Long-acting injectable composition using active microparticles comprising GLP-1 receptor agonist or pharmaceutically acceptable salt thereof and method for preparing same

Abstract

The present invention relates to: a long-acting injectable composition using active microparticles, comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof; and a method for preparing same. The GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof can be provided as a long-acting pharmaceutical product with extended administration intervals, and in particular, a long-acting injectable composition using active microparticles, comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof can be simply prepared using active microparticles without requiring separate facilities for preparing long-acting formulations.

Description

Long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles and a method for preparing the same

[0001] The present invention relates to a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles, and a method for producing the same.

[0002] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a group of drugs used in the treatment of type 2 diabetes and are highly effective in lowering blood sugar levels. Furthermore, their clinical importance is growing as they are known to have weight-loss effects, alleviate hypertension, hypoglycemia, and / or hyperlipidemia, and have cardiovascular protective effects. They also have the advantage of a lower risk of hypoglycemia compared to older insulin secretagogues such as sulfonylureas or meglitinides. However, their frequent injections are inconvenient for patients with chronic diseases who require long-term administration.

[0003] Therefore, there is a need for the development of long-acting drugs that can reduce the burden on patients, and the longer the administration cycle, the more convenient it is for patients, which is leading to greater market competitiveness. The first GLP-1 RA drug, Byetta (exenatide), was a twice-a-day injection, and later, Victoza (liraglutide), a once-a-day injection, was developed and led the market. Currently, products such as Ozempic (semaglutide) and Trulicity (dulaglutide), which are once-a-week injections, occupy most of the market.

[0004] The significant success of GLP-1 RA drugs has led to a growing demand for once-a-month or longer-acting medications with extended durations of action. However, due to technological limitations, long-acting medications with longer dosing intervals than once-a-month have not yet been developed.

[0005] In addition, for GLP-1 RA drugs that are currently under development and have an extended dosing schedule of once a month or more, additional facilities are required to manufacture them, and it has been impossible for companies that produce and sell existing GLP-1 RA drugs to produce GLP-1 RA drugs that have an extended dosing schedule of once a month or more.

[0006] To improve these production-related issues, development of GLP-1 RA drugs with extended dosing of once a month or more is needed.

[0007] [Prior Art Literature]

[0008] [Patent Document]

[0009] KR 10-2024-0095076 A1

[0010] The purpose of the present invention is to provide a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles, and a method for preparing the same.

[0011] Another object of the present invention is to provide a method for producing a long-acting injection composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof, which can be provided as a long-acting pharmaceutical product with a longer administration interval for a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof, and which can be produced simply by using active microparticles, without requiring separate equipment for producing a long-acting formulation.

[0012] In order to achieve the above-described object, the present invention comprises an active microparticle; and a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof supported on the active microparticle, wherein the active microparticle is a porous microparticle, and the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof is bound to the surface and / or internal pores of the porous microparticle, and relates to a long-acting injection composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using the active microparticle.

[0013] Additionally, the active microparticles include a biodegradable polymer and may be spherical porous microparticles.

[0014] Additionally, the biodegradable polymer may be selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and combinations thereof.

[0015] Additionally, the active microparticles may have an average diameter (D50) of 20 μm to 100 μm.

[0016] Additionally, the active microparticles may have a zeta potential of |4 mV to 25 mV|.

[0017] In addition, the above active particles have a specific surface area of ​​1 m 2 / g to 15 m 2 / g may be.

[0018] Additionally, the GLP-1 receptor agonist may be albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, or semaglutide.

[0019] In addition, the active microparticles may have multiple pores on the inside, but the pores on the outside may be closed by self-healing.

[0020] Another invention for achieving the above-described object relates to a method for producing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles, the method comprising the steps of: adding active microparticles to a buffer solution and stirring to produce a suspension solution containing active microparticles; and adding a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the suspension solution containing the active microparticles and stirring to bind the GLP-1 receptor agonist or the pharmaceutically acceptable salt thereof to the active microparticles.

[0021] In addition, after the step of binding a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the active microparticles, a step of incubating for 1 to 5 hours at a temperature higher than the Tg temperature of the biodegradable polymer included in the active microparticles may be additionally performed.

[0022] Additionally, the condition above the Tg temperature may be 40°C or higher.

[0023] Additionally, by the above incubating step, the pores formed on the outside of the active microparticles can be closed by self-healing.

[0024] In addition, the active microparticles may include a step of preparing a first aqueous solution by dissolving an activator in water; a step of preparing an oily solution by dissolving a biodegradable polymer in an organic solvent; a step of forming a first emulsion using the first aqueous solution and the oily solution; a step of preparing a second aqueous solution by dissolving a surfactant in water; a step of preparing a second emulsion using a solution including the first emulsion and the second aqueous solution; and a step of preparing active microparticles by freeze-drying the second emulsion.

[0025] In addition, the activator may be selected from the group consisting of polyvinyl alcohol (PVA), ammonium bicarbonate (ABC), bovine serum albumin (BSA), trehalose, ethanol, pluronic, polyethyleneimine (PEI), protamine sulfate, calcium chloride (CaCl2), surfactants, and mixtures thereof.

[0026] The present invention can provide a long-acting pharmaceutical composition having a longer administration interval for a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof, and in particular, can produce a long-acting injection composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles simply by using active microparticles without requiring separate equipment for producing a long-acting formulation.

[0027] Figure 1 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0028] Figure 2 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0029] Figure 3 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0030] Figure 4 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0031] Figure 5 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0032] Figure 6 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0033] Figure 7 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0034] Figure 8 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0035] Figure 9 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0036] Figure 10 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0037] Fig. 11 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0038] Figure 12 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0039] Figure 13 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0040] Figure 14 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0041] Figure 15 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0042] Figure 16 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0043] Figure 17 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0044] Figure 18 is an SEM photograph of active microparticles according to one embodiment of the present invention.

[0045] Figure 19 shows the release test results of active microparticles containing semaglutide according to one embodiment of the present invention.

[0046] The present invention relates to a long-acting injection composition comprising an active microparticle; and a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof supported on the active microparticle, wherein the active microparticle is a porous microparticle, and the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof is bound to the surface and / or internal pores of the porous microparticle.

[0047] Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement them. However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein.

[0048] WeGovi is a drug used for weight management and obesity treatment, and is a leading GLP-1 receptor agonist. WeGovi is administered as a subcutaneous injection once a week, and its effects can last as long as the drug remains in the body. With consistent use, weight loss typically lasts for several weeks to months. However, if the user discontinues use, the weight loss effect may gradually disappear.

[0049] As mentioned above, semaglutide is a GLP-1 (appetite-suppressing hormone) receptor agonist used to treat obesity and manage type 2 diabetes. However, currently commercialized products require users to take the medication once a week, consistently, and this consistent dosing can improve medication adherence. Furthermore, in situations requiring weight loss and blood sugar control, it's crucial to maintain a stable level of medication in the body. Semaglutide maximizes its effectiveness when blood concentrations remain stable. Therefore, users may feel more confident when they believe the medication will have a sustained effect, which can lead to psychological stability and continued motivation for treatment.

[0050] Consequently, in order to increase the effectiveness of treating diabetes or preventing and / or treating obesity by semaglutide, the lower the frequency of administration, the less burden there is on the user, and the more the therapeutic effect can be maintained.

[0051] However, the semaglutide mentioned above is currently only commercialized as a once-weekly product, and although a long-acting formulation that lasts for more than one month is under development, a representative technology for such a long-acting formulation is to manufacture particles using a biodegradable polymer. In the case of the formulation, the biodegradable polymer and semaglutide are evenly distributed within the particle, and as the biodegradable polymer decomposes in the body, semaglutide within the particle can be released into the body, thereby exhibiting a release effect of semaglutide for more than one month.

[0052] In order to manufacture a formulation that releases semaglutide for more than one month as described above, a manufacturing method such as a solvent evaporation method, a membrane method, or a microfluidic method must be used.

[0053] Solvent evaporation is one method for producing microparticles or nanoparticles, and is manufactured through the following steps. First, a polymer solution is prepared. This step involves dissolving a biodegradable polymer (e.g., polylactide (PLA) or polylactic acid-co-glycolic acid (PLGA)) in an organic solvent (e.g., acetone, chloroform, etc.). The polymer concentration and solvent selection are crucial in this step, as they can affect the size and structure of the final particles.

[0054] The second step is the emulsification step. This emulsification step involves mixing the dissolved polymer solution with water or another non-polar solution to facilitate the emulsification process. High-speed stirring or ultrasound can be used to ensure the two solutions are well mixed. This allows the polymer solution to be dispersed into small droplets.

[0055] The third step is the solvent evaporation step. This step involves the evaporation of the organic solvent from the emulsified mixture, causing the polymer to precipitate and form particles. Temperature, pressure, and ventilation rate are crucial in this step, and the evaporation rate can be controlled by these conditions. Once the solvent has completely evaporated, the polymer can aggregate to form particles.

[0056] The fourth step is particle collection and washing. The generated particles are collected through centrifugation or filtering and can be washed to remove any remaining solvent or impurities.

[0057] The fifth step is the drying step. Finally, the particles produced can be completely dried through freeze-drying or vacuum drying. This can increase particle stability and long-term storage potential. To apply the drug delivery system using the solvent evaporation method described above, semaglutide can be dissolved in the polymer solution during preparation.

[0058] In order to manufacture long-lasting micro-particles or nano-particles containing semaglutide using the solvent evaporation method described above, a mixer, an emulsifier, an evaporator, a centrifuge, a washing and drying device, a monitoring and control system, etc. are separately required.

[0059] In addition to the above solvent evaporation method, membrane method or microfluidic method also require separate equipment to carry out the corresponding process, such as solvent evaporation method.

[0060] Accordingly, in order to manufacture a long-acting formulation using semaglutide or a pharmaceutically acceptable salt thereof, a separate manufacturing process is required to carry out a specific process.

[0061] Accordingly, the present invention aims to provide a technology capable of manufacturing semaglutide or a pharmaceutically acceptable salt thereof as a long-acting formulation using a simple stirrer, evaporator, freeze-drying device, etc., to solve such problems.

[0062] In particular, when the active microparticles of the present invention are used, semaglutide or a pharmaceutically acceptable salt thereof can be bound to the inside or outside of the active microparticles by binding the active microparticles to semaglutide.

[0063] That is, when producing particles containing semaglutide or a pharmaceutically acceptable salt thereof by a conventional solvent evaporation method, membrane method or microfluidic method, it is characterized in that the biodegradable polymer and semaglutide or a pharmaceutically acceptable salt thereof are not combined, but are formed in a mixed form to form spherical particles.

[0064] On the other hand, the microparticles of the present invention are characterized in that semaglutide or a pharmaceutically acceptable salt thereof is chemically bonded by the charge of the pores formed therein. This means that when the active microparticles of the present invention are administered into the body, the biodegradable polymer of the active microparticles decomposes, and the chemically bonded semaglutide or a pharmaceutically acceptable salt thereof due to the charge of the biodegradable polymer is broken and released into the body.

[0065] There may not be a significant difference between the conventional long-lasting particles and the active microparticles of the present invention in the presence or absence of pores, that is, even in the case of the conventional long-lasting particles, they can also be provided in the form of particles having a large number of pores formed. The conventional long-lasting particles are particles in which the biodegradable polymer and the drug are uniformly mixed rather than combined, whereas the active microparticles of the present invention are in a form in which the biodegradable polymer forming the particles does not contain any drug at all, and the drug is chemically bonded to the pores formed inside and / or on the outer surface, which is the biggest difference.

[0066] Based on these differences, in order to manufacture semaglutide or a pharmaceutically acceptable salt thereof as a long-acting formulation, it is possible to simply manufacture the long-acting formulation using pre-manufactured active microparticles, so separate equipment for manufacturing the long-acting formulation is not required.

[0067] Therefore, in places where conventional semaglutide or a pharmaceutically acceptable salt thereof can be produced or purchased, it is possible to simply manufacture a long-acting formulation using active microparticles.

[0068] Specifically, a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles comprises: active microparticles; and a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof supported on the active microparticles; wherein the active microparticles are porous microparticles, and the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof can be bound to the surface and / or internal pores of the porous microparticles.

[0069] As described above, the active microparticles of the present invention are porous microparticles, and a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof is chemically bound to the surface and / or internal pores.

[0070] The GLP-1 receptor agonist may be albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide or semaglutide, preferably semaglutide, but is not limited to the above examples.

[0071] The above semaglutide is a peptide composed of amino acids, and can have a charge under certain pH and environmental conditions, but it is generally known that semaglutide mainly has a negative charge (-).

[0072] Accordingly, in order to chemically bond with negatively charged semaglutide, the active microparticles of the present invention may be characterized by having a positive charge.

[0073] The above-described active microparticles may have a zeta potential of |4 mV to 25 mV|. The above-described active microparticles may have a zeta potential of -25 mV to -4 mV or +4 mV to +25 mV. However, as described above, when the zeta potential of the active microparticles is negatively charged, such as -25 mV to -4 mV, an activator for changing the zeta potential of the active microparticles to a positive charge may be mixed in when preparing a suspension solution containing the active microparticles in the manufacturing step as described below.

[0074] That is, the active microparticles can be manufactured into particles with various charges according to the manufacturing method described below. The active microparticles can be manufactured to have various zeta potentials and pore sizes, as described below. This is for binding not only semaglutide but also various drugs, and the degree of binding can be controlled depending on the particle size and charge type of the drug, enabling the manufacture of a dosage form that continuously releases the drug for 1 month, 2 months, 3 months, or longer.

[0075] The above active microparticles include a biodegradable polymer and may be spherical porous microparticles.

[0076] In addition, the active microparticles are spherical porous microparticles, but in the process step described below, the pores on the outside may be closed by self-healing. That is, the active microparticles may include a plurality of pores on the inside, but the pores on the outside may be closed by self-healing. This is because when the active microparticles containing semaglutide or a pharmaceutically acceptable salt thereof are injected into the body, a process of decomposition of the biodegradable polymer occurs, and at this time, if pores are formed on the surface, moisture penetrates through the pores on the surface, and as moisture penetrates, hydrolysis is promoted, so that the release effect of semaglutide or a pharmaceutically acceptable salt thereof cannot be exhibited for a desired period of time due to excessively rapid decomposition.

[0077] To prevent such problems, the active microparticles comprising semaglutide or a pharmaceutically acceptable salt thereof of the present invention may be provided in a form in which all pores on the surface are closed.

[0078] The biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and combinations thereof, and may be selected from the group consisting of polylactic acid, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), and mixtures thereof, but is not limited to the above examples, and any biodegradable polymer that can be manufactured into active microparticles may be used without limitation.

[0079] The above active fine particles may have an average diameter (D50) of 20 µm to 100 µm, 20 µm to 95 µm, 20 µm to 90 µm, or 20 µm to 85 µm.

[0080] The above active particles have a specific surface area of ​​1 m 2 / g to 15 m 2 / g, 2m 2 / g to 14 m 2 / g. The above specific surface area is the total surface area of ​​the active microparticles, and may vary depending on whether pores are formed, the shape of the pores, the total number of pores, etc. When semaglutide or a pharmaceutically acceptable salt thereof is combined using active microparticles having a specific surface area within the above range, it is possible to manufacture a long-acting formulation that continuously releases semaglutide or a pharmaceutically acceptable salt thereof in the body for more than one month.

[0081] In the present invention, the composition may comprise active microparticles comprising a therapeutically effective amount of a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" is a substance that can be added to the active ingredient to aid in formulating or stabilizing the formulation, and does not cause significant harmful toxic effects to the patient.

[0082] The above carrier refers to a carrier or diluent that does not irritate the patient and does not inhibit biological activity and properties. In a composition formulated as a liquid solution, acceptable pharmaceutical carriers include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these components. If necessary, other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into injectable formulations such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.

[0083] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the preparation of extemporaneous sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions are preferably formulated for injection. The compositions may be formulated as solutions, microemulsions, liposomes, or other tailored structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In some cases, isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride, may be included in the composition.

[0084] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterile microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the other required ingredients from those enumerated above. For sterile powders for the preparation of sterile injectable solutions, some preparation methods are vacuum drying and freeze-drying (lyophilization), which produce a powder of the active ingredient and any additional desired ingredient from a previously sterile-filtered solution thereof.

[0085] Specifically, the composition may contain formulation materials to modify, maintain, or preserve the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or permeation of the composition. Suitable formulation materials include amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine), antimicrobial agents, antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite), buffers (e.g., borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (e.g., mannitol or glycine), chelating agents (e.g., ethylenediamine tetraacetic acid (EDTA)), complexing agents (e.g., caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (e.g., glucose, mannose, or dextrins), proteins (e.g., serum albumin, gelatin, or immunoglobulins), coloring agents, flavoring agents, and diluents, emulsifiers, hydrophilic agents. Polymers (e.g. polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (e.g. sodium), preservatives (e.g. benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide), solvents (e.g. glycerin, propylene glycol or polyethylene glycol), sugar alcohols (e.g. mannitol or sorbitol), suspending agents, surfactants or wetting agents (e.g. pluronics; PEG; sorbitan esters; polysorbates, such as polysorbate 20 or polysorbate 80; Triton; tromethamine; lecithin; cholesterol or tyloxapal), stability enhancers (e.g. sucrose or sorbitol), tonicity enhancers (e.g. alkali metal halides; preferably sodium chloride or potassium chloride; or mannitol sorbitol), delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants, including but not limited to.

[0086] In the present invention, the frequency of administration of the composition will vary depending on the pharmacokinetic parameters of the diacerine-containing nanoparticles in the formulation used. Typically, the clinician will administer the composition until the desired effect is achieved. Thus, the composition may be administered as a single dose, as two or more doses spaced apart (which may or may not contain the same amount of diacerine-containing nanoparticles), or as a continuous infusion via an implantable device or catheter. Further refinement of the appropriate dosage is routinely accomplished by those skilled in the art and falls within the scope of their routine practice.

[0087] The unit dosage for humans is 0.01 μg / kg to 100 mg / kg, specifically 1 μg / kg to 30 mg / kg. Although the above amount is the optimal amount, it may vary depending on the disease being treated and the presence or absence of side effects, and the optimal dosage can be determined through routine experiments.

[0088] According to another embodiment of the present invention, a method for producing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles may include the steps of: adding active microparticles to a buffer solution and stirring the solution to produce a suspension solution containing active microparticles; and adding a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the suspension solution containing active microparticles and stirring the suspension solution to bind the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the active microparticles.

[0089] The above active microparticles are manufactured using a biodegradable polymer as described below, and the manufactured active microparticles are manufactured as porous microparticles using only a biodegradable polymer without any separate drug bound thereto.

[0090] The above active microparticles can be placed in a buffer solution and stirred to prepare a suspension solution.

[0091] The above suspension solution typically refers to a state in which fine particles are uniformly dispersed within the solution. The fine particles within the solution may be uniformly dispersed without being dissolved. However, to prepare the above suspension solution, an activator may be additionally included depending on the potential state of the active fine particles.

[0092] When the zeta potential of the above-mentioned active microparticles is negative, the zeta potential can be changed to positive by including an activator.

[0093] As described above, the activator capable of changing the zeta potential of the active microparticles to a positive charge may be selected from the group consisting of protamine sulfate, polyethyleneimine (PEI), bovine serum albumin (BSA), calcium chloride (CaCl2), and mixtures thereof, preferably protamine sulfate, but not limited to the above examples. In order to prepare the suspension solution, the active microparticles and the activator may be included in a weight ratio of 1:0.5 to 1:1.5.

[0094] For preparing the above suspension solution, the buffer solution may be selected from the group consisting of HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), Tris (tris(hydroxymethyl)aminomethane) and mixtures thereof, preferably a HEPES buffer solution, but is not limited to the above examples, and any buffer solution that can be prepared as a suspension solution by mixing active microparticles may be used without limitation.

[0095] After preparing a suspension solution as described above, a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof may be added and stirred to bind the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the active microparticles.

[0096] The GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof mixed in the above suspension solution may be included in a weight ratio of 1:5 to 1:15, a weight ratio of 1:6 to 1:14, a weight ratio of 1:7 to 1:13, a weight ratio of 1:8 to 1:12, a weight ratio of 1:8 to 1:11, or a weight ratio of 1:8 to 1:10, relative to the active microparticles, and when mixed within the above range, the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof may be chemically bound to the active microparticles.

[0097] However, the active microparticles in which the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof is bound as described above may have a large number of pores formed on the surface. In this state, as described above, moisture may penetrate into the surface pores of the active microparticles, causing rapid decomposition of the microparticles due to hydrolysis. Due to this problem, the GLP-1 receptor agonist or the pharmaceutically acceptable salt thereof contained in the active microparticles may be rapidly released, resulting in a problem in which the GLP-1 receptor agonist or the pharmaceutically acceptable salt thereof may not be released for more than one month.

[0098] To prevent such problems, after the step of binding a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the active microparticles, an additional step of incubating the active microparticles at a temperature higher than the Tg temperature of the biodegradable polymer included in the active microparticles for 1 to 5 hours may be performed.

[0099] The condition above the Tg temperature may be 40°C or higher. The Tg temperature of the biodegradable polymer, when the biodegradable polymer is PLGA, may be more specifically 40°C to 50°C, 40°C to 49°C, 40°C to 48°C, 40°C to 47°C, 40°C to 46°C, 40°C to 45°C, 40°C to 44°C, 40°C to 43°C, or 40°C to 42°C. When incubated for 1 hour to 5 hours, 1 hour to 4 hours, 1 hour to 3 hours, or 1 hour to 2 hours under the above temperature conditions, the pores formed on the outside of the active microparticles may be closed by self-healing.

[0100] As described above, when the external pores of the active microparticles are closed, even if the active microparticles are administered into the body, moisture does not penetrate, preventing rapid decomposition.

[0101] As described above, the step of manufacturing active microparticles comprising the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof of the present invention is a process for chemically bonding the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using the already manufactured active microparticles, and does not require a separate device for performing the process.

[0102] Ultimately, it will be possible to manufacture long-acting formulations containing GLP-1 receptor agonists or pharmaceutically acceptable salts thereof using existing drug manufacturing facilities.

[0103] This means that production of long-acting formulations containing various GLP-1 receptor agonists or pharmaceutically acceptable salts thereof is possible, overcoming the problem that manufacturing was only possible in locations where equipment for manufacturing specific long-acting formulations was available.

[0104] Accordingly, in order to manufacture the active microparticles of the present invention, the method may include a step of dissolving an activator in water to manufacture a first aqueous solution; a step of dissolving a biodegradable polymer in an organic solvent to manufacture an oily solution; a step of forming a first emulsion using the first aqueous solution and the oily solution; a step of dissolving a surfactant in water to manufacture a second aqueous solution; a step of manufacturing a second emulsion using a solution including the first emulsion and the second aqueous solution; and a step of freeze-drying the second emulsion to manufacture active microparticles.

[0105] The above activator may be selected from the group consisting of polyvinyl alcohol (PVA), ammonium bicarbonate (ABC), bovine serum albumin (BSA), trehalose, ethanol, pluronic, polyethyleneimine (PEI), protamine sulfate, calcium chloride (CaCl2), surfactants, and mixtures thereof. The above activator may be used to form a plurality of pores when producing fine particles.

[0106] The above surfactants include methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate (e.g., Span 80). TM 80), polyoxyethylene sorbitan fatty acid esters (e.g., Tween 80) TM 80) etc.), polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, ester amine, linear diamine, patty amine and mixtures thereof, preferably polyvinyl alcohol, but not limited to the above examples, any surfactant that can be prepared into a completely spherical emulsion can be used.

[0107] In order to prepare the first aqueous solution, the first aqueous solution can be prepared by mixing an activator in a range of 10 mg to 500 mg per 1 ml of water.

[0108] The organic solvent for dissolving the biodegradable polymer may be selected from the group consisting of dichloromethane, ethyl acetate, benzyl alcohol, acetone, methanol, ethanol, dimethyl chloride, ethyl acetate, chloroform, chloroethane, dichloroethane, dichloromethane, trichloroethane and mixtures thereof, and preferably may be selected from the group consisting of dichloromethane, ethanol, ethyl acetate and mixtures thereof.

[0109] The step of forming a first emulsion using the first aqueous solution and the oily solution may be performed by mixing the first aqueous solution and the oily solution and stirring them using a homogenizer at 10,000 to 15,000 rpm for 30 to 120 seconds to form the first emulsion.

[0110] The step of preparing a second aqueous solution by dissolving a surfactant in water may be preparing a second aqueous solution by dissolving 0.5 wt% of the surfactant in water.

[0111] A step of preparing a second emulsion using a solution containing the first emulsion and a second aqueous solution, the second emulsion can be formed using a stirring method using the above-described homogenizer, a membrane method, a microfluidic method, etc.

[0112] In the present invention, a membrane having a pore size of 10 μm was used. A solution containing a first emulsion was injected through the first emulsion injection port of the membrane at an injection rate of 0.5 ml / min to 1.5 ml / min, and a second aqueous solution was injected at an injection rate of 20 ml / min to 40 ml / min through each connected pump, thereby forming a second emulsion.

[0113] The above second emulsion can be solidified at 20°C to 30°C for 20 to 30 hours, after which the remaining organic solvent is removed and freeze-dried.

[0114] After the above-mentioned drying step, vacuum drying may be additionally performed at 35°C to 50°C for 40 to 55 hours to minimize residual organic solvent.

[0115] Through the above process, active microparticles can be manufactured. As described above, the active microparticles have an average diameter (D50) of 20 μm to 100 μm, a zeta potential of |4 mV to 25 mV|, and a specific surface area of ​​1 m 2 / g to 15 m 2 / g. The active microparticles are spherical, porous microparticles. Specifically, since semaglutide or a pharmaceutically acceptable salt thereof is a large drug, it is important to form internal pores of an appropriate size so that they can enter and bind to the internal pores. Accordingly, the above-described activator can be used to manufacture the active microparticles.

[0116] Additionally, depending on the type of activator, the zeta potential may exhibit a positive or negative charge. As described above, semaglutide is known to primarily have a negative charge (-), and therefore, when the potential of the active microparticles is negative, the zeta potential may be prepared by mixing an activator so that the potential exhibits a positive charge when preparing a suspension solution to bind to semaglutide or a pharmaceutically acceptable salt thereof.

[0117] Manufacturing Example 1

[0118] Example 1_Manufacture of active microparticles

[0119] A first aqueous solution was prepared by dissolving 100 mg (range) of PVA, a water-soluble channel forming agent, in 1 mL of distilled water. An oily solution was prepared by dissolving 3 g (range) of PLGA 7525 polymer in an organic solvent (Dimethyl chloride). The weight ratio of PVA to PLGA content in the oily solution is shown in Table 1 below. The first aqueous solution and the oily solution were mixed, and a first emulsion was formed using a homogenizer (Polytron, 12,000 rpm, 1 min).

[0120] A second aqueous solution was prepared by dissolving 0.5% PVA (Polyvinyl alcohol) in purified water. The solution containing the first emulsion prepared above was injected into a membrane with a pore size of 10 μm using a pump at an injection rate of 1.0 mL / min, and the second aqueous solution was injected into a membrane with a pore size of 10 μm using a pump at an injection rate of 30.0 mL / min, respectively, to form a second emulsion.

[0121] The above second emulsion was solidified at 25°C for 24 hours, the organic solvent was removed, and the product was freeze-dried.

[0122] Example 2

[0123] The first aqueous solution was prepared by dissolving 30 mg of ABC, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0124] Example 3

[0125] The first aqueous solution was prepared by dissolving 300 mg of BSA, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0126] Example 4

[0127] A first aqueous solution was prepared by dissolving 30 mg of trehalose, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0128] Example 5

[0129] The first aqueous solution was prepared by dissolving 1 mL of ethanol, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0130] Example 6

[0131] A first aqueous solution was prepared by dissolving 60 mg of Pluronic 188, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0132] Example 7

[0133] A first aqueous solution was prepared by dissolving 150 mg of Surfactant Span 80, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0134] The SEM images of the active microparticles manufactured according to Examples 1 to 7 are as shown in FIGS. 1 to 7, and the average diameter (D50), zeta potential, and specific surface area measurement results are as shown in Table 1 below:

[0135] Morphological analysis of active microspheres using electron microscopy

[0136] 5 mg of microspheres were placed on an aluminum stub with carbon tape attached and coated with platinum. The aluminum stub was mounted in a field-emission scanning electron microscope (FE-SEM, JSM-6700F, JEOL, Japan), and the morphological characteristics of the microspheres were observed at an acceleration voltage of 15 kV.

[0137] Active particulate particle size analysis

[0138] 50 mg of fine particles were suspended in purified water (1.0 mL), mixed with a vortex mixer for 20 seconds, and then dispersed in an ultrasonic generator for 1 minute. The microsphere dispersion was analyzed using a Beckman Coulter laser particle size analyzer (LS 13 320 XR particle size analyzer, Beckman Coulter, USA) in a ULM (Universal Liquid Module) in the range of 0.01–3500 μm.

[0139] BET analysis of activated particulate matter

[0140] 0.25–1.0 g of fine particles were vacuum-dried at 40°C for 24 h. The specific surface area of ​​the dried fine particles was determined by N2 adsorption / desorption isotherm at -196°C using Micromeritics (TriStar II 3020 Version 3.02 / Micromeritics instrument corporation).

[0141] No. Channel former Weight ratio of channel former to the weight of biodegradable polymer Size (D 50 , ㎛)ZP(mV)BET surface area(m 2 / g)Example 1PVA3.33 wt%23.7-7.711.85Example 2ABC1 wt%26.3-10.505.24Example 3BSA10 wt%42.4-12.671.95Example 4Trehalose1 wt%22.6-8.232.12Example 5Ethanol33.33 wt%32.8-6.302.11Example 6Pluronic2 wt%19.7-5.291.02Example 7Surfactant5 wt%39.2-7.341.52

[0142] Example 8 75 mg of PEI, a water-soluble channel forming agent, was dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0143] Example 9

[0144] The first aqueous solution was prepared by dissolving 300 mg of BSA, a water-soluble activator, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0145] Example 10

[0146] The first aqueous solution was prepared by dissolving 30 mg of protamine sulfate, a water-soluble activator, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0147] Example 11

[0148] A first aqueous solution was prepared by dissolving 30 mg of CaCl2, a water-soluble channel forming agent, in 1 mL of distilled water, and the other manufacturing processes were the same as in Example 1.

[0149] The SEM images of the active microparticles manufactured according to Examples 8 to 11 are as shown in FIGS. 8 to 11, and the average diameter (D50), zeta potential, and specific surface area measurement results are as shown in Table 2 below:

[0150] No. Channel former Weight ratio of channel former to the weight of biodegradable polymer Size (D50, ㎛) ZP (mV) BET surface area (m2 / g) Example 8 PEI 2.5 wt% 27.1 + 14.3 7 1.05 Example 9 BSA 10 wt% 46.7 - 16.5 3 2.21 Example 10 Protamine Sulfate 1 wt% 50.2 + 6.3 9 6.23 Example 11 CaCl 2 1 wt% 32.3 - 5.5 9 2.33

[0151] Example 12: BSA and ABC, which are water-soluble channel forming agents, were mixed in a weight ratio of 1:1 (30 mg each), and 60 mg was dissolved in 1 mL of distilled water to prepare a first aqueous solution. The other manufacturing processes were the same as in Example 1.

[0152] Example 13

[0153] For the composite active microparticles, 3 mg of CaCl2 and 100 mg of PVA were dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0154] Example 14

[0155] For the composite active microparticles, 100 mg of PVA and 30 mg of ABC were dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0156] Example 15

[0157] For the composite active microparticles, 500 mg of ethanol and 30 mg of CaCl2 were dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0158] Example 16

[0159] For the composite active microparticles, 30 mg of ABC and 150 mg of Span 80 were dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0160] Example 17

[0161] For the composite active microparticles, 30 mg of ABC and 150 mg of Tween 20 were dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0162] Example 18

[0163] For the composite active microparticles, 75 mg of PEI and 30 mg of CaCl2 were dissolved in 1 mL of distilled water to prepare a first aqueous solution, and the other manufacturing processes were the same as in Example 1.

[0164] The SEM images of the active microparticles manufactured according to Examples 12 to 18 are as shown in FIGS. 12 to 18, and the average diameter (D50), zeta potential, and specific surface area measurement results are as shown in Table 3 below:

[0165] No. Channel forming agent Size (D50, ㎛) ZP (mV) BET surface area (m2 / g) Example 12 ABC + BSA 2 7.9-21.5 3 10.06 Example 13 PVA + CaCl 2 3 0.8-13.5 3 6.36 Example 14 PVA + ABC 3 1.3-7.4 5 4.11 Example 15 EtOH + CaCl 2 3 2.8-6.3 0 7.68 Example 16 ABC + Span 8 0 2 9.9-6.5 7 3.78 Example 17 ABC + Tween 2 0.4-7.8 4 2.94 Example 18 PEI + CaCl 2 8 2.2+16.0 13.55

[0166] Manufacturing example: Manufacturing of active microparticles containing semaglutide

[0167] Microparticles (270 mg) and the activator, Protamine sulfate (270 mg), were suspended in 0.1 mM HEPES buffer, pH 6.4 (1 mL) and stirred with a rotary mixer at 37°C for 24 hours to prepare a suspension solution containing active microparticles. Semaglutide (30 mg) was added to the suspension solution (pH 7.4 (0.75 mL)), suspended, and stirred with a rotary mixer at 37°C for 24 hours. An additional incubation was performed at 40°C to 42°C for 2 hours to control the initial release of the drug. Upon completion of the incubation, the supernatant was removed by centrifugation at 7012g for 5 minutes, and washed three times with 3.0 mL of purified water. Microparticles containing semaglutide were obtained by lyophilization.

[0168] Experimental example

[0169] Analysis of drug encapsulation rate in active microparticles

[0170] Using the active microparticles of Examples 2, 9, 12, and 13, active microparticles containing semaglutide were prepared according to the method of Manufacturing Example 2 described above. The microparticles (5 mg) were completely dissolved in ACN and then diluted with a mobile phase. 50 μL of the diluted solution was injected into HPLC and measured at a detection wavelength of 215 nm. The column used in this experimental example was INNO-P column C18, 5 μm, 4.6 × 250 mm, and the mobile phase was 0.025 M disodium hydrogen phosphate buffer solution, acetonitrile in gradient mode.

[0171] The calculation method for the encapsulation rate is as follows:

[0172] [ceremony]

[0173] Encapsulation Efficiency(%)=(weight of the drug in microsphere / weight of feeding drugs×100)

[0174] The measured encapsulation rates are shown in Table 4 below:

[0175] No. Encapsulation rate (%) Example 233.1 Example 918.5 Example 1290.2 Example 1377.1

[0176] According to the above test results, the encapsulation rate for semaglutide was confirmed to be superior when two types of channel-forming agents were used in combination compared to when only one type of activator was used. In-vitro drug dissolution rate analysis in active microparticles

[0177] Active microparticles containing semaglutide were prepared in the manner of Preparation Example 2 using the active microparticles of Examples 2, 12, 13, and 14. The drug release behavior of 25 mg of the above microparticles was confirmed using the Transwell method in 10 mM phosphate buffer (pH 7.4). The concentration of the eluted drug was measured using liquid chromatography (HPLC, Agilent, 1260 Infinity system). The mobile phase was 0.025 M disodium hydrogen phosphate buffer solution, acetonitrile gradient mode, and UV detection wavelength: 215 nm.

[0178] The test results are as shown in Fig. 19.

[0179] According to Fig. 19, Example 2 did not reach 28 days of semaglutide release due to excessively rapid release, and Example 14 may have a problem in that the initial semaglutide effect may not be observed due to excessively slow release. In contrast, Examples 12 and 13 were confirmed to exhibit stable semaglutide release effects for up to 28 days.

[0180] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

[0181] The present invention relates to a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles, and a method for producing the same.

Claims

1. Active particulate matter; and Comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof loaded in the above active microparticles, The above active microparticles are porous microparticles, and a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof is bound to the surface and / or internal pores of the porous microparticles. A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

2. In paragraph 1, The above active microparticles contain biodegradable polymers and are spherical porous microparticles. A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

3. In paragraph 2, The above biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and combinations thereof. A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

4. In paragraph 1, The above active fine particles have an average diameter (D50) of 20 μm to 100 μm. A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

5. In paragraph 1, The above active microparticles have a zeta potential of |4 mV to 25 mV| A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

6. In paragraph 1, The above active particles have a specific surface area of ​​1 m 2 / g to 15 m 2 / g person A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

7. In paragraph 1, The above GLP-1 receptor agonists are albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide or semaglutide. A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

8. In paragraph 1, The above active microparticles have multiple pores on the inside, but the pores on the outside are closed by self-healing. A long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

9. A step of adding active microparticles to a buffer solution and stirring to prepare a suspension solution containing active microparticles; and A step of adding a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to a suspension solution containing the active microparticles and stirring the solution to bind the GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the active microparticles. A method for preparing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

10. In paragraph 9, After the step of binding a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof to the above active microparticles, An additional step of incubating for 1 to 5 hours at a temperature higher than the Tg temperature of the biodegradable polymer included in the above active microparticles is performed. A method for preparing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

11. In paragraph 10, The condition above the above Tg temperature is 40℃ or higher. A method for preparing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

12. In paragraph 10, By the above incubation step, the pores formed on the outside of the active microparticles are closed by self-healing. A method for preparing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

13. In paragraph 9, The above active microparticles are, A step of preparing a first aqueous solution by dissolving an activator in water; A step of preparing an oily solution by dissolving a biodegradable polymer in an organic solvent; A step of forming a first emulsion using the first aqueous solution and the oily solution; A step of preparing a second aqueous solution by dissolving a surfactant in water; A step of preparing a second emulsion using a solution containing the first emulsion and a second aqueous solution; and A step of preparing the second emulsion into active microparticles by freeze-drying the second emulsion is included. A method for preparing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

14. In paragraph 13, The above activator is selected from the group consisting of polyvinyl alcohol (PVA), ammonium bicarbonate (ABC), bovine serum albumin (BSA), trehalose, ethanol, pluronic, polyethyleneimine (PEI), protamine sulfate, calcium chloride (CaCl2), surfactants, and mixtures thereof. A method for preparing a long-acting injectable composition comprising a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof using active microparticles.

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