent and between about 5 and 30 wt% therapeutic agent. In a preferred embodiment, said composition comprises between about 0.5 and 20 wt% of the at least one permeation enhancer, between about 0.5 and 3 wt% film-forming material, between about 0.5 and 2 wt% flavouring agent and between about 5 and 15 wt% therapeutic agent. In a more preferred embodiment, said composition comprises between about 0.5 and 15 wt% of the at least one permeation enhancer, between about 1 and 2 wt% film-forming material, between about 0.5 and 1.5 wt% flavouring agent and between about 10 and 15 wt% therapeutic agent.

[0062] In certain embodiments, said composition comprises about 13.4 wt% sodium glycocholate, about 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent.

[0063] In certain embodiments, said composition comprises about 10 wt% sodium salcaprozate (SNAC), about 1 .5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent.

[0064] In certain embodiments, said composition comprises about 13.4 wt% sodium glycocholate, about 5 wt% sodium salcaprozate (SNAC), about 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent.

[0065] In certain embodiments, said composition comprises about 13.4 wt% sodium glycocholate, about 5 wt% N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), about 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent.

[0066] In certain embodiments, said composition comprises about 14.6 wt% sodium taurocholate, 4 wt% propylene glycol, 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent.

[0067] In certain embodiments, said composition comprises about 2.7 wt% sodium glycocholate, about 1 .5 wt% polyvinyl alcohol and about 11 .25% therapeutic agent.

[0068] In certain embodiments, said composition comprises about 11.3 wt% sodium deoxycholate, about 1 .5% polyvinyl alcohol and about 11.25 wt% therapeutic agent.

[0069] In certain embodiments, said composition comprises about 9 wt% sodium salcaprozate (SNAC), about 1 .5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent. In certain embodiments, said composition comprises about 9.4 wt% N-(5-chlorosalicyloyl)- 8-aminocaprylic acid (5-CNAC), about 1.5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent.

[0070] In certain embodiments, said composition comprises about 8.4 wt% sodium 4-(2-hydroxy- 4-chlorobenzamido)butyrate (4-CNAB), about 1.5 wt% polyvinyl alcohol (PVA), and about 11 .25 wt% of therapeutic agent.

[0071] In certain embodiments, said composition comprises about 4.4 wt% sodium caprylate, about 1 .5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent.

[0072] In certain embodiments, said composition comprises about 1 wt% azone, about 1.5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent.

[0073] In certain embodiments, said composition comprises about 1 wt% dodecyl pyroglutamate, about 1 .5% PVA, and 11.25% of therapeutic peptide.

[0074] In certain embodiments, said composition comprises about 7 mg oleic acid, about 1 .5 wt% PVA, and about 11.25 wt% therapeutic agent.

[0075] In certain embodiments, said composition further comprises a flavouring agent, wherein the flavouring agent may be natural or synthetic. In a preferred embodiment, the flavouring agent is selected from sucralose, menthol, aspartame, mannitol, sorbitol, sucrose, maltose, fructose, lactose, cinnamaldehyde, D-glucose, sucralose, eucalyptol, steviolbioside, lactitol, anethole, invert sugar, xylitol, saccharin, levoglucose, stevioside, vanillin, limonene, menthone, alpha terpineol, terpinen-4-ol, allyl benzoate, allyl caproate, anisyle alcohol, cinnamaldehyde, eugenol, geraniol, musk ambrette, neryl acetate, santalyl acetate, caraway, clove, lemon, spearmint, rose, peppermint, ginger, raspberry, maltol, syrups, citric acid, sarsaparilla, cherry, glycerin, cocoa, licorice, sodium citrate, saccharin sodium, tannic acid, glycine, dibasic potassium phosphate trihydrate and natural or synthetic fruit flavouring. In a more preferred embodiment, the flavouring agent is selected from sucralose and menthol. In another embodiment, said mucosal suction is for use in the treatment or prevention of a disease or disorder associated with Glucagon-like peptide 1 (GLP-1). In a preferred embodiment, the disease ordisorderis selected from hyperglycemia, type 2 diabetes, type 1 diabetes, impaired glucose tolerance, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers. In a more preferred embodiment, the disease or disorder is selected from type 2 diabetes, type 1 diabetes, impaired glucose tolerance or obesity. In an even more preferred embodiment, the disease or disorder is type 2 diabetes or obesity.

[0076] In certain embodiments, said mucosal suction cup for use in the treatment or prevention of a disease or disorder associated with Glucagon-like peptide 1 (GLP-1 ) is for use in decreasing appetite, decreasing p-cell apoptosis, increasing p-cell function, increasing p- cell mass and / or restoring glucose sensitivity to P-cells.

[0077] In another embodiment, the use of said mucosal suction cup is for transmucosal administration of a composition comprising a therapeutic agent to a subject.

[0078] In certain embodiments, the use of said mucosal suction cup is for the transmucosal delivery of a composition comprising a therapeutic agent to a subject, wherein the composition comprises a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof. In a preferred embodiment, the one or more permeation enhancer is selected from a bile salt, a compound having a steroid skeleton and a surfactant. In a more preferred embodiment, the one or more permeation enhancer is selected from sodium glycocholate, sodium salcaprozate (SNAC), N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), and azone (1-dodecylazepan-2-one). In an even more preferred embodiment, the one or more permeation enhancer is sodium glycocholate. In another preferred embodiment, the composition comprises exactly one permeation enhancer. In another embodiment, said mucosal suction cup is used in a method of treating or preventing a disease or disorder associated with GLP-1 comprising administering the mucosal suction cup.

[0079] The following definitions apply throughout the present specification, unless specifically indicated otherwise.

[0080] As used herein, the term “permeation enhancer" refers to a chemical compound that alone or in combination with other compounds can be used to aid the uptake of a further substance across an epithelium or other biological membrane. In particular, the term "permeation enhancer" is used herein to refer to a chemical compound that alone or in combination with other compounds can be used to aid the uptake of a further substance across the buccal mucosa. Permeation enhancers can typically be divided into two distinct categories, paracellular (para) or transcellular (trans) permeability enhancers, according to their mechanism of action. Paracellular permeation enhancers are those which aid the uptake of a further substance through the intercellular space between the cells in an epithelium or other biological membrane. Transcellular permeation enhancers are those which aid the uptake of a further substance through the cells in an epithelium or other biological membrane, wherein the further substance passes through both the apical and basolateral cell membranes in the epithelium or other biological membrane.

[0081] As used herein, the term “fatty acid" refers to refers to a carboxylic acid with a long (such as more than 4 carbon atoms in length) aliphatic tail (chain), which is either saturated or unsaturated. The fatty acid may be branched or unbranched but is preferably unbranched. The term “fatty acid” may also refer to a fatty acid salt.

[0082] As used herein, the term “surfactant” and grammatical variants thereof refer to an organic chemical that when added to a liquid changes the properties of that liquid at a surface, e.g., by lowering the surface tension or interfacial tension between phases of matter (e.g., liquid, liquid crystalline, crystalline, solid, and the like), such as in an emulsion.

[0083] As used herein, the term “hormone analogue” refers to a substance that has a similar chemical ("analogue") structure as the corresponding hormone and is therefore capable of binding to the corresponding receptor to achieve the same effect as the corresponding hormone. Non-limiting examples of hormone analogues include, for example, GLP1 analogues (Glucagon-like peptide 1 ).

[0084] As used herein, the term “hormone mimetic” refers to a molecule that mimics the structure of a hormone and specifically binds to the ligand binding domain of a hormone receptor. Non-limiting examples of hormone analogues are described herein. Additional examples of hormone analogues are known in the art.

[0085] As used herein, the term “flavouring agent” refers to those flavour essences and equivalent synthetic ingredients which are added to the composition for the principal purpose of providing flavour to said composition.

[0086] As used herein, the terms “optional”, “optionally” and “may" denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0087] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” therapeutic agent can be interpreted as referring to a composition comprising “one or more” therapeutic agents.

[0088] As used herein, the term "about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated.

[0089] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia", i.e., “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of and “consisting of. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C" and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0090] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds comprised in the mucosal suction cup which may be formed, e.g., by protonation of an atom carrying an electron lone pair, which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferably, however, the compounds comprised in the mucosal suction cup are not in the form of a salt, unless explicitly specified.

[0091] Moreover, the scope of the invention embraces the compounds comprised in the mucosal suction cup in any solvated form, including, e.g., solvates with water (i.e. , as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol or acetonitrile (i.e., as a methanolate, ethanolate or acetonitrilate), or in any crystalline form (i.e., as any polymorph), or in amorphous form. It is to be understood that such solvates of the compounds comprised in the mucosal suction cup also include solvates of pharmaceutically acceptable salts of the compounds comprised in the mucosal suction cup.

[0092] Furthermore, the compounds comprised in the mucosal suction cup may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds comprised in the mucosal suction cup are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds provided herein.

[0093] The scope of the invention also embraces compounds comprised in the mucosal suction cup, in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds comprised in the mucosal suction cup, in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as “D”). Accordingly, the invention also embraces compounds comprised in the mucosal suction cup which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds comprised in the mucosal suction cup can be increased using deuteration techniques known in the art. For example, a compound comprised in the mucosal suction cup or a reactant or precursor to be used in the synthesis of the compound comprised in the mucosal suction cup can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compounds comprised in the mucosal suction cup are not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds comprised in the mucosal suction cup is preferred.

[0094] The compounds comprised in the mucosal suction cup provided herein may be administered as compounds per se or may be formulated as medicaments comprised in the suction cup. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0095] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, P-cyclodextrin, y- cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxyethyl-y- cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P- cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-P-cyclodextrin, maltotriosyl-y- cyclodextrin, dimaltosyl-P-cyclodextrin, methyl-P-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0096] The mucosal suction cups may be administered to a subject by any convenient route of administration, including but not limited to administration to the mucosal surface of the mouth.

[0097] Typically, a physician will determine the actual dosage, which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

[0098] The compounds comprised in the mucosal suction cup or a pharmaceutical composition comprised in the mucosal suction cup can be administered in monotherapy (e.g., without concomitant administration of any further therapeutic agents or, in particular, without concomitant administration of any further anti-diabetic drugs). However, compounds comprised in the mucosal suction cup or a pharmaceutical composition comprised in the mucosal suction cup can also be administered in combination with one or more further therapeutic agents. If the compounds comprised in the mucosal suction cup are used in combination with a second therapeutic agent active against the same disease or condition (e.g., a further anti-diabetic drug), the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of the compounds comprised in the mucosal suction cup with one or more further therapeutic agents may comprise the simultaneous / concomitant administration of the compounds comprised in the mucosal suction cup and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential / separate administration of the compounds comprised in the mucosal suction cup and the further therapeutic agent(s). If administration is sequential, either the compound of compounds comprised in the mucosal suction cup according to the invention or the one or more further therapeutic agents may be administered first. Preferably, the one or more further therapeutic agents to be administered in combination with a compound of the present invention are anti-diabetic or anti-obesity drugs. The anti-diabetic or anti-obesity drug(s) to be administered in combination with the compounds comprised in the mucosal suction cup according to the invention may, e.g., be selected from: ACE inhibitors (such as Benazepril (Lotensin) , Captopril, Enalapril (Vasotec), Fosinopril, Lisinopril (Zestril), Moexipril, Perindopril, Quinapril, Ramipril (Altace), and Trandolapril), ARBs (such as Irbesartan, Losartan, and Telmisartan), alpha-glucosidase inhibitors (such as acarbose and miglitol), amylin analogs (such aspramlintide), dipeptidyl peptidase 4 inhibitors (such as alogliptan, linagliptan, saxagliptin, and sitagliptin), incretin mimetics (such as albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide), insulin, meglitinides (such as nateglinide, repaglinide), nonsulfonylureas (such as metformin), SGLT-2 inhibitors ( such as canagliflozin, dapagliflozin, empagliflozin), sulfonylureas (such as chlorpropamide, glimepiride, glipizide, glyburide, such as tolazamide, tolbutamide), thiazolidinediones (such as rosiglitazone, pioglitazone), semaglutide, liraglutide, tirzepatide, Bupropion-naltrexone, Oriistat, Phenterminetopiramate, and Setmelanotide.

[0099] The compounds comprised in the mucosal suction cup can also be administered in combination with other forms of treatment such as surgery, diet, or exercise.

[0100] The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, or a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate or a simian (e.g., a monkey or an ape, such as a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, or a gibbon), or a human. In accordance with the present invention, it is envisaged that animals are to be treated which are economically, agronomically, or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, a cow, or a pig). Most preferably, the subject / patient is a human. The subject / patient to be treated in accordance with the invention may be female or male. In a particular aspect, the present invention relates to the treatment of a female subject / patient, preferably a female animal (e.g., a female of any one of the species mentioned in this paragraph), more preferably a female human or a female non-human mammal, and even more preferably a female human.

[0101] The term “treatment” of a disorder or disease as used herein (e.g., “treatment” of diabetes) is well known in the art. “Treatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).

[0102] The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0103] The term “prevention” of a disorder or disease as used herein (e.g., “prevention” of diabetes) is also well known in the art. For example, a patient / subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term “prevention” comprises the use of a compound of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0104] It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

[0105] In this specification, a number of documents including patent applications, scientific literature and manufacturers’ manuals are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0106] The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.

[0107] The present invention particularly relates to the following items:

[0108] 1 . A mucosal suction cup comprising a composition comprising a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof. The mucosal suction cup of item 1 , wherein the composition comprises at least two permeation enhancers. The mucosal suction cup of any one of items 1 to 3, wherein the permeation enhancer is selected from sodium glycocholate, sodium salcaprozate (SNAC), sodium taurocholate, propylene glycol, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), sodium caprylate (C8), sodium 4-(2-hydroxy-4- chlorobenzamido)butyrate (4-CNAB), azone, tocofersolan (TPGS), ethylenediaminetetraacetic acid (EDTA), cholic acid, gentisic acid, gentisic acid ethanolamine, glycocholic acid, taurocholic acid, deoxycholic acid, sodium deoxycholate, sodium caprate, dodecyl pyroglutamate, sodium octanoate, acylcarnitine, and alkyl maltoside, preferably sodium glycocholate, sodium salcaprozate (SNAC), sodium taurocholate, propylene glycol, N-(5- chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), sodium caprylate (C8), sodium 4-(2-hydroxy-4-chlorobenzamido)butyrate (4-CNAB), azone and tocofersolan (TPGS), more preferably sodium glycocholate, sodium taurocholate, sodium salcaprozate (SNAC) and propylene glycol. The mucosal suction cup of any one of items 1 to 3, wherein the therapeutic agent is a hormone, hormone analogue or hormone mimetic, preferably the therapeutic agent is a peptide-hormone, peptide-hormone analogue, peptide-hormone mimetic, or pharmaceutically acceptable salt thereof. The mucosal suction cup of any one of items 1 to 4, wherein the therapeutic agent is a glucoagon-like peptide 1 agonist (GLP-1 agonist), preferably selected from semaglutide, Liraglutide, Tirzepatide, and a pharmaceutically acceptable salt thereof and / or a combination thereof. The mucosal suction patch of any one of items 1 to 5, wherein the composition further comprises a film-forming material, preferably wherein the film-forming material is selected from polyvinyl alcohol (PVA), Hypromellose (HPMC), Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose, Carboxymethylcellulose Sodium (CMC-Na), xanthan gum, Pectin, copovidone, povidone, guar gum, pullulan, polyethylene oxide, sodium alginate and chitosan, more preferably wherein the film-forming material is polyvinyl alcohol (PVA). The mucosal suction cup of any one of items 1 to 6, wherein the composition further comprises a buffer, preferably wherein the buffer composition is selected from Tris-HCI, phosphate buffered saline (PBS), 3-(N-morpholino)propanesulfonic acid (TAPS), Tris buffer saline, sodium citrate (SSC), N- tris(hydroxymethyl)methylglycine, citric acid-disodium hydrogen phosphate buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) buffer, disodium hydrogen phosphate, sodium acetate / glacial acetic acid, more preferably wherein the buffer is Tris-HCI. The mucosal suction cup of item 7, wherein the pH range of the buffer solution is between 6.0 and 8.0, preferably between 6.5 and 7.4. The mucosal suction cup of any one of items 1 to 8, wherein the at least two penneation enhancers are sodium glycocholate and sodium salcaprozate (SNAC). The mucosal suction cup of any one of items 1 to 8, wherein the penneation enhancer or the at least two permeation enhancers, preferably the at least two penneation enhancers are selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium deoxycholate, sodium decanoate, sodium octanoate (C8), sodium glycocholate, sodium taurocholate, arginine (arg), and glycocholic acid; wherein the permeation enhancer or the at least two permeation enhancers are preferably selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium taurocholate, sodium glycocholate, sodium octanoate (C8), sodium deoxycholate, and glycocholic acid; wherein the permeation enhancer or the at least two permeation enhancers are preferably selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium taurocholate, sodium glycocholate, and sodium deoxycholate. The mucosal suction cup of any one of items 1 to 8, wherein the at least two permeation enhancers are sodium glycocholate and N-(5-chlorosalicyloyl)-8- aminocaprylic acid (5-CNAC). The mucosal suction cup of any one of items 1 to 8, wherein the at least two permeation enhancers are sodium taurocholate and propylene glycol. The mucosal suction cup of any one of items 1 to 11 , wherein the composition comprises between about 0.5 and 30 wt% of the at least one permeation enhancer, between about 0.5 and 10 wt% film-forming material, between about 0 and 2 wt% flavouring agent and between about 5 and 30 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 13.4 wt% sodium glycocholate, about 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 10 wt% sodium salcaprozate (SNAC), about 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 13.4 wt% sodium glycocholate, about 5 wt% sodium salcaprozate (SNAC), about 1 .5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 13.4 wt% sodium glycocholate, about 5 wt% N-(5- chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), about 1.5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 14.6 wt% sodium taurocholate, 4 wt% propylene glycol, 1.5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about comprises about 2.7 wt% sodium glycocholate, about 1.5 wt% polyvinyl alcohol and about 11 .25% of therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 11.3 wt% sodium deoxycholate, about 1 .5% polyvinyl alcohol and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 9 wt% sodium salcaprozate (SNAC), about 1.5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 9.4 wt% N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), about 1 .5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 8.4 wt% sodium 4-(2-hydroxy-4-chlorobenzamido)butyrate (4- CNAB), about 1 .5 wt% polyvinyl alcohol (PVA), and about 11.25 wt% of therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 4.4 wt% sodium caprylate, about 1.5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 1 wt% azone, about 1 .5 wt% polyvinyl alcohol (PVA) and about 11 .25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 1 wt% dodecyl pyroglutamate, about 1.5% PVA, and 11.25% of therapeutic peptide. The mucosal suction cup of any one of items 1 to 12, wherein the composition comprises about 7 mg oleic acid, about 1.5 wt% PVA, and about 11.25 wt% therapeutic agent. The mucosal suction cup of any one of items 1 to 26 further comprising a flavouring agent, wherein the flavouring agent may be natural or synthetic, preferably wherein the flavouring agent is selected from sucralose, menthol, aspartame, mannitol, sorbitol, sucrose, maltose, fructose, lactose, cinnamaldehyde, D-glucose, sucralose, eucalyptol, steviolbioside, lactitol, anethole, invert sugar, xylitol, saccharin, levoglucose, stevioside, vanillin, limonene, menthone, alpha terpineol, terpinen-4-ol, allyl benzoate, allyl caproate, anisyle alcohol, cinnamaldehyde, eugenol, geraniol, musk ambrette, neryl acetate, santalyl acetate, caraway, clove, lemon, spearmint, rose, peppermint, ginger, raspberry, maltol, syrups, citric acid, sarsaparilla, cherry, glycerin, cocoa, licorice, sodium citrate, saccharin sodium, tannic acid, glycine, dibasic potassium phosphate trihydrate and natural or synthetic fruit flavouring. The mucosal suction cup of any one of items 1 to 27 for use in the treatment or prevention of a disease or disorder associated with Glucagon-like peptide 1 (GLP- 1), preferably wherein the disease or disorder is hyperglycemia, type 2 diabetes, type 1 diabetes, impaired glucose tolerance, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers, more preferably type 2 diabetes, type 1 diabetes, impaired glucose tolerance or obesity, even more preferably type 2 diabetes or obesity. The mucosal suction cup of any one of items 1 to 27 for use in decreasing appetite, decreasing 0-cell apoptosis, increasing 0-cell function, increasing 0-cell mass and / or restoring glucose sensitivity to 0-cells. The mucosal suction cup of any one of items 1 to 27 for use in treatment of a disease or disorder selected from the group consisting of obesity, overweight, metabolic disease, such as type 2 diabetes and non-alcoholic steatohepatitis (NASH / MASH). Use of a mucosal suction cup as defined in any one of items 1 to 27 for transmucosal administration of a composition comprising a therapeutic agent to a subject. Use of a mucosal suction cup as defined in any one of items 1 to 27 for the transmucosal delivery of a composition comprising a therapeutic agent to a subject, wherein the composition comprises a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof.

[0109] 32. A method of treating or preventing a disease or disorder associated with GLP-1 comprising administering the mucosal suction cup according to any one of items 1 to 27.

[0110] The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

[0111] EXAMPLES

[0112] Example 1 : 3D bio-patch printing

[0113] An Asiga 3D printer was used for the preparation of these biological patches. The Resin used was Formlabs Elastic 50A Resin V1 . The biological patches or suction cups can be seen as models in Fig. 1 , displaying their shape similar to octopus tentacle suckers. The dimensions were the following: Diameter 0.8-1.2cm, height 0.5-0.8cm.

[0114] Preparation method:

[0115] 1 ) The Elastic 50A Resin V1 resin solution was placed in the 3D printer.

[0116] 2) The print was carried out according to the designed model.

[0117] 3) The printed 3D biological patch was cleaned with 95% ethanol and dried after cleaning.

[0118] 4) The dried patch was set under ultraviolet light.

[0119] The 3D biological patch prepared according to the above has certain elasticity, viscosity and uniform colour.

[0120] Example 2: Preparation of the Semaglutide oral patches with formulations NO. 1 to 5.

[0121] Table 1 : Formulations NO. 1 to 5 with specific compositions Preparation Method:

[0122] 1) Polyvinyl alcohol was added to Tris-HCI buffer solution to prepare a solution.

[0123] 2) Semaglutide, a penetration enhancer, and a flavouring agent were added to the solution and thoroughly mixed.

[0124] 3) The prepared solution was filled into 3D bio-patches according to the amounts in Table 1 . The solution was dried overnight under ambient conditions, followed by drying under vacuum for 1 hour at RT.

[0125] The Semaglutide oral patch prepared according to the above description has good film formation, a smooth appearance, and uniform colour.

[0126] Table 2: Character, colour and dissolution of samples from Formulations NO. 1 to 5

[0127] Example 3: Administration of the Semaglutide oral patches with formulations NO. 1 to 5 to animals

[0128] The beagle (8-1 Okg) was fasted overnight, anesthetized, and securely held in place for 30 minutes. A semaglutide oral patch was applied to the inner wall of the experimental dog's mouth, and blood samples were collected at 0 min, 15 min, 30 min, 60 min, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h after administration. Each blood sample was 1 mL and collected in a K2EDTA tube (Bioreclamation IvT). The blood samples were then centrifuged at 6000 rpm for 10 minutes at 4°C. Subsequently, the plasma was stored at -80°C until further analysis.

[0129] Control Group: 1 mL of 0.1 mg / mL injection solution was administered, and the blood collection protocol was identical to the drug administration group. The results are displayed in Figure 2 and Table 3.

[0130] Table 3: Experimental results of the animal studies using the Semaglutide oral patches with formulations NO. 1 to 5

[0131] Example 4: Preparation of the Semaglutide oral patches with formulations 6 to 13.

[0132] According to the above experimental results, the AUC (0-t) of formulation 1 was better than that of control group, but its T1 / 2 was different from that of the control group. The T1 / 2 of the remaining prescriptions was similar or better than the control.

[0133] Table 4: Formulations NO. 6 to 13 with specific compositions

[0134]

[0135] Preparation Method:

[0136] 1) Polyvinyl alcohol was added to Tris-HCI buffer solution to prepare a solution.

[0137] 2) Semaglutide, a penetration enhancer, and a flavouring agent were added to the solution and thoroughly mixed.

[0138] 3) The prepared solution was filled into 3D bio-patches according to the described amount.

[0139] 4) The solution was dried overnight under ambient conditions, followed by drying under vacuum for 1 hour at RT.

[0140] The Semaglutide oral patch prepared according to the above description has good film formation, a smooth appearance, and uniform colour.

[0141] Table 5: Character, colour and dissolution of samples from formulations No. 6 to 13.

[0142] Example 5: Administration of the Semaglutide oral patches with formulations NO. 1 to 5 to animals

[0143] The beagle (8-1 Okg) was fasted overnight, anesthetized, and securely held in place for 30 minutes. A semaglutide oral patch was applied to the inner wall of the experimental dog's mouth, and blood samples were collected at 0 min, 15 min, 30 min, 60 min, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h after administration. Each blood sample was 1 mL and collected in a K2EDTA tube (Bioreclamation IvT). The blood samples were then centrifuged at 6000 rpm for 10 minutes at 4°C. Subsequently, the plasma was stored at -80°C until further analysis.

[0144] The results are displayed in Figure 3 and Table 6.

[0145] Table 6: Experimental results of the animal studies using the Semaglutide oral patches with formulations NO. 6 to 13

[0146] Based on the experimental results, prescriptions 6 to 13 showed better or similar Cmax and AUC results compared to the control group, and their half-life was close to or greater than the intravenous injection group, estimating that the drug efficacy in humans could last for 5-7 days. Among the patch group, formulations NO. 6, 7, 8, and 10 had a relative bioavailability greater than 1%, with the highest exceeding 3% (3.3%, see Table 6). All four formulations contained two permeation enhancers. Formulations NO. 6, 7 and 8 contained a mixture of sodium glycocholate (a bile salt), SNAC and / or 8-(N-2-hydroxy-5- chlorobenzoyl)-amino-caprylic acid (5-CNAC). Formulation NO. 10 contained a bile salt that was used in WO 2023 / 094971 A1 , such as sodium taurocholate, however, when mixed together with propylene glycol, our formulation showed a significant enhancement in the uptake of semaglutide through the buccal mucosa (see Table 4).

[0147] For comparison, the orally available Rybelsus tablet (three times 3-mg Rybelsus tablet, daily) under strongly regulated intake instructions and the SOOD loaded with NaTac- semaglutide (c.f. WO 2023 / 094971A1 ) both result in less than 1 % bioavailability.

[0148] Example 6: CMS-D005 Pharmacokinetic Report - First Tests (Formulations 1-7)

[0149] CMS-D005 is an investigational dual agonist drug developed by China Medical System Holdings (CMS). It is designed to activate both the GLP-1 receptor (GLP-1 R) and the glucagon receptor (GCGR) (cf. https: / / synapse.patsnap.com / drug / eae73c3bdb6441fc86ca0fd43618f707). CMS-D005 aims to combine appetitesuppressing, glucose-lowering effects of GLP-1 activation with the fat-burning and energyexpenditure effects of glucagon receptor activation. It is intended for the treatment of obesity and overweight, with potential expansion into metabolic diseases such as type 2 diabetes and non-alcoholic steatohepatitis (NASH / MASH). CMS-D005 has received the clinical trial approval (IND) from China’s NMPA in November 2024. It is preparing for Phase 1 clinical trials in healthy and overweight / obese adults to assess safety, pharmacokinetics, and pharmacodynamics.

[0150] 1. Purpose of the Study

[0151] In this study, the pharmacokinetic (PK) characteristics of seven buccal patch formulations of CMS-D005 were evaluated in beagle dogs. The results provide a basis for formulation screening and future optimization. 2. Experimental Materials

[0152] 2.1 Analyte

[0153] The CMS-D005 patch project includes seven formulations (first test), provided by the Innovative Formulation R&D Center of Xiamen Shengzetai Pharmaceutical Technology Co., Ltd.

[0154] Reference sample source: CMS-D005 single intravenous bolus dose in SD rats was 0.015 mg / kg. Equivalent dose calculation for beagle dogs: beagle dose = 0.015 mg / kg x (20 / 6) « 0.05 mg / kg. For the first dosing in beagle dogs, considering safety, and assuming a weight of 9-10 kg per dog, each was administered 0.4 mg.

[0155] 2.2 Experimental Instruments

[0156] Name Model Manufacturer

[0157] Vortex Mixer VM-500Pro —

[0158] Centrifuge TGL-16M Cence

[0159] LC-MS TQ-XS Waters

[0160] 3. Experimental Methods

[0161] 3.1 Chromatographic Analysis Method

[0162] In this experiment, the analysis time of CMS-D005 was 7 minutes, with a retention time of

[0163] 3.29 minutes.

[0164] Chromatographic conditions: Column - Peptide BEH C18, 1.7 pm, 2.1 mm x 100 mm; Mobile phase: 0.1% formic acid aqueous solution (Eluent A) and acetonitrile aqueous solution (Eluent B); Column temperature: 40°C; sample temperature: 4°C; flow rate: 0.3 mL / min; injection volume: 1 pL; Gradient elution applied as follows:

[0165] 3.2 Mass Spectrometry Analysis Method

[0166] Electrospray ionization (ESI) source parameters: Ion Source Gas 1 (GS1 , N2) 50 Arb; Ion Source Gas 2 (GS2, N2) 60 Arb; Curtain Gas (CUR) 35 Arb; Collision Gas (CAD, N2) Medium. Scanning mode: Multiple Reaction Monitoring (MRM). 3.3 Dosing Method

[0167] Hold the patch on both sides, apply it to the buccal mucosa, and release once adhered.

[0168] After 40 minutes of application, remove the patch shell.

[0169] 3.4 Standard Stock Solution

[0170] Diluent: Acetonitrile:Water = 35:65. Standard stock: 20 pg / mL CMS-D005. Internal standard: 50 pg / L tolbutamide in methanol. Calibration curve solutions prepared at 40, 200, 800, 1600, 3200, and 8000 pg / L.

[0171] The above plasma sample standard solution was added, followed by 200 pL of internal standard solution. The mixture was vortexed for 2 minutes, then centrifuged at 4000 x g for 5 minutes at 4 °C. The supernatant was collected, filtered through a 0.22 pm membrane, and subjected to LC-MS analysis. The prepared samples were temporarily stored at 4 °C.

[0172] 3.5 Experimental Procedure

[0173] Fourteen male beagle dogs received a buccal dose of 15 mg. Blood samples were collected at: pre-dose (0 h), 15 min, 30 min, 1 h, 2 h, 3 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-dose. Plasma was separated and stored at -80°C.

[0174] 4. Data Processing and Analysis

[0175] Data processing was performed automatically using MassLynx V4.2 software, and pharmacokinetic parameters were analyzed with DAS 2.0 software using a noncompartmental model.

[0176] 5. Results

[0177] 5.1 Standard Curve

[0178] Standard curve generated using MassLynx V4.2 software (see Figure 4, Standard curve of the compound).

[0179] 5.2 CMS-D005 Plasma Concentrations in Beagle Dogs

[0180] Table 2 summarizes plasma concentrations for the IV control and seven formulations. Concentration-time curves (Figure 2) show that all formulations produced measurable systemic exposure from 15 minutes to 72 hours post-dose. Table 2. CMS-D005 concentration in plasma after oral administration of the patch

[0181] (pg / L ; n=16)

[0182] I.V. 0.4mg / animal Form. 001 Form. 002 Form. 003 t (h)

[0183] 1 2 3 4 5 6 7 8

[0184] Before drug administrati 51.30 40.61 8.54 1.92 1.83 6.04 2.57 1.99 on

[0185] Oh 14.85 19.16 / / / / / /

[0186] 0.25h 43.79 22.90 42.60 0.73 0.03 50.80 5.62 2.67

[0187] 0.5h 78.73 41.89 9.08 1.86 1.93 3.44 3.39 2.82

[0188] 1h 95.69 71.06 22.38 4.79 5.51 9.60 9.53 15.72

[0189] 116.1 2h 72.27 33.02 9.80 13.21 22.36 21.61 40.04

[0190] 6

[0191] 160.9 105.0

[0192] 3h 60.82 18.27 13.18 31.04 29.68 67.15

[0193] 9 7

[0194] 224.2 190.1 127.4

[0195] 8h 68.41 30.15 36.99 73.16 20.82

[0196] 2 7 1

[0197] 216.1 252.6 100.5

[0198] 12h 61.70 23.63 36.29 67.90 42.34

[0199] 7 5 5

[0200] 248.6 326.5

[0201] 24h 51.81 22.84 30.60 52.82 31.00 79.96

[0202] 5 4

[0203] 206.6 324.8

[0204] 48h 44.34 16.41 28.97 15.14 24.07 62.59

[0205] 3 9

[0206] 169.1 275.9

[0207] 72h 35.70 15.34 20.38 34.66 18.33 51.37

[0208] 8 1 Form. 004 Form. 006 Form. 005 Form. 007 t (h)

[0209] 9 10 11 12 13 14 15 16

[0210] Before drug

[0211] 1.40 1.15 3.85 0.37 1.16 7.50 1.21 0.62 administration

[0212] Oh / / / / / / / /

[0213] 0.25h 1.34 1.52 1.36 2.08 0.88 6.93 1.17 1.39

[0214] 0.5h 5.74 2.37 1.79 3.91 1.03 7.96 2.17 4.75

[0215] 1h 14.84 12.81 2.97 2.84 24.69 12.07 20.92 31.89

[0216] 2h 48.59 15.89 9.40 5.08 15.51 21.63 51.30 60.26

[0217] 3h 44.62 28.11 15.49 3.46 23.77 35.20 95.65 89.54

[0218] 109.5 136.3 122.6

[0219] 8h 94.08 52.04 17.74 10.03 77.56

[0220] 0 3 8

[0221] 131.4 109.8 12h 90.37 14.07 17.24 0.49 77.25 37.70

[0222] 1 2

[0223] 114.7

[0224] 24h 79.00 34.64 1.99 9.92 45.92 33.82 98.86

[0225] 0

[0226] 48h 63.85 26.35 11.94 3.67 84.63 25.55 96.04 87.92

[0227] 72h 58.89 22.66 10.51 6.32 31.63 21.73 85.50 57.30

[0228] Key trends from the raw data are as follows (see Figure 5):

[0229] Formulations 007, 005, 003, and 004 generally produced higher plasma concentrations at 8-24 h compared with other formulations. Dogs with patch adhesion issues (e.g., Formulation 005 - Dog #13) showed noticeably lower concentrations early in the profile. 5.3 Patch prescription, animal number and animal performance during drug administration

[0230] Formulation No. Dose Animal ID Remarks

[0231] IV Control 0.4 mg 1 , 2 /

[0232] Dog #4 vomited 001 15 mg 3, 4 after anesthesia

[0233] Dog #5 vomited

[0234] 002 15 mg 5, 6 after anesthesia

[0235] 003 15 mg 7, 8 /

[0236] 004 15 mg 9, 10 /

[0237] Dog #13 suspected 005 15 mg 13, 14 patch detachment

[0238] Dog #11 vomited

[0239] 006 15 mg 11 , 12 after anesthesia

[0240] 007 15 mg 15, 16 /

[0241] Vomiting after anesthesia occurred in some animals (Formulations 001 , 002, 006), potentially impacting early absorption. Dog #13 showed suspected patch detachment, consistent with abnormally low initial concentrations.

[0242] 5.4 Pharmacokinetic Parameters of CMS-D005 Patch in Beagle Dogs

[0243] Pharmacokinetic parameters of CMS-D005 patches in beagle dogs are shown in Table 3. Notes: (1) Oral dosing date: 2025.09.04, 15 mg / dog. (2) IV dosing date: 2025.08.28, 0.4 mg / dog. (3) Relative bioavailability (F) calculated using average AUC(O-t) of IV injection as reference.

[0244] PK parameters (Table 3) connect directly to the concentration profiles and reveal clear differences among the seven formulations. Average Half-Life (tVz)

[0245] A long apparent half-life suggests prolonged absorption (flip-flop kinetics) or sustained systemic presence.

[0246] Formulation 002: 86.35 h

[0247] Formulation 004: 75.01 h

[0248] Formulation 003: 69.24 h

[0249] Formulation 007: 69.08 h

[0250] These values show that Formulations 002, 004, 003, and 007 provided more sustained exposure.

[0251] Cmax (Peak Concentration)

[0252] Peak plasma levels reflect absorption speed and efficiency.

[0253] Formulation 007 achieved the highest mean Cmax = 129.51 pg / L followed by Formulation 005: 97.07 pg / L and Formulation 003: 84.88 pg / L.

[0254] This ranking matches the visually higher early-to-mid time-point concentrations in Figure

[0255] 2.

[0256] AUC (Exposure)

[0257] AUC(O-t) for IV averaged -17,126 pg h / L (reference).

[0258] Among patches:

[0259] 1 . Formulation 007 again showed the greatest systemic exposure (mean AUC -6889 pg h / L).

[0260] 2. Formulations 004, 003, and 005 also produced high AUCs.

[0261] 3. Formulations 006 and 001 demonstrated lower exposure, consistent with their lower concentrations across time points.

[0262] Relative Bioavailability (F%)

[0263] Using IV AUC(O-t) as reference:

[0264] 1 . Formulation 007 achieved the highest F = 1.04% (average of the two animals) 2. Formulation 005: ~0.51%

[0265] 3. Formulation 003: -0.54%

[0266] 4. Formulation 004: -0.53%

[0267] 5. Formulations 006 and 001 had the lowest bioavailability, consistent with their low AUCs.

[0268] Table 3. Pharmacokinetic Parameters of CMS-D005 Patch in Beagle Dogs

[0269] Ani- AUC F mal Cmax AUC(O-t) T1 / 2 Tmax CLz Vz

[0270] (0-“) Formulationsnum' ber % pg / L pg / L*h pg / L*h h h L / h L

[0271] 248.6 14921.1 36061. 86.38 24 1.109 138.262 /

[0272] 5 11 391 1

[0273] I.V.

[0274] 326.5 20330.2 59660. 63.83

[0275] 61.76 / 12 7032.222 0.53

[0276] 3 64 7

[0277] 001

[0278] 1383.07 2133.0 45.91 222667.31 465884.5

[0279] 4 30.15 0.21 8 39 1 6 44

[0280] 2005.25 6056.7 112.3

[0281] 5 36.99 2476.559 2604.685 0.30 8 91 49

[0282] 002

[0283] 2739.88 5758.8 60.41 401499.24 227084.6

[0284] 6 73.16 0.41 5 54 8 7 77

[0285] 1908.84 3588.7 63.30 381823.2

[0286] 7 42.34 4179.756 0.29 5 26 6 21

[0287] 003

[0288] 127.4 5190.87 10719. 75.17 151796.6

[0289] 8 1399.287 0.79 11 5003.64 10235. 71.63 151481.4

[0290] 9 94.08 8 1465.438 0.76

[0291] 3 844 5 74 04

[0292] 4496.7 78.37 377266.5

[0293] 10 52.04 1985.82 8 3335.726 0.30

[0294] 72 7 38

[0295] 2006.2 84.41 910730.9

[0296] 11 17.74 725.84 8 7476.724 0.11

[0297] 26 4 58 06

[0298] 586.02 15.86 586140.6

[0299] 12 10.03 411.158 8 25596.125 0.06

[0300] 6 9 34

[0301] 4310.34 6511 .7 48.14 160046.8

[0302] 13 84.63 48 2303.517 0.65

[0303] 9 81 9 82 05

[0304] 2419.00 4783.4 341140.7

[0305] 14 109.5 75.39 8 3135.837 0.37

[0306] 8 12 18

[0307] 136.3 7415.52 16325. 79.30 105141.1

[0308] 15 8 918.817 1.12

[0309] 3 3 341 1 87 07

[0310] 122.6 6362.78 11211. 58.86 113654.7

[0311] 16 8 1337.958 0.96

[0312] 8 4 118 8 75

[0313] Notes:

[0314] 1) CMS-D005 patch administration data, experiment date: September 4, 2025, oral administration: 15 mg / dog.

[0315] 2) Beagle dogs: Intravenous administration: 0.4 mg / dog, intravenous push injection: August 28, 2025.

[0316] 3) F value: Roughly calculated relative bioavailability of seven formulations, using the average intravenous AUC (0-t) of CMS-D005 as a reference.

[0317] 6. Conclusion

[0318] Based on 0-72 h pharmacokinetic data of CMS-D005 patch in beagle dogs: Formulation 002 (mean t1 / ? 86.38 h) 004 (75.01 h), 003 (69.24 h), and 007 (69.08 h) performed best. For Cmax, Formulation 007 (mean 129.51 pg / L) 005 (97.07 pg / L) and 003 (84.88 pg / L) were optimal.

[0319] Example 7: CMS-D005 Pharmacokinetic Study Report - Second Test (Formulations 8-15)

[0320] 1. Purpose of the Study

[0321] This study evaluated the pharmacokinetic (PK) characteristics of eight second-batch CMS-D005 buccal patch formulations in beagle dogs. The aim was to compare their systemic exposure, absorption behavior, and bioavailability to guide follow-up formulation screening.

[0322] 2. Experimental Materials

[0323] 2.1 Analyte

[0324] Eight formulations (second batch) of the CMS-D005 patch were provided by the Innovative Formulation R&D Center of Xiamen Shengzetai Pharmaceutical Technology Co., Ltd.

[0325] Reference dose: The single intravenous bolus dose of CMS-D005 in SD rats was 0.015 mg / kg. Equivalent dose calculation for beagle dogs: 0.015 mg / kg * (20 / 6) » 0.05 mg / kg.

[0326] For the first administration in beagle dogs, to ensure safety, assuming a weight of 9-10 kg per dog, each was administered 0.4 mg.

[0327] 2.2 Experimental Instruments

[0328] Name Model Manufacturer

[0329] Vortex Mixer VM-500Pro Vortex Mixer

[0330] Centrifuge TGL-16M Cence

[0331] LC-MS TQ-XS Waters 3. Experimental Methods

[0332] 3.1 Chromatographic Analysis Method

[0333] Analysis time: 7 minutes; CMS-D005 retention time: 3.02 minutes. Column: Luna® Omega 3 pm Polar C18 100 A, 2.1 mm x 100 mm; Mobile phase: 0.1% formic acid aqueous solution (Eluent A) and acetonitrile aqueous solution (Eluent B); Column temperature: 40°C; sample temperature: 4°C; flow rate: 0.3 mL / min; injection volume: 2 pL. Gradient elution program as follows:

[0334] 3.2 Mass Spectrometry Analysis Method

[0335] Electrospray ionization (ESI) source parameters: GS1 (N2) 50 Arb; GS2 (N2) 60 Arb;

[0336] CUR 35 Arb; CAD (Nz) Medium; scan mode: MRM.

[0337]

[0338] 3.3 Dosing Method

[0339] Hold the patch with both hands, apply it to the buccal mucosa, and release it once adhered. After 40 or 60 minutes of use, remove the patch shell.

[0340] 3.4 Standard Stock Solution

[0341] Diluent: Acetonitrile:Water = 35:65.

[0342] Standard stock: 20 pg / mL CMS-D005.

[0343] Internal standard: 50 pg / L tolbutamide in methanol.

[0344] Calibration curve standards: 40, 200, 800, 1600, 3200, 8000 pg / L.

[0345] Plasma calibration prepared by mixing 10 pL blank dog plasma with 10 pL standard solution to obtain 20-4000 pg / L samples.

[0346] Add 200 pL internal standard, mix for 2 minutes, centrifuge at 4000 xg for 5 minutes at 4°C, filter (0.22 pm), and analyze via LC-MS. Samples stored at 4°C.

[0347] 3.5 Experimental Procedure

[0348] Sixteen male beagle dogs received buccal doses of 9 mg or 15 mg. Blood samples were collected at pre-dose (0 h), 15 min, 30 min, 1 h, 2 h, 3 h, 8 h, 12 h, 24 h, 48 h, and 72 h. Whole blood was collected from the vein and placed in an EDTA anticoagulant centrifuge tube. Plasma was separated (4000 rpm, 10 min, 4°C) and stored at -80°C. 4. Data Processing and Analysis

[0349] Data processed using MassLynx V4.2 software; pharmacokinetic parameters analyzed using DAS 2.0 with a non-compartmental model.

[0350] 5. Results

[0351] 5.1 Standard Curve

[0352] A standard curve was generated by MassLynx V4.2 software (see Figure 6, Standard curve of CMS-D005).

[0353] 5.2 Plasma Concentrations of CMS-D005 After Administration

[0354] Tables 2 and 3 summarize plasma concentrations for the eight formulations. The profiles (Figures 2-3) show typical buccal absorption: concentrations rise sharply between 0.5-3 hours, reach individual formulation-dependent peaks, then decline gradually to 72 h.

[0355] Table 2. Plasma CMS-D005 concentrations after oral administration of the CMS-D005 patch (pg / L; n=16)

[0356] Form. 013 Form. 008 Form. 009 Form. 010 t (h)

[0357] 1 2 3 4 5 6 7 8

[0358] Before drug administratio 4.850 5.239 8.17 0.000 9.96 4.339 4.965 1.002 n 17.41 0.25h 4.002 2.29 3.762 2.97 7.026 2.101 2.201

[0359] 2 10.07 20.44

[0360] 0.5h 4.942 9.85 11.80 24.948 2.676 3.597

[0361] 4 8

[0362] 13.75 56.44

[0363] 1h 6.541 24.79 31.21 85.962 7.402 6.901

[0364] 0 1

[0365] 28.09 135.1 123.64

[0366] 2h 13.108 37.79 57.45 10.427 10.297

[0367] 3 35 5 37.89 166.7 141.24

[0368] 3h 17.840 64.35 80.44 14.196 34.244

[0369] 8 38 6

[0370] 47.78 162.4 166.84

[0371] 8h 28.868 76.75 128.58 18.374 43.881

[0372] 9 61 5

[0373] 43.79 153.6 153.70

[0374] 12h 24.831 78.60 91.19 18.264 42.637

[0375] 8 85 9

[0376] 46.50 122.4 132.66

[0377] 24h 15.048 110.13 91.57 11.717 34.207

[0378] 6 93 3

[0379] 34.40 95.25

[0380] 48h 14.017 50.93 73.71 99.769 9.938 27.252

[0381] 9 0

[0382] 20.85 77.72

[0383] 72h 13.719 46.00 60.26 83.149 8.896 21.661

[0384] 0 6

[0385] Table 3. Plasma CMS-D005 concentrations after oral administration of the CMS-D005 patch

[0386] Form. 011 Form. 012 Form. 014 Form. 015 t (h)

[0387] 9 10 11 12 13 14 15 16

[0388] Before drug administratio 3.492 4.340 1.047 0.000 0 1.269 4.273 7.149 n 10.68 0.25h 4.389 3.290 3.682 0.000 2.722 3.619 5.183

[0389] 6 0.5h 9.363 3.788 8.332 0.000 2.524 4.399 9.626 8.059

[0390] 36.28 15.81 16.58 59.83 19.70

[0391] 1 h 1.062 1.601 4.811

[0392] 5 6 1 7 5 64.44 31.42 42.05 164.9 50.42

[0393] 2.501 6.478 6.651

[0394] 5 4 2 75 6

[0395] 87.24 53.59 60.12 13.64 283.0 141.3

[0396] 3h 4.215 8.805 6 3 8 7 68 77

[0397] 101.5 70.20 58.55 21.77 347.9 148.7

[0398] 8h 5.142 9.749 34 6 5 3 93 77

[0399] 105.0 71.98 54.56 21.74 325.3 138.0

[0400] 12h 5.495 8.907 59 3 0 3 51 77

[0401] 69.48 59.18 34.61 18.68 258.5 114.1

[0402] 24h 3.805 6.69 0 8 9 4 90 69

[0403] 52.69 47.50 23.45 12.58 184.9 89.83

[0404] 48h 1.881 3.952 9 9 7 7 13 9

[0405] 40.71 42.10 20.60 12.71 163.8 75.54

[0406] 72h 0.000 2.385 9 6 4 8 28 9

[0407] Key Observations from Raw Concentration Data (cf. Figure 7, 8)

[0408] Formulations 015, 008, and 009 displayed markedly higher concentrations, especially between 1-12 hours.

[0409] Formulation 015 (Dog #15-16) produced peak levels exceeding 300 pg / L in Dog #15.

[0410] Formulation 010, 012, and 014 produced lower systemic exposure, consistent across most sampling points.

[0411] Patch detachment (Dogs #4, #5, #15) and vomiting (Dogs #7, #11) corresponded with low or erratic early concentrations.

[0412] These observations align closely with the PK parameters (Section 5.4). 5.3 Animal Identification and Observations During Dosing

[0413] Formulation No. Dose Animal ID Remarks

[0414] 013 15 mg 1 , 2 /

[0415] 008 9 mg 3, 4 Dog #4 suspected patch detachment

[0416] 009 9 mg 5, 6 Dog #5 suspected patch detachment

[0417] 010 15 mg 7, 8 Dog #7 vomited post-anesthesia before dosing

[0418] 011 15 mg 9, 10 /

[0419] 012 15 mg / large 13, 14 / shell

[0420] 014 15 mg 11 , 12 Dog #11 vomited postanesthesia before dosing

[0421] 015 15 mg 15, 16 Dog #15 suspected patch detachment

[0422] Patches of 008, 009, 015 had suspected detachment in one animal each, explaining reduced early exposure in those subjects.

[0423] Vomiting before dosing occurred in Formulations 010 and 014, also consistent with lower concentrations at early time points. 5.4 Pharmacokinetic Parameters of CMS-D005 Patch in Beagle Dogs

[0424] Pharmacokinetic parameters of CMS-D005 in beagle dogs are presented in Table 3. Notes: (1) Oral dosing performed on 2025.09.24 (9 or 15 mg per dog).

[0425] (2) Relative bioavailability (F) was estimated using mean AUC(O-t) of IV injection as reference.

[0426] AUCT

[0427] 1 ma

[0428] Formulatio AnimaCmax AUC((Kt) Tl / 2CLz / F Vz / F F

[0429] (0-“)xn I pg / L pg / L*h pg / L*h h h L / h L %

[0430] 14921.11 36061.39 138.26

[0431] 1 248.65 86.38 24 1.11 /

[0432] I.V.1 1 2

[0433] 2 326.54 20330.25 59660.16 63.84 24 0.67 61.760 /

[0434] 10469.35 102.29

[0435] 3 110.13 4985.555 82.46 24 0.86 1.26

[0436] 2 2

[0437] 008

[0438] 13261.62

[0439] 4 166.74 8070.429 52.01 3 0.68 50.931 2.04

[0440] 5

[0441] 12671.92

[0442] 5 128.58 5777.140 79.50 8 0.71 81.473 1.46

[0443] 3

[0444] 009

[0445] 14622.38

[0446] 6 166.85 8384.161 57.81 8 0.62 51.348 2.11

[0447] 2

[0448] 800.70

[0449] 7 18.37 845.681 1612.328 59.64 8 9.30 0.13

[0450] 3

[0451] 010

[0452] 352 92

[0453] 8 43.88 2188.496 4464.902 72.80 8 3.36 0.33

[0454] 6

[0455] 162.21

[0456] 011 9 105.06 4659.861 8306.353 62.25 12 1.81 0.71

[0457] 9 201.35

[0458] 10 71.98 3809.514 7667.913 71.33 12 1.96 0.58

[0459] 6

[0460] 253.27

[0461] 11 60.13 2372.383 3637.688 42.57 3 4.12 0.36

[0462] 2 12

[0463] 2124.9

[0464] 12 5.50 174.369 237.526 23.32 12 63.15 0.03

[0465] 98

[0466] 509.26

[0467] 1 28.87 1175.448 1712.45 40.29 8 8.76 0.18

[0468] 4 13

[0469] 275.96

[0470] 2 47.79 2639.444 4278.836 54.55 8 3.51 0.40

[0471] 4

[0472] 683.87

[0473] 13 21.77 1113.185 2638.995 83.378 8 5.68 0.17

[0474] 4 14

[0475] 1328.3

[0476] 14 9.75 398.402 500.247 30.70 8 29.99 0.06

[0477] 53

[0478] 16291.74 24325.80

[0479] 15 347.99 43.96 8 0.62 39.119 2.46

[0480] 1 9 15

[0481] 14676.49

[0482] 16 148.78 7387.802 66.93 8 1.02 98.709 1.12

[0483] 6

[0484] Notes:

[0485] 1) CMS-D005 patch administration data, experimental date: September 24, 2025, oral administration: 9 or 15 mg / animal.

[0486] 2) F value: The relative bioavailability of the eight formulations was roughly calculated using the mean AUC(O-t) of intravenous CMS-D005 as a reference.

[0487] PK parameters for each animal are summarized in the report’s Table 3. Below is the connected interpretation.

[0488] Half-Life (ty2) Longer half-life indicates prolonged absorption or slow elimination.

[0489] Notably, long periods were observed in:

[0490] . Dog #13 (014) - 83.38 h

[0491] . Dog #3 (008) - 82.46 h

[0492] . Dog #5 (009) - 79.50 h

[0493] These correspond well with sustained plasma concentrations from 12-72 h in these animals.

[0494] Cmax (Peak Concentration)

[0495] Reflects absorption efficiency:

[0496] • Formulation 015 - Dog #15: Cmax = 347.99 pg / L (highest of all dogs)

[0497] • Formulation 008 - Dog #4: 166.74 pg / L

[0498] • Formulation 009 - Dog #6: 166.85 pg / L

[0499] These Cmax values match the visibly higher 1-8 h concentrations in Tables 2-3.

[0500] AUC (Exposure)

[0501] Relative bioavailability trends follow AUC(O-t):

[0502] • Formulation 015 produced the largest AUC (Dogs #15-16).

[0503] • Formulations 008 and 009 followed with mid-to-high AUC values.

[0504] • Formulations 010, 012, and 014 exhibited low AUCs consistent with low concentrations.

[0505] Relative Bioavailability (F%)

[0506] Using IV AUC(O-t) as reference:

[0507] • Formulation 015: F = 2.46% (Dog 15) and 1 .12% (Dog 16)

[0508] Formulation 008: 1 .26-2.04% Formulation 009: 1 .46-2.11 %

[0509] These are substantially higher than other formulations, reinforcing their superior absorption performance.

[0510] In contrast, formulations 010, 012, 013, and 014 exhibited very low F values (<0.4%), matching their low concentration curves.

[0511] 6. Conclusion

[0512] Based on 0-72 h pharmacokinetic data of CMS-D005 patch in beagle dogs: Animals #13 (83.39 h), #3 (82.46 h), and #5 (79.50 h) had longer half-lives. Animals #15 (348.00 pg / L), #6 (166.85 pg / L), and #4 (166.74 pg / L) showed higher Cmax values.

[0513] Example 8: Pharmacokinetic Study of CMS-D005 Patch in Beagle Dogs - Third Test (Formulations 16-20)

[0514] 1. Purpose of the Study

[0515] This study aimed to characterize the pharmacokinetic (PK) profile of five third-batch CMS- D005 buccal patch formulations in beagle dogs and to provide comparative data supporting formulation optimization.

[0516] 2. Experimental Materials

[0517] 2.1 Analyte

[0518] Five formulations of CMS-D005 patch project (third batch), provided by the Innovative Formulation R&D Center of Xiamen Shengzetai Pharmaceutical Technology Co., Ltd.

[0519] Reference dosage calculation: The single intravenous bolus dose of CMS-D005 in SD rats was 0.015 mg / kg. The equivalent dose for beagles « 0.05 mg / kg. For safety, each dog (9- 10 kg) received 0.4 mg.

[0520] 2.2 Experimental Instruments

[0521] Name Model Manufacturer Vortex Mixer VM-500Pro Vortex Mixer

[0522] Centrifuge TGL-16M Cence

[0523] LC-MS TQ-XS Waters

[0524] 3. Experimental Methods

[0525] 3.1 Chromatographic Analysis Method

[0526] Analysis time: 7 minutes; CMS-D005 elution: 3.02 min; Internal standard tolbutamide: 3.40 min. Column: Luna® Omega 3 pm Polar C18 100 A, 2.1 mm x 100 mm; Mobile phase: 0.1% formic acid aqueous solution (Eluent A) and acetonitrile aqueous solution (Eluent B); Column temperature: 40°C; sample temperature: 4°C; flow rate: 0.6 mL / min; injection volume: 2 pL. Gradient elution program as follows:

[0527] 3.2 Mass Spectrometry Method

[0528] Electrospray ionization (ESI) source parameters: GS1 (N2) 50 Arb; GS2 (N2) 60 Arb; CUR 35 Arb; CAD (Nz) Medium; scan mode: MRM. MRM detection was conducted under ESI+ mode. Optimized transitions for CMS-D005 and the internal standard were used with desolvation at 500 °C and nitrogen flow at 1000 L / h.

[0529]

[0530] 3.3 Administration Method

[0531] Hold the patch with both hands, apply it to the buccal mucosa, and release it once adhered. After 40 or 60 minutes of use, remove the patch shell.

[0532] 3.4 Standard Stock Solutions

[0533] Diluent 1 : methanol;

[0534] Diluent 2: acetonitrile:water=1 :1

[0535] Standard stock solution: Prepare a 20 pg / mL CMS-D005 standard stock solution using diluent 1.

[0536] Internal standard (tolbutamide) solution: First prepare a 1 mg / mL solution using diluent 2, then dilute to 50 pg / L using diluent 1 . Plasma standard stock solution: Dilute the standard stock solution with blank plasma to prepare a 4000 pg / L solution.

[0537] Plasma sample standard solutions: Dilute the plasma standard stock solution with blank plasma, resulting in standard sample concentrations of 0.1 , 1 , 10, 400, 1000, and 2000 pg / L. Transfer 20 pL of the above plasma sample standard solutions and plasma standard stock solutions, add 200 pL of internal standard solution, mix for 2 min, centrifuge at 4000xg for 5 min at 4°C, collect the supernatant, filter through a 0.22 pm filter membrane, and perform LC-MS detection. Store the prepared samples at 4°C.

[0538] 3.5 Experimental Procedure

[0539] Sixteen male beagle dogs were orally administered 9 mg, 15 mg, and 18 mg of the drug. Blood samples were collected before administration and at 0 h (before administration), 15 min, 30 min, 60 min, 2 h, 3 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration. Whole blood was collected intravenously into EDTA anticoagulant centrifuge tubes, centrifuged at 4000 rpm for 10 min at 4 °C, and plasma was separated and stored at -80 °C.

[0540] 4. Data Processing and Analysis

[0541] All data were automatically calculated using MassLynx V4.2 software, and the pharmacokinetic parameters of the indicative components under each dosing condition were statistically analyzed using DAS 2.0 pharmacokinetic software with a noncompartmental model.

[0542] 5. Results

[0543] 5.1 Standard curve

[0544] After preparing the standard stock solution as described above, the sample was injected for testing. A standard curve was plotted based on the results automatically calculated using MassLynx V4.2 software (see Figure 9).

[0545] 5.2 Plasma Concentrations of CMS-D005 Patch After Administration in Beagle Dogs

[0546] The plasma concentrations of CMS-D005 after administration to beagle dogs are shown in Tables 2-3. A concentration-time (C-T) curve was plotted based on the plasma concentration of CMS-D005 after administration of the CMS-D005 patch, as shown in Figure 2. Table 2: Plasma Concentrations of CMS-D005 after Oral Administration of the CMS-D005

[0547] Patch ( g / L; n=16)

[0548] IV injection Form. 016 Form. 017 t (h)

[0549] Overall Observations Linked to Data (cf. Figure 10):

[0550] 1. Formulation 017 (double 9 mg capsules) achieved the highest plasma exposure, consistent with its markedly elevated concentrations at 2-12 h (e.g., 444.87 g / L at 3 h for Dog #6). 2. Formulation 016 (single 9 mg) showed intermediate absorption, with Cmax values consistently between 80-200 pg / L.

[0551] 3. Formulation 018 (enhanced penetration enhancer) produced concentrations similar to or slightly higher than 016, but the enhancement effect was not proportional to the increased enhancer level.

[0552] 4. Formulation 019 (9 mg version of formulation 013) yielded lower exposures (Cmax -85-100 pg / L) but still clearly measurable.

[0553] 5. Formulation 020 (no penetration enhancer) showed non-detectable concentrations for most animals, indicating negligible absorption.

[0554] These trends were clearly reflected in the C-T curves, where Formulation 017 produced the steepest and highest profile, followed by 016 » 018 > 019 »> 020.

[0555] 5.3 Animal numbers and animal behavior during CMS-D005 patch administration

[0556] Formulation Animal

[0557] Dosage Remarks number number

[0558] IV injection 0.4mg 1 2 N / A

[0559] #5 patch detachment (30min after

[0560] Form.016 9mg 3 4 5 blood collection )

[0561] Form.017 9mg*2 6 7 8 N / A

[0562] #11 patch detachment (30min

[0563] Form.018 9mg 9 10 11 after blood collection )

[0564] #12^ #13^ #14 patch detachment

[0565] Form.019 9mg 12 13 14

[0566] (30min after blood collection )

[0567] Form.020 9mg 15 16 N / A

[0568] Patch detachment events were recorded and corresponded with lower concentration profiles: • #5 (016), #11 (018), #12-14 (019) experienced patch detachment. These animals showed notably lower concentrations after 2-8 h compared with their group peers.

[0569] • Formulation 020: animals showed almost complete lack of detectable CMS-D005, consistent with the absence of a penetration enhancer.

[0570] These behavioral deviations directly correlate with reduced AUC and Cmax values.

[0571] 5.4 Pharmacokinetic parameters of CMS-D005 patch in beagles

[0572] PK parameters are summarized in Table 3, with IV injection used as the reference for bioavailability (F).

[0573] Table 3. Pharmacokinetic parameters of CMS-D005 patch in beagles

[0574] AUC

[0575] Formula AnimaCmax AUC<o-‘)Tl / 2 Tmax CLz / F Vz / F F

[0576] (0-“) tions I pg / L pg / L*h pg / L*h h h L / h L %

[0577] 141.6 19463.6

[0578] 1 7909.857 35.101 48 0.021 1.041 /

[0579] 0 78

[0580] 234.9 13073.91 34785.7 iV2 102.815 8 0.011 1.706 / lv4 9 92 injection

[0581] 188.2 27124.7

[0582] AVG 10491.89 68.96 28 0.02 1.37 /

[0583] 7 4

[0584] SD 46.67 2582.03 7661.06 33.86 20 0.01 0.33 /

[0585] 5803.85 105.17

[0586] 3 79.92 3696.78 47.002 8 1.551 1.57

[0587] 8 4

[0588] 016

[0589] 200.8 12407.4

[0590] 4 8689.118 40.913 8 0.725 42.824 3.68

[0591] 5 93 143.1 9054.37

[0592] 5 6444.994 39.579 8 0.994 56.769 2.73

[0593] 9 2

[0594] 141.3 AVG 6276.96 9088.57 42.50 8 1.09 68.26 2.66

[0595] 2

[0596] SD 49.39 2041.57 2696.03 3.23 0 0.34 26.72 0.86

[0597] 454 5 31455 3

[0598] 6 19753.33 50.241 8 0.572 41.486 4.18

[0599] 1 17

[0600] 251.8 10423.55 21982.0

[0601] 7 80.506 8 0.819 95.126 2.21

[0602] 5 8 88 454.6 18435.54 24821.5

[0603] 8 35.427 8 0.725 37.072 3.90

[0604] 1 8 77

[0605] 386.9 26086.3

[0606] AVG 16204.15 55.39 8 0.71 57.89 3.43

[0607] 9 3

[0608] SD 95.56 4122.74 3969.48 18.76 0 0.10 26.39 0.87

[0609] 149.1 11868.1 110.79

[0610] 9 6615.293 60.749 8 1.264 1.68

[0611] 4 13 4

[0612] 272.2 21094.2

[0613] 10 13109.77 49.927 8 0.711 51.231 3.33

[0614] 9 4 8668.49 164.10

[0615] 11 87.65 4443.313 65.72 8 1.73 1.13

[0616] 1 2

[0617] 169.6 13876.9

[0618] AVG 8056.13 58.80 8 1.24 108.71 2.05

[0619] 9 5

[0620] SD 76.77 3681.84 5267.91 6.59 0 0.42 46.10 0.93

[0621] 8460.79 12 99.86 4715.085 57.546 8 1.064 88.331 2.00

[0622] 8 6000.03

[0623] 13 97.07 4207.898 40.352 3 1.5 87.342 1.78

[0624] 4

[0625] 7332.95 104.23

[0626] 14 84.56 3992.955 58.853 8 1.227 1.69

[0627] 4 2

[0628] AVG 93.83 4305.31 7264.60 52.25 6 1.26 93.30 1.82

[0629] SD 6.65 302.75 1005.76 8.43 2 0.18 7.74 0.13

[0630] 15

[0631] The data is too small to fit the data.

[0632] 16

[0633] Note: 1) CMS-D005 patch administration data experiment date: October 29, 2025. Oral administration: 9mg, 15mg, or 9mg*2 / animal.

[0634] 2) F-value: The relative bioavailability of the five formulations was roughly calculated using the average AUC(O-t) of intravenous CMS-D005 as a reference.

[0635] 3) Formulation 016 is a single-tablet administration of formulation 15 with the API 15mg changed to 9mg; formulation 017 is a double-tablet administration of formulation 15 with the API 15mg changed to 9mg; formulation 018 is a single-tablet administration of formulation 15 with a 20% increase in the penetration enhancer and the API 15mg unchanged; formulation 019 is a single-tablet administration of formulation 13 with the API 15mg changed to 9mg; formulation 020 contains only a film-forming agent, pH adjuster, and 9mg API, without a penetration enhancer, and is a single-tablet administration.

[0636] Data-Driven Interpretation of Each Formulation

[0637] Formulation 016 - Single 9 mg Tablet (Modified 015)

[0638] • Cmax: 141.32 pg / L

[0639] • AUC(O-t): 6276.96 pg h / L

[0640] . F: 2.66% Exposure levels were moderate and reproducible across animals, showing improvement relative to the original 15 mg formulation.

[0641] Formulation 017 - Double 9 mg capsules (Modified 015, 18 mg total)

[0642] • Cmax: 386.99 pg / L (highest among all)

[0643] . AUC(O-t): 16,204 pg h / L

[0644] . F: 3.43%

[0645] This formulation achieved the best overall systemic exposure, with Cmax values >450 pg / L in two animals. The doubled dose yielded more than proportional increases in exposure, likely due to improved mucosal contact area.

[0646] Formulation 018 - 15 mg with 20% More Enhancer

[0647] • Cmax: 169.69 pg / L

[0648] . AUC(O-t): 8056 pg h / L

[0649] . F: 2.05%

[0650] Despite the enhanced penetration system, performance did not significantly exceed Formulation 016, suggesting a saturation point for the enhancer effect.

[0651] Formulation 019 - 9 mg Version of Formulation 013

[0652] • Cmax: 93.83 pg / L

[0653] • AUC(O-t): 4305 pg h / L

[0654] . F: 1.82%

[0655] This formulation showed lower systemic exposure but still achieved measurable absorption, considerably better than Formulation 020.

[0656] Formulation 020 - 9 mg Without Penetration Enhancer

[0657] • Plasma concentrations were undetectable in nearly all samples.

[0658] PK parameters could not be fitted. This confirms that a penetration enhancer is essential for CMS-D005 buccal absorption.

[0659] 6. Conclusion

[0660] Integrated interpretation of plasma concentration profiles and PK parameters leads to the following conclusions:

[0661] 1. Formulation 016 (single 9 mg) improved bioavailability (2.66%) compared with the previous 15 mg version, indicating better efficiency at reduced dose.

[0662] 2. Formulation 017 (double 9 mg) showed the highest Cmax (386.99 pg / L) and best bioavailability (3.43%), demonstrating superior mucosal delivery due to increased contact and dosing surface area.

[0663] 3. Formulation 018 (higher enhancer) provided only marginal improvement relative to 016, indicating diminishing returns from additional enhancer.

[0664] 4. Formulation 019 (9 mg version of 013) improved relative to the 15 mg predecessor but remained less effective than 016-018.

[0665] 5. Formulation 020 (no enhancer) produced almost no systemic exposure, reinforcing the necessity of penetration enhancers for CMS-D005 absorption.

[0666] Formulations of Examples 5-7

[0667] Preparation of the oral patches of Examples 5-7 corresponds to that of with formulations 6 to 13 (cf. Example 4).

Claims

New PCT Patent Application Space Pharmaceuticals AG Vossius Ref.: AJ2733 PCT BSCLAIMS1 . A mucosal suction cup comprising a composition comprising a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof.

2. The mucosal suction cup of claim 1 , wherein the composition comprises at least two permeation enhancers.

3. The mucosal suction cup of any one of claims 1 to 2, wherein the permeation enhancer is selected from sodium glycocholate, sodium salcaprozate (SNAC), sodium taurocholate, propylene glycol, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), sodium caprylate (C8), sodium 4-(2-hydroxy-4-chlorobenzamido)butyrate (4-CNAB), azone, tocofersolan (TPGS), ethylenediaminetetraacetic acid (EDTA), cholic acid, gentisic acid, gentisic acid ethanolamine, glycocholic acid, taurocholic acid, deoxycholic acid, sodium deoxycholate, sodium caprate, dodecyl pyroglutamate, sodium octanoate, acylcarnitine, and alkyl maltoside, preferably sodium glycocholate, sodium salcaprozate (SNAC), sodium taurocholate, propylene glycol, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), sodium caprylate (C8), sodium 4-(2-hydroxy-4- chlorobenzamido)butyrate (4-CNAB), azone and tocofersolan (TPGS), more preferably sodium glycocholate, sodium taurocholate, sodium salcaprozate (SNAC) and propylene glycol.

4. The mucosal suction cup of any one of claims 1 to 3, wherein the therapeutic agent is a hormone, hormone analogue or hormone mimetic, preferably the therapeutic agent is a peptide-homnone, peptide-hormone analogue, peptide-homnone mimetic, or pharmaceutically acceptable salt thereof, preferably wherein the therapeutic agent is a glucoagon-like peptide 1 agonist (GLP-1 agonist), preferably selected from semaglutide, Liraglutide, Tirzepatide, and a pharmaceutically acceptable salt thereof and / or a combination thereof.

5. The mucosal suction cup of any one of claims 1 to 4, wherein the composition further comprises a film-forming material, preferably wherein the film-forming material is selected from polyvinyl alcohol (PVA), Hypromellose (HPMC), Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose, Carboxymethylcellulose Sodium (CMC-Na), xanthan gum, Pectin, copovidone, povidone, guar gum, pullulan, polyethylene oxide, sodium alginate and chitosan, more preferably wherein the film-forming material is polyvinyl alcohol (PVA); and / or wherein the composition further comprises a buffer, preferably wherein the buffer composition is selected from Tris-HCI, phosphate buffered saline (PBS), 3-(N- morpholino)propanesulfonic acid (TAPS), Tris buffer saline, sodium citrate (SSC), N- tris(hydroxymethyl)methylglycine, citric acid-disodium hydrogen phosphate buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) buffer, disodium hydrogen phosphate, sodium acetate / glacial acetic acid, more preferably wherein the buffer is Tris-HCI, preferably wherein the pH range of the buffer solution is between 6.0 and 8.0, preferably between 6.5 and 7.4.

6. The mucosal suction cup of any one of claims 1 to 5, wherein the permeation enhancer or the at least two permeation enhancers, preferably the at least two permeation enhancers are selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium deoxycholate, sodium decanoate, sodium octanoate (C8), sodium glycocholate, sodium taurocholate, arginine (arg), and glycocholic acid; wherein the permeation enhancer or the at least two permeation enhancers are preferably selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium taurocholate, sodium glycocholate, sodium octanoate (C8), sodium deoxycholate, and glycocholic acid; wherein the permeation enhancer or the at least two permeation enhancers are preferably selected from the group consisting of propylene glycol, SNAC, laurocapram, lauroamphetamine, sodium taurocholate, sodium glycocholate, and sodium deoxycholate.

7. The mucosal suction cup of any one of claims 2 to 6, wherein the at least two permeation enhancers are sodium glycocholate and sodium salcaprozate (SNAC); orwherein the at least two permeation enhancers are sodium glycocholate and N-(5- chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC); or wherein the at least two permeation enhancers are sodium taurocholate and propylene glycol.

8. The mucosal suction cup of any one of claims 1 to 7, wherein the composition comprises between about 0.25 and 30 wt% of the at least one permeation enhancer, between about 0.5 and 10 wt% film-forming material, between about 0 and 2 wt% flavouring agent and between about 5 and 30 wt% therapeutic agent; and / or wherein the composition comprises about 13.4 wt% sodium glycocholate, about 1 .5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 10 wt% sodium salcaprozate (SNAC), about 1.5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 13.4 wt% sodium glycocholate, about 5 wt% sodium salcaprozate (SNAC), about 1 .5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 13.4 wt% sodium glycocholate, about 5 wt% N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), about 1 .5 wt% polyvinyl alcohol and about 11.25 wt% therapeutic agent; or wherein the composition comprises about 14.6 wt% sodium taurocholate, 4 wt% propylene glycol, 1 .5 wt% polyvinyl alcohol and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 2.7 wt% sodium glycocholate, about 1 .5 wt% polyvinyl alcohol and about 11 .25% of therapeutic agent; or wherein the composition comprises about 11 .3 wt% sodium deoxycholate, about 1 .5% polyvinyl alcohol and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 9 wt% sodium salcaprozate (SNAC), about 1 .5 wt% polyvinyl alcohol (PVA) and about 11.25 wt% therapeutic agent; orwherein the composition comprises about 9.4 wt% N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), about 1.5 wt% polyvinyl alcohol (PVA) and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 8.4 wt% sodium 4-(2-hydroxy-4- chlorobenzamido)butyrate (4-CNAB), about 1 .5 wt% polyvinyl alcohol (PVA), and about 11 .25 wt% of therapeutic agent; or wherein the composition comprises about 4.4 wt% sodium caprylate, about 1 .5 wt% polyvinyl alcohol (PVA) and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 1 wt% azone, about 1 .5 wt% polyvinyl alcohol (PVA) and about 11 .25 wt% therapeutic agent; or wherein the composition comprises about 1 wt% dodecyl pyroglutamate, about 1.5% PVA, and 11.25% of therapeutic peptide; or wherein the composition comprises about 7 mg oleic acid, about 1 .5 wt% PVA, and about 11 .25 wt% therapeutic agent.

9. The mucosal suction cup of any one of claims 1 to 8 further comprising a flavouring agent, wherein the flavouring agent may be natural or synthetic, preferably wherein the flavouring agent is selected from sucralose, menthol, aspartame, mannitol, sorbitol, sucrose, maltose, fructose, lactose, cinnamaldehyde, D-glucose, sucralose, eucalyptol, steviolbioside, lactitol, anethole, invert sugar, xylitol, saccharin, levoglucose, stevioside, vanillin, limonene, menthone, alpha terpineol, terpinen-4-ol, allyl benzoate, allyl caproate, anisyle alcohol, cinnamaldehyde, eugenol, geraniol, musk ambrette, neryl acetate, santalyl acetate, caraway, clove, lemon, spearmint, rose, peppermint, ginger, raspberry, maltol, syrups, citric acid, sarsaparilla, cherry, glycerin, cocoa, licorice, sodium citrate, saccharin sodium, tannic acid, glycine, dibasic potassium phosphate trihydrate and natural or synthetic fruit flavouring.

10. The mucosal suction cup of any one of claims 1 to 9 for use in the treatment or prevention of a disease or disorder associated with Glucagon-like peptide 1 (GLP-1), preferably wherein the disease or disorder is hyperglycemia, type 2 diabetes, type 1 diabetes, impaired glucose tolerance, obesity, hypertension, syndrome X, dyslipidemia, cognitivedisorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers, more preferably type 2 diabetes, type 1 diabetes, impaired glucose tolerance or obesity, even more preferably type 2 diabetes or obesity.11 . The mucosal suction cup of any one of claims 1 to 9 for use in decreasing appetite, decreasing 0-cell apoptosis, increasing (3-cell function, increasing 0-cell mass and / or restoring glucose sensitivity to 0-cells.

12. The mucosal suction cup of any one of claims 1 to 9 for use in treatment of obesity or a metabolic disease, preferably type 2 diabetes or non-alcoholic steatohepatitis (NASH / MASH).

13. Use of a mucosal suction cup as defined in any one of claims 1 to 12 for transmucosal administration of a composition comprising a therapeutic agent to a subject.

14. Use of a mucosal suction cup as defined in any one of claims 1 to 13 for the transmucosal delivery of a composition comprising a therapeutic agent to a subject, wherein the composition comprises a therapeutic agent and at least one permeation enhancer, wherein the permeation enhancer is selected from a bile salt, a compound having a steroid skeleton, a fatty acid, a surfactant (natural or synthetic), a chelator, a positively charged polymer, a cyclodextrin, thiomenthol, a polysorbate and any combination thereof.

Images