Microspheres comprising baricitinib inclusion compound using cyclodextrin derivative and preparation method therefor

Abstract

The present invention relates to microspheres comprising a baricitinib inclusion compound using a cyclodextrin derivative and a preparation method therefor, wherein barricitinib, which is a poorly soluble drug, or a pharmaceutically acceptable salt thereof is prepared as an inclusion compound using a cyclodextrin derivative to increase solubility, and are prepared together with a biodegradable polymer as microspheres by utilizing such dissolution characteristics, thereby exhibiting a sustained release effect of barricitinib or a pharmaceutically acceptable salt thereof for one month or longer. In addition, baricitinib or a pharmaceutically acceptable salt thereof is prepared as an inclusion compound using a cyclodextrin derivative, and the inclusion compound and a biodegradable polymer are used to prepare a W1 / O / W2 emulsion, which is then solidified to form microspheres, thereby suppressing initial burst release and exhibiting a consistent release pattern of baricitinib or a pharmaceutically acceptable salt thereof for one month or longer.

Description

Microspheres containing a baricitinib inclusion compound using a cyclodextrin derivative and a method for preparing the same

[0001] The present invention relates to microspheres comprising a baricitinib inclusion compound using a cyclodextrin derivative and a method for manufacturing the same.

[0002]

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] However, due to the poor water solubility of baricitinib, developing it into a long-acting formulation is not easy. Therefore, it is necessary to develop a long-acting formulation capable of exhibiting a sustained release effect of baricitinib by improving its solubility.

[0009] [Prior Art Literature]

[0010] [Patent Literature]

[0011] (Patent Document 1) WO 2020 / 236950 A1

[0012]

[0013] The object of the present invention is to provide microspheres comprising a baricitinib inclusion compound using a cyclodextrin derivative and a method for manufacturing the same.

[0014] Another objective of the present invention is to provide microspheres comprising a baricitinib inclusion compound using a cyclodextrin derivative, which can exhibit a sustained release effect of baricitinib or its pharmaceutically acceptable salt for more than one month by preparing a baricitinib inclusion compound using a cyclodextrin derivative to increase solubility of the poorly soluble drug baricitinib or its pharmaceutically acceptable salt, and by utilizing these improved solubility characteristics to prepare microspheres together with a biodegradable polymer.

[0015] Another objective of the present invention is to provide a method for preparing microspheres comprising a baricitinib inclusion compound capable of suppressing initial over-release and exhibiting a constant release pattern of baricitinib or its pharmaceutically acceptable salt for more than one month by preparing a baricitinib or its pharmaceutically acceptable salt as an inclusion compound using a cyclodextrin derivative, preparing a W1 / O / W2 emulsion using said inclusion compound and a biodegradable polymer, and solidifying the emulsion to produce microspheres.

[0016]

[0017] To achieve the above-mentioned purpose, the present invention relates to a baricitinib inclusion compound comprising a cyclodextrin derivative; and microspheres comprising a baricitinib inclusion compound comprising a biodegradable polymer.

[0018] In addition, the cyclodextrin derivative may be selected from the group consisting of HP-β-CD (2-hydroxypropyl-β-cyclodextrin), SBE-β-CD (Sulfobutylether-β-Cyclodextrin), and mixtures thereof.

[0019] In addition, the baricitinib inclusion compound containing the cyclodextrin derivative may contain baricitinib or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in a weight ratio of 1:1 to 1:3.

[0020] In addition, the baricitinib inclusion compound containing the above-mentioned cyclodextrin derivative may have a solubility in water increased by 100% to 200% compared to the solubility of baricitinib or its pharmaceutically acceptable salt itself.

[0021] In addition, the microspheres may contain a baricitinib inclusion compound containing a cyclodextrin derivative and a biodegradable polymer in a weight ratio of 1:5 to 1:15.

[0022] 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.

[0023] In addition, when the above microspheres are administered into the body as an injection, baricitinib may be released for more than one month.

[0024] Another invention for achieving the above-mentioned purpose relates to a method for preparing microspheres comprising a baricitinib inclusion compound, comprising the steps of: preparing a baricitinib inclusion compound by mixing baricitinib or a pharmaceutically acceptable salt thereof with a cyclodextrin derivative; preparing a first aqueous solution by dissolving the baricitinib inclusion compound in distilled water; preparing an oil phase solution by dissolving a biodegradable polymer in an organic solvent; preparing a second aqueous solution by dissolving a surfactant in distilled water; preparing a W1 / O emulsion by mixing the first aqueous solution and the oil phase solution; and preparing a W1 / O / W2 emulsion by adding the W / O emulsion to the second aqueous solution.

[0025] Additionally, the step of preparing the baricitinib inclusion compound may include: a step of preparing a solution containing the cyclodextrin derivative by dissolving the cyclodextrin derivative in distilled water; a step of preparing a solution containing baricitinib or its salt by dissolving baricitinib or its pharmaceutically acceptable salt in an organic solvent; and a step of preparing the baricitinib inclusion compound by mixing and stirring the solution containing the cyclodextrin derivative and the solution containing baricitinib or its salt.

[0026] In addition, the cyclodextrin derivative may be selected from the group consisting of HP-β-CD (2-hydroxypropyl-β-cyclodextrin), SBE-β-CD (Sulfobutylether-β-Cyclodextrin), and mixtures thereof.

[0027] In addition, the baricitinib inclusion compound containing the cyclodextrin derivative may contain baricitinib or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in a weight ratio of 1:1 to 1:3.

[0028] In addition, the W1 / O emulsion may contain a baricitinib inclusion compound containing a cyclodextrin derivative and a biodegradable polymer in a weight ratio of 1:5 to 1:15.

[0029] In addition, the step of preparing the W1 / O emulsion may include mixing the first aqueous solution and the oil solution and stirring using a homogenizer at 5,000 rpm to 15,000 rpm for 30 seconds to 90 seconds.

[0030] 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.

[0031] In addition, the surfactant may be selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, esteramine, linear diamine, patiamine, and mixtures thereof.

[0032]

[0033] The present invention can produce a poorly soluble drug, baricitinib or a pharmaceutically acceptable salt thereof, into an inclusion compound using a cyclodextrin derivative to increase solubility, and by utilizing these solubility characteristics to produce microspheres together with a biodegradable polymer, a sustained release effect of baricitinib or a pharmaceutically acceptable salt thereof can be exhibited for more than one month.

[0034] In addition, baricitinib or a pharmaceutically acceptable salt thereof can be prepared as an inclusion compound using a cyclodextrin derivative, and a W1 / O / W2 emulsion can be prepared using said inclusion compound and a biodegradable polymer, and then solidified to form microspheres, thereby suppressing initial over-release and exhibiting a constant release pattern of baricitinib or a pharmaceutically acceptable salt thereof for more than one month.

[0035]

[0036] Figure 1 is an SEM image of a baricitinib inclusion compound according to one embodiment of the present invention.

[0037] Figure 2 is an SEM image of a baricitinib inclusion compound according to one embodiment of the present invention.

[0038] Figure 3 is an SEM image of a microsphere containing a baricitinib inclusion compound according to one embodiment of the present invention.

[0039] Figure 4 is the result of NMR analysis of baricitinib according to one embodiment of the present invention.

[0040] Figure 5 is the result of NMR analysis of a cyclodextrin derivative according to one embodiment of the present invention.

[0041] Figure 6 is the result of NMR analysis of a baricitinib inclusion compound according to one embodiment of the present invention.

[0042] Figure 7 is the result of a release experiment for baricitinib in microspheres containing a baricitinib inclusion compound according to one embodiment of the present invention.

[0043] Figure 8 is the result of a release experiment for baricitinib in microspheres containing a baricitinib inclusion compound according to one embodiment of the present invention.

[0044] Figure 9 shows the results of a release test of Olumiant Tablet (Olumiant Tab. 4mg) currently on the market.

[0045]

[0046] 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.

[0047] 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:

[0048] [Chemical Formula]

[0049]

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] Methods such as phase separation and solvent evaporation have been proposed for manufacturing these microspheres.

[0059] However, in the case of a conventional method for manufacturing microspheres, a poorly soluble drug, baricitinib or a pharmaceutically acceptable salt thereof, was dissolved in an organic solvent to prepare an oil phase solution, and a method was used to manufacture microspheres using an aqueous solution in which a surfactant was dissolved.

[0060] However, in the case of conventional methods for manufacturing microspheres, they are merely produced as microspheres without improving the solubility of the poorly soluble drug baricitinib or its pharmaceutically acceptable salts at all, and thus retain their poorly soluble characteristics when actually injected into the body.

[0061] Typically, improving the solubility of poorly soluble drugs allows them to dissolve in water more quickly and become active in the body. This directly affects the rate of drug absorption and can ultimately contribute to increased bioavailability, enabling the drug to act more efficiently within the body. Additionally, as water solubility increases, unnecessary concentrations are reduced, which can lead to fewer side effects and enable more distinct pharmacological responses.

[0062] In light of the various benefits of improving the solubility characteristics of poorly soluble drugs as described above, the present invention is characterized by preparing an inclusion compound to improve the solubility characteristics of the poorly soluble drug baricitinib or its pharmaceutically acceptable salt, and providing it as microspheres using the same.

[0063] The above-mentioned cyclodextrin derivative is selected from the group consisting of HP-β-CD (2-hydroxypropyl-β-cyclodextrin), SBE-β-CD (Sulfobutylether-β-Cyclodextrin), and mixtures thereof, specifically HP-β-CD (2-hydroxypropyl-β-cyclodextrin) and SBE-β-CD (Sulfobutylether-β-Cyclodextrin). The above-mentioned cyclodextrin derivative may form an inclusion compound with baricitinib or a pharmaceutically acceptable salt thereof as described above, and the inclusion compound may have improved solubility characteristics and increase solubility in distilled water.

[0064] The baricitinib inclusion compound containing the above-mentioned cyclodextrin derivative may contain baricitinib or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in a weight ratio of 1:1 to 1:3. Specifically, the baricitinib inclusion compound may contain baricitinib or a pharmaceutically acceptable salt thereof and the cyclodextrin derivative in a weight ratio of 1:2 to 1:3 when the cyclodextrin derivative is HP-β-CD, and in a weight ratio of 1:1 to 1:3 when the cyclodextrin derivative is SBE-β-CD. When forming the inclusion compound within the above ratio range, solubility characteristics may be improved, and when the cyclodextrin derivative is included below the above range, the improvement in solubility characteristics may be insufficient, and when included above the above range, the degree of improvement in solubility characteristics may be insufficient.

[0065] A baricitinib inclusion compound containing the above-mentioned cyclodextrin derivative may have a solubility in water increased by 100% to 200%, increased by 110% to 190%, and increased by 110% to 185% compared to baricitinib or its pharmaceutically acceptable salt. A non-inclusion compound may exhibit a significant increase in solubility compared to baricitinib or its pharmaceutically acceptable salt.

[0066] The above microspheres may contain a baricitinib inclusion compound containing a cyclodextrin derivative and a biodegradable polymer in a weight ratio of 1:5 to 1:15, in a weight ratio of 1:6 to 1:14, in a weight ratio of 1:7 to 1:13, in a weight ratio of 1:8 to 1:12, and in a weight ratio of 1:9 to 1:11. When prepared as microspheres within the above ranges, microspheres containing an appropriate amount of baricitinib or a pharmaceutically acceptable salt thereof may be prepared, thereby allowing for a continuous release effect of baricitinib or a pharmaceutically acceptable salt thereof in the body for one month.

[0067] 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 selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), and combinations thereof, more preferably may include polylactide-co-glycolide (PLGA), but is not limited to the above examples, and any biodegradable polymer that includes a baricitinib inclusion compound and degrades in the body to produce a release effect of baricitinib or a pharmaceutically acceptable salt thereof for more than one month may be used without limitation.

[0068] When the above microspheres are administered into the body as an injection, baricitinib may be released for more than one month.

[0069] As described above, the microspheres of the present invention comprise a baricitinib inclusion compound comprising a cyclodextrin derivative; and a biodegradable polymer, wherein as the biodegradable polymer degrades in the body, the release of baricitinib or a pharmaceutically acceptable salt thereof may be exhibited. To achieve this effect, the microspheres of the present invention may be used in the form of an injectable.

[0070] To manufacture the above microspheres in the form of an injectable drug, they can be mixed with a suspension solvent to produce an injectable composition. The suspension solvent comprises an isotonic agent, a suspending agent, and a solvent.

[0071] More specifically, the isotonic agent may be selected from the group consisting of D-Mannitol, Maltitol, Sorbitol, Lactitol, Xylitol, Sodium chloride, and mixtures thereof, preferably D-Mannitol, but is not limited to the above examples.

[0072] The above-mentioned suspending agent is from the group consisting of sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyhydric alcohols, chitosan, chitosan derivatives, cellulose, cellulose derivatives, collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, polylysine, titin, fibrin, agarose, fluran, xanthan gum, and mixtures thereof. Selected, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0073] The above solvent may be injection water, and any solvent usable as injection water may be used without restriction.

[0074] A method for preparing microspheres comprising a baricitinib inclusion compound according to another embodiment of the present invention may include the steps of: preparing a baricitinib inclusion compound by mixing baricitinib or a pharmaceutically acceptable salt thereof with a cyclodextrin derivative; preparing a first aqueous solution by dissolving the baricitinib inclusion compound in distilled water; preparing an oil phase solution by dissolving a biodegradable polymer in an organic solvent; preparing a second aqueous solution by dissolving a surfactant in distilled water; preparing a W1 / O emulsion by mixing the first aqueous solution and the oil phase solution; and preparing a W1 / O / W2 emulsion by adding the W1 / O emulsion to the second aqueous solution.

[0075] The step of preparing the baricitinib inclusion compound may include: preparing a solution containing the cyclodextrin derivative by dissolving the cyclodextrin derivative in distilled water; preparing a solution containing baricitinib by dissolving baricitinib or a pharmaceutically acceptable salt thereof in an organic solvent; and preparing the baricitinib inclusion compound by mixing and stirring the solution containing the cyclodextrin derivative and the solution containing baricitinib.

[0076] In order to manufacture the microspheres of the present invention, the preparation of the baricitinib inclusion compound described above must be performed first. The baricitinib inclusion compound can be prepared by preparing a solution containing a cyclodextrin derivative, then preparing a solution containing baricitinib or a pharmaceutically acceptable salt thereof, and then mixing and stirring the two solutions to prepare the baricitinib inclusion compound.

[0077] As described above, the cyclodextrin derivative may be selected from the group consisting of HP-β-CD (2-hydroxypropyl-β-cyclodextrin), SBE-β-CD (Sulfobutylether-β-Cyclodextrin), and mixtures thereof. Cyclodextrin (CD) is a macromolecule with stereospecificity in which 6 to 7 glucose molecules are linked in a ring, and is classified into α-, β-, and γ-CD depending on the number of glucose molecules constituting the structure. The interior of the CD is hydrophobic due to hydrogen bonds and ester bonds, while simultaneously possessing hydrophilic properties due to the hydroxyl group at the C6 position exposed to the outside of the glucose constituting the CD. Due to this structural stereospecificity and the property of possessing both hydrophilicity and hydrophobicity, it can form inclusion complexes with various hydrophobic substances.

[0078] A first aqueous solution can be prepared by dissolving the baricitinib inclusion compound prepared as described above in distilled water. Subsequently, an oil phase solution can be prepared by dissolving a biodegradable polymer in an organic solvent. A W1 / O emulsion can be prepared by mixing the first aqueous solution and the oil phase solution.

[0079] The above W1 / O emulsion may contain a baricitinib inclusion compound containing a dextrin derivative and a biodegradable polymer in a weight ratio of 1:5 to 1:15, in a weight ratio of 1:6 to 1:14, in a weight ratio of 1:7 to 1:13, in a weight ratio of 1:8 to 1:12, and in a weight ratio of 1:9 to 1:11. When prepared as microspheres within the above ranges, microspheres containing an appropriate amount of baricitinib or a pharmaceutically acceptable salt thereof may be prepared, thereby allowing for a continuous release effect of baricitinib or a pharmaceutically acceptable salt thereof in the body for one month.

[0080] The above W1 / O emulsion can be prepared by dissolving a surfactant in distilled water and adding it to a second aqueous solution to make a W1 / O / W2 emulsion.

[0081] After preparing the above W1 / O / W2 emulsion, it can be stirred to solidify into microspheres and the organic solvent can be removed. The solidified microspheres can be washed by centrifugation and freeze-dried.

[0082] The organic solvent may be selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, acetone, dimethyl sulfoxide, and mixtures thereof, preferably dichloromethane, but is not limited to the above examples.

[0083] The above surfactant may be selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, esteramine, linear diamine, patiamine, and mixtures thereof, preferably polyvinyl alcohol, but is not limited to the above examples.

[0084]

[0085] Preparation Example

[0086] Baricitinib Solubility Test Using Cyclodextrin Derivatives

[0087] Test Example 1

[0088] 5.4 mg of baricitinib and 3.0 mL of triple-distilled water were weighed into a 20 mL brown glass vial and sufficiently dissolved in a 37 °C water bath while stirring at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate the undissolved active ingredient. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0089] Test Example 2

[0090] 5.4 mg of baricitinib and 5.4 mg of HP-β-CD were weighed into a 20 mL brown glass vial with 3.0 mL of triple-distilled water and sufficiently dissolved in a 37 °C water bath at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate any undissolved active ingredients. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0091] Test Example 3

[0092] 5.4 mg of baricitinib and 10.8 mg of HP-β-CD were weighed into a 20 mL brown glass vial with 3.0 mL of triple-distilled water and thoroughly dissolved in a 37 °C water bath at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate any undissolved active ingredients. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0093] Test Example 4

[0094] 5.4 mg of baricitinib and 16.2 mg of HP-β-CD were weighed into a 20 mL brown glass vial with 3.0 mL of triple-distilled water and sufficiently dissolved in a 37 °C water bath while stirring at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate any undissolved active ingredients. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0095] Test Example 5

[0096] Baricitinib 5.4 mg and SEB-β 5.4 mg were weighed into a 20 mL brown glass vial with 3.0 mL of triple-distilled water and sufficiently dissolved in a 37 °C water bath at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate any undissolved active ingredients. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0097] Test Example 6

[0098] Baricitinib 5.4 mg and SEB-β 10.8 mg were weighed into a 20 mL brown glass vial with 3.0 mL of triple-distilled water and sufficiently dissolved in a 37 °C water bath at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate any undissolved active ingredients. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0099] Test Example 7

[0100] Baricitinib 5.4 mg and SEB-β16.2 mg were weighed into a 20 mL brown glass vial with 3.0 mL of triple-distilled water and sufficiently dissolved in a 37 °C water bath at 100 rpm for 24 hours. After sufficient dissolution for 24 hours, the mixture was left to stand at room temperature (25 °C) to precipitate the undissolved active ingredients. 2.0 mL of the supernatant was taken at the 3-hour, 6-hour, and 24-hour points, filtered through a 0.22 μm syringe filter, and analyzed by HPLC.

[0101]

[0102] The inclusion compounds prepared by Test Examples 1 to 7 above can be confirmed through the SEM images of FIGS. 1 and FIGS. 2.

[0103]

[0104] Test method

[0105] The increase in the solubility of the poorly soluble drug baricitinib was confirmed using β-CD derivatives HP-β-CD (2-hydroxypropyl-β-cyclodextrin) and SBE-β-CD (Sulfobutylether-β-cyclodextrin). Considering the water solubility of the active ingredient, the study was conducted with n=3 within a concentration range where at least 5 times greater solubility was possible. The compositions for Test Examples 1 to 7 are as shown in Table 1 below.

[0106]

[0107] 1.2 Analysis Conditions The test solutions from Test Examples 1 to 7 above were filtered using a 0.22 µm syringe filter and analyzed by HPLC. The analysis conditions are as shown in Table 2.

[0108] Instrument Name: HPLC Wavelength: 255 nm Column Dimensions: 5 µm, 4.6 mm X 250 mm Column Temperature: 30°C Flow Rate: 1.0 mL / min Injection Volume: 10 µL Analysis Time: 6 min Mobile Phase Composition: A: Acetonitrile, B: Phosphate Buffer (pH 2.8), Mobile Phase Ratio: 35:65 (v / v)

[0109] 1.3 Test Results Solubility tests using β-CD derivatives HP-β-CD and SBE-β-CD showed that the solubility of baricitinib increased when combined with SBE-β-CD. In the case of HP-β-CD, there was no significant difference at a 1:1 ratio, but it increased by 112% at a 1:2 ratio and 141% at a 1:3 ratio. In the case of SBE-β-CD, it was confirmed that it increased by 114% at a 1:1 ratio, 126% at a 1:2 ratio, and 182% at a 1:3 ratio.

[0110] No. BC: HP-β-CD ratio BC: SBE-β-CD ratio BC Conc.(mg / mL) Test Example 11:0-0.091 Test Example 21:1-0.087 Test Example 32:1-0.102 Test Example 43:1-0.128 Test Example 5-1:10.104 Test Example 6-2:10.115 Test Example 7-3:10.166

[0111]

[0112] Method for preparing a baricitinib inclusion compound using a cyclodextrin derivative

[0113] Preparation of baricitinib inclusion compounds using HP-β-CD (2-hydroxypropyl-β-Cyclodextrin)

[0114] Preparation Example 1

[0115] 100 mg of HP-β-CD was added to triple-distilled water and dissolved at 50°C. 100 mg of baricitinib was dissolved in 100 mL of acetone. The HP-β-CD solution and the baricitinib solution were mixed and stirred at 50°C for 24 hours to prepare the complex. Once stirring was complete, the acetone and distilled water were evaporated using a rotary evaporator. Baricitinib that did not participate in the reaction was removed using acetone. The washed complex was dispersed by adding 10 mL of triple-distilled water and freeze-dried using a freeze-dryer.

[0116] Preparation Example 2

[0117] 200 mg of HP-β-CD was added to triple-distilled water and dissolved at 50°C. 100 mg of baricitinib was dissolved in 100 mL of acetone. The HP-β-CD solution and the baricitinib solution were mixed and stirred at 50°C for 24 hours to prepare the complex. Once stirring was complete, the acetone and distilled water were evaporated using a rotary evaporator. Baricitinib that did not participate in the reaction was removed using acetone. The washed complex was dispersed by adding 10 mL of triple-distilled water and freeze-dried using a freeze-dryer.

[0118] Preparation Example 3

[0119] 300 mg of HP-β-CD was added to triple-distilled water and dissolved at 50°C. 100 mg of baricitinib was dissolved in 100 mL of acetone. The HP-β-CD solution and the baricitinib solution were mixed and stirred at 50°C for 24 hours to prepare the complex. Once stirring was complete, the acetone and distilled water were evaporated using a rotary evaporator. Baricitinib that did not participate in the reaction was removed using acetone. The washed complex was dispersed by adding 10 mL of triple-distilled water and freeze-dried using a freeze-dryer.

[0120] No. HP-β-CD (mg) Baricitinib (mg) Ratio (W / W) Preparation Example 1 100 100 1:1 Preparation Example 2 200 100 2:1 Preparation Example 3 300 100 3:1

[0121]

[0122] Preparation of baricitinib inclusion compounds using SBE-β-CD (Sulfobutylether-β-Cyclodextrin)

[0123] Preparation Example 4

[0124] 100 mg of SBE-β-CD was added to triple-distilled water and dissolved at 50°C. 100 mg of baricitinib was dissolved in 100 mL of acetone. The SBE-β-CD solution and the baricitinib solution were mixed and stirred at 50°C for 24 hours to prepare the complex. Once stirring was complete, the acetone and distilled water were evaporated using a rotary evaporator. Baricitinib that did not participate in the reaction was removed using acetone. The washed complex was dispersed by adding 10 mL of triple-distilled water and freeze-dried using a freeze-dryer.

[0125] Preparation Example 5

[0126] 200 mg of SBE-β-CD was added to triple-distilled water and dissolved at 50°C. 100 mg of baricitinib was dissolved in 100 mL of acetone. The SBE-β-CD solution and the baricitinib solution were mixed and stirred at 50°C for 24 hours to prepare the complex. Once stirring was complete, the acetone and distilled water were evaporated using a rotary evaporator. Baricitinib that did not participate in the reaction was removed using acetone. The washed complex was dispersed by adding 10 mL of triple-distilled water and freeze-dried using a freeze-dryer.

[0127] Preparation Example 6

[0128] 300 mg of SBE-β-CD was added to triple-distilled water and dissolved at 50°C. 100 mg of baricitinib was dissolved in 100 mL of acetone. The SBE-β-CD solution and the baricitinib solution were mixed and a complex was prepared by stirring at 50°C for 24 hours. Once stirring was complete, the acetone and distilled water were evaporated using a rotary evaporator. Baricitinib that did not participate in the reaction was removed using acetone. The washed complex was dispersed by adding 10 mL of triple-distilled water and freeze-dried using a freeze-dryer.

[0129] No. SBE-β-CD (mg) Baricitinib (mg) Ratio (W / W) Preparation Example 4 100 100 1:1 Preparation Example 5 200 100 2:1 Preparation Example 6 300 100 3:1

[0130]

[0131] Microsphere preparation using cyclodextrin derivatives and baricitinib inclusion compounds

[0132] Microsphere preparation using HP-β-CD (2-Hydroxypropyl-β-Cyclodextrin) and baricitinib inclusion compounds

[0133] Example 1

[0134] Preparation of microspheres using HP-β-CD inclusion compound (Preparation Example 1)

[0135] 100 mg of the baricitinib / HP-β-CD inclusion compound prepared in Preparation Example 1 was dissolved in 5.0 mL of distilled water to prepare the first aqueous phase, and 1,000 mg of a biodegradable polymer (Poly L-lactic-co-glycolic acid, PLGA 7525) was weighed and dissolved in 20.0 mL of dichloromethane to prepare the oil phase. 1.5 g of polyvinyl alcohol was dissolved in 100 mL of distilled water to prepare the second aqueous phase. A primary emulsion was formed by homogenizing the first aqueous phase and the oil phase using a homogenizer at 10,000 rpm for 1 minute. A secondary emulsion was formed by dropwise adding the primary emulsion to 100 mL of the second aqueous phase. The formed emulsion was stirred at room temperature for 24 hours to solidify the microspheres and evaporate the organic solvent. The solidified microspheres were centrifuged at 2,500 rpm for 5 minutes to wash, and after washing, were freeze-dried to obtain.

[0136]

[0137] Example 2

[0138] Preparation of microspheres using HP-β-CD inclusion compound (Preparation Example 2)

[0139] The procedure is identical to Experimental Example 1, except for the step of preparing the first aqueous phase by dissolving 100 mg of the baricitinib / HP-β-CD inclusion compound prepared in Preparation Example 2 in 5.0 mL of distilled water.

[0140]

[0141] Example 3

[0142] Preparation of microspheres using HP-β-CD inclusion compound (Preparation Example 3)

[0143] The procedure is identical to Experimental Example 1, except for the step of preparing the first aqueous phase by dissolving 100 mg of the baricitinib / HP-β-CD inclusion compound prepared in Preparation Example 3 in 5.0 mL of distilled water.

[0144]

[0145] Example 4

[0146] Preparation of microspheres using HP-β-CD inclusion compound (Preparation Example 4)

[0147] The procedure is identical to Experimental Example 1, except for the step of preparing the first aqueous phase by dissolving 100 mg of the baricitinib / HP-β-CD inclusion compound prepared in Preparation Example 4 in 5.0 mL of distilled water.

[0148]

[0149] Example 5

[0150] Preparation of microspheres using SBE-β-CD inclusion compound (Preparation Example 5)

[0151] The procedure is identical to Experimental Example 1, except for the step of preparing the first aqueous phase by dissolving 100 mg of the baricitinib / SBE-β-CD inclusion compound prepared in Preparation Example 5 in 5.0 mL of distilled water.

[0152]

[0153] Example 6

[0154] Preparation of microspheres using SBE-β-CD inclusion compound (Preparation Example 6)

[0155] The procedure is identical to Experimental Example 1, except for the step of preparing the first aqueous phase by dissolving 100 mg of the baricitinib / SBE-β-CD inclusion compound prepared in Preparation Example 6 in 5.0 mL of distilled water.

[0156]

[0157] Analysis method for inclusion compounds and microspheres

[0158] Experimental Example 1: Morphological confirmation of baricitinib / β-CD inclusion compound and microspheres containing the same

[0159] A certain amount of the baricitinib / β-CD inclusion compound and the microspheres containing it were placed on carbon tape and images were analyzed using a scanning electron microscope (JSM-7600F, JEOL). Representative results are shown in Figure 3.

[0160] According to Figure 3, it can be confirmed that it was manufactured into spherical microspheres.

[0161]

[0162] Experimental Example 2: 1H-NMR Confirmation of Baricitinib / HP-β-CD Inclusion Compound

[0163] Baricitinib, HP-β-CD, and the inclusion compound of baricitinib and HP-β-CD were analyzed using a superconducting Fourier transform nuclear magnetic resonance spectrometer (NMR Spectrometer, Bruker, AVANCE III 500 MHz). The NMR results for each are shown in Figures 4 to 6. Upon examining the NMR of the inclusion compound in Figure 6, both the peak of baricitinib in Figure 4 and the peak of HP-β-CD in Figure 5 are observed, confirming that it is an inclusion compound of baricitinib and HP-β-CD.

[0164]

[0165] Experimental Example 3 Confirmation of microsphere particle size containing baricitinib / β-CD inclusion compound

[0166] Microspheres containing the baricitinib / β-CD inclusion compound were placed in a 5 mL brown vial and dispersed in a 1.0% PVA aqueous solution, after which they were analyzed using a particle size analyzer (Mastersizer 2000, Malvern Panalytical). The D50 values ​​for each are shown in Table 6.

[0167]

[0168] Experimental Example 4: Confirmation of microball loading amount containing baricitinib / β-CD inclusion compound

[0169] A portion of the microspheres containing the baricitinib / β-CD inclusion compound 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 by 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. The results for each are shown in Table 6.

[0170] [Equation 1]

[0171]

[0172]

[0173] Experimental Example 5 Confirmation of microball encapsulation rate containing baricitinib / β-CD inclusion compound

[0174] A portion of the microspheres containing the baricitinib / β-CD inclusion compound 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 by 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 encapsulation rate was calculated using the following formula. The results for each are shown in Table 6.

[0175] [Equation 2]

[0176]

[0177] No. D 50(um) Loading Amount (%) Encapsulation Rate (%) Example 1 59 3.5 27 3.3 Example 2 31 2.7 18 4.7 Example 3 24 2.2 09 1.6 Example 4 61 3.5 77 4.4 Example 5 28 2.7 78 6.6 Example 6 26 2.2 99 5.4

[0178]

[0179] Experimental Example 6 Confirmation of microsphere elution containing baricitinib / β-CD inclusion compound

[0180] 5.0 mg of microspheres containing the baricitinib / β-CD inclusion compound 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 dissolution test was then conducted for 28 days in a 37 °C water bath with stirring at 100 rpm. At predetermined time points, 1.0 mL of the supernatant was taken, mixed with fresh PBS buffer pH 7.4, filtered using a 0.45 µm filter, and analyzed by HPLC. Representative dissolution profiles are shown in Figures 7 and 8.

[0181] According to Figure 7 above, it can be confirmed that Example 1 and Example 2 exhibit initial over-release, and in the case of Example 1, no continuous release occurred for 28 days. On the other hand, Example 3 exhibited a stable release effect for 28 days without initial over-release.

[0182] In addition, according to FIG. 8, it can be confirmed that Example 4 and Example 5 exhibited initial over-emission, and Example 4 did not exhibit continuous emission for 28 days. On the other hand, Example 6 exhibited a stable emission effect for 28 days without initial over-emission.

[0183] Figure 9 shows the release profile of the commercially available Olumiant tablet (Olumiant Tab. 4mg), which shows an 88% dissolution rate within 10 minutes. As described above, in the case of the existing commercially available Olumiant tablet, daily administration is essential, whereas in the case of the microspheres of the present invention, a single administration can produce a continuous release effect of baricitinib for 28 days, thereby greatly improving convenience of administration.

[0184] 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.

Claims

1. A baricitinib inclusion compound comprising a cyclodextrin derivative and baricitinib or a pharmaceutically acceptable salt thereof; and Biodegradable polymers Microspheres containing a baricitinib inclusion compound.

2. In Paragraph 1, The above cyclodextrin derivative is a microsphere comprising a baricitinib inclusion compound selected from the group consisting of HP-β-CD (2-Hydroxypropyl-β-Cyclodextrin), SBE-β-CD (Sulfobutylether-β-Cyclodextrin), and mixtures thereof.

3. In Paragraph 1 or 2, The baricitinib inclusion compound comprising the above-mentioned cyclodextrin derivative is, Microspheres comprising a baricitinib inclusion compound comprising baricitinib or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in a weight ratio of 1:1 to 1:

3.

4. In any one of paragraphs 1 through 3, A baricitinib inclusion compound comprising the above-mentioned cyclodextrin derivative is a microsphere comprising a baricitinib inclusion compound having a solubility in water increased by 100% to 200% compared to baricitinib or a pharmaceutically acceptable salt thereof.

5. In any one of paragraphs 1 through 4, The above microspheres are microspheres comprising a baricitinib inclusion compound comprising the baricitinib inclusion compound and the biodegradable polymer in a weight ratio of 1:5 to 1:

15.

6. In any one of paragraphs 1 through 5, The above-mentioned biodegradable polymer is a microsphere comprising a baricitinib inclusion compound 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.

7. In any one of paragraphs 1 through 6, When the above microspheres are administered into the body as an injection, baricitinib is released for more than one month. Microspheres containing a baricitinib inclusion compound.

8. A step of preparing a baricitinib inclusion compound by mixing baricitinib or a pharmaceutically acceptable salt thereof with a cyclodextrin derivative; A step of preparing a first aqueous solution by dissolving the above-mentioned baricitinib inclusion compound in distilled water; A step of preparing an oil phase solution by dissolving a biodegradable polymer in an organic solvent; A step of preparing a second aqueous solution by dissolving a surfactant in distilled water; A step of preparing a W1 / O emulsion by mixing the first aqueous solution and the oil solution; and A method for preparing microspheres containing a baricitinib inclusion compound, comprising the step of adding the above W1 / O emulsion to a second aqueous solution to prepare a W1 / O / W2 emulsion.

9. In Paragraph 8, The step of preparing the above-mentioned baricitinib inclusion compound is, A step of preparing a solution containing a cyclodextrin derivative by dissolving the cyclodextrin derivative in distilled water; A step of preparing a solution containing baricitinib or a pharmaceutically acceptable salt thereof by dissolving baricitinib or a pharmaceutically acceptable salt thereof in an organic solvent; and A method for preparing microspheres containing a baricitinib inclusion compound, comprising the step of mixing and stirring a solution containing the above-mentioned cyclodextrin derivative and a solution containing baricitinib or a pharmaceutically acceptable salt thereof to prepare a baricitinib inclusion compound.

10. In Paragraph 8 or 9, A method for preparing microspheres comprising a baricitinib inclusion compound selected from the group consisting of HP-ββSBE-ββ and mixtures thereof, wherein the above-mentioned cyclodextrin derivative is a cyclodextrin derivative.

11. In any one of paragraphs 8 through 10, The baricitinib inclusion compound comprising the above-mentioned cyclodextrin derivative is, A method for preparing microspheres comprising a baricitinib inclusion compound comprising baricitinib or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in a weight ratio of 1:1 to 1:

3.

12. In any one of paragraphs 8 through 11, A method for preparing microspheres comprising a baricitinib inclusion compound comprising a cyclodextrin derivative in the above W1 / O emulsion and a biodegradable polymer in a weight ratio of 1:5 to 1:

15.

13. In any one of paragraphs 8 through 12, The step of preparing the above W1 / O emulsion is, Mixing the first aqueous solution and the oil solution, and stirring using a homogenizer at 5,000 rpm to 15,000 rpm for 30 seconds to 90 seconds, Method for preparing microspheres containing a baricitinib inclusion compound.

14. In any one of paragraphs 8 through 13, A method for preparing microspheres comprising a baricitinib inclusion compound selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, acetone, dimethyl sulfoxide, and mixtures thereof.

15. In any one of paragraphs 8 through 14, A method for preparing microspheres comprising a baricitinib inclusion compound selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sodium lauryl sulfate, sodium stearate, esteramine, linear diamine, patiamine, and mixtures thereof.

Images