Pharmaceutical compositions of semaglutide and salts thereof for intranasal administration

Abstract

A pharmaceutical composition of semaglutide or its salts for intranasal administration for the treatment of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), or neurodegenerative diseases. Compared to oral tablets, intranasal delivery of semaglutide avoids repeated injections and improves systemic absorption.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions of semaglutide and its salts for intranasal administration, and their use in the treatment of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), or neurodegenerative diseases. Background Technology

[0002] Semaglutide (C 187 H 291 N 45 O 59 Semaglutide is a long-acting GLP-1 receptor agonist with 94% structural similarity to natural GLP-1 (Knudsen et al., 2019). It is also known as N6,26-{18-[N-(17-carboxyheptadecanoyl)-L-glutamyl]-10-oxo-3,6,12,15-tetraoxin-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propionic acid),34-L-arginine]human glucagon-like peptide-1 (7-37), as described in WO2020 / 084126. The preparation method of semaglutide is described in Example 4 of WO2006 / 097537. Semaglutide can be present in the composition in a completely or partially ionized form.

[0003] Semaglutide is an antidiabetic drug used to treat type 2 diabetes and for long-term weight management. Semaglutide works similarly to human glucagon-like peptide-1 (GLP-1), increasing glucose metabolism by increasing insulin secretion. Semaglutide has been found to reduce hyperglycemia, weight, fatty degeneration, and improve cognitive function in patients with neurodegenerative diseases (Mahapatra et al., 2022). Currently, two semaglutide products have been approved by the US Food and Drug Administration (USFDA), Health Canada, the European Medicines Agency (EMA), and the Japanese Ministry of Health for the treatment of type 2 diabetes, including... (Subcutaneous injection, once weekly; available in 0.5 mg and 1.0 mg strengths) and (Oral tablets, once daily; available in 3, 7, and 14 mg strengths).

[0004] Using an injection pen is complex and requires training from experienced healthcare professionals. Long-term and frequent injections of semaglutide can cause inconvenience and discomfort for patients, and carry risks of infection and adverse reactions (such as erythema) at the injection site (see FDA guidelines). (Packaging instructions). Semaglutide oral tablets offer an alternative treatment option for patients who are unwilling or unable to self-medicate with injectable hypoglycemic agents; however, despite these advantages, the oral bioavailability of semaglutide is very low (0.4-1%) due to the low permeability of the semaglutide molecule and its extensive degradation and metabolism in the gastrointestinal (GI) tract, and varies greatly from person to person. To achieve a systemic absorption equivalent to injectable semaglutide, the weekly dose of oral semaglutide tablets is 49 to 98 mg, significantly higher than the weekly dose of 0.5 to 1.0 mg for injections (approximately 100 times). Oral tablets must be taken at least 30 minutes before the first meal or drink of water daily. Each tablet also contains up to 300 mg of a saturation enhancer (SNAC), which may cause gastrointestinal adverse reactions such as nausea, abdominal pain, and vomiting (see FDA guidelines). Packaging instructions).

[0005] Given the drawbacks of commercially available semaglutide products, nasal administration is an alternative and promising option because the drug can enter the bloodstream directly from the absorption site, completely avoiding degradation in the gastrointestinal tract and hepatic metabolism. It is also convenient for patients and more readily accepted by the general public. The advantages of intranasal semaglutide administration include, but are not limited to: non-invasiveness, convenience, and self-administration; rapid and complete absorption through the nasal epithelial mucosa, resulting in a rapid onset of action; improved bioavailability due to avoidance of GI degradation and hepatic metabolism; lower dosage and frequency of administration (i.e., 1-2 doses per week) compared to oral tablets; effective control of local and systemic adverse reactions; absence of drug interactions and food effects; and no dosage adjustment required for special populations.

[0006] WO2007 / 146488 discloses a nasal liquid composition of the GLP-1 agonist liraglutide. To maintain the physicochemical stability of the formulation, the pH is adjusted to 8.5 or higher, which is much higher than the pH of nasal mucus under normal physiological conditions (5.5-6.5). Long-term use will cause various local adverse reactions. Furthermore, liraglutide is a short-acting GLP-1 agonist, with a subcutaneous injection dose of 1.25-1.9 mg daily. Based on the pharmacokinetic results of the drug in rabbits as described in the patent, the inventors concluded that in order to achieve the same absorption as injection, the intranasal formulation must reach a drug concentration of 50 mg / mL, administered 2-4 times daily. Frequent nasal administration may lead to toxicity and poor patient compliance.

[0007] WO2007 / 0611434 describes a pharmaceutical composition for intranasal exenatide that uses a formulation technique similar to that in WO2007 / 146488, with the addition of a dipeptidyl aminopeptidase (DPP) IV inhibitor to minimize the enzymatic degradation of exenatide. Due to the short half-life of exenatide (2.4 hours), the effective drug concentration in the bloodstream and its hypoglycemic effect can only be maintained for 3-4 hours. To maintain the therapeutic effect, at least 6-8 intranasal administrations per day are required. Therefore, this composition is not suitable for clinical use in the treatment of metabolic syndrome in mammals. Summary of the Invention

[0008] This invention relates to pharmaceutical compositions of semaglutide and its salts for intranasal administration, for the treatment of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), or neurodegenerative diseases. Compared to commercially available injection pens or oral tablets, intranasal delivery of semaglutide avoids long-term injections and improves systemic absorption. Attached Figure Description

[0009] Figure 1 Mean plasma concentration versus time curves of semaglutide in rats after single intranasal administration of PT-N01, PT-N02, and PT-N03 at a dose of 0.2 mg / animal.

[0010] Figure 2 Mean plasma concentration versus time curves of semaglutide in rabbits after single intranasal administration of PT-N01, PT-N04, and PT-N05 at a dose of 4 mg / animal and single subcutaneous injection of PT-S01 at a dose of 0.25 mg / animal.

[0011] Figure 3 Mean blood glucose versus time curves after single intranasal administration of PT-N01, PT-N04, PT-N05 at a dose of 4 mg / animal and single subcutaneous injection of PT-S01 at a dose of 0.25 mg / animal in rabbits.

[0012] Figure 4 Mean body weight versus time curves after rabbits were given a single intranasal dose of PT-N01, PT-N04, and PT-N05 at a dose of 4 mg / animal and a single subcutaneous injection of PT-S01 at a dose of 0.25 mg / animal.

[0013] Figure 5 Average food intake versus time curves in rabbits after single intranasal administration of PT-N01, PT-N04, and PT-N05 at a dose of 4 mg / animal and single subcutaneous injection of PT-S01 at a dose of 0.25 mg / animal.

[0014] Figure 6In beagles, PT-N06 was administered intranasally at a single dose of 7 mg / animal and orally. Average semaglutide plasma concentration versus time curve after 7 mg tablets. Detailed Implementation

[0015] This invention relates to pharmaceutical compositions capable of delivering sufficient doses of semaglutide via intranasal administration. Marketed oral semaglutide can cause several adverse reactions, such as high first-pass effect and extremely low bioavailability, high inter-subject variability, drug interactions and food effects, and gastrointestinal adverse reactions caused by permeation enhancers. The intranasal composition of this invention allows for rapid absorption of semaglutide through the nasal mucosa, completely avoiding gastrointestinal degradation and metabolism, thus effectively overcoming the aforementioned drawbacks of oral administration. Intranasal drug absorption is rapid and complete, convenient to use, and has few side effects.

[0016] The compositions according to the present invention comprise an active ingredient, namely semaglutide or a pharmaceutically acceptable salt thereof. Semaglutide used in the present invention comprises either a free base form or a pharmaceutically acceptable salt form. Pharmaceutically acceptable salts include, but are not limited to, sodium, potassium, calcium, magnesium, lithium, cesium, palladium, and ammonium. The salt preferably used in the present invention is sodium semaglutide, which is formed by combining semaglutide and sodium in a mass ratio of 1:1 to 100:1.

[0017] Use of semaglutide or its pharmaceutical salts according to the invention includes formulations in which a therapeutic dose of semaglutide is delivered to the nasal mucosa. Preferred dosage forms are liquid dosage forms, including solutions, suspensions, emulsions, bioadhesives or in-situ gels, microspheres, nanoparticles, self-emulsifying drug delivery systems; or solid dosage forms, including powders, granules; or semi-solid dosage forms, including ointments, creams, hydrogels; or other forms suitable for intranasal delivery in the art.

[0018] Semaglutide is a hydrophilic compound with a high molecular weight (MW: 4113.64), exceeding the maximum molecular weight cutoff for intranasal delivery (Pathak K., 2011). Therefore, nasal absorption of semaglutide is very low. In our pharmacokinetic and pharmacodynamic studies in rabbits, the intranasal bioavailability of semaglutide aqueous solution was only 0.09%. Even with a high intranasal dose of 4 mg per animal, the drug plasma concentration was far below the minimum effective concentration. Therefore, utilizing various mucosal drug delivery absorption-enhancing techniques to improve intranasal absorption is imperative.

[0019] Surprisingly, this invention demonstrates that the bioavailability of semaglutide can be effectively improved by comprehensively utilizing a variety of absorption enhancers. These absorption enhancers include, but are not limited to: i) cell-penetrating peptides (CPPs) as carriers to achieve transcellular drug transport; ii) tight junction regulators that increase intercellular permeability; and iii) bioadhesive polymers that prolong residence time on the nasal mucosa and minimize drug clearance by nasal cilia.

[0020] A key aspect of this invention is the promotion of semaglutide transcellular transport using cell-penetrating peptides (CPPs). Studies have shown that physical mixing or covalent coupling of semaglutide molecules with CPPs can significantly improve intranasal absorption of semaglutide. CPPs are positively charged short peptides, 5-30 amino acids in length, capable of penetrating biological membranes and serving as novel carriers for intracellular delivery (Derakhshankhah H, Jafari S. 2018). CPPs have been extensively studied due to their high intracellular transport efficiency and low cytotoxicity, and can be used for the delivery of large molecules. Preferred CPPs for this invention include, but are not limited to, TAT, R6, R8, permein, protamine, transport proteins, and their derivatives. CPPs can form complexes with semaglutide and significantly enhance transnasal delivery through endocytosis.

[0021] Another important aspect of this invention is the further improvement of semaglutide transcellular bypass transport across the nasal mucosa via tight junction modulators. The tight junction modulators of this invention may be selected from: (i) phospholipid surfactants, including dodecylphosphocholine (DPC), 1,2-decylphosphatidylcholine (DDPC), 1,2-distearyl-sn-glycerol-3-phosphocholine (DSPC), 1-decanoyl-1-sn-glycerol-3-phosphocholine (LLPC), 1,2-dioctanoyl-sn-glycerol-3-phosphocholine (D8PC), and 1-1-palmitoyl-2-glutaryl-sn-glycerol-3-phosphocholine (PGPC), with preferred phospholipid surfactants being DPC and DSPC, due to their better solubility and stability in liquid formulations, as well as low mucosal toxicity; (ii) cyclodextrin derivatives. The compounds include α-cyclodextrin, β-cyclodextrin, dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and γ-cyclodextrin, with preferred cyclodextrin derivatives being dimethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin; (iii) chelating agents, including EDTA, EGTA, and BAPTA, with EDTA being preferred; (iv) bile salts, including sodium cholate, dehydrocholate, and taurocholate; (v) fatty acids and phosphate esters, including oleic acid, sodium decanoate, palmitoylcarnitine, and lysophosphatidic acid; (vi) cationic polymers, such as chitosan derivatives and protamine; (vii) surfactants, including sodium dodecyl sulfate (SDS) and Tween 20; and (viii) nitric oxide donors or bradykinin.

[0022] A major obstacle to nasal delivery is the rapid clearance of drug formulations (aqueous solutions or dry powders) from the nasal cavity by the rapidly moving nasal mucocili, with a clearance half-life of approximately 15 minutes, resulting in low bioavailability (Merkus et al., 1998). This is particularly true for semaglutide and other peptides with high molecular weights and low nasal mucosal permeability, where nasal ciliary clearance leads to extremely low bioavailability. Therefore, the addition of components with mucosal adhesion properties, including bioadhesives / mucosal adhesives and / or in-situ gelling agents, should be considered to increase drug retention time in the nasal cavity and prolong drug release time for sustained therapeutic effects.

[0023] In some embodiments of the present invention, the pharmaceutically acceptable bioadhesive / mucosal adhesive is selected from methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hyaluronic acid, sodium alginate, chitosan, gelatin, lectin, poly(acrylic acid), gum arabic, carbomer 934P, xanthan gum, guar gum, and carrageenan, and combinations thereof.

[0024] In-situ gelling agents are water-soluble polymers with bioadhesive properties that can alter their rheological behavior in response to changes in ions, pH, and temperature. When the drug solution is mixed in a spray device, it forms a free-flowing, non-Newtonian fluid; when mixed or atomized, it forms a viscous gel. In some embodiments of the present invention, pharmaceutically acceptable in-situ gelling agents are selected from poloxamer, gellan gum, pectin, carbomer, carrageenan, cellulose acetate phthalate, and combinations thereof.

[0025] The first aspect relates to a pharmaceutical composition comprising semaglutide in a dose of 0.01 mg to 100 mg for use in a suitable formulation. This composition is suitable for intranasal administration, typically via a nasal spray device.

[0026] Pharmaceutically acceptable buffers can be used to maintain optimal pH conditions for physicochemical stability and to minimize local irritation to the nasal mucosa. According to the invention, a suitable pH range is 3.0 to 9.0, preferably 4.0 to 7.0. Preferred buffer systems include, but are not limited to, phosphate buffers, acetate buffers, borate buffers, citrate buffers, tartrate buffers, and Tris buffers.

[0027] This composition also contains one of the following pharmaceutical preservatives, including but not limited to: benzalkonium chloride, benzyl ammonium chloride, benzyl alcohol, chlorobutanol, chlorhexidine, methylparaben and propylparaben, phenylethanol, phenylmercuric acetate, and thimerosal. Preservatives that do not cause adverse reactions to the nasal mucosa are preferred, including but not limited to benzyl alcohol, benzalkonium chloride, chlorhexidine, and thimerosal.

[0028] Finally, the composition of the present invention may further include: (1) a chelating agent, namely sodium EDTA; (2) an antioxidant, namely sodium metabisulfite; and (3) an osmotic pressure regulator, including glucose, glycerol, hydroxypropyl betadextrin, mannitol, sorbitol, potassium chloride and sodium chloride.

[0029] Semaglutide, preferably in aqueous or semi-solid form, or a pharmaceutical salt composition thereof, is sprayed into the nasal cavity using an atmospheric pressure nasal spray device. Suitable spray devices include a spray pump and a bottle, and can deliver single or multiple doses of the drug by mechanical force. The spray volume per nostril ranges from 10 to 200 μL, more preferably from 50 to 150 μL, and most preferably from 80 to 120 μL.

[0030] Another aspect of the invention relates to the preparation of a therapeutic medicament for intranasal delivery, comprising a therapeutic dose of semaglutide in a suitable pharmaceutical carrier of 0.1 to 50 mg, for the treatment of diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), or neurodegenerative diseases.

[0031] The pharmacokinetic and pharmacodynamic profiles of semaglutide pharmaceutical compositions (PT-N01 to PT-N06) administered intranasally to rats, rabbits, and beagle dogs are described in Examples 3 to 5. To the inventors' knowledge, no patents or publications currently demonstrate intranasal delivery of semaglutide. Compared with commercially available oral tablets... In comparison, intranasal administration of the semaglutide drug composition exhibits unexpectedly rapid and significantly improved absorption. Based on animal pharmacokinetic results, the intranasal dose can be further reduced from 7-14 mg of oral semaglutide daily to 8-10 mg or less once weekly intranasally, while systemic absorption and efficacy will be comparable to or superior to oral tablets, with faster control of blood glucose and weight, and no gastrointestinal toxicity, food effects, or drug interactions.

[0032] Example

[0033] Example 1. Semaglutide nasal spray

[0034] PT-N01: Dissolve 200 mg of semaglutide completely in 10 mL of PBS 7.0 buffer solution with stirring at ambient temperature. Then filter the solution through a 0.45 μm filter membrane and fill into a glass vial equipped with a metered-dose nasal spray pump. Each spray delivers 2 mg of semaglutide intranasally at a volume of 0.10 mL.

[0035] PT-N02: In an exemplary composition of the present invention having the ingredients listed in Table 1, a cell-penetrating peptide, permein, is used as a permeation enhancer to prepare the nasal spray composition.

[0036] Table 1. Composition of PT-NO2

[0037] Element weight unit Semaglutide 60 mg Penetrant 60 mg PBS 5.0 buffer Add appropriate amount to 6mL mL

[0038] Preparation process:

[0039] (a) Place 60 mg of semaglutide into a glass vial equipped with a magnetic stir bar.

[0040] (b) Add an appropriate amount of PBS 5.0 buffer and stir at room temperature to dissolve the API.

[0041] (c) Add 60 mg of osmotic acid to the solution and stir the mixture until completely dissolved.

[0042] (d) Check the pH and adjust the pH of the solution to 5.0 using HCl or NaOH solution.

[0043] (e) Dilute with PBS 5.0 buffer to the required volume (5 mL).

[0044] (f) Filter the solution using a 0.45-micron filter.

[0045] (g) Fill the solution into a 3.5 mL nasal spray bottle. Each press of the spray pump delivers 1.2 mg of semaglutide (0.1 mL).

[0046] PT-N03: In an exemplary composition of the present invention, a nasal spray composition having the components listed in Table 2 is prepared using a penetration enhancer such as dodecyl phosphate choline (DPC), 2,6-dimethyl-β-cyclodextrin and disodium edetate (EDTA-2Na).

[0047] Table 2. Composition of PT-N03

[0048] Element weight unit Semaglutide 100 mg dodecyl choline phosphoric acid 300 mg 2,6-Dimethyl-β-cyclodextrin 1000 mg Sodium edetate 100 mg Hydroxypropyl methylcellulose 50 mg PBS 6.5 buffer Add appropriate amount to 10mL mL

[0049] Preparation process:

[0050] (a) Weigh semaglutide and place it into a glass bottle equipped with a magnetic stir bar.

[0051] (b) Add an appropriate amount of PBS 6.5 buffer and stir at room temperature until the API is dissolved.

[0052] (c) Add n-dodecyl phosphate choline to the solution and stir the mixture until it is completely dissolved.

[0053] (d) Add 2,6-dimethyl-β-cyclodextrin and disodium edetate to the solution and stir until dissolved.

[0054] (e) Add HPMC to the solution and dissolve the excipient by stirring.

[0055] (f) Dilute with PBS 6.5 buffer to the required volume (10 mL).

[0056] (g) Check the pH value and adjust the pH value of the solution to 6.5 with HCl or NaOH solution.

[0057] (h) Filter the solution using a 0.45-micron filter.

[0058] (i) Fill the solution into a 3.5 mL nasal spray bottle, and deliver 1 mg of semaglutide (0.1 mL) with each press of the spray pump.

[0059] PT-N04: In an exemplary composition of the present invention, a nasal spray composition having the components listed in Table 3 is prepared using penetration enhancers such as dodecyl phosphate choline (DPC), 2,6-dimethyl-β-cyclodextrin, and disodium edetate (EDTA-2Na). Bioadhesive polymers such as hydroxypropyl methylcellulose (HPMC K100LV) are used to prolong the residence time of the drug in the nasal cavity. First, 200 mg of semaglutide is completely dissolved in approximately 8 mL of PBS 7.0 buffer solution at ambient temperature; then, dodecyl phosphate choline, 2,6-dimethyl-β-cyclodextrin, and disodium edetate are added and stirred to dissolve at ambient temperature; subsequently, HPMC is added and stirred until dissolved; finally, PBS 7.0 buffer solution is added to a final volume of 10 mL. The final concentration of semaglutide in the solution is 20 mg / mL.

[0060] Table 3. Composition of PT-N04

[0061]

[0062] After preparation, the drug solution is filtered through a 0.22 μm filter membrane and then bottled into a metered nasal spray (0.10 mL per spray), delivering 2 mg of semaglutide intranasally each time.

[0063] PT-N05: At ambient temperature, semaglutide and the absorption enhancer sodium N-(8-[2-hydroxybenzoylamino])octanoate (SNAC) were completely dissolved in approximately 8 mL of PBS 7.0 buffer solution; then dimethyl-β-cyclodextrin and disodium edetate (EDTA-2Na) were added to the solution; hydroxypropyl methylcellulose (HPMC K100LV) was added to the solution and stirred at ambient temperature until completely dissolved; finally, an appropriate amount of PBS 7.0 buffer solution was added to the final solution containing the components listed in Table 4 to a final volume of 10 mL. The concentration of semaglutide in the final spray solution was 20 mg / mL.

[0064] Table 4. Composition of PT-N05

[0065]

[0066] After preparation, the drug solution is filtered through a 0.22 μm filter membrane and then bottled into a metered nasal spray (0.10 mL per spray), delivering 2 mg of semaglutide intranasally each time.

[0067] PT-N06: Semaglutide and the absorption enhancer dodecyl phosphate choline (DPC) were completely dissolved in approximately 8 mL of PBS 7.0 buffer at ambient temperature; then disodium edetate (EDTA-2Na) was added to the solution; hydroxypropyl methylcellulose (HPMC K100LV) was then added to the solution and stirred at ambient temperature until completely dissolved; finally, PBS 7.0 buffer was added to 10 mL of the final solution containing the components listed in Table 5. The concentration of sesmaglutide in the final spray solution was 35 mg / mL.

[0068] Table 5. Composition of PT-N06

[0069]

[0070] After preparation, the drug solution is filtered through a 0.22 μm filter membrane and then bottled into a metered nasal spray (0.10 mL per spray), delivering 3.5 mg of semaglutide intranasally each time.

[0071] Example 2. Other Semaglutide Nasal Sprays

[0072] PT-B01: In one composition of the present invention having the ingredients listed in Table 6, sodium carboxymethyl cellulose (CMC-Na) is used as a thickener to prepare a bioadhesive semaglutide nasal spray.

[0073] Table 6. Composition of PT-B01

[0074] Element Weight (per 100 mL) Semaglutide 2g dodecyl choline phosphoric acid 3g Sodium edetate 1g CMC-Na 0.5g PBS 6.5 buffer Add appropriate amount to 100mL

[0075] Preparation process:

[0076] (a) Weigh semaglutide and place it in a glass bottle equipped with a magnetic stirrer.

[0077] (b) Add phosphate buffer solution (pH 6.5) to a glass bottle and stir to dissolve API at room temperature.

[0078] (c) Add n-dodecyl phosphate choline to the solution and stir the mixture at room temperature until dissolved.

[0079] (d) Add disodium edetate and CMC-Na, and stir to dissolve the excipients at room temperature.

[0080] (e) Add PBS 6.5 buffer solution to the required volume (100 mL).

[0081] (f) Check the pH and adjust the pH of the solution to 6.0-7.0 with HCl or NaOH solution.

[0082] (g) Filter the solution using a 0.45-micron filter.

[0083] (h) Fill the solution into a 3.5 mL nasal spray and administer 2 mg of semaglutide into the nose each time (0.1 mL per spray).

[0084] PT-B02: A bioadhesive nasal spray is prepared using sodium hyaluronate in one composition of the present invention having the components listed in Table 7.

[0085] Table 7. Composition of PT-B02

[0086] Element Weight (per 100 mL) Semaglutide 1g dodecyl phosphate choline 3g Sodium edetate 1g Sodium hyaluronate 0.2g PBS 6.5 buffer Add appropriate amount to 100mL

[0087] Preparation process:

[0088] (a) Weigh dodecyl phosphate choline (DPC) and place it into a glass bottle equipped with a magnetic stirrer.

[0089] (b) Add an appropriate amount of PBS 6.5 buffer and stir the mixture at room temperature until dissolved.

[0090] (c) Add semaglutide to the solution and stir at room temperature until completely dissolved.

[0091] (d) Add disodium edetate to the solution and stir to dissolve the excipient at room temperature.

[0092] (e) Add sodium hyaluronate to the solution and stir the mixture at room temperature until it is completely dissolved.

[0093] (f) Add PBS 6.5 buffer solution to the required volume (100 mL).

[0094] (g) Check the pH and adjust the pH of the solution to 6.0-7.0 with HCl or NaOH solution.

[0095] (h) Filter the solution using a 0.45-micron filter.

[0096] (i) Fill the solution into a 3.5 mL nasal spray and administer 1 mg of semaglutide into the nose each time (0.1 mL per spray).

[0097] Semaglutide nasal spray containing poloxamer:

[0098] PT-B03: A nasal spray composition is prepared using poloxamer in one composition of the present invention having the components listed in Table 8.

[0099] Table 8. Composition of PT-B03

[0100] Element Weight (per 100 mL) Semaglutide 2g dodecyl choline phosphoric acid 3g Sodium edetate 1g Polosham 188 1g Polosham 407 18g PBS 6.5 buffer Add appropriate amount to 100mL

[0101] Preparation process:

[0102] (a) Weigh semaglutide and place it in a glass bottle equipped with a magnetic stirrer.

[0103] (b) Add an appropriate amount of PBS 6.5 buffer to the glass bottle and stir to dissolve the API at room temperature.

[0104] (c) Add n-dodecyl phosphate choline to the solution and stir the mixture at room temperature until it is completely dissolved.

[0105] (d) Add disodium edetate to the solution and stir to dissolve at room temperature.

[0106] (e) Add poloxamer 188 to the solution and stir in an ice bath until completely dissolved, then add poloxamer.

[0107] Add 407 to the solution and stir to dissolve in an ice bath.

[0108] (f) Add PBS 6.5 buffer solution to the required volume (100 mL).

[0109] (g) Check the pH and adjust the pH of the solution to 6.0-7.0 with HCl or NaOH solution.

[0110] (h) Place the solution at 4°C overnight until a clear solution is obtained.

[0111] (i) Filter the solution through a 0.45-micron filter.

[0112] (j) Fill the solution into a 3.5 mL nasal spray and administer 2 mg of semaglutide (0.1 mL per spray) into the nose each time.

[0113] Semaglutide nasal spray containing carbomer 934P.

[0114] PT-B04: A nasal spray composition is prepared using carbomer 934P in one composition of the present invention having the components listed in Table 9.

[0115] Table 9. Composition of PT-B04

[0116] Element Weight (per 100 mL) Semaglutide 2g dodecyl phosphate choline 3g Sodium edetate 1g Carbomer 934P 0.2g PBS 6.5 buffer Add appropriate amount to 100mL

[0117] Preparation process:

[0118] (a) Weigh semaglutide and place it in a glass bottle equipped with a magnetic stir bar.

[0119] (b) Add an appropriate amount of PBS 6.5 buffer to the glass bottle and stir to dissolve the API at room temperature.

[0120] (c) Add n-dodecyl phosphate choline to the solution and stir the mixture until it is completely dissolved.

[0121] (d) Add disodium edetate to the solution and stir the mixture until dissolved.

[0122] (e) Add Carbomer 934P to the above solution and stir the mixture until completely dissolved.

[0123] (f) Add PBS 6.5 buffer solution to the required volume (100 mL).

[0124] (g) Check the pH and adjust the pH of the solution to 6.0-7.0 with HCl or NaOH solution.

[0125] (h) Filter the solution using a 0.45-micron filter.

[0126] (i) Fill the solution into a 3.5 mL nasal spray and administer 2 mg of semaglutide into the nose each time (0.1 mL per spray).

[0127] Semaglutide nasal spray containing chitosan hydrochloride.

[0128] PT-B05: A nasal spray composition is prepared using chitosan hydrochloride in one composition of the present invention having the components listed in Table 10.

[0129] Table 10. Composition of PT-B05

[0130] Element Weight (per 100 mL) Semaglutide 3.5g dodecyl phosphate choline 3g Sodium edetate 1g Chitosan hydrochloride 0.3g PBS 6.5 buffer Add appropriate amount to 100mL

[0131] Preparation process:

[0132] (a) Weigh semaglutide and place it in a glass bottle equipped with a magnetic stir bar.

[0133] (b) Add an appropriate amount of PBS 6.5 buffer solution to the glass bottle and dissolve the API by mixing at room temperature.

[0134] (c) Add n-dodecyl phosphate choline and disodium edetate to the solution and stir the mixture until completely dissolved.

[0135] (d) Add chitosan·HCl to the solution and stir to dissolve the excipient at room temperature.

[0136] (e) Add PBS 6.5 buffer solution to the required volume (100 mL).

[0137] (f) Check the pH and adjust the pH of the solution to 6.0-7.0 with HCl or NaOH solution.

[0138] (g) Pass the solution through a 0.45-micron filter.

[0139] (h) Fill the solution into a 3.5 mL nasal spray and administer 3.5 mg of semaglutide into the nose each time (0.1 mL per spray).

[0140] Semaglutide nasal spray containing hydroxypropyl cellulose.

[0141] PT-B06: In one composition of the present invention having the ingredients listed in Table 11, a nasal spray composition is prepared using hydroxypropyl cellulose (HPC).

[0142] Table 11. Composition of PT-B06

[0143]

[0144]

[0145] Preparation process:

[0146] (a) Weigh semaglutide and n-dodecyl phosphate choline and place them in a glass bottle equipped with a magnetic stir bar.

[0147] (b) Add an appropriate amount of PBS 6.5 buffer and stir the mixture at room temperature until completely dissolved.

[0148] (c) Add disodium edetate to the solution and stir to dissolve.

[0149] (d) Add hydroxypropyl cellulose to the solution and stir to dissolve the excipient at room temperature.

[0150] (e) Add phosphate buffer solution (pH 6.5) to the required volume (100 mL).

[0151] (f) Check the pH and adjust the pH of the solution to 6.0-7.0 with HCl or NaOH solution.

[0152] (g) Pass the solution through a 0.45-micron filter.

[0153] (h) Fill the solution into a 3.5 mL nasal spray and administer 3.5 mg of semaglutide into the nose each time (0.1 mL per spray).

[0154] Semaglutide subcutaneous injection.

[0155] PT-S01: At ambient temperature, completely dissolve 20 mg of semaglutide in 20 mL of PBS 7.0 buffer. Then filter the solution through a 0.22 μm filter membrane. Finally, transfer the filtrate to a glass vial for subcutaneous injection. The concentration of semaglutide injection is 1 mg / mL.

[0156] Example 3. Pharmacokinetic study of semaglutide composition in rats.

[0157] This study aimed to investigate the intranasal absorption of semaglutide liquid formulation. SD rats were divided into three groups (n=3 per group), and each group received an intranasal administration (0.2 mg / animal) of a solution composition (PT-N01, PT-N02, or PT-N03) prepared according to Example 1. During the experiment, multiple blood samples were collected from the rat's tail vein up to 24 hours later. The concentration of semaglutide in rat plasma was determined using a validated LC-MS method. Pharmacokinetic parameters were generated using standard non-compartmental methods. Figure 1 The graphs showing the mean semaglutide plasma concentration versus time after intranasal administration of PT-N01, PT-N02, and PT-N03 are presented. Pharmacokinetic parameters are summarized in Table 12. Compared to the extremely low intranasal absorption of PT-N01 (semaglutide dissolved in PBS), the incorporation of penetration enhancers, Penetration (PT-N02) or dodecylphosphocholine (DPC), resulted in more rapid intranasal absorption in rats and higher semaglutide plasma concentrations. Penetration or DPC also significantly improved bioavailability.

[0158] Table 12. Pharmacokinetic parameters of semaglutide after intranasal administration of PT-N01, PT-N02 and PT-N03 in rats.

[0159] (n=3)

[0160]

[0161] Example 4. Pharmacokinetics and pharmacodynamics of semaglutide administered intranasally or subcutaneously in rabbits.

[0162] The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of semaglutide after intranasal spray and subcutaneous injection. Three groups of rabbits (n=3 per dose) received a single intranasal dose (4 mg / animal) of one of three nasal spray compositions (PT-N01, PT-N04, PT-N05), prepared according to Example 1 of the present invention, or a single subcutaneous injection of PT-S01 (0.25 mg / animal) prepared according to Example 2 of the present invention. Multiple blood samples were collected from the ear vein at 0 (before administration) and at 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 144 hours after administration. The concentration of semaglutide in rabbit plasma was determined using a validated LC / MS / MS method. Pharmacokinetic parameters were generated using a standard non-compartmental method. Blood glucose was measured at 0 (before administration) and at 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 144 hours after administration, and body weight and food intake were recorded once daily.

[0163] Figure 2 The mean semaglutide plasma concentration versus time curves are shown after a single intranasal administration of PT-N01, PT-N04, and PT-N05 at a single dose of 4 mg / animal, and a single subcutaneous injection of PT-S01 at a single dose of 0.25 mg / rabbit. Pharmacokinetic parameters are summarized in Table 13. The results indicate that intranasal administration of our optimal formulation (PT-N04) achieves plasma drug concentrations comparable to a single subcutaneous dose solution, and the bioavailability of PT-N04 is approximately 28 times that of semaglutide in PBS solution (PT-N01). In contrast, the enhancement achieved using SNAC as a penetration enhancer (PT-N05) was less pronounced (approximately 9-fold).

[0164] Table 13. Pharmacokinetic parameters of semaglutide in rats after intranasal administration of PT-N01, PT-N04, and PT-N05 at a dose of 4 mg / animal or subcutaneous injection of PT-S01. (n=3)

[0165]

[0166] Pharmacodynamic parameters, including blood glucose, body weight, and food intake, such as Figure 2-4 As shown, on day 2 after a single intranasal administration of PT-N04, the animals experienced a weight loss of over 15%, comparable to the subcutaneous PT-S01 group; daily food intake decreased by over 70% on days 2-3 after a single intranasal administration of PT-N04, also comparable to the subcutaneous PT-S01 group. During the study period, the PT-N05 and PT-S01 groups exhibited more stable blood glucose levels compared to the fluctuating and elevated blood glucose levels observed in the saline and PT-N01 groups.

[0167] Example 5. Pharmacokinetics of semaglutide after intranasal and oral administration in beagle dogs.

[0168] The aim of this study was to compare a single intranasal spray of PT-N06 (7 mg) with a single oral dose. Pharmacokinetics of semaglutide after administration of tablets (7 mg). Pharmacokinetic parameters are shown in Table 14. Eight beagle dogs (4 males and 4 females) participated in this study. All were fasted overnight before administration and given unlimited water throughout the study. Food was provided 4 hours after administration. Group 1 (2 males and 2 females) received a single intranasal dose (7 mg / animal) of PT-N06 nasal spray prepared according to Embodiment 1 of the present invention; Group 2 (2 males and 2 females) received a single oral dose of... Semaglutide tablets (7 mg / animal). Multiple blood samples were collected at 0 (before administration) and at 0.167, 0.333, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 144 hours post-administration. Semaglutide concentrations in canine plasma were determined using a validated LC / MS / MS method. Pharmacokinetic parameters were generated using standard non-compartmental methods. Blood glucose, body weight, and food intake were also recorded during the study.

[0169] Table 14. Nasal spray PT-N06 or oral administration Pharmacokinetic parameters of semaglutide after tablet administration.

[0170] (n = 3 - 4)

[0171]

[0172] References

[0173] 1. Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019; 10:155.

[0174] 2. Mahapatra MK, Karuppasamy M·Sahoo BM. Therapeutic Potential of Semaglutide, a Newer GLP 1Receptor Agonist, in Abating Obesity, Non Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review. Pharmaceutical Research. 2022; 39: 1233-1248.

[0175] 3.Merkus FW,Verhoef JC,NG Schipper,E Marttin.Nasal mucociliaryclearance as afactor in nasal drug delivery.Adv.Drug Deliv Rev.1998;5;29(1-2):13-38.

[0176] 4.Pathak K.Mucoadhesion;A prerequisite or a constraint in nasal drugdelivery?Int JPharm Investig.2011;1(2):62-63.

[0177] 5.Derakhshankhah H,Jafari S.Cell penetrating peptides:A concisereview withemphasis on biomedical applications.Biomed Pharmacother.2018;108:1090-1096.

Claims

1. A pharmaceutical composition for intranasal administration, said pharmaceutical composition being a liquid solution, wherein the components are distributed in the following proportions:

2. A pharmaceutical composition for intranasal administration, said pharmaceutical composition being a liquid solution, wherein the components are distributed in the following proportions:

3. The pharmaceutical composition according to any one of claims 1-2, characterized in that: The liquid solution is formulated as a nasal spray or nasal drops for intranasal administration to mammals.

4. The pharmaceutical composition according to claim 3, characterized in that: The intranasal administration device includes a bottle and a metered multidose pump.

5. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition is formulated and delivered intranasally in a volume of 0.05 mL to 0.25 mL per spray.

6. The pharmaceutical composition according to claim 1, characterized in that: The intranasal administration is achieved by delivering a dose of 0.005 mg to 50 mg semaglutide per spray via a spray device.

7. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating diabetes or obesity.

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