Method for producing long-acting microspheres comprising baricitinib and long-acting microspheres comprising baricitinib produced by method

Abstract

The present invention relates to a method for producing long-acting microspheres comprising baricitinib and long-acting microspheres comprising baricitinib produced by the method. By deriving optimal ranges for temperature conditions, spray rate, the weight ratio of a biodegradable polymer to baricitinib, and the viscosity range of a suspension comprising baricitinib through a spray drying method, the present invention can provide a method for producing microspheres that can be produced at high speed, are suitable for mass production, and have an average diameter allowing administration as an injectable formulation. In addition, as long-lasting microspheres comprising baricitinib are produced by a spray drying method, when used as an injection, they can continuously release baricitinib in vivo for one month or longer, thereby maintaining a certain level of blood baricitinib concentration and exhibiting a therapeutic effect.

Description

A method for manufacturing long-acting microspheres containing baricitinib and long-acting microspheres containing baricitinib manufactured by the method thereof

[0001] The present invention relates to a method for manufacturing long-acting microspheres containing baricitinib and long-acting microspheres containing baricitinib manufactured by the method.

[0002] Baricitinib is a drug that must be taken daily to treat rheumatoid arthritis, atopic dermatitis, alopecia areata, and COVID-19. Baricitinib is a JAK (Janus Kinase) inhibitor that has the function of reducing the immune response by blocking signaling pathways associated with inflammation.

[0003] The above-mentioned JAK (Janus Kinase) inhibitor is a drug used to treat inflammatory and autoimmune diseases, and it plays a role in regulating the immune response by blocking the action of the JAK enzyme. The above-mentioned JAK enzyme plays an important role in intracellular signaling pathways and is activated, in particular, when a signaling molecule called a cytokine binds to it.

[0004] The JAK system is linked to cytokine receptors, and when these are activated, JAK enzymes are activated, promoting an inflammatory response through downstream signaling pathways. JAK inhibitors can help reduce inflammation by blocking the activation of these enzymes.

[0005] The above-mentioned baracitinib is typically taken orally, and a daily dose of 2 mg or 4 mg is generally recommended. When taken orally, the absolute bioavailability is approximately 79%, and the corresponding half-life is known to be 12 hours.

[0006] However, as mentioned above, when using baricitinib to treat rheumatoid arthritis, atopic dermatitis, alopecia areata, and COVID-19, there is the inconvenience of having to take it continuously for a long time, as it is difficult to see effects with short-term use.

[0007] To improve this, it is necessary to develop a formulation that enables continuous treatment with baricitinib for a long period of time through a single administration.

[0008] [Prior Art Literature]

[0009] [Patent Literature]

[0010] WO 2020 / 236950 A1

[0011] The object of the present invention is to provide a method for manufacturing long-acting microspheres containing baricitinib and long-acting microspheres containing baricitinib manufactured by the method.

[0012] Another objective of the present invention is to provide a method for producing microspheres having an average diameter suitable for mass production and administration as an injectable, which enables high-speed production and is suitable for mass production, by deriving an optimal range for temperature conditions, spray speed, weight ratio of biodegradable polymer and baricitinib, and viscosity range of a suspension containing baricitinib by a spray drying method.

[0013] Another objective of the present invention is to provide long-acting microspheres containing baricitinib that can produce a therapeutic effect by maintaining a certain level of blood baricitinib concentration, by manufacturing long-acting microspheres containing baricitinib by a spray drying method, thereby continuously releasing baricitinib in the body for more than one month when used as an injectable.

[0014] To achieve the above-mentioned objective, the present invention may relate to a method for producing long-acting microspheres containing baricitinib, comprising the steps of: dissolving baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent to prepare a suspension; and spray-drying the suspension to produce long-acting microspheres containing baricitinib.

[0015] In addition, when spray-drying the above suspension, the temperature condition of the spray part inside the spray dryer may be 40℃ to 60℃.

[0016] In addition, when spray-drying the above suspension, the spray speed of the suspension using a spray dryer may be 1 mL / min to 18 mL / min.

[0017] In addition, the suspension may contain baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:2 to 1:9.

[0018] In addition, the viscosity of the suspension may be 10 cp to 100 cp.

[0019] In addition, 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, polyhydroxyvalrate, polyhydroxybutyrate, polyamino acid, and combinations thereof.

[0020] In addition, the organic solvent may be selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, acetone, dimethyl sulfoxide, and mixtures thereof.

[0021] Another invention for achieving the above-described purpose may be a long-acting microsphere comprising baricitinib produced by the above-described manufacturing method.

[0022] In addition, the above microspheres may have an average diameter (D50) of 10 μm to 30 μm.

[0023] In addition, the microspheres may have an encapsulation rate of baricitinib or a pharmaceutically acceptable salt thereof of 90% or more.

[0024] The present invention provides a method for producing microspheres having an average diameter suitable for mass production and administration as an injectable, which enables high-speed production and is suitable for mass production, by deriving an optimal range for temperature conditions, spray speed, weight ratio of biodegradable polymer and baricitinib, and viscosity range of a suspension containing baricitinib through a spray drying method.

[0025] In addition, by manufacturing long-acting microspheres containing baricitinib using a spray drying method, when used as an injectable, baricitinib is continuously released in the body for more than one month, thereby maintaining a certain level of blood baricitinib concentration and exhibiting a therapeutic effect.

[0026] Figure 1 is an SEM image of a long-acting microsphere containing baricitinib according to one embodiment of the present invention.

[0027] FIG. 2 is an SEM image of a long-acting microsphere containing baricitinib according to one embodiment of the present invention.

[0028] FIG. 3 is an SEM image of a long-acting microsphere containing baricitinib according to one embodiment of the present invention.

[0029] Figure 4 is an SEM image of a long-acting microsphere containing baricitinib according to one embodiment of the present invention.

[0030] Figure 5 is the result of a release experiment for long-acting microspheres containing baricitinib according to one embodiment of the present invention.

[0031] Figure 6 is the result of a release experiment for long-acting microspheres containing baricitinib according to one embodiment of the present invention.

[0032] Figure 7 is the result of a release experiment for long-acting microspheres containing baricitinib according to one embodiment of the present invention.

[0033] Figure 8 is the result of a release experiment for long-acting microspheres containing baricitinib according to one embodiment of the present invention.

[0034] The present invention relates to a method for producing long-acting microspheres containing baricitinib, comprising the steps of: dissolving baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent to prepare a suspension; and spray-drying the suspension to produce long-acting microspheres containing baricitinib.

[0035] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein.

[0036] Baricitinib is a Janus kinase (JAK) inhibitor (and more specifically, a selective JAK 1 and JAK 2 inhibitor) with the chemical name {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-3-yl}acetonitrile. Baricitinib has the following structural chemical formula:

[0037] [Chemical Formula]

[0038]

[0039] Baricitinib is a known medicine approved in the United States and Europe (and other countries) for the treatment of rheumatoid arthritis and is commercially available under the brand name Olumiant®. The European Medicines Agency has also approved baricitinib for the treatment of moderate to severe atopic dermatitis.

[0040] In some jurisdictions, Olumiant® is available in the form of pills, wherein the pills comprise a specified amount of baricitinib and the following excipients: sodium croscarmellose, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soybean), polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. In a preferred embodiment of the present invention, the amount of baricitinib used to treat a patient is administered by providing the patient with one or more Olumiant® pills. Of course, other forms of administration, pharmaceutical compositions of baricitinib, etc. may also be used.

[0041] A person skilled in the art will also recognize that, in other embodiments, pharmaceutically acceptable salts of baricitinib may be used. Pharmaceutically acceptable salts are known. As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the baricitinib of the present invention in which the baricitinib of the present invention is modified by preparing its acid or base salt. Pharmaceutically acceptable salts and methods of preparing them are widely known in the art (see, for example, the literature [Remington: The Science and Practice of Pharmacy, LV Allen, Ed., 22nd Edition, Pharmaceutical Press, 2012]). For example, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues, such as amines, or alkali or organic salts of acidic residues, such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the baricitinib of the present invention formed from non-toxic inorganic or organic acids. These conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, parmolic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc. Pharmaceutically acceptable salts are such forms of the baricitinib of the present invention suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications corresponding to a reasonable benefit / risk ratio.Pharmaceutically acceptable salt forms of baricitinib of the present invention may be synthesized by conventional chemical methods to contain a basic or acidic moiety. Generally, such salts are prepared, for example, by reacting a free acid or basic form of the compound with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; generally, a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is preferred.

[0042] As described above, conventional baricitinib or its pharmaceutically acceptable salts are drugs used to treat rheumatoid arthritis, atopic dermatitis, alopecia areata, and COVID-19, but currently marketed baricitinib is sold in oral formulations, so it is necessary to take it daily to treat the aforementioned rheumatoid arthritis, atopic dermatitis, alopecia areata, and COVID-19.

[0043] Furthermore, in the case of the aforementioned disease groups, since the disease is not treated by taking baricitinib or its pharmaceutically acceptable salts for a short period, there is a problem in that consistent management is not easy due to the need for long-term administration.

[0044] Specifically, to treat the aforementioned disease, it is necessary to take oral medication daily, and there is the inconvenience of having to visit hospitals and pharmacies regularly to purchase the medicine.

[0045] Furthermore, since the aforementioned diseases are all diseases of the immune system, they require consistent management; however, when taken orally, it is difficult to take them consistently, which presents a problem that makes it even more difficult to enhance the therapeutic effect.

[0046] To address these issues, attempts are being made to develop long-acting formulations. To develop such long-acting formulations, microspheres using biodegradable polymers are typically manufactured and utilized as long-acting formulations. Specifically, microspheres using biodegradable polymers contain baricitinib or a pharmaceutically acceptable salt thereof within them in various ways; when injected into the body, baricitinib or a pharmaceutically acceptable salt thereof is released as the microspheres degrade. At this time, the degradation rate of the microspheres can be controlled to ensure that baricitinib or a pharmaceutically acceptable salt thereof is continuously released for at least one week or one month.

[0047] Methods such as phase separation and solvent evaporation have been proposed for manufacturing these microspheres.

[0048] The aforementioned phase separation method involves dissolving a biodegradable polymer in an excess amount of an organic solvent, such as methylene chloride, and adding a small amount of a drug dissolved in water while stirring. Silicone oil is then added at a constant rate to form embryonic microspheres. Subsequently, an excess amount of a non-solvent, such as trichlorofluoromethane, is used to extract the organic solvent from within the embryonic microspheres. The solidified microspheres are then filtered and recovered, followed by drying under reduced pressure to obtain the microspheres. As such, the phase separation method utilizes toxic solvents like methylene chloride during the manufacturing process; consequently, residual solvents are not sufficiently removed by the reduced-pressure drying process alone, thereby compromising the stability of the formulation and potentially posing a health risk when administered to the human body. Furthermore, since large quantities of non-solvents such as Freon, hexane, heptane, cyclohexane, and trichlorofluoromethane must be used to solidify the embryonic microspheres, serious environmental pollution issues arise alongside economic challenges during mass production.

[0049] The aforementioned solvent evaporation method is primarily used for encapsulating lipid-soluble drugs and involves dissolving a drug and a biodegradable polymer together in a mixture of suitable organic solvents (e.g., methanol and methylene chloride) and then dispersing the mixture in an aqueous phase. In both methods, as the polymer in the organic solvent is dispersed into the aqueous phase, the organic solvent is removed through processes such as extraction or evaporation, which reduces the solubility of the polymer, causes solidification, and consequently forms microspheres. The solvent evaporation method can increase the drug encapsulation rate by appropriately increasing the concentration of the biodegradable polymer (PLGA) dissolved in the organic solvent. However, similar to the phase separation method, the production of microspheres by the solvent evaporation method presents challenges such as the difficulty of removing the organic solvent used for dissolving the biodegradable polymer and process difficulties arising from variations in the solvent removal rate during mass production.

[0050] Spray drying is a method generally used to obtain micronized particles by uniformly dissolving a solution of the substance to be dried, or a biodegradable polymer and drug, into a solution, suspension, or emulsion, supplying it to a nozzle, and simultaneously supplying high-temperature air to evaporate the solvent. Particularly when manufacturing sustained-release microspheres, the drug release rate of the produced microspheres is significantly influenced by conditions such as the composition or content of the biodegradable polymer, the drug content, the type or content of additives, and the composition of the solvent. In addition to the aforementioned manufacturing variables, the characteristics, size, and properties of the microspheres are determined by the nozzle type used to spray the solution (e.g., a method that atomizes droplets using compressed air, a method that atomizes droplets by centrifugal force by flowing the solution over a high-speed rotating disc, or a method that atomizes droplets using ultrasound generated by vibrating a vibrator), the supply speed of the solution, and the temperature, amount, and speed of the drying air. Furthermore, unlike other methods for manufacturing sustained-release microspheres, spray drying offers the advantage of facilitating production through a continuous process, making it easy to transition from small-scale to large-scale production.

[0051] Accordingly, the present invention aims to provide a method for producing long-acting microspheres using baricitinib or a pharmaceutically acceptable salt thereof by utilizing the spray drying method described above. Specifically, the present invention may comprise the steps of: preparing a suspension by dissolving baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent; and spray-drying the suspension to produce long-acting microspheres containing baricitinib.

[0052] To produce long-acting microspheres containing baricitinib according to the present invention, first, a suspension may be prepared by dissolving baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent. In the case of methods for producing microspheres other than the conventional spray-drying method, an organic solvent is used in which baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer can all be completely dissolved; however, in the case of the present invention, unlike this, the biodegradable polymer is completely dissolved in the organic solvent, but baricitinib or a pharmaceutically acceptable salt thereof is not dissolved, so it can be prepared in the form of a suspension.

[0053] When prepared in the form of a suspension as described above and injected into a spray drying device to spray-dry and produce in the form of microspheres, it has an average diameter as described below and can continuously release baricitinib or a pharmaceutically acceptable salt thereof for more than one month.

[0054] In other words, as previously explained, the spray drying method has advantages such as mass production, but it has the problem of difficulty in forming uniform particles. Failure to form uniform particles may mean that there is a large variation in the average diameter each time microspheres are manufactured, which may result in a problem of not having a stable release pattern of baricitinib or its pharmaceutically acceptable salt.

[0055] Accordingly, in the present invention, when selecting an organic solvent, an organic solvent was selected that is not completely dissolved for baricitinib or its pharmaceutically acceptable salt, while completely dissolving the biodegradable polymer so as to be prepared as a suspension.

[0056] When prepared as a suspension as described above, when the suspension is sprayed at the inlet by the spray drying method described later, that is, by a spray drying device, it is sprayed in the form of fine particles. At this time, when the organic solvent is rapidly evaporated by the temperature conditions inside the device, the biodegradable polymer completely dissolved in the organic solvent of the suspension forms fine particles with baricitinib or a pharmaceutically acceptable salt thereof that was uniformly dispersed in the suspension, and is obtained in a product collection container.

[0057] The above-mentioned 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, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, and combinations thereof, preferably polylactide-co-glycolide (PLGA), more preferably has an intrinsic viscosity of 0.2 dl / g or less, and the molar ratio of lactide to glycolide may be 75:25. When microspheres are prepared using the above-mentioned biodegradable polymer, release of baricitinib or a pharmaceutically acceptable salt thereof may occur from the beginning without a lag time, and a continuous release effect may be exhibited for more than one month.

[0058] The above organic solvent is selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, acetone, dimethyl sulfoxide, and mixtures thereof, and preferably may be acetone. As described above, the organic solvent must be able to completely dissolve the biodegradable polymer, but must not completely dissolve baricitinib or its pharmaceutically acceptable salts so that a suspension can be prepared. Accordingly, in the present invention, acetone is used as the organic solvent, and a suspension is prepared using said acetone, and microspheres can be prepared using this.

[0059] The above suspension may contain baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:2 to 1:9. Within this range, not only can a uniform particle release effect of baricitinib or a pharmaceutically acceptable salt thereof be exhibited for more than one month, but when used as a long-acting injectable, an appropriate amount of microspheres may be mixed into the injectable.

[0060] In addition, the viscosity of the suspension is 10 cp to 100 cp, 10 cp to 90 cp, 10 cp to 80 cp, 10 cp to 70 cp, 10 cp to 60 cp, 10 cp to 50 cp, 10 cp to 40 cp, 10 cp to 30 cp, 10 cp to 29 cp, 10 cp to 28 cp, 10 cp to 27 cp, 10 cp to 28 cp, 10 cp to 27 cp, 10 cp to 26 cp, 10 cp to 25 cp, 10 cp to 24 cp, 10 cp to 23 cp, and 10 cp to 22 cp. The viscosity range is 10 to 21 cp, and may be 10 to 20 cp. The above viscosity range is an important condition for manufacturing microspheres with a uniform average diameter. When spray-drying, if the viscosity is too high, it is not easy to spray into fine particles, and if the viscosity is too low, the average diameter (D50) of the particles is 5㎛ or less, so phagocytosis by macrophages occurs when injected into the body, resulting in a problem where the release effect of baricitinib or its pharmaceutically acceptable salt is not achieved.

[0061] After preparing the suspension as described above, microspheres can be produced using a spray drying device.

[0062] In order to manufacture the above-mentioned microspheres, the spray drying conditions are also an important factor. Specifically, the temperature condition of the spray section within the spray dryer may be 40°C to 60°C, 40°C to 55°C, 40°C to 50°C, and preferably 40°C to 45°C. When spray drying within the above temperature range, clumping between microparticles can be prevented. That is, clumping between microparticles occurs when the temperature is high during spray drying, as the biodegradable polymer melts and clumping occurs between the microparticles. Accordingly, the spray drying process must be carried out within the temperature condition range of the present invention described above to prevent clumping between microparticles.

[0063] The spray rate of the suspension using a spray dryer may be 1 mL / min to 18 mL / min, 1 mL / min to 15 mL / min, 1 mL / min to 14 mL / min, 1 mL / min to 13 mL / min, 1 mL / min to 12 mL / min, 1 mL / min to 11 mL / min, 2 mL / min to 11 mL / min, 3 mL / min to 11 mL / min, 3 mL / min to 10 mL / min, 3 mL / min to 9 mL / min, 3 mL / min to 8 mL / min, 3 mL / min to 7 mL / min, and preferably 3 mL / min to 6 mL / min. The spray rate of the suspension may also correspond to a condition for preventing clumping between fine particles, just like the temperature condition described above. If the suspension is sprayed at too high a speed, a problem arises in which the sprayed fine particles clump together. Therefore, the spray drying process must be carried out within the spray speed range of the present invention described above to prevent the clumping of fine particles.

[0064] According to another embodiment of the present invention, a long-acting microsphere comprising baricitinib prepared by the manufacturing method described above may be used. The microsphere may be used as an injectable, and the injectable may exhibit a continuous release effect of baricitinib or its pharmaceutically acceptable salt for at least one week or one month or more by a single administration. Furthermore, rather than a simple release of baricitinib or its pharmaceutically acceptable salt, the blood concentration may be maintained at a level capable of exhibiting the effect of baricitinib or its pharmaceutically acceptable salt, thereby exhibiting a long-lasting effect by a single administration.

[0065] The above microspheres may have an average diameter (D50) of 10 µm to 30 µm, 10 µm to 29 µm, 10 µm to 29 µm, 10 µm to 27 µm, 10 µm to 26 µm, and 10 µm to 25 µm. Within the above average diameter range, when injected as an injectable, the occurrence of pain can be reduced, and a stable release effect of baricitinib or its pharmaceutically acceptable salt can be exhibited for a long time even after injection into the body.

[0066] In addition, the microballs may have an encapsulation rate of 90% or more of baricitinib or its pharmaceutically acceptable salt. As the encapsulation rate is excellent as described above, when injecting the microballs, not only can the amount of microballs required for a single injection be clearly specified, but an excessive amount of microballs is not required to meet the amount of baricitinib or its pharmaceutically acceptable salt required for a single injection.

[0067]

[0068] Experimental Method 1

[0069] Confirmation of baricitinib microsphere morphology

[0070] After sieving microspheres containing baricitinib using a 355 µm sieve, a certain amount was taken onto carbon tape and analyzed as an SEM image using a scanning electron microscope (JSM-7600F, JEOL).

[0071] Check baricitinib microparticle loading amount

[0072] A portion of the microspheres containing baricitinib was accurately weighed, completely dissolved in 10 mL of DMSO, diluted 10-fold with the mobile phase, filtered through a 0.45 µm syringe filter, and quantified using HPLC (Alliance e2695, Waters). The analytical column used for this experiment was a C18 (100 mm x 4.6 mm ID 5 µm), and the drug loading amount was calculated using the following formula.

[0073]

[0074] Confirmation of baricitinib microcell encapsulation rate

[0075] A portion of the microspheres containing baricitinib was accurately weighed, completely dissolved in 10 mL of DMSO, diluted 10-fold with the mobile phase, filtered through a 0.45 µm syringe filter, and quantified using HPLC (Alliance e2695, Waters). The analytical column used for this experiment was a C18 (100 mm x 4.6 mm ID 5 µm), and the drug loading amount was calculated using the following formula.

[0076]

[0077] Preparation Example 1

[0078] Preparation of microspheres according to temperature conditions during spray drying

[0079] Example 1

[0080] 1,000 mg of baricitinib and 3,000 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 500 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 40°C.

[0081] Example 2

[0082] 1,000 mg of baricitinib and 3,000 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 500 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0083] Example 3

[0084] 1,000 mg of baricitinib and 3,000 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 500 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 50°C.

[0085] Example 4

[0086] 1,000 mg of baricitinib and 3,000 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 500 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 60°C.

[0087] The spray drying conditions for the manufacturing methods of Examples 1 to 4 above are as shown in Table 1 below:

[0088] No. Inlet Temp. (℃) Aspirator capa. (%) Feeding rate (mL / min.) Drug: Polymer Polymer Concrete (%) Solvent (mL) Example 1 40 1006.01:30.6500 Example 2 45 1006.01:30.6500 Example 3 50 1006.01:30.6500 Example 4 60 1006.01:30.6500

[0089] The results of analyzing the microspheres prepared by the manufacturing methods of Examples 1 to 4 using the aforementioned Experimental Method 1 are as shown in Table 2 and Figure 1 below:

[0090] No.D 50 (um)LE (%)EE (%) Example 1 2.01 23.49 3.6 Example 2 14.37 23.59 4.0 Example 3 49.24 24.69 8.4 Example 4 63.67 24.29 6.8

[0091] According to Examples 1 to 4 above, it was confirmed that when spray-drying, under conditions where the temperature is 50°C or higher, clumping between particles occurs, resulting in a large average diameter (D50). Additionally, in the case of Example 1, the temperature during spray-drying is low at 40°C, which presents a problem in that it is not easy to form microspheres. Under the temperature conditions of Example 2, the average diameter was 14.37, and both the drug loading amount and encapsulation rate were excellent.

[0092] Example 5

[0093] 225 mg of baricitinib and 675 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 3.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0094] Example 6

[0095] 225 mg of baricitinib and 675 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 12.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0096] Example 7

[0097] 225 mg of baricitinib and 675 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 18.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0098] The spray drying conditions for the manufacturing methods of Examples 5 to 7 above are as shown in Table 3 below:

[0099] No. Inlet Temp. (℃) Aspirator Capacitance (%) Feeding rate (mL / min.) Drug: Polymer Polymer Concrete (%) Solvent (mL) Example 5 45 100 3.01:30.225 300 Example 2 45 100 6.01:30.225 300 Example 6 45 100 12.01:30.225 300 Example 7 45 100 18.01:30.225 300

[0100] The results of analyzing the microspheres prepared by the manufacturing methods of Examples 2 and 5 to 7 using the aforementioned Experimental Method 1 are as shown in Table 4 and Figure 2 below:

[0101] No.D 50 (um)LE (%)EE (%) Example 5 10.13 23.19 2.4 Example 2 14.37 23.59 4.0 Example 6 31.91 22.48 9.6 Example 7 56.47 22.79 0.8

[0102] According to the experimental results above, it can be confirmed through average diameter analysis results and SEM images that clumping occurs between microparticles when the spray speed is adjusted to 12 mL / min or higher. On the other hand, when the experiment was conducted under conditions of 3 mL / min to 6 mL / min, the average diameter was 10 µm or higher, and both the drug loading amount and encapsulation rate were excellent.

[0103] Example 8

[0104] 300 mg of baricitinib and 600 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0105] Example 9

[0106] 150 mg of baricitinib and 750 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0107] Example 10

[0108] 90 mg of baricitinib and 810 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0109] The spray drying conditions for the manufacturing methods of Examples 8 to 10 above are as shown in Table 5 below:

[0110] No. Inlet Temp. (℃) Aspirator Capacitance (%) Feeding rate (mL / min.) Drug: Polymer Polymer Concrete (%) Solvent (mL) Example 8 45 100 6.01: 20.200 300 Example 2 45 100 6.01: 30.225 300 Example 9 45 100 6.01: 50.250 300 Example 10 45 100 6.01: 90.270 300

[0111] The results of analyzing the microspheres prepared by the manufacturing methods of Examples 2, 8 to 10 above using the aforementioned Experimental Method 1 are as shown in Table 6 and Figure 3 below:

[0112] No.D 50 (um)LE (%)EE (%) Example 8 13.49 30.19 1.2 Example 2 14.37 23.59 4.0 Example 9 15.38 16.29 7.2 Example 10 12.619.49 4.0

[0113] According to the experimental results above, it was confirmed that there was no significant difference in the average diameter of the particles when the spray speed and temperature conditions of the suspension were all the same. However, it was confirmed that there was a difference in the loading amount of the drug depending on the difference in the weight ratio of baricitinib and the biodegradable polymer. In other words, it was confirmed that when the weight of the biodegradable polymer relative to the drug is excessively high in the suspension, a problem may arise where the amount of drug contained in the microspheres decreases when the microspheres are manufactured. Accordingly, it is considered more desirable to manufacture the suspension with a weight ratio of baricitinib and the biodegradable polymer in the range of 1:2 to 1:5.

[0114] Example 11

[0115] 75 mg of baricitinib and 375 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0116] Example 12

[0117] 300 mg of baricitinib and 1500 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0118] Example 13

[0119] 600 mg of baricitinib and 3000 mg of biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) were weighed and dissolved in 300 mL of acetone. Microspheres were prepared by spraying the solution dissolved in acetone at a feeding rate of 6.0 mL / min with the inlet temperature of a spray dryer set to 45°C.

[0120] The spray drying conditions for the manufacturing methods of Examples 11 to 13 above are as shown in Table 7 below:

[0121] No. Inlet Temp. (℃) Feeding rate (mL / min.) Drug: Polymer Viscosity (cP) Polymer Concrete (%) Solvent (mL) Example 1 1456.01:517.20.125300 Example 9 456.01:518.20.250300 Example 12 456.01:518.50.500300 Example 13 456.01:519.71.000300

[0122] The results of analyzing the microspheres prepared by the manufacturing methods of Examples 9, 11 to 13 using the aforementioned Experimental Method 1 are as shown in Table 8 and Figure 4 below:

[0123] No.D 50 (um)LE (%)EE (%) Example 11 15.2 116.0 96.0 Example 9 15.38 16.2 97.2 Example 12 15.9 416.2 97.3 Example 13 16.27 16.3 97.8

[0124] According to Table 8 above, when microspheres are prepared using a suspension within the viscosity range of Table 7, it is possible to produce microspheres with a uniform average diameter and excellent drug loading and encapsulation rates. Therefore, it is preferable to prepare the suspension with a viscosity of approximately 17 cP to 20 cP and to prepare microspheres using a spray drying method. Experimental Example 2

[0125] 5.0 mg each of the microspheres from Examples 2 and 9 were placed in a 20 mL light-shielding glass vial, 10 mL of PBS buffer pH 7.4 solution was added, and the vial was sealed. The elution test was then conducted for 28 days in a 37 ℃ water bath with stirring at 100 rpm. At the designated time points, 1.0 mL of the supernatant was taken, the solution was rehydrated with fresh PBS buffer pH 7.4, filtered using a 0.45 µm filter, and analyzed by HPLC.

[0126] The experimental results are as shown in Figures 5 to 8.

[0127] Figure 5 shows the results of release experiments using microspheres of Examples 1 to 4, and Figure 6 shows the results of release experiments on microspheres of Examples 2, 5, 6, and 7. According to the experimental results, it can be confirmed that in the case of Example 1, release is completed in too short a time, while in Examples 3 and 4, the release of the drug is too insufficient. Only in the case of Example 2 was continuous release observed for one month.

[0128] In addition, according to Figure 6, it can be seen that Example 5 is released similarly to Example 2, but the initial release amount is too high, so it can be seen that 90% of the drug is almost completely released within 14 days. In the case of Example 6, it can be seen that drug release can be shown for more than one month, and Example 7 has a problem of insufficient release.

[0129] Looking at the release patterns in Fig. 7, it can be seen that release continues for one month for all of Examples 8 to 10, similar to Example 2; however, Example 8 has the problem of an excessive initial release amount. In the case of Example 10, it can also be seen that the initial release amount is large. Compared to Example 2, it can be seen that 85% of the drug is released from the microspheres of Example 9 around day 28. Given that it is generally considered that release is complete when 80% of the drug is released when conducting a dissolution test, this implies that Example 9 exhibits stable release without initial over-release compared to Example 2.

[0130] The results of the emission tests for Examples 11 to 13 are shown in Fig. 8, and it was confirmed that Examples 11 to 13 exhibited a continuous emission pattern for 28 days at a level equivalent to Example 9.

[0131] Although 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 by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

[0132] The present invention relates to a method for manufacturing long-acting microspheres containing baricitinib and long-acting microspheres containing baricitinib manufactured by the method.

Claims

1. A step of preparing a suspension by dissolving baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent; and A step comprising spray-drying the above suspension to produce long-acting microspheres containing baricitinib. Method for manufacturing long-acting microspheres containing baricitinib.

2. In Paragraph 1, When spray-drying the above suspension, the temperature condition of the spray section inside the spray dryer is 40℃ to 60℃. Method for manufacturing long-acting microspheres containing baricitinib.

3. In Paragraph 1, When spray-drying the above suspension, the spray rate of the suspension using a spray dryer is 1 mL / min to 18 mL / min. Method for manufacturing long-acting microspheres containing baricitinib.

4. In Paragraph 1, The above suspension comprises baricitinib or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:2 to 1:

9. Method for manufacturing long-acting microspheres containing baricitinib.

5. In Paragraph 1, The viscosity of the above suspension is 10 cp to 100 cp. Method for manufacturing long-acting microspheres containing baricitinib.

6. In Paragraph 1, The above-mentioned 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, polyhydroxyvalrate, polyhydroxybutyrate, polyamino acid, and combinations thereof. Method for manufacturing long-acting microspheres containing baricitinib.

7. In Paragraph 1, The above organic solvent is selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, acetone, dimethyl sulfoxide, and mixtures thereof. Method for manufacturing long-acting microspheres containing baricitinib.

8. Manufactured by a manufacturing method according to any one of paragraphs 1 to 7 Long-acting microspheres containing baricitinib.

9. In Paragraph 8, The above microspheres have an average diameter (D50) of 10 μm to 30 μm. Long-acting microspheres containing baricitinib.

10. In Paragraph 8, The above microspheres have an encapsulation rate of 90% or more of baricitinib or a pharmaceutically acceptable salt thereof. Long-acting microspheres containing baricitinib.

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