Pharmaceutical compositions comprising GLP-1R agonists

Abstract

The present invention relates to a pharmaceutical composition comprising a GLP-1R agonist, such as liraglutide or semaglutide, a buffer selected from tromethamine buffer and phosphate buffer, and an isotonicity agent selected from glucose, polyethylene glycol and glycerol. The present invention also relates to said pharmaceutical composition for use in a method for treating a joint disease.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising a GLP-1R agonist such as liraglutide or semaglutide.The present invention also relates to a pharmaceutical composition comprising a GLP-1R agonist such as liraglutide or semaglutide for use in the treatment of joint diseases, the pharmaceutical composition being administered, for example, by intra-articular injection. [Background technology]

[0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone that binds to the GLP-1 receptor expressed on pancreatic beta cells and increases glucose transporter 2 expression and insulin secretion in response to elevated blood glucose concentrations. In addition, GLP-1 reduces the secretion of some proinflammatory cytokines. GLP-1R agonists are commonly used as treatments for type 2 diabetes.

[0003] Among chronic joint diseases, osteoarthritis (OA) is the most common disease, affecting almost 50% of people over 65 years of age, and can also occur in younger people due to anatomical abnormalities, after joint injury, or in cases of obesity. Approximately 250 million people worldwide suffer from OA; the disease has economic and social impacts.

[0004] Recently, it has been found that GLP-1R agonists such as liraglutide target mechanisms related to inflammation, anti-degradation, and regeneration processes associated with OA. WO2020104833 therefore relates to a pharmaceutical composition comprising a GLP-1R agonist such as liraglutide for use in the treatment of joint diseases, such as OA. The pharmaceutical composition according to WO2020104833 is in particular in the form of a gel comprising liraglutide and albumin.

[0005] However, there is a need to find new formulations, including GLP-1R agonists such as liraglutide or semaglutide, that are at least as effective as those already on the market and that, when administered by intra-articular injection, can induce a long-lasting effect, specifically an effect lasting at least 3 weeks, more specifically an effect lasting at least 4 weeks. Indeed, limiting the frequency of intra-articular injections would simplify patient treatment, improve patient comfort, and limit the number of medical procedures requiring caregiver intervention.

[0006] The inventors have surprisingly found that a formulation of a pharmaceutical composition comprising a GLP-1R agonist such as liraglutide or semaglutide according to the present invention is capable of inducing a long-lasting effect when administered via intra-articular injection, in particular an effect lasting for at least 3 weeks, more particularly an effect lasting for at least 4 weeks. Summary of the Invention

[0007] The present invention relates to a pharmaceutical composition for use in a method for treating joint diseases, particularly osteoarthritis and / or joint pain, more particularly inflammatory joint pain, wherein said pharmaceutical composition is in liquid phase to be administered by intra-articular injection, in particular by intra-articular injection into the joint cavity, wherein the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0008] Advantageously, the liquid phase may be selected from the group consisting of a solution, a suspension and an emulsion.

[0009] The present invention relates to a pharmaceutical composition for use in a method for treating joint diseases, particularly osteoarthritis and / or joint pain, more particularly inflammatory joint pain, wherein said pharmaceutical composition is a solution or suspension administered by intra-articular injection, in particular by intra-articular injection into the joint cavity, wherein the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0010] In one embodiment, the pharmaceutical composition is a solution.

[0011] In another embodiment, the pharmaceutical composition is a suspension.

[0012] Advantageously: - the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof; preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof; more preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide, and combinations thereof; even more preferably, the GLP-1R agonist is liraglutide; the buffer is a phosphate buffer, preferably a phosphate buffer containing dibasic sodium phosphate dihydrate as buffering agent, -The isotonic agent is propylene glycol.

[0013] Advantageously, the GLP-1R agonist is liraglutide or semaglutide, the buffer is a phosphate buffer, preferably a phosphate buffer containing dibasic sodium phosphate dihydrate as buffering agent, and the isotonicity agent is propylene glycol.

[0014] More advantageously, the GLP-1R agonist is liraglutide, the buffer is a phosphate buffer, preferably a phosphate buffer containing dibasic sodium phosphate dihydrate as the buffering agent, and the isotonicity agent is propylene glycol.

[0015] More advantageously, the GLP-1R agonist is semaglutide, the buffer is a phosphate buffer, preferably a phosphate buffer containing dibasic sodium phosphate dihydrate as the buffering agent, and the isotonicity agent is propylene glycol.

[0016] Advantageously, said pharmaceutical composition comprises: - the GLP-1R agonist, preferably the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof; more preferably the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof; even more preferably the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide, and combinations thereof; even more preferably the GLP-1R agonist is liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, and an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0017] Advantageously, said pharmaceutical composition comprises: - a GLP-1R agonist, preferably the GLP-1R agonist is liraglutide or semaglutide; a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, and an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0018] Advantageously, said pharmaceutical composition comprises: - the GLP-1R agonist, preferably the GLP-1R agonist is liraglutide; a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, and an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0019] Advantageously, said pharmaceutical composition comprises: - the GLP-1R agonist, preferably the GLP-1R agonist is semaglutide; a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, and an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0020] Advantageously, the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof; preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof, more preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide, and combinations thereof, even more preferably, the GLP-1R agonist is liraglutide.

[0021] More preferably, the GLP-1R agonist is liraglutide. Even more preferably, the GLP-1R agonist is liraglutide and the pharmaceutical composition is administered at a dose of 0.0245 mg to 6.3 mg of liraglutide, preferably at a dose of 0.7 mg to 6.3 mg of liraglutide.

[0022] More preferably, the GLP-1R agonist is liraglutide. Even more preferably, the GLP-1R agonist is liraglutide and the pharmaceutical composition is administered at a dose of 0.0245 mg to 6.3 mg of liraglutide, preferably at a dose of 0.3 mg, 1.0 mg, 3.0 mg or 6.0 mg of liraglutide.

[0023] More advantageously, the GLP-1R agonist is semaglutide. Even more advantageously, the GLP-1R agonist is semaglutide and the pharmaceutical composition is administered at a dose of 0.0245 mg to 6.3 mg of semaglutide, preferably at a dose of 0.7 mg to 6.3 mg of semaglutide, more preferably at a dose of 0.25 mg, 0.5 mg or 1 mg of semaglutide.

[0024] More preferably, the GLP-1R agonist is exenatide.

[0025] More preferably, the GLP-1R agonist is lixisenatide.

[0026] More preferably, the GLP-1R agonist is albiglutide.

[0027] More preferably, the GLP-1R agonist is veinaglutide.

[0028] More preferably, the GLP-1R agonist is dulaglutide.

[0029] More preferably, the GLP-1R agonist is pegapamodutide.

[0030] More preferably, the GLP-1R agonist is taspoglutide.

[0031] Advantageously, a dose of said pharmaceutical composition is administered in one or at least two intra-articular injections.

[0032] Preferably, the doses of the pharmaceutical composition are administered monthly.

[0033] Advantageously, the total dose of GLP-1R agonist administered during one year is between 0.18 mg and 72 mg, preferably between 0.7 mg and 8.4 mg.

[0034] The present invention also relates to a pharmaceutical composition, said pharmaceutical composition being in liquid phase, -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0035] Advantageously, the liquid phase may be selected from the group consisting of a solution, a suspension and an emulsion.

[0036] The present invention also relates to a pharmaceutical composition, said pharmaceutical composition being a solution or a suspension, -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0037] In one embodiment, the pharmaceutical composition is a solution.

[0038] In another embodiment, the pharmaceutical composition is a suspension.

[0039] Advantageously, the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof; preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof, more preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide, and combinations thereof, even more preferably, the GLP-1R agonist is liraglutide.

[0040] More preferably, the GLP-1R agonist is liraglutide or semaglutide.

[0041] Even more advantageously, the GLP-1R agonist is semaglutide.

[0042] Even more advantageously, the GLP-1R agonist is liraglutide.

[0043] Even more advantageously, the GLP-1R agonist is exenatide.

[0044] Even more advantageously, the GLP-1R agonist is lixisenatide.

[0045] Even more advantageously, the GLP-1R agonist is albiglutide.

[0046] Even more advantageously, the GLP-1R agonist is veinaglutide.

[0047] Even more advantageously, the GLP-1R agonist is dulaglutide.

[0048] Even more advantageously, the GLP-1R agonist is pegapamodutide.

[0049] Even more advantageously, the GLP-1R agonist is taspoglutide.

[0050] Advantageously, the pharmaceutical composition contains between 2 mg / mL and 20 mg / mL, preferably between 4 mg / mL and 8 mg / mL, more preferably about 6 mg / mL of the GLP-1R agonist.

[0051] Advantageously, the pharmaceutical composition comprises between 0.01 mg / mL and 20 mg / mL, preferably between 0.5 mg / mL and 2 mg / mL, more preferably between 1 mg / mL and 1.5 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist.

[0052] Advantageously, the buffer is a tromethamine buffer comprising tromethamine as the buffering agent, preferably the pharmaceutical composition comprises between 0.1 mg / mL and 10 mg / mL, more preferably between 0.5 mg / mL and 1 mg / mL, even more preferably about 0.97 mg / mL of tromethamine.

[0053] More advantageously, the buffer is a phosphate buffer comprising dibasic sodium phosphate as a buffering agent, preferably the pharmaceutical composition comprises from 0.1 mg / mL to 10 mg / mL, more preferably from 0.75 mg / mL to 1.5 mg / mL, even more preferably about 1.14 mg / mL of dibasic sodium phosphate.

[0054] Advantageously, the isotonicity agent is glucose, and preferably said pharmaceutical composition comprises between 10 mg / mL and 50 mg / mL, more preferably between 20 mg / mL and 40 mg / mL, even more preferably about 30 mg / mL of glucose.

[0055] Advantageously, the isotonic agent has a concentration of 800 g.mol -1 Less than 100 g.mol -1 ~600g.mol -1Preferably, the isotonicity agent is PEG 400. Preferably, the pharmaceutical composition comprises 20 mg / mL to 100 mg / mL, more preferably 40 mg / mL to 80 mg / mL, even more preferably about 60 mg / mL of polyethylene glycol.

[0056] Advantageously, the isotonicity agent is glycerol, preferably said pharmaceutical composition comprises 5 mg / mL to 50 mg / mL, preferably 10 mg / mL to 25 mg / mL, more preferably about 17 mg / mL or about 18 mg / mL of glycerol.

[0057] definition In the present invention, the following terms have the following meanings: "About" before a number or number refers to plus or minus 10% of the face value of that number or number. In one embodiment, "about" before a number or number refers to plus or minus 5% of the face value of that number or number.

[0058] "Active agent" refers to an agent that has a therapeutic effect. The agent may be a chemical or biological substance. The therapeutic effect may be the prevention, delay, reduction or inhibition of the severity and / or frequency of at least one symptom associated with a pathological condition, or the prevention, slowing or inhibition of the underlying cause of a pathological condition, or the amelioration or repair of damage.

[0059] "Acute illness" refers to a non-chronic illness.

[0060] "Administration in combination" refers to the sequential, simultaneous or separate administration of at least two active agents. When administration in combination is simultaneous, the active agents that are administered simultaneously can be in the same pharmaceutical composition.

[0061] "Buffer" refers to a mixture of a weak acid and its conjugate base, or a weak base and its conjugate acid, whose pH remains constant when small amounts of strong acid or strong base are added to it. In one embodiment, the buffer is a phosphate buffer. In one embodiment, the buffer is a tromethamine buffer. A "phosphate buffer" is a buffer that contains phosphate or a derivative thereof as a buffering agent. A "tromethamine buffer" is a buffer that contains tromethamine or a derivative thereof as a buffering agent.

[0062] "Buffering agent" refers to a specific chemical that exists in both acidic and basic forms in a buffer solution and ensures that the pH of the pharmaceutical composition remains constant. In one embodiment, the buffering agent is a phosphate or a derivative thereof. In one embodiment, the buffering agent is tromethamine or a derivative thereof.

[0063] "Cartilage" or "cartilage matrix" or "articular cartilage" refers to the elastic, translucent connective tissue in mammals, including humans. Cartilage is composed of chondrocytes, type II collagen, small amounts of other collagen types, other non-collagenous proteins, proteoglycans, and water. Most cartilage becomes bone at maturity, but some cartilage remains in its original form in some places, such as the nose, ears, and knees. Cartilage has no blood or nerve supply.

[0064] "Chronic disease" refers to a long-term, progressive illness that is often accompanied by the threat of disability and serious complications. A chronic disease progresses more or less rapidly over a period of at least several months, particularly over a period of at least 3 months.

[0065] "Complex of a GLP-1R agonist" refers to a multi-atomic structure consisting of one or more interacting separate entities (ions or molecules), which structure includes a GLP-1R agonist.

[0066] "Comprising" or "comprise" is to be interpreted in an open and inclusive sense, but is not limited to this. In one embodiment, "comprising" means "consisting essentially of." In one embodiment, "comprising" means "consisting of," and is to be interpreted as being limited thereto.

[0067] A "dose" refers to the cumulative amount of GLP-1R agonist administered over 2 weeks to 1 month. In one embodiment, a "dose" refers to the cumulative amount of GLP-1R agonist administered over 2 weeks. In another embodiment, a "dose" refers to the cumulative amount of GLP-1R agonist administered over 3 weeks. In another embodiment, a "dose" refers to the cumulative amount of GLP-1R agonist administered over 1 month.

[0068] An "effective amount" of an active agent refers to a non-toxic but sufficient amount of active agent to provide the desired therapeutic effect.

[0069] "Excipient" refers to any inactive ingredient required for the formulation of an active agent in a suitable dosage form. In one embodiment, "excipient" refers to any and all solvents, diluents, carriers, fillers, bulking agents, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonicity agents, thickening or emulsifying agents, stabilizers, absorption enhancers, flavoring agents, preservatives, antioxidants, buffers, or any combination thereof. Those skilled in the art are familiar with how to select suitable excipients to obtain a formulation suitable for intra-articular injection, especially in terms of viscosity, solvent, etc.

[0070] "X~Y" refers to a range of values ​​between X and Y, where the ends of the interval between X and Y are included in the range.

[0071] "Gel" refers to a non-fluid colloidal or polymeric network that is expanded throughout its entire volume by a fluid, which is referred to as the "swelling agent." "Hydrogel" refers to a gel in which the swelling agent is water. "Colloidal" refers to a finely divided state, meaning that the molecules or polymeric particles dispersed in a medium have a dimension of approximately 1 nm to 1 μm in at least one direction. "Network" refers to a highly branched structure in which essentially each building block is connected to each other building blocks and to macroscopic phase boundaries by many paths through the structure, the number of such paths increasing with the average number of intervening building blocks; these paths should, on average, be coextensive with the structure.

[0072] "GLP-1" or "glucagon-like peptide 1" refers to a 30 or 31 amino acid long peptide hormone derived from post-translational processing of the proglucagon peptide to "GLP-1(1-37)", which is further truncated at the N-terminus by tissue-specific post-translational processing in the L-cells of the intestine to yield two truncated and equipotent biologically active forms, "GLP-1(7-36)amide" and "GLP-1(7-37)". In humans, GLP-1(1-37) has the amino acid sequence set forth in SEQ ID NO:1; GLP-1(7-36)amide has the amino acid sequence set forth in SEQ ID NO:2; and GLP-1(7-37) has the amino acid sequence set forth in SEQ ID NO:3.

[0073] "GLP-1R agonist" or "GLP-1 receptor agonist" refers to an agonist of the GLP-1 receptor (GLP1R). The GLP-1R agonist may be a GLP-1 analogue. The GLP-1R agonist may be selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, semaglutide, pegapamodutide, and taspoglutide. According to the present invention, the term "GLP-1G agonist" includes GLP-1R agonist enantiomers, GLP-1R agonist esters, GLP-1R agonist racemates, salts of GLP-1R agonists, solvates of GLP-1R agonists, hydrates of GLP-1R agonists, polymorphs of GLP-1R agonists, and complexes of GLP-1R agonists.

[0074] "GLP-1R agonist enantiomer" refers to a molecule that has the same molecular formula and bond atom arrangement as a GLP-1R agonist, but differs from the GLP-1R agonist in the three-dimensional orientation of its atoms in space. A GLP-1R agonist and its enantiomer are mirror images of each other and are not superimposable.

[0075] "GLP-1R agonist ester" refers to a GLP-1R agonist attached to another chemical molecule via an ester group.

[0076] "GLP-1R agonist racemic" refers to a mixture of equal proportions of the levo- and dextro-enantiomers of a GLP-1R agonist.

[0077] A "hydrate of a compound" refers to a molecular complex comprising the compound and one or more pharma- ceutically acceptable solvent molecules, where the solvent is water.

[0078] "Intra-articular injection" refers to an injection directly into the closed cavity of a joint in the human body.

[0079] "Isotonicity agent" refers to an agent added to a pharmaceutical composition to ensure isotonicity between the pharmaceutical composition and the biological medium in which the pharmaceutical composition is administered.

[0080] "Joint" and "articulation" are used interchangeably.

[0081] "Joint disease" refers to any disease that affects at least one joint of the human body. Examples of joint diseases include, but are not limited to, inflammatory arthritis (particularly osteoarthritis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, ankylosing spondylitis, lupus and related connective tissue diseases, synovitis, crystal arthropathy (gout, chondrocalcinosis, oochronsis, hydroxyapatitis), abarticular pathology (tendinitis, capsulitis, enthesitis), septic arthritis, subchondral bone pathology (osteonecrosis, insufficiency fracture, bone marrow lesion), hereditary arthropathy, inflammatory joint pain, or other joint pain. Joint diseases can be characterized by one or more symptoms, including, but not limited to, limited movement, joint pain, joint inflammation, joint tenderness, joint stiffness, and joint swelling.

[0082] "Liraglutide" refers to a 3.7 kDa 32 amino acid peptide. It is a synthetic acylated analogue of human GLP-1(7-37) in which the lysine residue at position 28 (numbering SEQ ID NO: 3) is replaced by an arginine residue and a C16 fatty acid (palmitic acid) is attached via a γ-glutamyl linker to the ε-amino group of the lysine residue at position 20 (numbering SEQ ID NO: 3). The chemical structure of liraglutide is as follows: [ka]

[0083] "Osteoarthritis" or "OA" is a joint disease. Osteoarthritis is a disease that can affect any mobile joint in the body, such as the knee, hip, and / or hand. It can manifest as tissue destruction and abnormal changes in the cellular structure of the joint, which can be caused by injury. As the joint tries to repair itself, other problems can result. Osteoarthritis first manifests as changes in the biological processes within the joint, followed by abnormal changes in the joint, such as destruction of cartilage, bone remodeling, bone masses, joint inflammation, and loss of joint function. This can result in pain, stiffness, and loss of movement. There are certain factors that predispose some people to developing osteoarthritis, such as genetic factors, other joint diseases (such as rheumatoid arthritis), joint damage from accidents or surgery, being overweight, or engaging in strenuous physical activity in sports or human work.

[0084] A "pharmaceutical composition" refers to a combination of at least one active agent and at least one pharma- ceutically acceptable excipient.

[0085] "Pharmaceutically acceptable" generally refers to something that is safe, non-toxic, and not biologically, physiologically, or otherwise undesirable to animals, especially humans.

[0086] "Polymorphs of a GLP-1R agonist" refers to alternative crystal structures of said GLP-1R agonist.

[0087] "Preservative" refers to any substance or chemical added to a composition to prevent degradation of the composition by microbial growth or by undesirable chemical changes.

[0088] "Salt of a GLP-1R agonist" refers to an acid or base addition salt of a GLP-1R agonist. Acid addition salts are formed with pharmaceutically acceptable organic or inorganic acids; base addition salts are formed when an acid proton in the GLP-1R agonist is replaced by a metal ion or coordinated with a pharmaceutically acceptable organic or inorganic base.

[0089] "Solution" refers to a liquid homogeneous phase comprising at least one solvent in which at least one solute is dissolved, the at least one solute being a minor component of the solution. According to the present invention, the solution is not a gel and therefore does not contain a non-fluid colloidal or polymeric network. Advantageously, the solution does not contain a polymer selected from the group consisting of non-ionic surfactants, cellulose, polyethers, glucans, glycerophospholipids, polysaccharides, proteins, and combinations thereof.

[0090] A "solvate of a GLP-1R agonist" refers to a molecular complex comprising a GLP-1R agonist and one or more pharma- ceutically acceptable solvent molecules. A "hydrate of a GLP-1R agonist" refers to a molecular complex comprising a GLP-1R agonist and one or more pharma- ceutically acceptable solvent molecules, where the solvent is water.

[0091] "Subject" or "patient" refers to animals, particularly mammals. In one embodiment, "subject" refers to an animal selected from the group consisting of dogs, cats, horses, cows, sheep, goats, and non-human primates. In a preferred embodiment, "subject" refers to a human (male or female). According to a preferred embodiment, "subject" refers to a human aged 18 years or older, preferably aged 50 years or older, more preferably aged 65 years or older.

[0092] "Suspension" refers to a homogeneous phase of liquid comprising at least one solvent in which at least one solute is dispersed, the at least one solute being a solid particle and a minor component of the solution. According to the present invention, the suspension is not a gel and therefore does not contain a non-fluid colloidal or polymeric network. Advantageously, the suspension does not contain a polymer selected from the group consisting of non-ionic surfactants, cellulose, polyethers, glucans, glycerophospholipids, polysaccharides, proteins, and combinations thereof.

[0093] A "therapeutically effective amount" of an active agent refers to a non-toxic but sufficient amount of active agent to provide the desired therapeutic effect.

[0094] "Treat" or "treatment" refers to any action that prevents, delays, reduces, or inhibits the severity and / or frequency of at least one symptom associated with a pathological condition, or prevents, slows down, or inhibits the underlying cause of a pathological condition, or allows for the amelioration or repair of damage. In particular, in the context of the present invention, the term "treat" or "treatment" may more specifically refer to the inhibition or slowing down of arthritic destruction of cartilage. In particular, in the context of the present invention, the term "treat" or "treatment" may more specifically refer to the reduction or even inhibition of joint pain. In one embodiment, "treatment" refers to curative treatment. In another embodiment, "treatment" refers to prophylactic treatment. In another embodiment, "treatment" refers to prophylactic and / or curative treatment.

[0095] "Water for injection" is water intended either for the preparation of a parenteral drug with an aqueous vehicle (bulk water for injection), or for the dissolution or dilution of an active agent, or for preparations for parenteral administration (sterile water for injection). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0096] Pharmaceutical Compositions The present invention relates to pharmaceutical compositions comprising at least one GLP-1R agonist, or a pharma- ceutically acceptable ester, salt, complex, polymorph, hydrate, solvate, enantiomer or racemate thereof, a buffering agent and at least one isotonicity agent.

[0097] As stated in the definition above, reference in the present invention to a GLP-1R agonist also encompasses any pharma- ceutically acceptable ester, salt, complex, polymorph, hydrate, solvate, enantiomer or racemate of the GLP1-R agonist.

[0098] The pharmaceutical compositions of the present invention comprise a GLP1-R agonist as an active agent and a mixture of excipients suitable for intra-articular injection, preferably comprising a buffer and at least one isotonicity agent.

[0099] The pharmaceutical composition according to the invention is a solution or a suspension. The solvent of the pharmaceutical composition according to the invention can be advantageously water, more advantageously water for injection.

[0100] Detailed Compounds of Pharmaceutical Composition Advantageously, the GLP-1R agonist is selected from the group consisting of polypeptide, antibody, nucleic acid, aptamer and small molecule.Preferably, the GLP-1R agonist is a polypeptide.The polypeptide can be selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, semaglutide and taspoglutide.In a preferred embodiment, the GLP-1R agonist is liraglutide or semaglutide.In a more preferred embodiment, the GLP-1R agonist is liraglutide.In another more preferred embodiment, the GLP-1R agonist is semaglutide.

[0101] In one embodiment, the GLP-1R agonist is liraglutide.

[0102] In another embodiment, the GLP-1R agonist is exenatide.

[0103] In another embodiment, the GLP-1R agonist is lixisenatide.

[0104] In another embodiment, the GLP-1R agonist is albiglutide.

[0105] In another embodiment, the GLP-1R agonist is veinaglutide.

[0106] In another embodiment, the GLP-1R agonist is dulaglutide.

[0107] In another embodiment, the GLP-1R agonist is semaglutide.

[0108] In another embodiment, the GLP-1R agonist is pegapamodutide.

[0109] In another embodiment, the GLP-1R agonist is taspoglutide.

[0110] Advantageously, the buffer is selected from the group consisting of tromethamine buffer, phosphate buffer, and any combination thereof.

[0111] Advantageously, the buffer is a tromethamine buffer. The tromethamine buffer may comprise a buffering agent selected from the group consisting of tromethamine (Tris), tromethamine acetate (Tris), tromethamine phosphate (Tris), and any combination thereof. More preferably, the buffer is a tromethamine buffer comprising tromethamine (Tris) as a buffering agent.

[0112] Advantageously, the buffer is a phosphate buffer. The phosphate buffer may comprise a buffering agent selected from the group consisting of dibasic calcium phosphate, tribasic calcium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, monobasic sodium phosphate, dibasic sodium phosphate dihydrate, and any hydrate or combination thereof. More preferably, the buffer is a phosphate buffer comprising dibasic sodium phosphate or dibasic sodium phosphate dihydrate as a buffering agent. Even more preferably, the buffer is phosphate buffered saline (PBS).

[0113] Advantageously, the isotonicity agent is selected from the group consisting of glucose, polyethylene glycol, propylene glycol, glycerol, and any combination thereof.

[0114] Advantageously, the isotonicity agent is selected from the group consisting of glucose, polyethylene glycol, glycerol, and any combination thereof.

[0115] Advantageously, the isotonic agent is propylene glycol.

[0116] Advantageously, the isotonic agent is polyethylene glycol. -1 Less than 100 g.mol -1 ~800g.mol -1 , more preferably 100 g.mol -1 ~600g.mol -1 and even more preferably polyethylene glycol having a molecular weight of 200 g.mol -1 ~400g.mol -1 and even more preferably polyethylene glycol having a molecular weight of 400 g.mol -1 (=PEG400) or 200g.mol -1 (=PEG200). In one embodiment, the polyethylene glycol may be a polyethylene glycol having a molecular weight of 100 g.mol -1 , 200 g.mol -1 , 300 g.mol -1 , 400 g.mol -1 , 500 g.mol -1 , 600 g.mol -1 , 700 g.mol -1 or 800 g.mol -1 It is a polyethylene glycol having a molecular weight of

[0117] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0118] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0119] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, and glycerol; Includes.

[0120] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose and polyethylene glycol, Includes.

[0121] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, propylene glycol, and glycerol, Includes.

[0122] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0123] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, propylene glycol, and glycerol, Includes.

[0124] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, -glucose, Includes.

[0125] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, tromethamine buffer; -glucose, Includes.

[0126] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0127] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0128] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0129] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0130] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0131] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0132] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0133] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0134] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol and glycerol, Includes.

[0135] Advantageously, the pharmaceutical composition comprises: -GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0136] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0137] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0138] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0139] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, -glucose as an isotonic agent Includes.

[0140] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, polyethylene glycol, preferably PEG 400, as an isotonic agent; Includes.

[0141] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, with glycerol as an isotonic agent; Includes.

[0142] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, - propylene glycol as an isotonic agent, Includes.

[0143] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0144] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0145] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0146] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, -glucose as an isotonic agent Includes.

[0147] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, as isotonicity agents, polyethylene glycol, preferably PEG 400; Includes.

[0148] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, with glycerol as an isotonic agent; Includes.

[0149] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, - propylene glycol as an isotonic agent, Includes.

[0150] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0151] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, tromethamine buffer; an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0152] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, phosphate buffer solution, an isotonicity agent selected from the group consisting of glucose, polyethylene glycol and glycerol, Includes.

[0153] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, -glucose as an isotonic agent Includes.

[0154] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, as isotonicity agents, polyethylene glycol, preferably PEG 400; Includes.

[0155] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, - glycerol as an isotonic agent, Includes.

[0156] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, - propylene glycol as an isotonic agent, Includes.

[0157] In a preferred embodiment, the pharmaceutical composition comprises: -GLP-1R agonist, phosphate buffer solution, - propylene glycol as an isotonic agent, Includes.

[0158] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, phosphate buffer solution, - propylene glycol as an isotonic agent, Includes.

[0159] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide or semaglutide, phosphate buffer solution, Propylene glycol as an isotonic agent; -phenol, Includes.

[0160] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, phosphate buffer solution, - propylene glycol as an isotonic agent, Includes.

[0161] In a preferred embodiment, the pharmaceutical composition comprises: -Liraglutide, phosphate buffer solution, Propylene glycol as an isotonic agent; -phenol, Includes.

[0162] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, phosphate buffer solution, - propylene glycol as an isotonic agent, Includes.

[0163] In a preferred embodiment, the pharmaceutical composition comprises: -Semaglutide, phosphate buffer solution, Propylene glycol as an isotonic agent; -phenol, Includes.

[0164] Advantageously, the pharmaceutical composition according to the invention does not contain propylene glycol.

[0165] Advantageously, the pharmaceutical composition of the present invention further comprises at least one additional excipient.The additional excipient may be a preservative.The preservative may be selected from the group consisting of phenol, cresol, resorcinol, paraben, and any combination thereof.Preferably, the preservative is phenol.

[0166] Advantageously, the pharmaceutical composition of the present invention comprises at least one further active agent used in the treatment of joint diseases, particularly osteoarthritis.The further active agent used in the treatment of joint diseases, particularly osteoarthritis, is an incretin such as GIP (glucose-dependent insulin releasing polypeptide), an inhibitor of dipeptidyl peptidase IV enzyme, a growth factor or growth factor targeting agent (FGF-18, BMP7, anti-NGF agent), a Wnt pathway molecular targeting agent (DYRK1A targeting agent, CLK2 targeting agent), a metalloprotease and / or aggrecanase targeting agent (ADAMTS4 targeting agent, ADAMTS5 targeting agent, MMP targeting agent), an aging pathway targeting agent. The therapeutic agent may be selected from the group consisting of anti-inflammatory agents, bone resorption molecular targeting agents (cathepsin K targeting drugs), analgesics (e.g., opioids, tramadol, acetaminophen, capsaicin), non-steroidal anti-inflammatory drugs (modified angiopoietin-like 3 (ANGPTL3) protein (e.g., LNA043) and anti-IL1 (e.g., anakinra, canakinumab)), steroidal anti-inflammatory drugs, symptomatic delayed-acting anti-arthritic agents (SYSADOA), hyaluronic acid, platelet-rich plasma (PRP)), alpha-1 glycoprotein and albumin.

[0167] Advantageously, the pharmaceutical composition of the present invention comprises at least one further active agent used in the treatment of joint diseases, in particular osteoarthritis.At least one further active agent used in the treatment of joint diseases, in particular osteoarthritis, is an incretin such as GIP (glucose-dependent insulin-releasing polypeptide), an inhibitor of dipeptidyl peptidase IV enzyme, a growth factor or growth factor targeting agent (FGF-18, BMP7, anti-NGF agent), a Wnt pathway molecule targeting agent (DYRK1A targeting agent, CLK2 targeting agent), a metalloprotease and / or aggrecanase targeting agent (ADAMTS4 targeting agent, ADAMTS5 targeting agent, MMP targeting agent), an aging pathway targeting agent, a bone resorption molecule targeting agent (cathepsin K targeting agent), an analgesic agent (e.g. , opioids, tramadol, acetaminophen, capsaicin), non-steroidal anti-inflammatory drugs (e.g., ibuprofen, ketoprofen, diclofenac, celecoxib, indomethacin), anti-arthritic drugs (modified angiopoietin-like 3 (ANGPTL3) protein (e.g., LNA043) anti-IL1 (e.g., anakinra, canakinumab)), steroidal anti-inflammatory drugs, symptomatic delayed-acting anti-arthritic agents (SYSADOA), hyaluronic acid, platelet rich plasma (PRP)), alpha-1 glycoprotein and albumin, and cell therapy (such as injection of stem cells and mesenchymal stromal cells).

[0168] The glucose-dependent insulin releasing polypeptide may be selected from the group consisting of GIP receptor antagonists (eg, anti-GIPR monoclonal antibody from Amgen) and tirzepatide (from Lilly).

[0169] The inhibitor of the dipeptidyl peptidase IV enzyme may be selected from the group consisting of sitagliptin, saxagliptin, vildagliptin, alogliptin and linagliptin.

[0170] The growth factor may be selected from the group consisting of fibroblast growth factor (FGF-18 sprifermin), NGF and BMP7 protein.

[0171] The growth factor targeting agent may be selected from the group consisting of a fibroblast growth factor targeting agent, an anti-NGF agent such as tanezumab, and a BMP7 protein targeting agent.

[0172] The Wnt pathway molecule targeting agent may be selected from the group consisting of a CLK2 inhibitor, a DYRK1A inhibitor, and loresivivint.

[0173] The metalloprotease and aggrecanase may be selected from the group consisting of an ADAMTS5 inhibitor and an ADAMTS5 antibody.

[0174] Targeting the senescence pathway can be an inhibitor of the MDM2-p53 interaction.

[0175] The bone resorbing molecule can be cathepsin K.

[0176] The analgesic agent may be selected from the group consisting of acetylsalicylic acid, lysine acetylsalicylate, phenylbutazone, sulindac, diclofenac potassium or sodium, aceclofenac, tiaprofenic acid, ibuprofen, ketoprofen, alminoprofen, fenoprofen, naproxen, flurbiprofen, indomethacin, mefenamic acid, niflumic acid, tenoxicam, meloxicam, piroxicam, celecoxib, etoricoxib, betamethasone, dexamethasone, prednisone, prednisolone, tixocortol, triamcinolone, CNTX-4975, and bedinvetomab.

[0177] The nonsteroidal anti-inflammatory drug may be selected from the group consisting of acetylsalicylic acid, lysine acetylsalicylate, phenylbutazone, sulindac, diclofenac potassium or sodium, aceclofenac, tiaprofenic acid, ibuprofen, ketoprofen, alminoprofen, fenoprofen, naproxen, flurbiprofen, indomethacin, mefenamic acid, niflumic acid, tenoxicam, meloxicam, piroxicam, celecoxib and etoricoxib.

[0178] The steroidal anti-inflammatory agent may be selected from the group consisting of betamethasone, dexamethasone, prednisone, prednisolone, tixocortol and triamcinolone.

[0179] The symptomatic slow acting anti-arthritic agent may be selected from the group consisting of chondroitin, chondroitin sulfate, glucosamine, glucosamine sulfate, diacerein, and unsaponifiable extracts of avocado and soybean (such as in the commercial product Piascledine®).

[0180] According to one embodiment, the at least one further active agent used in the treatment of a joint disease is selected from the group consisting of hyaluronic acid, albumin and alpha-1 glycoprotein.

[0181] In one embodiment, the pharmaceutical composition is a solution. The solution may be an aqueous solution. The aqueous solution may be an aqueous solution for injection, more particularly an aqueous solution for intra-articular injection.

[0182] In one embodiment, the pharmaceutical composition is a suspension. The solution may be an aqueous suspension. The aqueous suspension may be an aqueous suspension for injection, and more particularly an aqueous suspension for intra-articular injection.

[0183] Concentration of Compound in Pharmaceutical Composition Advantageously, the pharmaceutical composition comprises 2 mg / mL to 20 mg / mL, preferably 2 mg / mL to 8 mg / mL, more preferably 4 mg / mL to 8 mg / mL, even more preferably about 6 mg / mL of the GLP-1R agonist. In one embodiment, the pharmaceutical composition comprises about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of the GLP-1R agonist. In one embodiment, the pharmaceutical composition comprises about 2, 3, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist.

[0184] Advantageously, the pharmaceutical composition comprises 0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, Contains 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist.

[0185] Advantageously, the pharmaceutical composition comprises between 0.01 mg / mL and 100 mg / mL, preferably between 0.5 mg / mL and 80 mg / mL, more preferably between 1 mg / mL and 60 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 ...8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5 4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist.

[0186] Advantageously, the pharmaceutical composition comprises 2mg / mL to 20mg / mL, preferably 2mg / mL to 8mg / mL, more preferably 4mg / mL to 8mg / mL, even more preferably about 6mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is liraglutide. In one embodiment, the pharmaceutical composition comprises about 2, 3, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is liraglutide.

[0187] Advantageously, the pharmaceutical composition comprises from 0.01 mg / mL to 20 mg / mL, preferably from 0.5 mg / mL to 2 mg / mL, more preferably from 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is semaglutide. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7 , 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, where the GLP-1R agonist is semaglutide.

[0188] Advantageously, the pharmaceutical composition comprises from 0.01 mg / mL to 20 mg / mL, preferably from 0.5 mg / mL to 4 mg / mL, more preferably from 2.5 mg / mL to 3.5 mg / mL, even more preferably about 3.01 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is exenatide. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7 , 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is exenatide.

[0189] Advantageously, the pharmaceutical composition comprises from 0.01 mg / mL to 20 mg / mL, preferably from 0.01 mg / mL to 2 mg / mL, more preferably from 0.05 mg / mL to 1.0 mg / mL, even more preferably about 0.1 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is lixisenatide. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is lixisenatide.

[0190] Advantageously, the pharmaceutical composition comprises 0.01 mg / mL to 100 mg / mL, preferably 10 mg / mL to 80 mg / mL, more preferably 50 mg / mL to 70 mg / mL, even more preferably about 60 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is albiglutide. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is albiglutide.

[0191] Advantageously, the pharmaceutical composition comprises from 0.01 mg / mL to 20 mg / mL, preferably from 0.5 mg / mL to 2 mg / mL, more preferably from 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is veinaglutide. In one embodiment, the pharmaceutical composition comprises about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is veinaglutide.

[0192] Advantageously, the pharmaceutical composition comprises 0.01 mg / mL to 20 mg / mL, preferably 1.5 mg / mL to 9 mg / mL, more preferably 3 mg / mL to 9 mg / mL, even more preferably about 9 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is dulaglutide. In one embodiment, the pharmaceutical composition comprises about 00.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 ...4, 3.5, 3.6, 3.8, 3.9, 3.1, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.1, 3.2, 3.3, 3.4, 3. 0.8, 1.9, 2, 3, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is dulaglutide.

[0193] Advantageously, the pharmaceutical composition comprises 0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is pegapamodutide. In one embodiment, the pharmaceutical composition comprises about 00.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 ...8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.1, 3. 8, 1.9, 2, 3, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is pegapamodutide.

[0194] Advantageously, the pharmaceutical composition comprises 0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of the GLP-1R agonist, wherein the GLP-1R agonist is taspoglutide. In one embodiment, the pharmaceutical composition comprises about 00.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 ...4, 3.5, 3.6, 3.8, 3.9, 3.1, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.1, 3.2, 3.3, 3.4, 3. 0.8, 1.9, 2, 3, 4, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL of a GLP-1R agonist, wherein the GLP-1R agonist is taspoglutide.

[0195] Advantageously, the pharmaceutical composition comprises 0.1 mg / mL to 10 mg / mL, more preferably 0.5 mg / mL to 1 mg / mL, even more preferably about 0.97 mg / mL of tromethamine. In one embodiment, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 mg / mL of tromethamine.

[0196] Advantageously, the pharmaceutical composition comprises 0.80 mM to 80 mM, preferably 2 mM to 20 mM, more preferably 6 mM to 10 mM, even more preferably about 8 mM of tromethamine.

[0197] Advantageously, the pharmaceutical composition comprises between 0.1 mg / mL and 10 mg / mL, preferably between 0.75 mg / mL and 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate. In one embodiment, the pharmaceutical composition comprises between about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 mg / mL dibasic sodium phosphate. In one embodiment, the pharmaceutical composition comprises 0.70 mM to 70 mM, preferably 2 mM to 20 mM, more preferably 3 mM to 10 mM, even more preferably about 8 mM or about 3 mM dibasic sodium phosphate.

[0198] Advantageously, the pharmaceutical composition comprises dibasic sodium phosphate dihydrate at 0.05 mg / mL to 10 mg / mL, preferably at 0.25 mg / mL to 2.0 mg / mL. Preferably, the pharmaceutical composition comprises about 0.47 mg / mL dibasic sodium phosphate dihydrate. More preferably, the pharmaceutical composition comprises about 1.42 mg / mL dibasic sodium phosphate dihydrate. In one embodiment, the pharmaceutical composition comprises about 0.05, 0.1, 0.2, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.30, 1.31, 1.32, 1.33, 1.34, 1. Contains 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 mg / mL dibasic sodium phosphate dihydrate.

[0199] Advantageously, the pharmaceutical composition comprises between 10 mg / mL and 50 mg / mL, preferably between 20 mg / mL and 40 mg / mL, more preferably about 30 mg / mL glucose.In one embodiment, the pharmaceutical composition comprises about 10, 15, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45 or 50 mg / mL glucose.

[0200] Advantageously, the pharmaceutical composition comprises between 20 mg / mL and 100 mg / mL, preferably between 40 mg / mL and 80 mg / mL, more preferably about 60 mg / mL of polyethylene glycol, in particular PEG 400 or PEG 200, more particularly PEG 400. In one embodiment, the pharmaceutical composition comprises about 20, 25, 30, 35, 40, 45, 50, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 70, 75, 80, 85, 90, 95 or 100 mg / mL of polyethylene glycol, in particular PEG 400 or PEG 200, more particularly PEG 400.

[0201] Advantageously, the pharmaceutical composition comprises 5 mg / mL to 50 mg / mL, preferably 10 mg / mL to 25 mg / mL, more preferably about 17 mg / mL or about 18 mg / mL of glycerol.In one embodiment, the pharmaceutical composition comprises about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50 mg / mL of glycerol.

[0202] Advantageously, the pharmaceutical composition comprises 1 mg / mL to 20 mg / mL of propylene glycol. Preferably, the pharmaceutical composition comprises 1 mg / mL to 10 mg / mL, more preferably 4 mg / mL to 6 mg / mL, even more preferably about 4.7 mg / mL of propylene glycol. Preferably, the pharmaceutical composition comprises 10 mg / mL to 20 mg / mL, more preferably 12 mg / mL to 16 mg / mL, even more preferably about 14 mg / mL of propylene glycol. In one embodiment, the pharmaceutical composition comprises about 1, 2, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9 ...1, 10.2, 10.3, 10.4, 1 Contains 8, 6.9, 7, 8, 9, 10, 11, 12.0, 12.5, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.5, 16, 17, 18, 19 or 20 mg / mL propylene glycol.

[0203] Advantageously, the pharmaceutical composition comprises phenol at 0.1 mg / mL to 10 mg / mL, preferably 1 mg / mL to 7.5 mg / mL. Preferably, the pharmaceutical composition comprises phenol at 1 mg / mL to 2.5 mg / mL, more preferably about 1.8 mg / mL. Preferably, the pharmaceutical composition comprises phenol at 2.5 mg / mL to 7.5 mg / mL, more preferably about 5.5 mg / mL. In one embodiment, the pharmaceutical composition comprises phenol at about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 ...4, 3.5, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.8, 3.9, 3.1, 3.2, 3.4, 3.5, 3.5, 3.6, 3. Contains phenol at 0.5, 4.0, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 mg / mL.

[0204] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; -0.1 mg / mL to 10 mg / mL, preferably 0.75 mg / mL to 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate; - 10 mg / mL to 50 mg / mL, preferably 20 mg / mL to 40 mg / mL, more preferably about 30 mg / mL glucose, and -Water for injection It comprises or consists of:

[0205] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; - 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 1 mg / mL, more preferably about 0.97 mg / mL tromethamine; - 10 mg / mL to 50 mg / mL, preferably 20 mg / mL to 40 mg / mL, more preferably about 30 mg / mL glucose, and -Water for injection It comprises or consists of:

[0206] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; -0.1 mg / mL to 10 mg / mL, preferably 0.75 mg / mL to 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate; - PEG 400 at 20 mg / mL to 100 mg / mL, preferably at 40 mg / mL to 80 mg / mL, more preferably at about 60 mg / mL, and -Water for injection It comprises or consists of:

[0207] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; - 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 1 mg / mL, more preferably about 0.97 mg / mL tromethamine; - PEG 400 at 20 mg / mL to 100 mg / mL, preferably at 40 mg / mL to 80 mg / mL, more preferably at about 60 mg / mL, and -Water for injection It comprises or consists of:

[0208] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; -0.1 mg / mL to 10 mg / mL, preferably 0.75 mg / mL to 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate; - 5 mg / mL to 50 mg / mL, preferably 10 mg / mL to 25 mg / mL, more preferably about 17 mg / mL glycerol, and -Water for injection It comprises or consists of:

[0209] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; - 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 1 mg / mL, more preferably about 0.97 mg / mL tromethamine; - 5 mg / mL to 50 mg / mL, preferably 10 mg / mL to 25 mg / mL, more preferably about 18 mg / mL glycerol, and -Water for injection It comprises or consists of:

[0210] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; - dibasic sodium phosphate dihydrate, from 0.05 mg / mL to 10 mg / mL, preferably from 0.25 mg / mL to 2.0 mg / mL, more preferably about 0.47 mg / mL; - 1 mg / mL to 20 mg / mL, preferably 4 mg / mL to 6 mg / mL, more preferably about 4.7 mg / mL propylene glycol, and -Water for injection It comprises or consists of:

[0211] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; - dibasic sodium phosphate dihydrate, from 0.05 mg / mL to 10 mg / mL, preferably from 0.25 mg / mL to 2.0 mg / mL, more preferably about 0.47 mg / mL; - 1 mg / mL to 20 mg / mL, preferably 4 mg / mL to 6 mg / mL, more preferably about 4.7 mg / mL propylene glycol; - phenol at 0.1 mg / mL to 10 mg / mL, preferably 1 mg / mL to 2.5 mg / mL, more preferably about 1.8 mg / mL, and -Water for injection It comprises or consists of:

[0212] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; -0.05 mg / mL to 10 mg / mL, preferably 0.25 mg / mL to 2.0 mg / mL, more preferably about 1.42 mg / mL of dibasic sodium phosphate dihydrate; - 1 mg / mL to 20 mg / mL, preferably 12 mg / mL to 16 mg / mL, more preferably about 14 mg / mL propylene glycol, and -Water for injection It comprises or consists of:

[0213] Advantageously, the pharmaceutical composition comprises: -2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of liraglutide; -0.05 mg / mL to 10 mg / mL, preferably 0.25 mg / mL to 2.0 mg / mL, more preferably about 1.42 mg / mL of dibasic sodium phosphate dihydrate; - propylene glycol from 1 mg / mL to 20 mg / mL, preferably from 12 mg / mL to 16 mg / mL; - phenol at 0.1 mg / mL to 10 mg / mL, preferably 2.5 mg / mL to 7.5 mg / mL, more preferably about 5.5 mg / mL, and -Water for injection It comprises or consists of:

[0214] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; -0.1 mg / mL to 10 mg / mL, preferably 0.75 mg / mL to 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate; - 10 mg / mL to 50 mg / mL, preferably 20 mg / mL to 40 mg / mL, more preferably about 30 mg / mL glucose, and -Water for injection It comprises or consists of:

[0215] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; - 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 1 mg / mL, more preferably about 0.97 mg / mL tromethamine; - 10 mg / mL to 50 mg / mL, preferably 20 mg / mL to 40 mg / mL, more preferably about 30 mg / mL glucose, and -Water for injection It comprises or consists of:

[0216] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; -0.1 mg / mL to 10 mg / mL, preferably 0.75 mg / mL to 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate; - PEG 400 at 20 mg / mL to 100 mg / mL, preferably at 40 mg / mL to 80 mg / mL, more preferably at about 60 mg / mL, and -Water for injection It comprises or consists of:

[0217] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; - 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 1 mg / mL, more preferably about 0.97 mg / mL tromethamine; - PEG 400 at 20 mg / mL to 100 mg / mL, preferably at 40 mg / mL to 80 mg / mL, more preferably at about 60 mg / mL, and -Water for injection It comprises or consists of:

[0218] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; -0.1 mg / mL to 10 mg / mL, preferably 0.75 mg / mL to 1.5 mg / mL, more preferably about 1.14 mg / mL dibasic sodium phosphate; - 5 mg / mL to 50 mg / mL, preferably 10 mg / mL to 25 mg / mL, more preferably about 17 mg / mL glycerol, and -Water for injection It comprises or consists of:

[0219] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; - 0.1 mg / mL to 10 mg / mL, preferably 0.5 mg / mL to 1 mg / mL, more preferably about 0.97 mg / mL tromethamine; - 5 mg / mL to 50 mg / mL, preferably 10 mg / mL to 25 mg / mL, more preferably about 18 mg / mL glycerol, and -Water for injection It comprises or consists of:

[0220] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; - dibasic sodium phosphate dihydrate, from 0.05 mg / mL to 10 mg / mL, preferably from 0.25 mg / mL to 2.0 mg / mL, more preferably about 0.47 mg / mL; - 1 mg / mL to 20 mg / mL, preferably 4 mg / mL to 6 mg / mL, more preferably about 4.7 mg / mL propylene glycol, and -Water for injection It comprises or consists of:

[0221] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; - dibasic sodium phosphate dihydrate, from 0.05 mg / mL to 10 mg / mL, preferably from 0.25 mg / mL to 2.0 mg / mL, more preferably about 0.47 mg / mL; - 1 mg / mL to 20 mg / mL, preferably 4 mg / mL to 6 mg / mL, more preferably about 4.7 mg / mL propylene glycol; - phenol at 0.1 mg / mL to 10 mg / mL, preferably 1 mg / mL to 2.5 mg / mL, more preferably about 1.8 mg / mL, and -Water for injection It comprises or consists of:

[0222] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; -0.05 mg / mL to 10 mg / mL, preferably 0.25 mg / mL to 2.0 mg / mL, more preferably about 1.42 mg / mL of dibasic sodium phosphate dihydrate; - 1 mg / mL to 20 mg / mL, preferably 12 mg / mL to 16 mg / mL, more preferably about 14 mg / mL propylene glycol, and -Water for injection It comprises or consists of:

[0223] Advantageously, the pharmaceutical composition comprises: -0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of semaglutide; -0.05 mg / mL to 10 mg / mL, preferably 0.25 mg / mL to 2.0 mg / mL, more preferably about 1.42 mg / mL of dibasic sodium phosphate dihydrate; - propylene glycol from 1 mg / mL to 20 mg / mL, preferably from 12 mg / mL to 16 mg / mL; - phenol at 0.1 mg / mL to 10 mg / mL, preferably 2.5 mg / mL to 7.5 mg / mL, more preferably about 5.5 mg / mL, and -Water for injection It comprises or consists of:

[0224] The inventors have surprisingly found that the above-mentioned pharmaceutical composition according to the invention induces a long-lasting effect when administered via intra-articular injection, in particular an effect lasting for at least 3 weeks, more particularly an effect lasting for at least 4 weeks.

[0225] Pharmaceutical composition for use in treating at least one joint disease The present invention also relates to a pharmaceutical composition according to the invention as described above for use in the treatment of at least one joint disease.

[0226] The present invention also relates to a method for treating at least one joint disease by administering to a patient in need thereof an effective amount of the pharmaceutical composition according to the present invention described above.

[0227] The present invention also relates to the use of the pharmaceutical composition according to the invention as described above for the manufacture of a medicament for the treatment of at least one joint disease.

[0228] The present invention also relates to the use of the pharmaceutical composition according to the invention described above for the treatment of at least one joint disease.

[0229] The present invention also relates to a pharmaceutical composition according to the invention as described above for use in a method for treating at least one joint disease.

[0230] All the above mentioned features relating to the pharmaceutical composition according to the invention apply mutatis mutandis to the pharmaceutical composition according to the invention for use in the treatment of at least one joint disease, to a method for treating at least one joint disease by administering an effective amount of the pharmaceutical composition according to the invention to a patient in need thereof, to the use of the pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment of at least one joint disease, to the use of the pharmaceutical composition according to the invention for the treatment of at least one joint disease and to the pharmaceutical composition according to the invention for use in a method for treating at least one joint disease.

[0231] Joint disorders Advantageously, said at least one joint disease is a chronic disease. The chronic disease may be osteoarthritis.

[0232] Advantageously, said at least one joint condition is an acute condition. The acute condition may be acute pain.

[0233] Advantageously, said at least one joint disease is selected from the group consisting of osteoarthritis, joint pain, and combinations thereof.In a preferred embodiment, said at least one joint disease is joint pain.Joint pain can be inflammatory joint pain or non-inflammatory joint pain.

[0234] The joint disease to be treated, particularly osteoarthritis, may affect any joint, such as the hip joint (osteoarthritis), knee joint (osteoarthritis), ankle joint, ankle joint, wrist joint, elbow joint, shoulder joint, spinal joint, and / or temporomandibular joint.Preferably, the joint disease to be treated, particularly osteoarthritis, affects the hip joint, knee joint, wrist joint, and / or spinal joint.

[0235] Treating at least one joint disease can include reducing existing joint inflammation in a subject in need thereof.

[0236] Treating at least one joint disease may include increasing chondrocyte proliferation and / or chondrocyte differentiation, and / or reducing synovitis in a subject in need thereof.

[0237] Administration In one embodiment, the pharmaceutical composition is or will be administered by intra-articular injection, in particular by intra-articular injection into the joint cavity.

[0238] The pharmaceutical composition may be administered in combination with at least one other locally acting substance, such as hyaluronic acid, a nonsteroidal anti-inflammatory drug, a stem cell, a growth factor (such as sprifermin or BMP7), an MMP inhibitor, a Wnt inhibitor and / or an analgesic substance.

[0239] Advantageously, the pharmaceutical composition is administered or will be administered at a dose of 0.7 μg to 180 μg of liraglutide, preferably 20 μg to 180 μg, more preferably 20 μg to 120 μg of liraglutide. One dose refers to the cumulative amount of GLP-1R agonist administered over 2 weeks to 1 month. In one embodiment, the pharmaceutical composition is administered at a dose of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 1 are administered or will be administered at a dose of 51, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179 or 180 μg of liraglutide.

[0240] Advantageously, the pharmaceutical composition is or will be administered in a dose of 0.7 μg to 180 μg of liraglutide, preferably 20 μg to 180 μg, more preferably 20 μg to 120 μg of liraglutide. One dose refers to the cumulative amount of GLP-1R agonist administered over 2 weeks to 1 month. In one embodiment, the pharmaceutical composition comprises 0.7, 1, 2, 2.2, 3, 4, 5, 6, 6.7, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 10 5, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 25 170, 171, 172, 173, 174, 175, 176, 177, 178, 179 or 180 μg of liraglutide.

[0241] Advantageously, the pharmaceutical composition is or will be administered in a dose of 0.7 μg to 180 μg of semaglutide, preferably 20 μg to 180 μg, more preferably 20 μg to 120 μg of semaglutide. One dose refers to the cumulative amount of GLP-1R agonist administered over 2 weeks to 1 month. In one embodiment, the pharmaceutical composition comprises 0.7, 1, 2, 2.2, 3, 4, 5, 6, 6.7, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 10 5, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 25 semaglutide doses of 170, 171, 172, 173, 174, 175, 176, 177, 178, 179 or 180 μg.

[0242] Advantageously, the pharmaceutical composition is or will be administered in a dose of 0.0245 mg to 6.3 mg of liraglutide, preferably 0.7 mg to 6.3 mg of liraglutide. According to one embodiment, the pharmaceutical composition is or will be administered in a dose of 0.0245 mg to 6.3 mg of liraglutide, preferably 0.3 mg to 6.0 mg of liraglutide. One dose refers to the cumulative amount of GLP-1R agonist administered over 2 weeks to 1 month. In one embodiment, the pharmaceutical composition comprises 0.0245, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0. .38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.1 6, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.2 0, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4 In one embodiment, the pharmaceutical composition is or will be administered at a dose of 0.3 mg, 1.0 mg, 3.0 mg or 6.0 mg of liraglutide.

[0243] Advantageously, the pharmaceutical composition is or will be administered in a dose of 0.0245 mg to 6.3 mg of semaglutide, preferably 0.7 mg to 6.3 mg, preferably 0.25 to 1 mg of semaglutide. One dose refers to the cumulative amount of GLP-1R agonist administered over 2 weeks to 1 month. In one embodiment, the pharmaceutical composition comprises 0.0245, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41 ,0.42,0.43,0.44,0.45,0.46,0.47,0.48,0.49,0.50,0.51,0.52,0.53,0.54,0.55,0.56,0.57,0.58,0.59,0.60,0.61,0.62,0.63,0.64,0.65,0.66,0.67,0.67,0.68,0.69,0.70,0.71,0.72,0.73,0.74,0.75,0.76,0.77,0.78,0.79,0.80,0.81,0.82,0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1 .27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2. 00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.5 5, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.1 In one embodiment, the pharmaceutical composition is or will be administered at a dose of 0, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55, 5.60, 5.65, 5.70, 5.75, 5.80, 5.85, 5.90, 5.95, 6.00, 6.05, 6.10, 6.15, 6.20, 6.25 or 6.3 mg of semaglutide. In one embodiment, the pharmaceutical composition is or will be administered at a dose of 0.25, 0.5 or 1 mg of semaglutide.

[0244] Advantageously, said doses of said pharmaceutical composition are or will be administered in one or at least two intra-articular injections.

[0245] Advantageously, said doses of said pharmaceutical composition are or will be administered in one or at least two intra-articular injections in the same joint.

[0246] In one embodiment, the above-mentioned dose of the above-mentioned pharmaceutical composition is administered or will be administered in one intra-articular injection. For example, the dose is 20 μg of liraglutide or semaglutide, and is administered or will be administered in one intra-articular injection. For example, the dose is 20 μg of liraglutide, and is administered or will be administered in one intra-articular injection. For example, the dose is 20 μg of semaglutide, and is administered or will be administered in one intra-articular injection. As another example, the dose is 0.3 mg, 1.0 mg, 3.0 mg or 6.0 mg of liraglutide, and is administered or will be administered in one intra-articular injection. As another example, the dose is 0.25, 0.5 or 1 mg of semaglutide, and is administered or will be administered in one intra-articular injection. This intra-articular injection can be repeated every 2 weeks. This intra-articular injection can be repeated every 3 weeks. This intra-articular injection may be repeated monthly.

[0247] Advantageously, the dose is 0.3 mg of liraglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0248] Advantageously, the dose is 1.0 mg of liraglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0249] Advantageously, the dose is 3.0 mg of liraglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0250] Advantageously, the dose is 6.0 mg of liraglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0251] Advantageously, the dose is 0.25 mg of semaglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0252] Advantageously, the dose is 0.5 mg of semaglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0253] Advantageously, the dose is 1 mg of semaglutide, administered or to be administered in a single intra-articular injection, which is repeated every 2 weeks, every 3 weeks or monthly.

[0254] In another embodiment, the dose of the pharmaceutical composition is or will be administered in two intra-articular injections, for example, both intra-articular injections are or will be administered on the same day, or both injections are or will be administered on different days, especially in the same joint.In particular, the dose of the pharmaceutical composition can be administered in two intra-articular injections: for example, one at J1 and the second at J8, or one at J1 and the second at J15.

[0255] If this dose is administered or will be administered in multiple injections, each injection may contain the same amount of GLP-1R agonist or different amounts of GLP-1R agonist.For example, the dose is 20 μg of liraglutide, and is administered or will be administered in two intra-articular injections of 10 μg of liraglutide: the first injection at J1 and the second injection at J8, or the first injection at J1 and the second injection at J15; these two injections may be repeated every three weeks, i.e., the first additional injection is J22. These two injections may be repeated every month, i.e., the first additional injection is J29. If the first injection is J1 and the second injection is J8, the two injections may be repeated every two weeks, i.e., the first additional injection is J15. For example, the dose is 0.3 mg, 1.0 mg, 3.0 mg or 6.0 mg of liraglutide, which is administered or will be administered with two intra-articular injections of 0.15 mg, 0.5 mg, 1.5 mg or 3.0 mg of liraglutide, respectively: one injection at J1 and a second injection at J8, or one injection at J1 and a second injection at J15; these two injections may be repeated every three weeks, i.e., the further first injection is J22. These two injections may be repeated monthly, i.e., the further first injection is J29. If the first injection is J1 and the second injection is J8, the two injections may be repeated every two weeks, i.e., the further first injection is J15. In yet another example, the dose is 20 μg of semaglutide and two intra-articular injections of 10 μg of semaglutide are administered or will be administered: a first injection at J1 and a second injection at J8, or a first injection at J1 and a second injection at J15; these two injections may be repeated every three weeks, i.e. the first further injection is J22. These two injections may be repeated monthly, i.e. the first further injection is J29. If the first injection is J1 and the second injection is J8, the two injections may be repeated every two weeks, i.e. the first further injection is J15.In yet another example, the dose is 0.25, 0.5 or 1 mg of semaglutide, which is or will be administered with two intra-articular injections of 0.125 mg, 0.25 mg or 0.5 mg of semaglutide, respectively: one injection at J1 and a second injection at J8, or one injection at J1 and a second injection at J15; these two injections may be repeated every three weeks, i.e. the further first injection is J22. These two injections may be repeated monthly, i.e. the further first injection is J29. If the first injection is J1 and the second injection is J8, the two injections may be repeated every two weeks, i.e. the further first injection is J15.

[0256] Indeed, the present inventors have surprisingly found that two intra-articular injections of half the dose of liraglutide (one injection at J1 and one injection at J8) induce the same analgesic effect and the same duration of analgesic effect as one intra-articular injection of a dose of liraglutide (at J1). For example, two intra-articular injections of 10 μg of liraglutide (one injection at J1 and one injection at J8) induce the same analgesic effect and the same duration of analgesic effect as one intra-articular injection of 20 μg of liraglutide (at J1).

[0257] In one embodiment, several doses of the pharmaceutical composition are administered or will be administered to the subject, and the doses are administered every two weeks to one month. In a preferred embodiment, several doses of the pharmaceutical composition are administered or will be administered to the subject, and the doses are administered every three weeks. In a more preferred embodiment, several doses of the pharmaceutical composition are administered or will be administered to the subject, and the doses are administered monthly.

[0258] Indeed, the inventors of the present invention have surprisingly found that the pharmaceutical composition according to the present invention has an analgesic effect lasting for 3 weeks after acute intra-articular administration, in particular an analgesic effect lasting for 4 weeks after acute intra-articular administration. [Brief description of the drawings]

[0259] [Figure 1] Determination of IC50 on NO secretion by liraglutide preformulation 1 at different concentrations ranging from 4.1 nM to 3 μM in LPS-stimulated conditions (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Diagram 2] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 2 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n=4 (each condition performed in quadruplicate). [Diagram 3] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 3 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 4] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 4 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Diagram 5] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 5 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 6] Determination of IC50 on NO secretion by liraglutide preformulation 6 at different concentrations ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 7] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 7 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 8] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 8 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 9]Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 9 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 10] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 10 ranging from 4.1 nM to 3 μM in LPS stimulated condition (nM). Mean ± SEM, n = 4 (each condition performed in quadruplicate). [Figure 11] Determination of IC50 on NO secretion by Victoza® at different concentrations ranging from 4.1 nM to 3 μM under LPS-stimulated conditions (nM). Mean ± SEM, n=4 (each condition performed in quadruplicate). [Figure 12] Determination of IC50 on NO secretion by different concentrations of liraglutide preformulation 2 ranging from 4.1 nM to 3 μM under IL-1β stimulated condition (nM). Mean ± SEM, n=4 (each condition performed in quadruplicate) [Figure 13] Determination of IC50 on NO secretion by liraglutide preformulation 6 at different concentrations ranging from 4.1 nM to 3 μM under IL-1β stimulated condition (nM). Mean ± SEM, n=4 (each condition performed in quadruplicate) [Figure 14] Measurement of IC50 on NO secretion by Victoza® (PBS) at different concentrations ranging from 4.1 nM to 3 μM under IL-1β stimulation conditions (nM). Mean ± SEM, n = 4 (each condition was performed in quadruplicate). [Figure 15] Von Frey test of withdrawal threshold in the right hind paw up to day 11. Mean ± SEM, n = 8 / group. [Figure 15A] Preformulation-2 compared to control vehicle, MIA / vehicle and Victoza (20 μg) groups. [Figure 15B]Preformulation-6 compared to control vehicle, MIA / vehicle and Victoza (20μg) groups. -***p<0.001 control / vehicle (1M) vs. MIA / vehicle group (2M) on D2, D7 and D10. -***p<0.001 Victoza 20μg group (3M) vs. MIA / vehicle group (2M) on D7 and D10; -***p<0.001 MIA / vehicle group (2M) vs. preformulation-2 and -6 (9M, 8M, 6M and 5M) on D7 and D10 in 20μg and 120μg groups. -**p<0.001 preformulation-2 with MIA / vehicle (2M) vs. 3.3μg (4M) at D7; -***p<0.001 preformulation-2 with MIA / vehicle (2M) vs. 3.3μg (4M) at D10; -**p<0.01 preformulation-2 with MIA / vehicle (2M) vs. 3.3μg (7M) at D7; -***p<0.01 preformulation-2 with MIA / vehicle (2M) vs. 3.3μg (7M) at D10; [Figure 16] Von Frey test of withdrawal threshold in the right hind paw up to day 32. Mean ± SEM, n=8 / group. **p<0.01, ***p<0.001 vs. MIA / vehicle group 2M. [Figure 17]Von Frey test of withdrawal threshold in the right hind paw by day 31. Mean ± SEM, n = 8 per group. Figure 17A: Three of the six doses of preformulation-2 compared to the control vehicle, MIA / vehicle, MIA / Victoza® (20 μg) and MIA / Ozempic® (20 μg) groups. Figure 17B: Three other doses of preformulation-2 compared to the control vehicle, MIA / vehicle, MIA / Victoza® (20 μg) and MIA / Ozempic® (20 μg) groups. ***p<0.001 control / vehicle (11M) vs. MIA / vehicle group (12M) at D2, D7, D10, D18, D25, and D31. **p<0.01 preformulation at D7-20.7μg group (13M) vs. MIA / vehicle group (2M);*p<0.05 preformulation at D10-20.7μg group (13M) vs. MIA / vehicle group (2M);**p<0.01 preformulation at D7 and D10-22.2μg group (14M) vs. MIA / vehicle group (2M);***p<0.001 preformulation at D7 and D10-26.7μg, 20μg, and 60μg groups (15M, 16M, and 17M) vs. MIA / vehicle group (2M).***p<0.001 preformulation at D7, D10, D18, D25, and D31-2180μg group (18M) vs. MIA / vehicle group (2M). ***p<0.001 Victoza 20μg (19M) vs. MIA / vehicle (2M) at D7, D10, D18, D25 and D31. ***p<0.001 Ozempic 20μg (19M) vs. MIA / vehicle (2M) at D7, D10, D18, D25 and D31.

[0260] [Figure 18]Von Frey filament test results for withdrawal threshold in the right hind paw. $$$p<0.001 control / vehicle (31M) vs. MIA / vehicle and treatments (32M, 33M, 34M, 35M, 36M, and 37M) on day 2. *p<0.05 MIA / vehicle (32M) vs. exenatide (E2) treatment (35M) on day 7. **p<0.01 MIA / vehicle (32M) vs. lixisenatide (36M) on day 7. **p<0.01 MIA / vehicle (32M) vs. exenatide (E1) treatment (34M) on days 10 and 30. ***p<0.001 MIA / vehicle group (32M) vs. liraglutide treatment group (37M) on days 7, 10, 18, 24 and 30. ***p<0.001 MIA / vehicle group (32M) vs. lixisenatide treatment group (36M) on days 7, 10, 18, 24 and 30. ***p<0.001 MIA / vehicle group (32M) vs. exenatide (E2) treatment group (35M) on days 10, 18, 24 and 30. ***p<0.001 MIA / vehicle group (32M) vs. exenatide (E1) treatment group (34M) on days 10, 18 and 24. ***p<0.001 MIA / vehicle group (32M) vs. dulaglutide-treated group (33M) on days 7, 10, 18, 24, and 30. ***p<0.001 MIA / vehicle group (32M) vs. vehicle / control group (31M) on days 2, 7, 10, 18, 24, and 30. Mean ± SEM, n=4 / group up to day 7. Mean ± SEM, n=7-8 / group from day 10 onwards. All scores in the 31M-vehicle group were ≥15(g). [Figure 19] Mechanical pain assessment (incapacitance test) for groups 41M, 42M, 43M, and 44M. *p<0.05, **p<0.01, ***p<0.001. There were no significant differences between control group 41M and treatment groups 43M and 44M, so they are not shown in FIG. 19. [Figure 20]Von Frey test results for withdrawal threshold in the right hind paw. MIA / vehicle (46M) vs. control / vehicle (45M) (Mann-Whitney test; ***p<0.001). MIA / vehicle (46M) vs. MIA pre-formulation 2 and pre-formulation 11 (47M and 48M) (Mann-Whitney test; *p<0.05, **p<0.01, ***p<0.001). [Figure 21] Plasma dose of liraglutide for groups 51M, 52M, and 53M. [Figure 22] Liraglutide synovial doses for groups 54M, 55M, and 56M.

[0261] Working Example The present invention is further illustrated by the following examples. Example 1: pH and osmolality of compositions according to the invention Six pharmaceutical compositions were prepared.

[0262] Preformulation 1 contained: 6 mg / mL liraglutide, 8 mM dibasic sodium phosphate, 30 mg / mL glucose and water for injection.

[0263] Preformulation 2 contained: 6 mg / mL liraglutide, 8 mM tromethamine, 30 mg / mL glucose and water for injection.

[0264] Preformulation 5 contained: 6 mg / mL liraglutide, 8 mM dibasic sodium phosphate, 60 mg / mL PEG 400 and water for injection.

[0265] Preformulation 6 contained: 6 mg / mL liraglutide, 8 mM tromethamine, 60 mg / mL PEG400 and water for injection.

[0266] Preformulation 7 contained: 6 mg / mL liraglutide, 8 mM dibasic sodium phosphate, 17 mg / mL glycerol and water for injection.

[0267] Preformulation 8 contained: 6 mg / mL liraglutide, 8 mM tromethamine, 18 mg / mL glycerol and water for injection.

[0268] The pH and osmolality of the compositions were measured.

[0269] [Table 1]

[0270] The osmolality and particle size measurements are shown in the following table.

[0271] [Table 2]

[0272] The six compositions appeared to have a pH that allowed solubilization of liraglutide. Moreover, the osmolality values ​​after 48 hours and one month were similar to those obtained at T0. The osmolality of the compositions was therefore stable.

[0273] Example 2: In vitro efficacy of ten compositions according to the invention on the murine macrophage cell line RAW264.7 Test Systems The cell line used was RAW264.7 (macrophage from Balb / C male mice transformed with Abelson murine leukemia virus) and its ATCC reference number is TIB-71.

[0274] Test Articles and Test Article Vehicles

[0275] [Table 3]

[0276] Preformulations 1, 2, 5, 6, 7 and 8 of Example 2 are identical to preformulations 1, 2, 5, 6, 7 and 8 of Example 1, respectively.

[0277] formulation For the 10 preformulations, unless another reference is indicated, Glucose is Sigma 16325-SZBF2860V, Dibasic Sodium Phosphate is Sigma-04276-90900, Tromethamine is Sigma T6687-WXBC2569V, Dulbecco's Phosphate Buffered Saline is Sigma D8662-RNBJ0600, Propylene Glycol is Sigma 16033-SZBC2900V, PEG400 is Sigma 81172-BCBT2825, and Glycerol is Fluka 49783-BCBD0423.

[0278] LPS (Sigma), supplied as a powder, was prepared at 1 mg / ml in PBS. A concentrated stock solution was diluted in DMEM treatment medium to a final concentration of 100 ng / ml for the experiments.

[0279] Liraglutide preformulations (1-10) supplied as a solution at 6 mg / ml liraglutide were diluted in PBS as stock solutions. The concentrated stock solutions were then diluted in DMEM treatment medium to reach final concentrations of 3 μM, 1 μM, 333.3 nM, 111.1 nM, 37.0 nM, 12.3 nM and 4.1 nM.

[0280] Victoza® (Novo Nordisk) is a commercially available liraglutide drug. The test article, supplied as a solution at 6 mg / ml, was diluted in PBS as a stock solution. The concentrated stock solution was then diluted in DMEM treatment medium to reach final concentrations of 3 μM, 1 μM, 333.3 nM, 111.1 nM, 37.0 nM, 12.3 nM and 4.1 nM. Victoza® and test articles derived from Victoza® are compositions according to the present invention, since they contain a GLP-1R agonist (liraglutide), a phosphate buffer and propylene glycol as an isotonic agent.

[0281] Vehicle (PBS) was provided "ready to use" and diluted in cell treatment medium at a final concentration of 1:100.

[0282] Experimental design

[0283] cell culture Cells were grown to 80% confluence, harvested using a cell scraper, and resuspended in new flasks until sufficient cells were obtained to begin the study.

[0284] sowing Cells were harvested at 70-80% confluence using a cell scraper, counted, and plated at 1x10 in seeding medium (DMEM high glucose + 1% P / S). 6 The cells were resuspended to a final concentration of 1000 cells / ml. The cells were then seeded into 96-well microtiter plates (100 μl / well to 100,000 cells / well). The cell cultures were maintained under sterile conditions in an incubator at 37° C. with 5% CO for 24 hours.

[0285] treatment Seeding medium was aspirated from the 96 microtiter plate. Then, 200 μl of medium containing vehicle or LPS at 00 ng / ml with different doses of pre-formulated liraglutide or Victoza® (4.1 nM to 3 μM) or vehicle was added to each well according to Table 4 for study design and Table 5 for study timeline. Plates were incubated at 37° C., 5% CO2 for 24 hours.

[0286] [Table 4] TIFF2024524277000006.tif195159TIFF2024524277000007.tif52159

[0287] Each condition treatment was performed in quadruplicate.

[0288] [Table 5]

[0289] Testing and Evaluation At the end of the test, the culture medium (±200 μl) of each well was collected into 1.5 ml tubes (1 tube / well), centrifuged at 4000 rpm at room temperature, and the supernatant was added to a new 1.5 ml tube.

[0290] Nitrite oxide dosage (Griess reagent) The nitrite reagent assay was performed according to the manufacturer's instructions (Nitrite Reagent Assay, Promega). The test system is based on a chemical reaction that converts sulfanilamide to an azo compound in the presence of nitrite ion (NO2-) and N-1-naphthylethylenediamine dihydrochloride (NED). The coloration of the azo compound is detectable at 540 nm. The solution is "ready to use". Nitrite standards were diluted in culture medium to obtain a reference curve (0-100 μM) for quantification. 50 μl of blank, standard, or culture supernatant was added to the wells of a 96-well microtiter plate. 50 μl of sulfanilamide solution was added to the wells and the plate was incubated for 5-10 min in the dark. Then, 50 μl of NED solution was added to the wells and the plate was incubated for 5-10 min in the dark. A purple / magenta color developed immediately and the absorbance was measured within 30 min at 540 nm. The average optical density (OD) of the blank wells read was subtracted from each reading. The nitrite concentration was calculated from the reference curve.

[0291] As expected, NO production in vehicle conditions was below the detection limit, which was 1.56 μM. In LPS-stimulated conditions, detection of nitrite oxide in the culture medium was significantly increased compared to vehicle. This secretion was significantly reduced by each tested dose of the liraglutide composition according to the invention (i.e., preformulations 1-10 and Victoza® test article) compared to the LPS-only condition, with a sigmoidal dose-response pattern. The results are shown in Figures 1-11. IC 50was calculated for each formulation using Prism software and the results are summarized in Table 6.

[0292] IC of liraglutide preformulation 1 on NO secretion in RAW264.7 cells cultured under high glucose conditions 50 The dose was 53 nM with a confidence interval of 48 nM to 59 nM (Figure 1); IC of liraglutide preformulation 2 on NO secretion 50 The dose was 51 nM with a confidence interval of 44 nM to 59 nM (Figure 2); IC of liraglutide preformulation 3 on NO secretion 50 The dose was 50 nM with a confidence interval of 43 nM to 59 nM (Figure 3); IC of liraglutide preformulation 4 on NO secretion 50 The dose was 61 nM with a confidence interval of 52 nM to 72 nM (Figure 4); IC of liraglutide preformulation 5 on NO secretion 50 The dose was 53 nM with a confidence interval of 47 nM to 61 nM (Figure 5); IC of liraglutide preformulation 6 on NO secretion 50 The dose was 49 nM with a confidence interval of 42 nM to 57 nM (Figure 6); IC of liraglutide preformulation 7 on NO secretion 50 The dose was 54 nM with a confidence interval of 47 nM to 62 nM (Figure 7); IC of liraglutide preformulation 8 on NO secretion 50 The dose was 48 nM with a confidence interval of 43 nM to 55 nM (Figure 8); IC of liraglutide preformulation 9 on NO secretion 50 The dose was 53 nM with a confidence interval of 47 nM to 59 nM (Figure 9); IC of liraglutide preformulation 10 on NO secretion 50 The dose was 50 nM with a confidence interval of 42 nM to 58 nM (Figure 10); IC of Victoza® (PBS) on NO secretion 50 The dose was 52 nM with a confidence interval of 46 nM to 58 nM (Figure 11).

[0293] [Table 6]

[0294] conclusion The objective of this study was to test seven doses of ten preformulated liraglutide in comparison with the commercially available liraglutide drug, Victoza® (4.1 nM to 3 μM), in RAW264.7 cells, a mouse macrophage cell line.

[0295] The inventors demonstrated that all compositions according to the present invention (i.e., liraglutide preformulations 1-10 and Victoza® test article) were able to dose-dependently inhibit LPS-induced NO production in RAW264.7 cells.

[0296] IC of liraglutide preformulations 1-10, liraglutide API and Victoza® on NO production in RAW264.7 cell line model under LPS-stimulated conditions 50 Doses were calculated. The inventors confirmed that the ten tested liraglutide preformulations 1-10 generally had the same anti-inflammatory effect as Victoza®.

[0297] Preformulations 1-10 demonstrated in vitro efficacy with average IC values ​​ranging from 48 nM to 61 nM. 50 It has a value.

[0298] Example 3: In vitro efficacy of preformulations 2 and 6 from Example 2 on mouse primary chondrocytes Test Systems

[0299] Mouse primary chondrocytes derived from C57Bl / 6 newborn mice.

[0300] Test Articles and Test Article Vehicles [Table 7]

[0301] Preformulations 2 and 6 are identical to preformulations 2 and 6 of Example 1, respectively.

[0302] Formulation: Interleukin-1β (IL-1β) (PeproTech), supplied as a powder, was dissolved in water as a stock solution at 0.1 mg / ml. The concentrated stock solution was then diluted to a final concentration (2 ng / ml) in medium containing supplements (P / S, BSA, + / - liraglutide).

[0303] Liraglutide preformulations (2 and 6) supplied as a solution at 6 mg / ml were diluted in PBS as stock solutions. The concentrated stock solutions were then diluted in DMEM medium to reach final concentrations of 3 μM, 1 μM, 333.3 nM, 111.1 nM, 37.0 nM, 12.3 nM and 4.1 nM.

[0304] Victoza® is a commercially available liraglutide drug. The test article, supplied as a solution at 6 mg / ml, was diluted in PBS as a stock solution. The concentrated stock solution was then diluted in DMEM medium to reach final concentrations of 3 μM, 1 μM, 333.3 nM, 111.1 nM, 37.0 nM, 12.3 nM and 4.1 nM. Victoza® and test articles derived from Victoza® are compositions according to the present invention since they contain a GLP-1R agonist (liraglutide), a phosphate buffer and propylene glycol as an isotonic agent.

[0305] Vehicle (PBS) was provided "ready to use" and diluted in cell seeding medium at a final concentration of 1:100.

[0306] Experimental design Isolation of mouse articular cartilage Immature mouse chondrocytes were derived from neonatal mice (C57Bl / 6, 5-6 days old). The joint was cleared from the surrounding tissue with a scalpel, then cut in half to separate it into two spheres, which were then cut in half again. This facilitates digestion. The femoral head, condyle, and tibial plateau were also placed in 30 ml of 1X PBS.

[0307] Isolation of immature mouse chondrocytes Cartilage pieces were incubated twice in 10 ml of digestion solution (DMEM, 2 mM L-glutamine, 1 g / L glucose + 1% P / S + collagenase 3 mg / ml) in a 100 mm Petri dish in an incubator at 37°C and 5% CO2 for 45 minutes. Between the two digestions, the cartilage pieces were removed and placed in a new Petri dish. After the two digestions, dispersion of aggregates was performed to obtain a suspension of isolated cells. Cartilage pieces were incubated overnight in an incubator at 37°C and 5% CO2 in 10 ml of DMEM, 2 mM L-glutamine, 1 g / L glucose + 1% P / S containing collagenase D solution (diluted 1 / 6) at 0.5 mg / ml.

[0308] Chondrocyte seeding After overnight digestion, 10 ml of DMEM, 2 mM L-glutamine, 1 g / L glucose + 10% FBS + 1% P / S was added to the Petri dish to stop the action of collagenase D. After reducing the pipette size to disperse the aggregates, a suspension of isolated cells was obtained and filtered through a sterile 70 μm cell strainer. The cells were then centrifuged at 400 g for 10 min at 20° C. The medium was removed and the pellet was resuspended in 5 ml of PBS to wash the cells. The cells were centrifuged at 400 g for 10 min at 20° C. and the PBS was replaced by 15 ml of DMEM, 2 mM L-glutamine, 1 g / L glucose + 10% FBS + 1% P / S. The chondrocytes were counted in a Neubauer hemocytometer and observed to assess the viability of the extracted cells. Chondrocytes were cultured at 40x10 per well in 12-well plates in 2 ml of DMEM containing 2 mM L-glutamine, 1 g / L glucose + 10% FBS + 1% P / S. 3 Cells were seeded at a density of 1000×, ...2000×, 3000×, 4000×, 5000×, 6000×, 7000×, 8000×, and 900×. Cultures were maintained under sterile conditions in an incubator at 37° C. and 5% CO2.

[0309] Chondrocyte culture Immature mouse articular chondrocytes are expected to reach confluence by 6-7 days of culture. Culture medium was changed after 3 days of culture. On day 7, DMEM medium with 10% FBS was removed, wells were rinsed twice with 1 ml PBS, and 1 ml DMEM, 2 mM L-glutamine, 1 g / L glucose + 1% P / S + 0.1% BSA was added. On day 8, medium was removed. 500 μl of fresh DMEM with 2 mM L-glutamine, 1 g / L glucose + 1% P / S + 0.1% BSA, containing 2 ng / ml IL-1β ± liraglutide preformulation or Victoza® was added to each well according to Table 8. Plates were incubated at 37°C + 5% CO2 for 24 hours.

[0310] [Table 8]

[0311] Each condition treatment was performed in quadruplicate.

[0312] [Table 9]

[0313] Testing and Evaluation At the end of the study, the culture medium from each well (±500 μl) was collected into 1.5 ml tubes (1 tube / well), centrifuged at 4000 rpm at room temperature, and the supernatant was added to a new 1.5 ml tube. Samples were stored at 2-8°C for 2-3 days or frozen at -70°C if the Griess reagent assay was not performed on the same day.

[0314] As expected, NO production in vehicle conditions was below the detection limit, at 1.56 μM. In IL-1β stimulated conditions, detection of nitrite oxide in the culture medium was significantly increased compared to vehicle. This secretion was significantly reduced by each tested dose of liraglutide preformulation or Victoza® compared to IL-1β alone conditions, with a sigmoidal dose-response pattern. IC 50was calculated for each formulation using Prism software and summary results are shown in Table 10.

[0315] IC of liraglutide preformulation 2 on NO secretion in mouse primary chondrocytes cultured under low glucose conditions 50 The dose was 60 nM with a confidence interval of 53 nM to 69 nM (Figure 12); IC of liraglutide preformulation 6 on NO secretion 50 The dose was 55 nM with a confidence interval of 46 nM to 64 nM (Figure 13); IC of Victoza® on NO secretion 50 The dose was 52 nM with a confidence interval of 46 nM to 59 nM (Figure 14).

[0316] [Table 10]

[0317] conclusion The objective of this study was to test seven doses of two selected liraglutide preformulations 2 and 6 in comparison with Victoza®, a commercially available liraglutide drug (4.1 nM to 3 µM), in mouse primary chondrocytes.

[0318] The inventors have demonstrated that compositions according to the present invention (i.e., liraglutide preformulations 2 and 6, and Victoza® test article) can dose-dependently inhibit IL-1β-induced NO production in mouse primary chondrocytes. IC of liraglutide preformulations 2 and 6 and Victoza® on NO production in mouse primary chondrocyte model under IL-1β stimulated condition 50 Doses were calculated. The inventors confirmed that the two liraglutide preformulations tested had the same overall anti-inflammatory and anti-degradative effects as Victoza®.

[0319] The in vitro efficacy of compositions 2 and 6 was demonstrated, with average IC values ​​of 52 nM to 60 nM. 50 It has a value.

[0320] Example 4: Efficacy of a single intra-articular (IA) knee injection of three ascending doses of preformulations 2 and 6 utilizing an MIA-induced model of osteoarthritis and inflammatory pain in rats

[0321] Test Systems

[0322] Sprague Dawley rats.

[0323] Test item [Table 11]

[0324] Preformulations 2 and 6 are identical to preformulations 2 and 6 of Example 1, respectively.

[0325] Formulation: Liraglutide preformulations (2 and 6) supplied as a solution at 6 mg / ml were diluted in PBS to reach final concentrations of 3, 3 μg, 20 μg, and 120 μg in 30 μL.

[0326] Victoza® is a commercially available liraglutide drug. The test article, supplied as a solution at 6 mg / ml, was diluted in PBS to reach a final concentration of 20 μg in 30 μL. Victoza® and Victoza® derived test articles are compositions according to the invention since they contain a GLP-1R agonist (liraglutide), phosphate buffer and propylene glycol as an isotonic agent.

[0327] Vehicle (PBS) was provided "ready to use" and diluted in cell seeding medium at a final concentration of 1:100.

[0328] Experimental design Induction of OA by intra-articular (IA) injection of MIA (monosodium iodoacetate) Animals were anesthetized by chamber induction technique using inhalation anesthesia (5% isoflurane). During the procedure, animals were maintained under a level of isoflurane of 1.5-3% with an air flow rate of 1-2 liters / min. After induction of anesthesia, hair was clipped from the skin surface of the right hind limb using electric animal clippers. After shaving, the area around the knee joint was wiped with alcohol. A volume of 30 μL containing 3 mg of MIA (monosodium iodoacetate) was injected intra-articularly (IA) into the knee joint via the patellar tendon. A 29-gauge, 0.5-inch needle fitted with a cannulation tube was used to allow only 3-4 mm of the needle to pierce the joint. After injection, the knee was massaged to ensure uniform distribution of the solution. Animals were injected once on day 1 (groups 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M). In group 1M (sham control), 30 μL of injectable saline was injected into the knee joint.

[0329] Mechanical pain assessment (von Frey test) Von Frey tests in rats after MIA (monosodium iodoacetate) injection were performed according to 4P-Pharma standard operating procedures (SOPs). Rats were placed individually in designated transparent plexiglass chambers and allowed to acclimate for 10-15 min. Withdrawal responses to mechanical stimulation were measured using an electronic Von Frey apparatus (BIO-EVF5, Bioseb) with a 0.5 mm diameter tip on the stimulator handle applied from underneath the cage through an opening (12x12 mm) in the plastic mesh floor. The withdrawal response in grams weight for each rat was calculated from three trials. Von Frey tests were performed on animals a total of three times, on days 2 (as pre-treatment baseline for group allocation), 7 and 10 (4 and 7 days after treatment, respectively). The experimenter(s) were blinded regarding the identity of the groups.

[0330] [Table 12]

[0331] [Table 13]

[0332] Statistical Planning Regarding statistics, we applied a sequential testing strategy that reflects experimental expectations while retaining the central Mann-Whitney (non-parametric) test. Sequential statistics were created to compare the following in order: 1. Control / vehicle group (1M) and MIA / vehicle group (2M). 2. MIA / vehicle group (2M) and MIA / Victoza® treated animals (20 μg) (3M). 3. MIA / vehicle group (2M) and higher doses of preformulation-2 or -6 (120 μg) (6M and 9M). Then compare the MIA / vehicle group (2M).

[0333] Testing and Evaluation Mechanical pain assessment (von Frey test)

[0334] Allodynia in rats after OA induction on day 1 was assessed on day 2 as a baseline for group assignment, and then on days 7 and 10 to evaluate the effect of treatment on mechanically induced pain. For each group, the mean withdrawal response, obtained by electronic von Frey apparatus, for the left and right hind paws was calculated. Group mean animal withdrawal response results are shown in Table 14 for the right hind paw. Results for the right hind paw are shown in Figure 15. Figure 15A compares the vehicle control, MIA / vehicle and MIA / Victoza® groups (1M-3M) with the three groups of preformulation 2 (4M-6M), and Figure 15B compares the vehicle control, MIA / vehicle and MIA / Victoza® groups (1M-3M) with the three groups of preformulation 6 (7M-9M).

[0335] On day 7, there was a significant increase in paw withdrawal threshold in MIA-injected animals between the Victoza®-treated 3M and the MIA / vehicle 2M groups (mean ± SD; p<0.001). A significant dose effect was observed on day 7 for the preformulated groups 120 μg (9M and 6M), 20 μg (8M and 5M), and 3.3 μg (7M and 4M) versus the MIA / vehicle 2M group (mean ± SD; p<0.001 for the 120 μg and 20 μg doses, mean ± SD; p<0.01 for the 3.3 μg dose).

[0336] A significant decrease in withdrawal thresholds on D7-D10 was observed using 20 μg of preformulation-2 (5M) (mean ± SD; p<0.05). The withdrawal threshold effect persisted on D7-D10 using preformulation-2 (4M and 6M) and preformulation-6 (7M, 8M, and 9M) at 3.3 and 120 μg, since non-statistical differences were observed on D7-D10 in these groups (4M, 6M, 7M, 8M, and 9M). Higher paw withdrawal thresholds were observed when comparing 20 μg of Victoza® IA injection with 20 μg of preformulations 2 and 6.

[0337] [Table 14] MIA / vehicle (2M) vs. control / vehicle (1M) (Mann-Whitney test; *** p<0.001). MIA / vehicle (2M) versus MIA preformulations 2 and 6 (4M, 5M, 6M, 7M, 8M, and 9M) (Mann-Whitney test; ** p<0.01, *** p<0.001).

[0338] conclusion In conclusion, in this comparative study between IA injection of 20 μg Victoza® and three doses of preformulations 2 and 6 (3.3, 20, and 120 μg), it was observed that both preformulations 2 and 6 showed dose-dependent analgesic effects.

[0339] Example 5: Efficacy of intra-articular (IA) knee injections of Victoza® using an MIA-induced model of osteoarthritis and inflammatory pain in rats

[0340] the purpose: The objective of this study was two-fold: to perform a dose-response study using Victoza® utilizing the monoiodoacetate (MIA)-induced osteoarthritis and inflammatory pain model in rats to calculate the 50% effective concentration EC50 (short-term MIA model) and to determine the duration of analgesic effect of Victoza® after a single intra-articular administration in five selected groups (long-term MIA model).Dexamethasone was used as the reference positive control group in this study.

[0341] method: Nine groups, including 8 SD rats per group, were assigned to this study, which was carried out in 4 cycles. Chemically induced OA disease was performed on 8 of the 9 groups. On day 1, 3 mg of MIA in 30 μL was injected intra-articularly (IA) into the right knee joint. The last group (sham control) received 30 μL of saline IA into the right knee joint. The 9 groups were as follows: one sham control group (1M) treated with vehicle (water), 8 MIA groups treated with vehicle (2M), 0.7 μg (3M), 2.2 μg (4M), 6.7 μg (5M), 20 μg (6M), 60 μg (7M) or 180 μg (8M) of Victoza®, and 120 μg (9M) of dexamethasone. Victoza® and Victoza® derived test articles are compositions according to the invention since they contain a GLP-1R agonist (liraglutide), a phosphate buffer and propylene glycol as an isotonic agent. All animals were injected IA once on day 3. Mortality and morbidity observations were performed during the study, as well as von Frey testing using an electronic von Frey device. Group allocation was performed on day 2 based on the von Frey results. Knee harvesting was performed at the end of the study (day 11 for short-term MIA model, day 32 for long-term MIA model) for optional analysis.

[0342] result: EC50, short-term MIA model for all groups (up to day 11): Mortality / Morbidity: No mortality or morbidity was observed during the study.

[0343] Von Frey test: As expected, there was a significant decrease in paw withdrawal threshold after MIA injection compared to sham control (group 1M), confirming model induction. This effect persisted until the end of the study for group 2M. On day 7, a significant dose-dependent increase in paw withdrawal threshold was observed between MIA / Victoza® treated groups 5M, 6M, 7M and 8M, as well as group 9M treated with 120 μg dexamethasone, and MIA / vehicle group 2M. The calculated EC50 was 3.3 μg. On day 10, a significant dose-dependent increase in paw withdrawal threshold was observed between MIA / Victoza® treated groups 4M, 5M, 6M, 7M and 8M, as well as group 9M (dexamethasone) and MIA / vehicle group 2M. The calculated EC50 was 2.1 μg.

[0344] Long-term MIA model (up to day 32) for five selected groups: The five groups selected were: 1M (sham / vehicle), 2M (MIA / vehicle), 7M (MIA / Victoza® 60 μg), 8M (MIA / Victoza® 180 μg), and 9M (MIA / dexamethasone).

[0345] Mortality / Morbidity: No mortality or morbidity was observed during the study.

[0346] Von Frey test: After day 10 (i.e., 1 week after acute treatment), the von Frey test was performed once a week on days 18, 25, and 31 until the end of the study. A significant decrease in paw withdrawal threshold after MIA injection continued until the end of the study in group 2M compared to the sham control group 1M, confirming the induction and maintenance of the model until day 31. For the other groups, the results showed that the analgesic effect of Victoza® 60 μg (group 7M) and 180 μg (group 8M) and dexamethasone 120 μg (group 9M) was significantly maintained until day 25 (i.e., 3 weeks after the acute phase), but disappeared at day 31 (i.e., 4 weeks after acute injection). The results are shown in Figure 16.

[0347] Conclusion: In conclusion, this study confirms that locally administered compositions according to the invention (e.g. Victoza®) target relevant mechanisms involved in pain in MIA-induced OA and inflammatory pain models in rats. The calculated 50% effective concentrations are 2.1 μg on day 7 and 3.3 μg on day 10. Furthermore, we now demonstrate a 4-week sustained analgesic effect of compositions according to the invention (e.g. Victoza®) after acute IA administration, comparable to the analgesic effect of the dexamethasone positive control.

[0348] Example 6: Efficacy of a single intra-articular (IA) knee injection of six ascending doses of Ozempic® and preformulation 2 utilizing an MIA-induced model of osteoarthritis and inflammatory pain in rats

[0349] Test Systems Sprague Dawley rats.

[0350] Test item [Table 15]

[0351] Preformulation 2 is identical to Preformulation 2 in Example 1.

[0352] Formulation:

[0353] Liraglutide preformulation 2, supplied as a solution at 6 mg / ml, was diluted in PBS to reach final concentrations of 0.7 μg, 2.2 μg, 6.7 μg, 20 μg, 60 μg, and 180 μg in 30 μL.

[0354] Victoza® is a commercially available liraglutide drug. The test article, supplied as a solution at 6 mg / ml, was diluted in PBS to reach a final concentration of 20 μg in 30 μL. Victoza® and Victoza® derived test articles are compositions according to the invention since they contain a GLP-1R agonist (liraglutide), phosphate buffer and propylene glycol as an isotonic agent.

[0355] Ozempic® is a marketed semaglutide drug. The test article, supplied as a solution at 1.34 mg / ml, was diluted in PBS to reach a final concentration of 20 μg in 30 μL.

[0356] Vehicle (PBS) was provided "ready to use" and diluted in cell seeding medium at a final concentration of 1:100.

[0357] Experimental design Induction of OA by intra-articular (IA) injection of MIA (monosodium iodoacetate)

[0358] Animals were anesthetized by chamber induction technique using inhalation anesthesia (5% isoflurane). During the procedure, animals were maintained under a level of isoflurane between 1.5 and 3% with an air flow rate of 1 to 2 liters / min. After induction of anesthesia, hair was clipped from the skin surface of the right hind limb using electric animal clippers. After shaving, the area around the knee joint was wiped with alcohol. A volume of 30 μL containing 3 mg of MIA (monosodium iodoacetate) was injected intra-articularly (IA) into the knee joint via the patellar tendon. A 29-gauge, 0.5-inch needle fitted with a cannulation tube was used to allow only 3 to 4 mm of the needle to pierce the joint. After injection, the knee was massaged to ensure uniform distribution of the solution. Animals were injected once on day 1 (groups 12M, 13M, 14M, 15M, 16M, 17M, 18M, 19M and 20M). In group 11M (sham control), 30 μL of injectable saline was injected into the knee joint.

[0359] Mechanical pain assessment (von Frey test) Von Frey tests in rats after MIA (monosodium iodoacetate) injection were performed according to 4P-Pharma standard operating procedures (SOPs). Rats were placed individually in designated transparent plexiglass chambers and allowed to acclimate for 10-15 min. Withdrawal responses to mechanical stimulation were measured using an electronic Von Frey apparatus (BIO-EVF5, Bioseb) with a 0.5 mm diameter tip on the stimulator handle applied from underneath the cage through an opening (12x12 mm) in the plastic mesh floor. The withdrawal response in grams of weight for each rat was calculated from three trials. Von Frey tests were performed on animals a total of six times, on days 2 (as pre-treatment baseline for group allocation), 7, 10, 18, 25, and 31 (4, 7, 15, 22, and 28 days after treatment, respectively). The experimenter(s) were blinded regarding the identity of the groups.

[0360] [Table 16]

[0361] N = number of animals

[0362] [Table 17]

[0363] Statistical Planning Regarding statistics, we applied a sequential testing strategy that reflects experimental expectations while retaining the central Mann-Whitney (non-parametric) test. Sequential statistics were created to compare the following in order: 1. Control / vehicle group (11M) and MIA / vehicle group (12M). 2. MIA / vehicle group (12M) and MIA / Victoza® treated animals (20 μg) (19M). 3. MIA / vehicle group (12M) and a higher dose of preformulation 2 (180 μg) (18M). The MIA / vehicle group (12M) was then compared with MIA / Ozempic®-treated animals (20 μg) (20M).

[0364] Testing and Evaluation Mechanical pain assessment (von Frey test)

[0365] Allodynia in rats after OA induction on day 1 was evaluated on day 2 as a baseline for group assignment, and then on days 7, 10, 18, 25, and 31 to evaluate the effect of treatment on mechanically induced pain. For each group, the mean withdrawal response obtained by electronic von Frey apparatus for left and right hind paws was calculated. Group average animal withdrawal response results are shown in Table 18A and Table 18B for the right hind paw. Results for the right hind paw are shown in Figure 17. FIG. 17A compares the vehicle control, MIA / vehicle, MIA / Victoza® and MIA / Ozempic® groups (11M, 12M, 19M, 20M) to three of the six groups in preformulation-2 (13M-15M), and FIG. 17B compares the vehicle control, MIA / vehicle, MIA / Victoza® and MIA / Ozempic® groups (11M, 12M, 19M, 20M) to the other three groups in preformulation-2 (16M-18M).

[0366] There was a significant increase in paw withdrawal threshold in MIA-injected animals between Victoza®-treated 19M and MIA / vehicle 12M on days 7, 10, 18, 25, and 31 (mean ± SD; p<0.001). A significant dose effect was observed in the preformulated groups (13M-18M) versus MIA / vehicle 12M (mean ± SD; p<0.001, p<0.01, and p<0.05) on days 7, 10, 18, 25, and 31. A significant dose effect was observed in the Ozempic®-treated groups (20M) versus MIA / vehicle 12M (mean ± SD; p<0.001) on days 7, 10, 18, 25, and 31. There were no significant differences in paw withdrawal thresholds among all treatment groups (13M to 20M).

[0367] [Table 18]

[0368] [Table 19] MIA / vehicle (12M) vs. control / vehicle (11M) (Mann-Whitney test; *** p<0.001). MIA / vehicle (12M) versus MIA preformulation-2, Victoza and Ozempic (14M, 15M, 16M, 17M, 18M, 19M and 20M) (Mann-Whitney test; * p<0.05, ** p<0.01, *** p<0.001).

[0369] conclusion In conclusion, in this comparative study between IA injections of 20 μg Victoza®, 20 μg Ozempic®, and six doses of preformulation-2 (0.7 μg, 2.2 μg, 6.7 μg, 20 μg, 60 μg, and 180 μg), it was observed that all preformulations-2 (i.e., compositions according to the present invention) exhibited a dose-dependent analgesic effect. Furthermore, Victoza® (i.e., compositions according to the present invention) and Ozempic® also exhibited analgesic effects.

[0370] Example 7: Evaluation of the analgesic effects of various GLP-1R agonists using MIA-induced models of osteoarthritis and inflammatory pain in rats the purpose: The objective of this study was to evaluate the analgesic efficacy of maximum achievable doses of the GLP-1R agonists dulaglutide®, exenatide and lixisenatide in liquid homogenous compositions, specifically in solution, compared with liraglutide in liquid homogenous compositions, specifically in solution, in an MIA-induced model of osteoarthritis and inflammatory pain in rats.

[0371] method: Nine groups, including 8 SD rats per group, were assigned to this study, which was conducted in two cycles (4 SD rats per cycle). Chemically induced OA disease was performed in six of the seven groups by intra-articular (IA) injection of 3 mg MIA in 30 μL into the right knee joint on day 1. The control group (sham / vehicle control) received 30 μL saline IA into the right knee joint. The seven groups were: a sham / vehicle control group (Group 31M) treated with vehicle (NaCl 0.9%), and six MIA groups treated with vehicle (Group 32M), 270 μg dulaglutide (Group 33M), 92.31 μg exenatide (E1) (Group 34M), 70.6 μg exenatide (E2) (Group 35M), 3 μg adlixin (Group 36M), and 180 μg Victoza® (Group 37M). All Groups 31M-37M received 1 IA injection of either saline (Group 31M) or MIA (Groups 32M-37M) on day 1 and treatment injections on day 3. During the study, body weight measurements (twice weekly), von Frey testing using an electronic von Frey apparatus (days 2 and 7 for C1) and von Frey filaments (days 10, 18, 24, and 30 for C1; days 2, 7, 10, 18, 24, and 30 for C2) were performed. Group allocation was performed on day 2 based on von Frey results. Knee sampling was performed for optional analysis at the end of the study on day 32.

[0372] Formulation: NaCl 0.9% (vehicle) is provided "ready to use" for intra-articular injection (30 μL) in groups 31M and 32M.

[0373] A solution containing dulaglutide is prepared from the product Trulicity®, which is a commercially available dulaglutide drug. Trulicity® is provided as a "ready to use" solution at 4.5 mg / 0.50 mL. It is diluted in an appropriate amount of vehicle (NaCl 0.9%) for injection into the knee joint, 270 μg in 30 μL per rat in group 33M.

[0374] A solution containing exenatide (E1) is prepared from the product Bydureon®, which is a commercially available exenatide drug. Bydureon® is provided as a "ready to use" solution at 2 mg / 0.65 mL. It is diluted in an appropriate volume of vehicle (NaCl 0.9%) for injection into the knee joint, 92.31 μg in 30 μL per rat for group 34M.

[0375] Another solution containing exenatide (E2) is prepared from the product Bydureon Bcise®, which is a commercially available sustained release exenatide drug. Bydureon Bcise® is provided as a "ready to use" solution at 2.35 mg / mL. It is diluted in an appropriate volume of vehicle (NaCl 0.9%) for injection into the knee joint, 70.6 μg in 30 μL per rat for group 35M.

[0376] A solution containing lixisenatide is prepared from the product Adlixin®. Adlixin® is the commercially available lixisenatide drug. Adlixin® is provided as a "ready to use" solution at 100 μg / mL. It is diluted in an appropriate volume of vehicle (NaCl 0.9%) for injection into the knee joint, 3 μg in 30 μL per rat in group 36M.

[0377] A solution containing liraglutide is prepared from the product Victoza®, which is a commercially available liraglutide drug. Victoza® is provided as a "ready to use" solution at 6 mg / mL. It is diluted in an appropriate volume of vehicle (NaCl 0.9%) for injection into the knee joint, 180 μg in 30 μL per rat in group 37M.

[0378] Experimental design Induction of OA by intra-articular (IA) injection of MIA (monosodium iodoacetate)

[0379] Fifty-six male SD rats, 9 weeks of age, were anesthetized by a chamber induction technique using inhalation anesthesia (5% isoflurane). During the procedure, the animals were maintained under a level of isoflurane of 1.5-3% with an air flow rate of 1-2 liters / min. After induction of anesthesia, hair was clipped from the skin surface of the right hind limb using electric animal clippers. After shaving, the area around the knee joint was wiped with alcohol. A volume of 30 μL containing 3 mg of MIA was injected intra-articularly (IA) into the knee joint via the patellar tendon. A 29-gauge, 0.5-inch needle fitted with a cannulation tube was used to allow only 3-4 mm of the needle to pierce the joint. After injection, the knee was massaged to ensure uniform distribution of the solution. Animals were injected once on day 1 (groups 32M, 33M, 34M, 35M, 36M, 37M). In group 31M (sham control), 30 μL of saline injection was injected into the knee joint.

[0380] The study was conducted in two cycles according to Table 19 for study design and Table 20 for study timeline. Group allocation was done on Day 2 from von Frey.

[0381] [Table 20]

[0382] N = number of animals

[0383] [Table 21]

[0384] Mechanical pain assessment (von Frey test) Von Frey testing in rats after MIA injection was performed according to 4P-Pharma's procedure "Mechanical Neuropathic Pain Evaluation (electronic Von Frey)" and 4P-Pharma's procedure "Mechanical Neuropathic Pain Evaluation (Von Frey)". Rats were placed individually in designated clear plexiglass chambers and allowed to acclimate for 10-15 min. Withdrawal responses to mechanical stimulation were measured using an electronic Von Frey apparatus (BIO-EVF5, Bioseb) with a 0.5 mm diameter tip placed on the stimulator handle applied from underneath the cage through an opening (12x12 mm) in the plastic mesh floor or by von Frey filaments (Bio-VF-M, Bioseb). Withdrawal responses in grams of weight for each rat were calculated from three trials with the von Frey apparatus and one trial with the von Frey filaments. Von Frey tests were performed on animals on days 2 (as a pre-treatment baseline for group allocation), 7, and 10 (4 and 7 days after treatment, respectively). The experimenter(s) were blinded to group identity.

[0385] Statistical Planning For statistics, mechanical pain assessment was performed by applying a sequential testing strategy that reflects the expectation of the experiment while retaining the central Mann-Whitney (non-parametric) test.First, the difference between sham (group 31M) and MIA / vehicle (group 32M) was compared. Since the difference was found to be significant, the difference between MIA / liraglutide-treated animals (group 37M) and MIA / vehicle (group 32M) animals was then compared. Since the result was found to be significant, we tested the statistical difference between MIA / vehicle and the remaining GLP-1 analogue-treated animals (groups 33M, 34M, 35M and 36M).

[0386] Results: Assessment of mechanical pain (von Frey test): Evaluation of allodynia in a long-term MIA model Allodynia in rats after OA induction on day 1 was assessed on day 2 as a baseline for group assignment, and then on days 7, 10, 18, 24 and 30 to evaluate the effect of treatment on mechanically induced pain. For each group, the mean withdrawal response obtained by the electronic von Frey apparatus (animals on days 2 and 7 of cycle 1) (Table 21) or the von Frey filament (animals on day 7 of cycle 1 and day 2 of cycle 2) (Tables 22 and 22bis, Figure 18) was calculated for the right hind paw. Figure 18 compares vehicle control and MIA / vehicle groups (31M, 32M) with the treatment groups (33M-37M).

[0387] Withdrawal responses of individual animals are shown for the right hind paw in Table 21. MIA IA injection on day 1 resulted in a significant decrease in paw withdrawal thresholds characterized on day 2 between the saline group (31M) and the remaining MIA groups (32M-37M) (mean ± SD; $ p<0.005, $$$ p<0.001). In group 32M, this effect persisted until the end of the study, thus validating the MIAIA injection and MIA rat models for rapid pain-like responses in the ipsilateral paw in rats (FIG. 18).

[0388] Comparing only four animals per group and using the von Frey filament method on day 7, results showed that there was a significant increase in paw withdrawal thresholds in MIA-injected animals (35M, 36M, and 37M) treated with 70.6 μg exenatide (E2), 3 μg lixisenatide, and 180 μg liraglutide compared to the MIA / vehicle-treated group (32M) (mean ± SD; * p<0.05, ** p<0.01, *** p<0.001) (FIG. 18). From days 10 to 30, all treatment groups (33M, 34M, 35M, 36M, and 37M) showed a significant increase in paw withdrawal thresholds compared to the MIA / vehicle-treated group (32M) for each day (mean±SD; ** p<0.01, *** p<0.001) (Figure 18). [Table 22]

[0389] [Table 23]

[0390] [Table 24] Regarding Table 22 and Table 22bis: $$$ p<0.001 on day 2 for the control / vehicle group (31M) versus the MIA / vehicle group and the treatment groups (32M, 33M, 34M, 35M, 36M, and 37M). * p<0.05 MIA / vehicle group (32M) vs. exenatide (E2)-treated group (35M) on day 7. ** p<0.01 on day 7 in the MIA / vehicle group (32M) versus the lixisenatide-treated group (36M). ** p<0.01 MIA / vehicle group (32M) vs. exenatide (E1)-treated group (34M) on days 10 and 30. *** p<0.001 MIA / vehicle group (32M) vs. liraglutide-treated group (37M) on days 7, 10, 18, 24 and 30. *** p<0.001 MIA / vehicle group (32M) vs. lixisenatide-treated group (36M) on days 7, 10, 18, 24 and 30. *** p<0.001 MIA / vehicle group (32M) vs. exenatide (E2)-treated group (35M) on days 10, 18, 24 and 30. *** p<0.001 MIA / vehicle group (32M) vs. exenatide (E1)-treated group (34M) on days 10, 18 and 24. ***p<0.001 MIA / vehicle group (32M) vs. dulaglutide-treated group (33M) on days 7, 10, 18, 24 and 30. *** p<0.001 MIA / vehicle group (32M) vs. vehicle / control group (31M) on days 2, 7, 10, 18, 24, and 30. Up to day 7, mean ± SEM, n = 4 / group. From day 10, mean ± SEM, n = 7–8 / group.

[0391] conclusion On average, all groups had responses within the normal range (within the range of 15-50 g) using von Frey filaments for the left (healthy) hind paw at each time point tested. There were no differences between groups for the left hind paw.

[0392] For the right hind paw, MIA IA injection on day 1 resulted in a significant decrease in paw withdrawal thresholds characterized on day 2 between the saline group (31M) and the remaining MIA groups (32M–37M) (mean ± SD; $ p<0.005, $$$ p<0.001). In group 32M, this effect persisted until the end of the study, thus validating the MIAIA injection and MIA rat models for rapid pain-like responses in the ipsilateral paw in rats (FIG. 18).

[0393] Comparing only four animals per group and using the von Frey filament method on day 7, results showed that there was a significant increase in paw withdrawal thresholds in MIA-injected animals (35M, 36M, and 37M) treated with 70.6 μg exenatide (E2), 3 μg lixisenatide, and 180 μg liraglutide compared to the MIA / vehicle-treated group (32M) (mean ± SD; * p<0.05, ** p<0.01, *** p<0.001) (Figure 18).

[0394] From days 10 to 30, all treatment groups (33M, 34M, 35M, 36M, and 37M) showed a significant increase in paw withdrawal thresholds compared to the MIA / vehicle-treated group (32M) for each day (mean ± SD; ** p<0.01, *** p<0.001) (Figure 18).

[0395] Comparison Test: Von Frey Filament vs. Electronic Von Frey Allodynia in rats after OA induction on day 1 was assessed on days 2 and 7 using both electronic filaments (for cycle 1) and von Frey filaments (for cycle 2). Both tests are reliable and valid for the assessment of mechanical sensitivity in the ipsilateral hindpaw of rats. Furthermore, von Frey filament scores provide an equivalent electronic von Frey score (grams / mm 2 The von Frey filament score can be approximately replaced by the theoretical pressure in units of pressure. To ensure the results obtained, three rats from three different groups (31M, 32M, and 37M) were tested using both the von Frey filament and the electronic von Frey apparatus. The equivalent electronic von Frey scores replaced by the von Frey filament scores were found to be comparable to the average scores using the electronic von Frey apparatus in the same animals.

[0396] The equivalent electronic von Frey scores were calculated from the results obtained with the von Frey filaments using the "Aesthesio Precision Tactile sensory data chart". Therefore, in order to have a more representative view of the results obtained in previous experiments using the electronic von Frey device, both the electronic von Frey scores obtained from cycle 1 (days 2 and 7) and the equivalent scores calculated from the results obtained with the von Frey filaments in cycle 1 (from day 10) and cycle 2 were combined. Furthermore, in order to have an idea of ​​the paw withdrawal effect in rats of different treatments compared to the vehicle group, the previous results (electronic equivalent scores from the von Frey filaments + electronic von Frey scores on days 2 and 7 of cycle 1) were normalized to the corresponding vehicle group (%) from cycle 1 or cycle 2 on each day. When the von Frey scores were normalized to the vehicle group (31M), the liraglutide / MIA treatment group (37M) reached a score of 70% on day 10 and maintained this level for 20 days. Similarly, the lixisenatide / MIA-treated group (36M) increased to and maintained a score of 60%. The dulaglutide / MIA- (33M), exenatide (E1) / MIA- (34M), and exenatide (E2) / MIA- (35M)-treated groups progressively reached scores of 50-60% at day 30 when compared to the vehicle group (31M), which was normalized to 100%.

[0397] conclusion In conclusion, this comparative study between IA injections of solutions containing 180 μg liraglutide, 270 μg dulaglutide, 92.31 μg exenatide (E1), 70.6 μg exenatide (E2) and 3 μg lixisenatide observed the following: -All GLP-1 analogues show increasing anti-inflammatory / analgesic effects over 30 days with a similar profile. - The von Frey filament assay in rats can be converted into a similar electronic von Frey score by the "Aesthesio Precision Tactile sensory data chart" for the purpose of comparing different experiments using different but complementary methods.

[0398] In conclusion, this study confirms that topical administration (IA administration) of a solution containing liraglutide 180 μg, dulaglutide 270 μg, exenatide 92.31 μg (E1), exenatide 70.6 μg (E2) and lixisenatide 3 μg targets relevant mechanisms related to pain in MIA-induced OA and inflammatory pain models in rats. Thus, IA administration of a solution containing various GLP-1R agonists such as liraglutide, dulaglutide, exenatide, and lixisenatide targets relevant mechanisms related to pain in MIA-induced OA and inflammatory pain models in rats and may therefore be used in methods for treating joint diseases, particularly osteoarthritis and / or joint pain.

[0399] Example 8: Comparison of analgesic effects between a composition according to the prior art and a composition according to the present invention Test Systems Sprague Dawley rats.

[0400] Test item [Table 25]

[0401] Preformulation 2 is identical to Preformulation 2 in Example 1.

[0402] [Table 26]

[0403] Hydrogel formulations P6, P8, and P20 are identical to formulations no. 6, 8, and 20, respectively, disclosed in Table 3, pages 23-24 of patent application WO 2020 / 104833.

[0404] Formulation: Liraglutide preformulation 2, supplied as a solution at 6 mg / ml, was diluted in PBS to reach a final concentration of 180 μg in 30 μL.

[0405] Liraglutide preformulation 11 was obtained from the commercially available liraglutide drug, Victoza®. The test article (Victoza®), supplied as a solution at 6 mg / ml, was diluted in PBS to reach a final concentration of 20 μg in 30 μL.

[0406] The vehicle (PBS) was provided "ready to use" and was diluted in cell seeding medium at a final concentration of 1:100.

[0407] Experimental design Surgery-induced OA: Induction of OA by medial ligament section (MLT) procedure followed by medial meniscectomy (MMx): Groups 41M, 42M, 43M, 44M

[0408] Anesthesia was induced in each rat by chamber induction technique using inhalation anesthesia (4.0% isoflurane). During surgery, animals were maintained with isoflurane at a level of 1.5-2.5% with an oxygen flow rate of 1-2 liters / min. Ophthalmic ointment was applied to the eyes to prevent tissue drying during the anesthesia period. After induction of anesthesia, the hair was clipped from the skin surface of the right leg using electric animal clippers. After shaving the knee joint, the skin was disinfected with iodine and a parapatellar skin incision was made medial to the joint. The medial side of the joint cavity was incised. The medial ligament was cut and the medial meniscus was excised using a microsurgical knife. The wound was closed with Vicryl 5 / 0 braided absorbable suture. All surgical procedures were performed using a surgical microscope. Group assignments are shown in Table 25 and the study timeline in Table 26.

[0409] [Table 27]

[0410] [Table 28]

[0411] OA induction by intra-articular (IA) injection of MIA (monosodium iodoacetate): Groups 45M, 46M, 47M, and 48M

[0412] The protocol for OA induction by intra-articular (IA) injection of MIA (monosodium iodoacetate) for groups 46M, 47M and 48M was as disclosed in Example 6, and animals were injected with MIA once on day 1. In group 45M (sham control), 30 μL of injectable saline was injected into the knee joint.

[0413] Mechanical pain assessment (von Frey test): Groups 45M, 46M, 47M, and 48M

[0414] The mechanical pain assessment protocol was as disclosed in Example 6.

[0415] [Table 29]

[0416] N = number of animals

[0417] [Table 30]

[0418] Statistical plan for groups 45M, 46M, 47M, and 48M

[0419] Regarding statistics, we applied a sequential testing strategy that reflects experimental expectations while retaining the central Mann-Whitney (non-parametric) test. Sequential statistics were created to compare the following in order: 1. Control / vehicle group (45M) and MIA / vehicle group (46M). 2. MIA / vehicle group (46M) and MIA / preformulation 11 treated animals (20 μg) (48M). 3. MIA / vehicle group (46M) and animals treated with MIA / preformulation 2 (180 μg) (47M).

[0420] Mechanical pain assessment (von Frey test) in groups 45M, 46M, 47M, and 48M Allodynia in rats after OA induction on day 1 was assessed on day 2 as a baseline for group assignment, and then on days 7, 10, 18, 25, and 31 to evaluate the effect of treatment on mechanically induced pain. For each group, the mean withdrawal response for the left and right hind paws obtained by the electronic von Frey apparatus was calculated. The group mean withdrawal response results for the animals are shown in Tables 29 and 30 for the right hind paw. The results for the right hind paw are shown in Figure 20. Figure 20 compares the MIA / vehicle group (46M) with the MIA / preformulation 11 (48M) and the MIA / vehicle (46M) with the preformulation-2 group (47M).

[0421] There was a significant increase in paw withdrawal threshold in MIA-injected animals between the preformulation 11 treatment group 48M and the MIA / vehicle group 46M on days 7, 10, 18, 25 and 31 (mean ± SD; p<0.001). A significant dose effect and a significant increase in paw withdrawal threshold in MIA-injected animals was observed in the preformulation 2 group (47M) versus the MIA / vehicle group 46M on days 7, 10, 18, 25 and 31 (mean ± SD; p<0.001, p<0.01 and p<0.05).

[0422] Statistical analysis revealed significant differences between the control group and the groups (47M, 48M) treated with liquid formulations according to the invention (preformulation 11 and preformulation 2) up to 4 weeks after a single IA injection in the right knee. There is no significant difference between the paw withdrawal thresholds of preformulation 11 treated group 48M and preformulation 2 treated group 47M. The analgesic effect was maintained up to 4 weeks after a single intra-articular injection of preformulations 2 and 11 according to the invention, with a curve plateau that was stable up to day 31, as can be seen in FIG. 20.

[0423] [Table 31]

[0424] [Table 32] MIA / vehicle (46M) vs. control / vehicle (45M) (Mann-Whitney test; *** p<0.001). MIA / vehicle (46M) versus MIA preformulation 2 and preformulation 11 (47M and 48M) (Mann-Whitney test; * p<0.05, ** p<0.01, *** p<0.001).

[0425] Mechanical pain assessment (incapacitance test) for groups 41M, 42M, 43M, and 44M. Weight-bearing changes in rats with OA were measured using an incapacitance tester. Postural imbalance, which reportedly indicates changes in pain threshold and limb weight distribution, is reduced. Each rat was positioned so that each hind paw was placed on a separate force plate on the incapacitance device, and the weight borne by each hind paw was measured for 5 seconds. The ratio of weight borne by the right versus left hind paw is calculated. The average of five consecutive measurements was recorded for each rat. Weight-bearing function (incapacitance testing) was performed a total of four times, at baseline (day -1), days 14, 28, and 35. The experimenter(s) were blinded to the groups.

[0426] The rats were sacrificed by CO2 asphyxiation on day 36. The knee joint structures were fixed in 4% buffered formalin solution for further histological analysis. The contralateral (uninjured) knee was also fixed in 4% buffered formalin solution.

[0427] Numerical results were given as mean ± SD. Outlier data points (marked by an asterisk) were identified after Grubbs test analysis at alpha = 5% and were not included in the calculation of group means. Where applicable, statistical analysis was performed using two-way ANOVA (followed by Bonferroni post-hoc test) or one-way ANOVA (followed by Dunnett's multiple comparison post-hoc test). A probability of 5% (p < 0.05) was considered significant. In the figures, the degree of statistically significant differences between groups is indicated by the following formula: * p<0.05, ** p<0.01, *** Shown as p<0.001.

[0428] The results are shown in Table 19. Statistical analysis revealed a significant difference between the control group 41M and the group 42M treated with the gel formulation P6 only on the 14th day, e.g., 7 days after a single IA injection in the right knee. There was no significant difference between the control group 41M and the group 42M treated with the gel formulation on the 28th day (e.g., 14 days after a single IA injection in the right knee) and on the 35th day (e.g., 21 days after a single IA injection in the right knee). Thus, the effect induced by the prior art formulation P6 was noticeable on the 7th day after a single IA injection in the right knee, but did not start until 14 days after a single IA injection in the right knee. This can be seen in Figure 19, where the effect obtained on the 14th day (e.g., 7 days after a single IA injection in the right knee) is not maintained thereafter (i.e., on the 28th day (e.g., 14 days after a single IA injection in the right knee) and on the 35th day (e.g., 21 days after a single IA injection in the right knee). Furthermore, there is no significant difference between the control group 41M and the treatment groups 43M and 44M, which explains why there are no curves relating to groups 43M (formulation P8) and 44M (formulation P20) in FIG.

[0429] conclusion In conclusion, in this comparative study between solution IA injection and gel formulations, it was observed that the solution formulations according to the invention (groups 47M and 48M) provided an analgesic effect for up to 4 weeks after a single IA injection in the right knee, whereas the gel formulations according to the prior art (groups 42M, 43M and 44M) did not provide a statistically significant analgesic effect or provided an analgesic effect only on the 14th day, e.g. 7 days, after a single IA injection in the right knee.

[0430] Example 9: Comparison of pharmacokinetics in synovial fluid and plasma between three preformulations according to the invention Test Systems Dog, Beagle, 3-6 years old

[0431] Test item

[0432] [Table 33]

[0433] Preformulations 2 and 6 are identical to preformulations 2 and 6, respectively, of Example 1. Preformulations 2, 6 and 12 are pharmaceutical compositions according to the present invention.

[0434] Formulation: Preformulation 2: Liraglutide 6 mg / ml, tromethamine (8 mM) and glucose (30 mg / ml) in water for injection.

[0435] Preformulation 6: Liraglutide 6 mg / ml, tromethamine (8 mM) and PEG 400 (60 mg / ml) in water for injection.

[0436] Preformulation 12: Victoza®, for example: liraglutide 6 mg / ml, dibasic sodium phosphate dihydrate 1.42 mg / ml, propylene glycol 14 mg / ml, phenol 5.5 mg / ml in water for injection. Victoza® is a commercially available liraglutide drug.

[0437] method: Three groups with 2 or 3 dogs per group were assigned to study the pharmacokinetics in plasma and three groups with 3 dogs per group were assigned to study the pharmacokinetics in synovial fluid.

[0438] [Table 34]

[0439] N = number of animals

[0440] [Table 35]

[0441] Statistical Planning Statistics were performed using one-way analysis of variance + Tukey post-hoc test.

[0442] result: Plasma dose of liraglutide for groups 51M, 52M, and 53M.

[0443] The plasma doses of liraglutide for groups 51M, 52M, and 53M are shown in Figure 21. Tukey's multiple comparison test allowed us to conclude that there were no significant differences in the AUC of liraglutide plasma concentrations during the 24 hours following IA injection for preformulation 12 vs. preformulation 2, preformulation 12 vs. preformulation 6, and preformulation 2 vs. preformulation 6.

[0444] The measured AUC (=area under the curve) are summarized in the table below.

[0445] [Table 36]

[0446] Liraglutide synovial doses for groups 54M, 55M, and 56M.

[0447] The synovial fluid doses of liraglutide for groups 54M, 55M and 56M are shown in FIG.

[0448] The measured AUC (=area under the curve) are summarized in the table below.

[0449] [Table 37]

[0450] conclusion In conclusion, the AUC of liraglutide plasma concentrations over 24 hours after IA or subcutaneous injection of liraglutide is similar. However, when liraglutide is administered by the subcutaneous route, no liraglutide is present in the synovial fluid for 24 hours after intradermal injection, whereas when liraglutide is administered by the intra-articular route, liraglutide is present in the synovial fluid for 24 hours after intra-articular injection.

[0451] Example 10: Clinical Trial Phase 1 A Phase I clinical trial evaluating the safety, tolerability, pharmacokinetics and efficacy of single ascending doses of 4P004 versus placebo injected into the target knee joint in patients with osteoarthritis (Kellgren-Lawrence (KL) stages 2-4). 4P004 refers to a composition according to the present invention, i.e. a composition comprising a GLP-1R agonist for IA injection.

[0452] the purpose Main purpose To evaluate the clinical and biological safety, and the general and local tolerability of liraglutide when administered as a single ascending dose intra-articularly (IA) in the knee in patients with osteoarthritis.

[0453] Secondary Objectives To determine the plasma PK of liraglutide when administered as a single IA dose at escalating dose levels in patients with osteoarthritis (stages KL2-4).

[0454] Evaluation items Primary endpoint 1. Difference between 4P004-treated subjects and placebo in the number of adverse events [time period: from screening to last follow-up visit] 2. Difference between 4P004-treated subjects and placebo in the number of abnormal vital signs [time period: from screening to final follow-up visit] 3. Difference between 4P004-treated subjects and placebo in the number of abnormal clinical laboratory assessments [time period: from screening to final follow-up visit] 4. Difference between 4P004 treated subjects and placebo in the number of abnormal physical examinations [time period: from screening to final follow-up visit]

[0455] Secondary endpoints Assessment of PK parameters: (Cmax, Tmax, AUC0-t, AUC0-∞, T1 / 2) on days 1 and 2.

[0456] Exploratory endpoints: Collection of body fluids (urine, blood, synovial fluid) to assess fluid biomarkers related to the effects of 4P004.

[0457] Overall Design This Phase I is a randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of single ascending doses of 0.3 mg, 1 mg, 3 mg, and 6 mg of intra-articular 4P004 in patients with: 18 to 80 years old, -Having osteoarthritis.

[0458] A total of 32 participants will be enrolled in four cohorts, with each cohort receiving 4P004 or placebo (6:2). The dose of 4P004 will be escalated in cohorts 1-4.

[0459] Inclusion criteria Patients who are capable of giving informed consent and who are willing to submit to all procedures and evaluations related to the study (consent by a legally authorized representative will not be accepted) Patients must be between 18 and 80 years old. Patients diagnosed with locally assessed primary osteoarthritis (stages KL2-4).

[0460] Exclusion criteria Treatment with more than 10 mg of prednisone per day or equivalent systemic glucocorticoids within 4 weeks prior to screening Any known active infection Any chronic condition that has not been adequately controlled for at least three months History of malignancy of any organ system within the past 2 years (excluding localized basal cell carcinoma of the skin or intraepithelial cervical carcinoma) Patients with type I and type II diabetes mellitus controlled with GLP-1 analogues Patients exposed to glucagon peptide 1 analog hormones Treatment of the targeted knee with intra-articular injections (steroids, hyaluronic acid derivatives) within 3 months Use of topical analgesics (gels, creams, or patches) for treatment of knee OA within 7 days of screening Target knee effusion requiring aspiration within 3 months Use of electrotherapy or acupuncture for OA within 4 weeks Significant and clinically evident misalignment of the target knee Any condition, including clinical laboratory findings, which in the opinion of the investigator may constitute a risk or contraindication to participation in the study or may interfere with the objectives, conduct, or evaluation of the study. Participation in a clinical research trial within 12 weeks · Hypersensitivity to the active substance or to any of the excipients: dibasic sodium phosphate dihydrate, propylene glycol, phenol.

[0461] result We expect to demonstrate that 4P004 is safe and well tolerated in humans at doses within the doses tested, and we expect to determine the pharmacokinetic parameters of a single intra-articular injection into the knee joint in patients.

[0462] Example 11: Clinical Trial Phase 2 Phase 2 trials A dose ranging study to evaluate the efficacy and safety of 4P004 administered by intra-articular injection in patients with mild to moderate knee osteoarthritis. 4P004 refers to a composition according to the present invention, i.e. a composition comprising a GLP-1R agonist for IA injection.

[0463] the purpose Main purpose To demonstrate the efficacy of 4P004 in osteoarthritis and to determine the optimal dose regimen.

[0464] Secondary Objectives To evaluate the safety and tolerability of different dose regimens of 4P004 versus placebo.

[0465] To evaluate the complementary clinical efficacy of 4P004 versus placebo.

[0466] exploratory purpose

[0467] Biomarkers Clinical signs of structural changes on imaging

[0468] Evaluation items

[0469] Primary endpoint To demonstrate significant improvement in pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain score versus placebo at three months.

[0470] Change from baseline in OMERACT-OARSIS scores

[0471] Secondary endpoints -Clinical and laboratory safety - Change from baseline pain using a visual analog scale (VAS) for Phase II study participants - Change from baseline on Physician Global Assessment of Illness scale - Change from baseline Patient Global Assessment (PGA) - Change from baseline in OMERACT-OARSIS score - Change from baseline in synovitis as assessed by MRI at 6 and 12 months -Changes in the joint space narrowing in the target knee.

[0472] Inclusion criteria Male or female, aged 18-80 years; - Clinical trial participants will use contraception in accordance with local regulations regarding contraception methods. Be willing and able to provide written informed consent Established clinical diagnosis of OA (clinical and radiographic criteria) in the target knee joint for at least 6 months - Kellgren-Lawrence grade of knee OA, radiographic (X-ray) disease stage 2 or 3 in the target knee The main cause of pain throughout the body is OA in the target knee. Pain visual analog scale (VAS) scores of 30–80 mm (on a 100 mm VAS) and WOMAC total A score of 72–192 (out of 240) for the target knee at screening Ambulation; assistive devices (e.g., canes) were permitted if needed less than 50% of the time, but any use of a walker was excluded. BMI<40

[0473] Exclusion criteria Major knee surgery in the target knee within 12 months prior to the study or surgery scheduled during the study period Partial or total joint replacement in the target knee Currently requires permanent use of a mobility assistive device (e.g., wheelchair, parallel bars, walker, cane, or crutches) Co-morbidities that may affect the primary study outcome in the target knee, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, gout or pseudogout, and fibromyalgia Patients with type I and type II diabetes Patients exposed to glucagon peptide 1 analog hormones -History of malignant tumor within the past 3 years Participation in a clinical research trial within 12 weeks Treatment of the target knee with intra-articular steroids within 2 months or hyaluronic acid derivatives within 6 months Treatment with more than 10 mg of prednisone per day or equivalent systemic glucocorticoids within 4 weeks prior to screening Effusion in the target knee requiring aspiration within 3 months Use of electrotherapy or acupuncture for OA within 4 weeks Significant and clinically evident misalignment of the target knee Any known active infection Any chronic condition that has not been adequately controlled for at least 3 months Use of centrally acting analgesics (e.g., duloxetine) within 12 weeks prior to screening Use of anticonvulsants within 12 weeks prior to screening, except when used for seizure or migraine prophylaxis Use of topical analgesics (gels, creams, or patches) for the treatment of knee OA within 7 days of screening Any condition, including clinical laboratory findings, which in the opinion of the investigator may constitute a risk or contraindication to participation in the study or may interfere with the objectives, conduct, or evaluation of the study.

[0474] Overall Design this is, 18 to 80 years old, Have mild or moderate osteoarthritis This is a dose-ranging, randomized, double-blind, and placebo-controlled study to evaluate the efficacy and safety of three ascending doses of intra-articular 4P004 or placebo in patients.

[0475] Approximately 500 participants will be randomized into one of four treatment arms to receive one of three fixed doses of 4P004 or a placebo.

[0476] result It is hoped that 4P004 will demonstrate significant reduction in pain compared to placebo based on the WOMAC evaluation study, and will provide clinical evidence of improved function in patients with osteoarthritis.

Claims

1. A pharmaceutical composition for use in a method for treating joint diseases, particularly osteoarthritis and / or joint pain, more specifically inflammatory joint pain, which is a solution or suspension administered by intra-articular injection, particularly by intra-articular injection into the joint cavity, and comprises a GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, and an isotonic agent selected from the group consisting of glucose, polyethylene glycol, propylene glycol, and glycerol. A pharmaceutical composition comprising the same.

2. The GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, baaglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof, preferably the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof, more preferably the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide, and combinations thereof, even more preferably the GLP-1R agonist is liraglutide, the buffer is a phosphate buffer, preferably a phosphate buffer containing disodium hydrogen phosphate dihydrate as a buffer, and the isotonic agent is propylene glycol. A pharmaceutical composition for use according to claim 1.

3. A GLP-1R agonist, preferably selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, baaglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof, more preferably selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof, even more preferably selected from the group consisting of liraglutide, semaglutide, and combinations thereof, most preferably liraglutide, a GLP-1R agonist, a buffer selected from the group consisting of tromethamine buffer and phosphate buffer, and an isotonic agent selected from the group consisting of glucose, polyethylene glycol, and glycerol. A pharmaceutical composition for use according to claim 1.

4. The GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, baioglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide and combinations thereof, preferably the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide and combinations thereof, more preferably the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide and combinations thereof, even more preferably the GLP-1R agonist is liraglutide. A pharmaceutical composition for use according to claim 1.

5. The GLP-1R agonist is liraglutide and is preferably administered at a dose of 0.0245 mg to 6.3 mg of liraglutide, preferably at a dose of 0.7 mg to 6.3 mg of liraglutide, more preferably at a dose of 0.3 mg, 1.0 mg, 3.0 mg or 6.0 mg of liraglutide, for use according to claim 4.

6. The GLP-1R agonist is semaglutide and is preferably administered at a dose of 0.0245 mg to 6.3 mg of semaglutide, preferably at a dose of 0.7 mg to 6.3 mg of semaglutide, more preferably at a dose of 0.25 mg, 0.5 mg or 1 mg of semaglutide, for use according to claim 4.

7. The pharmaceutical composition is intended to be administered by one or at least two intra-articular injections, for use according to claim 5.

8. The dose of the pharmaceutical composition is intended to be administered monthly, for use according to any one of claims 1 to 7.

9. The total dose of the GLP-1R agonist administered in one year is 0.18 mg to 72 mg, preferably 0.7 mg to 8.4 mg, for use according to any one of claims 1 to 7.

10. A GLP-1R agonist, A buffer selected from the group consisting of tromethamine buffer and phosphate buffer, An isotonic agent selected from the group consisting of glucose, polyethylene glycol and glycerol, A pharmaceutical composition comprising.

11. The GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, albiglutide, baioglutide, dulaglutide, semaglutide, pegapamodutide, taspoglutide, and combinations thereof; preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, exenatide, lixisenatide, dulaglutide, semaglutide, and combinations thereof; more preferably, the GLP-1R agonist is selected from the group consisting of liraglutide, semaglutide, and combinations thereof; even more preferably, the GLP-1R agonist is liraglutide. The pharmaceutical composition according to claim 10.

12. The pharmaceutical composition according to claim 10 or 11, comprising 2 mg / mL to 20 mg / mL, preferably 4 mg / mL to 8 mg / mL, more preferably about 6 mg / mL of a GLP-1R agonist.

13. The pharmaceutical composition according to claim 10 or 11, comprising 0.01 mg / mL to 20 mg / mL, preferably 0.5 mg / mL to 2 mg / mL, more preferably 1 mg / mL to 1.5 mg / mL, even more preferably about 1.34 mg / mL of a GLP-1R agonist.

14. The buffer solution is a tromethamine buffer solution containing tromethamine as a buffer, preferably containing 0.1 mg / mL to 10 mg / mL, more preferably 0.5 mg / mL to 1 mg / mL, even more preferably about 0.97 mg / mL of tromethamine. The pharmaceutical composition according to claim 10.

15. The buffer solution is a phosphate buffer solution containing sodium dihydrogen phosphate as a buffer, preferably containing 0.1 mg / mL to 10 mg / mL, more preferably 0.75 mg / mL to 1.5 mg / mL, even more preferably about 1.14 mg / mL of sodium dihydrogen phosphate. The pharmaceutical composition according to claim 10.

16. The pharmaceutical composition according to claim 10, wherein the isotonic agent is glucose, preferably containing 10 mg / mL to 50 mg / mL, more preferably 20 mg / mL to 40 mg / mL, even more preferably about 30 mg / mL of glucose.

17. The isotonic agent is 800 g·mol －１ less than, preferably 100 g·mol−1 to 600 g·mol －１ and is polyethylene glycol having a molecular weight, preferably the isotonic agent is PEG400, and The pharmaceutical composition according to claim 10, comprising polyethylene glycol, preferably at 20 mg / mL to 100 mg / mL, more preferably at 40 mg / mL to 80 mg / mL, and still more preferably at about 60 mg / mL.

18. The pharmaceutical composition according to claim 10, wherein the isotonic agent is glycerol, preferably at 5 mg / mL to 50 mg / mL, more preferably at 10 mg / mL to 25 mg / mL, and still more preferably at about 17 mg / mL or about 18 mg / mL.

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