Solid preparation comprising dutasteride and method for manufacturing the same

Abstract

The present invention provides a solid preparation comprising, based on 100 parts by weight of the solid preparation, a self-emulsifying composition comprising 0.1 to 0.5 parts by weight of dutasteride, 6 to 110 parts by weight of oil and 6 to 110 parts by weight of a surfactant and 5 to 185 parts by weight of a coating excipient with pores that accommodate the self-emulsifying composition formed on a surface thereof and a method of manufacturing the solid preparation.

Description

1 / 25 “SOLID PREPARATION COMPRISING DUTASTERIDE AND METHOD FOR MANUFACTURING THE SAME” Technical field

[001] The present invention relates to a solid preparation comprising dutasteride and a method of manufacturing the same. Precedent Technique

[002] Dutasteride is known to be useful in the treatment of benign prostatic hyperplasia and male pattern baldness, and has the structure of Chemical Formula 1 below, as disclosed in US Patent Number 5565467. Chemical Formula 1

[003] US Patent Application Publication number 2009 / 0069364 describes the equilibrium solubility of dutasteride as 3.06 g / 100 g in isopropanol, 2.75 g / 100 g in Capmul MCM NF, 2.41 g / 100 g in Transcutol, 1.34 g / 100 g in propylene glycol, 0.39 g / 100 g in PEG 400, and 4.40 g / 100 g in ethanol, and International Publication number W02006-099121 reveals that dutasteride is insoluble in water. Simply put, dutasteride is widely known as a very poorly soluble drug.

[004] Currently, Dutasteride is commercially available as a soft capsule product under the trademark AVODART®, and AVODART is a product configured such that 0.5 mg of dutasteride is dissolved in 349.5 mg of a mixture of caprylic / capric acid mono- and diglyceride oil and butylated hydroxytoluene (BHT) and is loaded into a soft capsule, being Petition 870260053808, dated 03 / 06 / 2026, page 11 / 72 2 / 25 used as a therapeutic agent for the treatment of benign prostatic hyperplasia or alopecia areata.

[005] However, since the soft capsule product is in the form of a liquid drug contained in a soft gelatin capsule, it softens easily at high temperatures and, moreover, dissolution is delayed due to the curing of the gelatin and oil at low temperatures, requiring a separate production facility to manufacture and load a chemical composition into the soft capsule, undesirably incurring very high manufacturing costs. Furthermore, since capsules can rupture during manufacturing, storage, and dispensing due to the characteristics of soft capsule products, there is a need for preparations capable of overcoming the above problems.

[006] Consequently, many researchers are working on solid preparations, especially tablets, that show pharmacokinetic parameters and bioavailability equivalent to or superior to the AVODART soft capsule product, and considering that the solubility or dissolution rate of the drug is a very important factor in determining the absorption and bioavailability of the drug, several solubilization methods have been attempted to increase the solubility of solid particles comprising dutasteride. In particular, many studies have been carried out with the aim of manufacturing solid particles adsorbing a self-emulsifying composition, prepared by dissolving dutasteride in oil and adding a surfactant and similar agents to a predetermined excipient (adsorbent).However, when tablets are manufactured using solid particles produced by the above method, clinical trials have shown lower bioavailability issues compared to the AVODART soft capsule product, and different pharmacokinetic parameters.

[007] As a result of repeated research to overcome the problems Petition 870260053808, dated 03 / 06 / 2026, page 12 / 72 3 / 25 above, the present inventors developed solid particles that significantly improved solubility compared to the chemical composition in the AVODART soft capsule, and in which dutasteride can be homogeneously distributed, thus determining the development of solid preparations exhibiting a dissolution rate and bioavailability equivalent to or superior to the AVODART soft capsule product, culminating in the present invention. Patent Document 1 - US Patent number 5565467 Patent Document 2 - Publication of US Patent Application number 2009 / 0069364 Patent Document 3 - International Publication number WO2006099121 REVELATION Technical Problem

[008] One objective of the present invention is to provide solid particles that have a very high solubility, compared to the chemical composition in the AVODART soft capsule, and in which dutasteride can be homogeneously distributed.

[009] Another objective of the present invention is to provide a solid preparation, such as a tablet, that exhibits pharmacokinetic parameters and bioavailability equivalent to or superior to AVODART, using the solid particles of the present invention. Technical Solution

[010] In order to achieve the above objectives, the present invention provides a solid preparation comprising, based on 100 parts by weight of the solid preparation:

[011] a self-emulsifying composition comprising 0.1 parts in Petition 870260053808, dated 03 / 06 / 2026, page 13 / 72 4 / 25 weight to 0.5 weight parts of dutasteride, 6 weight parts to 110 weight parts of oil and 6 weight parts to 110 weight parts of a surfactant and 5 weight parts to 185 weight parts of a coated porous excipient accommodating the self-emulsifying composition formed on a surface thereof.

[012] In addition, the present invention provides a method for manufacturing a solid preparation, comprising: manufacturing a self-emulsifying composition by mixing dutasteride, oil and a surfactant;

[013] obtaining a coated porous excipient that accommodates the self-emulsifying composition formed on its surface, coating a porous excipient, having pores that accommodate the self-emulsifying composition formed on its surface, with a coating agent; and

[014] manufacture of solid particles in which the self-emulsifying composition is accommodated in the pores of the coated porous excipient that accommodate the self-emulsifying composition formed on its surface, mixing the self-emulsifying composition and the coating excipient having pores that accommodate the self-emulsifying composition formed on its surface. Advantageous Effects

[015] According to the present invention, the solid preparation comprises, based on 100 parts by weight of the solid preparation, a self-emulsifying composition comprising 0.1 parts by weight to 0.5 parts by weight of dutasteride, 6 parts by weight to 110 parts by weight of oil and 6 parts by weight to 110 parts by weight of a surfactant and 5 parts by weight to 185 parts by weight of a coated porous excipient that accommodates the self-emulsifying composition formed on a surface thereof. In the present document, a coating agent functions to form a coating film on the surface of a porous excipient, and the coating film controls the depth of the pores on the surface of the porous excipient, making the surface Petition 870260053808, dated 03 / 06 / 2026, page 14 / 72 5 / 25 fine homogeneous and blocking pores with narrow entrances or very small pores between the pores on the surface of the porous excipient, thus avoiding cases where the self-emulsifying composition introduced into pores with narrow entrances or very small pores is not released from the pores or where the release is delayed. A water-soluble polymer dissolves rapidly in body fluids, helping the self-emulsifying composition to produce emulsions quickly. Therefore, when the dutasteride solid preparation enters the aqueous solution environment of the body, after the solid preparation comprising dutasteride, the coating agent on the surface of the coated porous excipient that accommodates the self-emulsifying composition formed on the surface is dissolved and, thus, the self-emulsifying composition accommodated in the pores of the coating excipient can be easily released from the pores, ultimately achieving a high dissolution rate.Furthermore, the solid preparation is released uniformly and rapidly and, therefore, can exhibit a high dissolution rate and high bioavailability, making it applicable to a formulation such as a tablet or a hard capsule. BRIEF DESCRIPTION OF THE DRAWINGS

[016] Figure 1 shows images of the solid particles of Examples 2-1 to 2-3 according to the present invention and the solid particles of Comparative Example 1-3;

[017] Figure 2 is a graph showing the results of comparing the dissolution rate of the solid particles of Examples 2-1 to 2-3 according to the present invention and the solid particles of Comparative Examples 1-1 and 1-2;

[018] Figure 3 is a graph showing the results of comparing the dissolution rate of the solid particles of Examples 2-1 to 2-3 according to the present invention and the solid particles of Comparative Example 1-2; and

[019] Figure 4 is a graph showing the results of the comparison of Petition 870260053808, dated 03 / 06 / 2026, page 15 / 72 6 / 25 bioavailability of the tablet of Example 3 according to the present invention and the commercially available preparation of Comparative Example 2. BEST WAY

[020] The present invention relates to a solid preparation comprising, based on 100 parts by weight of the solid preparation,

[021] a self-emulsifying composition comprising 0.1 parts by weight to 0.5 parts by weight of dutasteride, 6 parts by weight to 110 parts by weight of oil and 6 parts by weight to 110 parts by weight of a surfactant and 5 parts by weight to 185 parts by weight of a coated porous excipient accommodating the self-emulsifying composition formed on its surface.

[022] In one embodiment of the present invention, the solid preparation may comprise a self-emulsifying composition comprising 0.1 to 0.5 mg of dutasteride, 6 mg to 110 mg of oil and 6 mg to 110 mg of a surfactant and 5 mg to 185 mg of a coated porous excipient that accommodates the self-emulsifying composition formed on its surface and, preferably, comprises a self-emulsifying composition comprising 0.5 mg of dutasteride, 30 mg to 110 mg of oil and 30 mg to 110 mg of a surfactant and 25 mg to 185 mg of a coated porous excipient that accommodates the self-emulsifying composition formed on its surface. More preferably, the solid preparation comprises a self-emulsifying composition comprising 0.5 mg of dutasteride, 30 mg to 75 mg of oil, 30 mg to 75 mg of a surfactant, and 93.5 mg to 123.5 mg of a coated porous excipient that accommodates the self-emulsifying composition formed on its surface.

[023] In the present invention, the coating excipient is configured such that the surface of a porous excipient is coated with a coating agent. The coated porous excipient that accommodates the self-emulsifying composition formed on its surface is obtained by coating the excipient Petition 870260053808, dated 03 / 06 / 2026, page 16 / 72 7 / 25 porous with pores that accommodate the self-emulsifying composition formed on its surface with the coating agent. For example, the coating excipient can be formed in a way where the porous excipient is mixed with a coating solution, obtained by mixing an organic solvent and a coating agent, and then dried.

[024] In the present invention, the self-emulsifying composition may further comprise at least one water-soluble polymer selected from polyethylene glycol, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyvinyl alcohol / polyethylene glycol graft copolymer. The water-soluble polymer is preferably at least one selected from hydroxypropylmethylcellulose, polyvinyl alcohol / polyethylene glycol graft copolymer, and polyvinylpyrrolidone, more preferably at least one from polyvinylpyrrolidone and hydroxypropylmethylcellulose, and most preferably polyvinylpyrrolidone.

[025] In the present invention, the self-emulsifying composition can be a dutasteride self-emulsifying emulsion composition with an average emulsion particle size of 15 to 180 nm and a size distribution of 15 to 250 nm when dispersed in an aqueous phase.

[026] The oil, which is a solubilizer for dissolving dutasteride, may be at least one selected from glyceryl caprylate / caprate, glycerol tricaprylate / caprate, glyceryl tricaprylate / tricaprate, propylene glycol monocaprylate / tricaprate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprurate, propylene glycol monolaurate and glyceryl monooleate, and is preferably at least one selected from glyceryl caprylate / caprate, glycerol tricaprylate / caprate and propylene glycol monocaprylate.

[027] The surfactant works to stably emulsify the oil component in water to form a stable emulsion, and the agent Petition 870260053808, dated 03 / 06 / 2026, page 17 / 72 8 / 25 surfactant may be at least one selected from castor oil polyoxyl and its derivatives, polyoxyethylene-polyoxypropylene block copolymer, Tweens, Tweens hydroxystearate, Macrogol 15 and sodium dodecyl sulfate and is preferably castor oil polyoxyl and its derivatives, and more preferably castor oil polyoxyl 35.

[028] In the present invention, the porous excipient can be at least one selected from magnesium aluminosilicate, calcium silicate, light anhydrous magnesium silicate, cellulose powder, microcrystalline cellulose, talc, silicon dioxide, lactose and calcium phosphate, and is preferably at least one of magnesium aluminosilicate and calcium silicate and more preferably magnesium aluminosilicate.

[029] In the present invention, the self-emulsifying composition may have an average emulsion particle size of 15 to 180 nm and a size distribution of 15 to 250 nm when dispersed in an aqueous phase and, preferably, the self-emulsifying composition may have an average emulsion particle size of 15 to 100 nm and a size distribution of 15 to 150 nm when dispersed in an aqueous phase.

[030] In the present invention, the solid preparation may further comprise at least one stabilizer selected from butylated hydroxyanisole, butylated hydroxytoluene and dibutyl hydroxytoluene in order to inhibit oxidation and hydrolysis.

[031] In the present invention, the solid preparation can be provided in the form of a formulation, such as a tablet, a hard capsule, a compression-coated tablet, a two-layer tablet or a three-layer tablet, and is preferably a tablet.

[032] In the present invention, the coating agent can be at least one selected from polyethylene glycol, carboxymethylcellulose, Petition 870260053808, dated 03 / 06 / 2026, page 18 / 72 9 / 25 hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol graft copolymer and is preferably at least one selected from hydroxypropylmethylcellulose, polyvinyl alcohol / polyethylene glycol graft copolymer and polyvinylpyrrolidone, more preferably at least one from polyvinylpyrrolidone and hydroxypropylmethylcellulose, and most preferably polyvinylpyrrolidone.

[033] The coating agent is responsible for forming a coating film on the surface of the porous excipient, and the coating film controls the depth of the pores on the surface of the porous excipient and blocks pores with a very small diameter, thus facilitating the movement of the self-emulsifying composition into and out of the pores.

[034] In one embodiment of the present invention, the solid preparation may comprise 0.1 to 0.5 mg of dutasteride, taking into account a known typical daily dose.

[035] In one embodiment of the present invention, the solid preparation is preferably administered orally.

[036] The present invention relates to a method of manufacturing a solid preparation, comprising manufacturing a self-emulsifying composition by mixing dutasteride, oil and a surfactant; Obtaining a coated porous excipient that accommodates the self-emulsifying composition formed on its surface, coating a porous excipient having pores that accommodate the self-emulsifying composition formed on its surface with a coating agent; and manufacturing solid particles in which the self-emulsifying composition is accommodated in the pores of the coated porous excipient that accommodate the self-emulsifying composition formed on its surface, mixing the self-emulsifying composition and the coating excipient having pores that accommodate the Petition 870260053808, dated 03 / 06 / 2026, page 19 / 72 10 / 25 self-emulsifying composition formed on its surface.

[037] In the present invention, the oil can be at least one selected from glyceryl caprylate / caprate, glycerol tricaprylate / caprate, glycerol tricaprylate / tricaprate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol monolaurate and glyceryl monooleate, and is preferably at least one selected from glyceryl caprylate / caprate, glycerol tricaprylate / caprate and propylene glycol monocaprylate.

[038] In the present invention, the surfactant can be at least one selected from polyoxyl castor oil and its derivatives, polyoxyethylene-polyoxypropylene block copolymer, Tweens, Macrogol 15 hydroxystearate and sodium dodecyl sulfate, and is preferably polyoxyl castor oil and its derivatives and more preferably polyoxyl castor oil 35.

[039] In the present invention, the coating agent can be at least one selected from polyethylene glycol, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol graft copolymer and is preferably at least one selected from hydroxypropylmethylcellulose, polyvinyl alcohol / polyethylene glycol graft copolymer and polyvinylpyrrolidone, more preferably at least one from polyvinylpyrrolidone and hydroxypropylmethylcellulose, and most preferably polyvinylpyrrolidone.

[040] The coating agent is responsible for forming a coating film on the surface of the porous excipient, and the coating film controls the depth of the pores on the surface of the porous excipient and blocks pores with a very small diameter, thus facilitating the movement of the self-emulsifying composition into and out of the pores.

[041] The amount of porous excipient can be from 4 to 130 parts in Petition 870260053808, dated 03 / 06 / 2026, page 20 / 72 11 / 25 by weight. When the quantity of the porous excipient falls within the above range, the quantity of the coating agent can be from 1 to 55 parts by weight.

[042] In a preferred embodiment, the amount of porous excipient is preferably from 4 to 130 mg. When the amount of porous excipient is from 4 to 130 mg, the amount of coating agent is preferably from 1 to 55 mg. In particular, if the amount of coating agent exceeds 55 mg, the pores with a diameter that facilitates the movement of the self-emulsifying composition into and out of the pores may also become excessively blocked.

[043] In the present invention, the water-soluble polymer may be at least one selected from polyethylene glycol, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol graft copolymer and is preferably at least one selected from hydroxypropylmethylcellulose, polyvinyl alcohol / polyethylene glycol graft copolymer and polyvinylpyrrolidone, more preferably at least one from polyvinylpyrrolidone and hydroxypropylmethylcellulose and, most preferably, polyvinylpyrrolidone. Due to the coating agent and the water-soluble polymer, rapid and homogeneous release of the drug into body fluids and a high rate of dissolution and bioavailability are achieved.

[044] In the present invention, the manufacture of the self-emulsifying composition by mixing dutasteride, oil and surfactant may comprise stirring and mixing of at least one oil selected from glyceryl caprylate / caprate, glycerol tricaprylate / caprate, glycerol tricaprylate / caprate, glycerol tricaprylate / tricaprate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol monolaurate and glyceryl monooleate, addition of the stirred oil with dutasteride, followed by mixing and complete dissolution; and addition of the stirred oil in which the dutasteride is completely dissolved. Petition 870260053808, dated 03 / 06 / 2026, page 21 / 72 12 / 25 with at least one surfactant selected from castor oil polyoxyl and its derivatives, polyoxyethylene-polyoxypropylene block copolymer, Tweens, Macrogol 15 hydroxystearate and sodium dodecyl sulfate, followed by further stirring and mixing.

[045] In the present invention, during the addition of the oil stirred with dutasteride, followed by mixing and complete dissolution, the stirred oil can also be added with a stabilizer selected from butylated hydroxyanisole, butylated hydroxytoluene and dibutyl hydroxytoluene, and can thus be completely dissolved. Method of Invention

[046] A better understanding of the present invention will be provided by the following examples. Examples

[047] The present invention is specified below, but the present invention is not limited to the following examples. Example 1. Manufacturing of a coated porous excipient that accommodates a self-emulsifying composition formed on its surface.

[048] A commercially available porous excipient was coated with a water-soluble polymer comprising components in the amounts shown in Table 1 below (hereinafter referred to as the coating agent), thereby making the coating excipient for each of Examples 1-1 and Example 1-2, having pores that accommodate a self-emulsifying composition formed on its surface.

[049] Specifically, a water-soluble polyvinylpyrrolidone polymer (PVP K-25) was added as a coating agent and mixed in a container containing anhydrous ethanol to provide a coating solution. Magnesium aluminometasilicate (Neusilin US2) was mixed in as an excipient. Petition 870260053808, dated 03 / 06 / 2026, page 22 / 72 13 / 25 porous excipient with pores formed on its surface, with the coating solution using a high-speed mixer, and the resulting mixture was dried at approximately 60°C, thus obtaining a coated porous excipient accommodating a self-emulsifying composition formed on its surface. In the coating excipient that has pores that accommodate the self-emulsifying composition formed on its surface, the pore entrances with a very small diameter between the pores on the surface of the porous excipient are blocked with the coating agent, or the internal parts of the pores are filled with it, and the pores with a diameter that facilitates the movement of the self-emulsifying composition particles into and out of the pores are maintained in the state in which their internal surface is coated.In the present document, pores that have a very small diameter have an inlet diameter or internal diameter similar to or smaller than the self-emulsifying composition comprising dutasteride and indicate pores with an inlet diameter or internal diameter that does not facilitate the movement of the self-emulsifying composition into and out of the pores. This prevents delayed release or non-release of the self-emulsifying composition comprising dutasteride, which is retained in the pores of the porous excipient in the body of a patient who ingests the solid preparation according to the present invention. Table 1 (unit: mg) Component Example 1-1 Example 1-2 Coating agent (polyvinylpyrrolidone K-25) 10 40 Porous excipient (magnesium aluminometasilicate) 83.5 83.5

[050] In this document, calcium silicate, light anhydrous magnesium silicate, powdered cellulose, microcrystalline cellulose, talc, silicon dioxide, lactose and Petition 870260053808, dated 03 / 06 / 2026, page 23 / 72 14 / 25 calcium phosphate can be used as a porous excipient instead of magnesium aluminometasilicate, and as a coating agent, at least one selected from hydroxypropylmethylcellulose, polyvinyl alcohol / polyethylene glycol graft copolymer, and polyvinylpyrrolidone can be used. The amount of porous excipient is preferably 20 to 130 mg, and the amount of coating agent is preferably 5 to 55 mg. In particular, if the amount of coating agent exceeds 55 mg, the pores, with a diameter that facilitates the movement of the self-emulsifying composition into and out of the pores, may also become excessively blocked. Example 2. Manufacture of solid particles comprising dutasteride

[051] Solid particles containing dutasteride were manufactured using components in the quantities shown in Table 2 below.

[052] Specifically, glyceryl caprylate / caprate (Capmul MCM NF) and glyceryl tricaprylate / caprate (Captex 355) as oil were placed in a container, stirred and thoroughly mixed; after a predetermined time, the stirred oil was added with dutasteride and butylated hydroxytoluene as stabilizer, mixed and completely dissolved; and the stirred oil in which the dutasteride was completely dissolved was added with polyoxyl castor oil 35 (Kolliphor EL) as surfactant and re-stirred to provide an oily solution. Polyvinylpyrrolidone (PVP K-25), as a water-soluble polymer, was placed in a container containing anhydrous ethanol and mixed to provide a homogeneous solution, which was then mixed with the oily solution, thus preparing a self-emulsifying composition.The self-emulsifying composition thus prepared has an average emulsion particle size of 15 to 180 nm and a size distribution of 15 to 250 nm when dispersed in an aqueous phase.

[053] In the present invention, the amount of oil and the amount of surfactant are controlled, making it possible to obtain solid particles exhibiting Petition 870260053808, dated 03 / 06 / 2026, page 24 / 72 15 / 25 a dissolution rate equivalent to or greater than the AVODART chemical composition. Furthermore, in the present example, the water-soluble polymer interacts with the coating agent to facilitate the movement of the self-emulsifying composition into and out of the pores in the coating excipient and also to allow the rapid formation of a homogeneous emulsion in the body, resulting in rapid and homogeneous drug release and high dissolution rate and bioavailability.

[054] The self-emulsifying composition was mixed with the coating excipient having pores that accommodate the self-emulsifying composition formed on its surface manufactured in Example 1-1, using a high-speed mixer, and dried at about 60°C, thus manufacturing the solid particles of Example 2-1 to Example 2-3, in which the self-emulsifying composition was accommodated in the pores on the surface of the coating excipient having pores that accommodate the self-emulsifying composition formed on its surface. Table 2 (unit: mg) Component Example 2-1 Example 2-2 Example 2-3 Dutasteride 0.5 0.5 0.5 Oil (glyceryl caprylate / caprate) 15 25 37.5 Oil (glycerol tricaprate / caprate) 15 25 37.5 Surfactant (polyoxyl 35 castor oil) 30 50 75 Stabilizer (butylated hydroxytoluene) 0.2 0.2 0.2 Coating agent (polyvinylpyrrolidone K-25) 10 10 10 Petition 870260053808, dated 03 / 06 / 2026, page 25 / 72 16 / 25 Component Example 2-1 Example 2-2 Example 2-3 Water-soluble polymer (polyvinylpyrrolidone K-25) 10 10 10 Porous excipient (magnesium aluminometasilicate) 83.5 83.5 83.5

[055] Meanwhile, the present inventors found that when the amounts of surfactant and / or oil are excessive, the solid particles may clump together, making it difficult to ensure the homogeneity of the preparation and manufacture of a solid preparation, such as a tablet or hard capsule. The preferred amount of each surfactant and oil was 30 mg to 110 mg based on 0.5 mg of dutasteride, in order to avoid such clumping and exhibit a dissolution rate of a certain level or higher.

[056] Not only polyoxyl castor oil can be used as a surfactant, but also its derivatives, polyoxyethylene-polyoxypropylene block copolymer, Tweens, Tweens hydroxystearate, Macrogol 15 and sodium dodecyl sulfate.

[057] In addition to the oil used in Table 2, glyceryl caprylate / caprate, glycerol tricaprylate / caprate, glyceryl tricaprylate / tricaprate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol monolaurate and glyceryl monooleate may be used. Example 3. Manufacture of tablets (solid preparation) comprising solid particles of dutasteride.

[058] A tablet was manufactured using the solid particles of Example 2-2 and the external excipient and lubricant shown in Table 3 below, and coated with an external coating agent.

[059] Specifically, the solid particles and the external excipient Petition 870260053808, dated 03 / 06 / 2026, page 26 / 72 A 17 / 25 blend comprising crospovidone, lactose hydrate, anhydrous calcium phosphate, and microcrystalline cellulose was placed in a V-mixer and combined. After mixing was complete, sodium stearyl fumarate as a lubricant was additionally added to the mixture in the V-mixer, followed by final mixing to complete the lubrication process. The resulting mixture was manufactured into a tablet using a rotary tablet machine. Here, the tablet hardness was 7 to 9 kp and the wear test result was less than 1%.

[060] An external coating solution was prepared by stirring the external coating agent shown in Table 3 below in a mixed solution of anhydrous ethanol and purified water in an amount corresponding to 10 times the amount of the external coating agent. Here, the ratio of anhydrous ethanol to purified water was 8:2. The tablet was coated with the external coating solution prepared above to provide a coated tablet. Table 3 (unit: mg) Classification Component Example 3 Solid particles Dutasteride 0.5 Oil (glyceryl caprylate / caprate) 25 Oil (glycerol tricaprate / caprate) 25 Surfactant (polyoxyl castor oil 35) 50 Coating agent (polyvinylpyrrolidone K-25) 10 Water-soluble polymer (polyvinylpyrrolidone K25) 10 Stabilizer (butylated hydroxytoluene) 0.2 Porous excipient (magnesium aluminometasilicate) 83.5 Total solid preparation 204.2 Petition 870260053808, dated 03 / 06 / 2026, page 27 / 72 18 / 25 Classification Component Example 3 External excipient Microcrystalline cellulose 45 Lactose hydrate 40.1 Anhydrous calcium hydrogen phosphate 170 Crospovidone 37.2 Lubricant Sodium stearyl fumarate 3.5 Total tablets 500 External coating agent Opadry Yellow 20 Total coated tablets 520 Comparative Example 1. Solid particles comprising dutasteride containing low or excessive amounts of oil and surfactant compared to the present invention.

[061] The dutasteride-containing solid particles of Comparative Examples 1-1 to 1-3 were manufactured using components in the quantities shown in Table 4 below. The quantities of the components, except for the oil and surfactant, and the method of preparation were the same as in Example 2. Table 4 (unit: mg) Component Example Comparative 1-1 Example Comparative 1-2 Example Comparative 1-3 Dutasteride 0.5 0.5 0.5 Oil (glyceryl caprylate / caprate) 5 10 60 Oil (glycerol tricaprate / caprate) 5 10 60 Petition 870260053808, dated 03 / 06 / 2026, page 28 / 72 19 / 25 Component Comparative Example 1-1 Comparative Example 1-2 Comparative Example 1-3 Surfactant (polyoxyl 35 castor oil) 10 20 120 Stabilizer (butylated hydroxytoluene) 0.2 0.2 0.2 Coating agent (polyvinylpyrrolidone K-25) 10 10 10 Water-soluble polymer (polyvinylpyrrolidone K-25) 10 10 10 Porous excipient (magnesium aluminometasilicate) 83.5 83.5 83.5 Component Comparative Example 1-1 Comparative Example 1-2 Comparative Example 1-3 Dutasteride 0.5 0.5 0.5 Oil (glyceryl caprylate / caprate) 5 10 60 Oil (glycerol tricaprate / caprate) 5 10 60 Surfactant (polyoxyl 35 castor oil) 10 20 120 Stabilizer (butylated hydroxytoluene) 0.2 0.2 0.2 Coating agent 10 10 10 Petition 870260053808, dated 03 / 06 / 2026, page 29 / 72 20 / 25 Component Comparative Example 1-1 Comparative Example 1-2 Comparative Example 1-3 (polyvinylpyrrolidone K-25) Water-soluble polymer (polyvinylpyrrolidone K-25) 10 10 10 Porous excipient (magnesium aluminometasilicate) 83.5 83.5 83.5 Comparative Example 2. AVODART

[062] A soft capsule currently available on the market, AVODART® 0.5 mg, corresponding to 0.5 mg of dutasteride, was used as Comparative Example 2. Experimental Example 1. Comparative evaluation of the external appearance of solid particles from Examples 2-1 to 2-3 and solid particles from Comparative Example 1-3.

[063] In order to evaluate the external surface of the solid particles of Examples 2-1 to 2-3 and Comparative Example 1-3, the external appearance was observed using a scanning electron microscope at magnifications of 1,000x and 3,000x. The results are shown in Figure 1. As shown in Figure 1, as the amounts of oil and surfactant increased, the pores on the surface of the coating excipient were filled and approximated spheres were formed. In Comparative Example 1-3, when 120 mg of oil and 120 mg of surfactant were added based on 0.5 mg of dutasteride, agglomeration of the coating excipients occurred and the particle shape was not uniform; furthermore, it was not easy to manufacture the solid preparation because a portion of the self-emulsifying composition was not accommodated in the pores of the coating excipient. Petition 870260053808, dated 03 / 06 / 2026, page 30 / 72 21 / 25 Experimental Example 2. Average particle size of emulsion and distribution of solid particles in example 2.

[064] The size distribution and average size of the emulsion particles formed by dispersing the solid particles of Examples 2-1 to 2-3 in 50 mL of purified water were measured using an ELS-Z particle size analyzer. The results are shown in Table 5 below. As shown in Table 5, the solid particles of Examples 2-1 to 2-3 of the present invention did not differ much in size and distribution from the emulsion particles and were homogeneous, even with changes in the amounts of oil and surfactant. Table 5 Number Average size and size distribution (nm) Example 2-1 79.3 (70.1-87.5) 2-2 32.8 (24.9-40.7) 2-3 27.8 (21.9-41.8) Experimental Example 3. Evaluation 1 of the dissolution rate of solid particles from examples 2-1 to 2-3 and comparative examples 1-1 and 1-2.

[065] The solid particles of Examples 2-1 to 2-3 and Comparative Examples 1-1 and 1-2 were subjected to a dissolution test under the following conditions.

[066] In evaluating the dissolution of the present invention, the dissolution test was performed without the addition of a surfactant in a pH 1.2 medium similar to gastric juice conditions. According to the paddle dissolution method, among the dissolution test methods described in the Korean Pharmacopoeia, the rotation speed was set to 50 rpm and the dissolution medium was sampled after 5 min., 10 min., 15 min., 30 min., 45 min., 60 min., 90 min. and 120 min. and then filtered using a 0.45 µm membrane filter, and the Petition 870260053808, dated 03 / 06 / 2026, page 31 / 72 The resulting 22 / 25 filtrate was used as a test solution. High-performance liquid chromatography was used for analysis, and the measurement wavelength was 210 nm.

[067] The results of these are shown in Figure 2. As illustrated in Figure 2, the solid particles of Examples 2-1 to 2-3 according to the present invention were dissolved even under average conditions without the surfactant, however, when the amount of each oil and surfactant was less than 30 mg based on 0.5 mg of dutasteride, the resulting dissolution rate was lower than the dissolution rate of the solid particles of Examples 2-1 to 2-3. Experimental Example 4. Evaluation 2 of the dissolution rate of solid particles from Examples 2-1 to 2-3 and Comparative Example 1-2

[068] The solid particles of Examples 2-1 to 2-3 and Comparative Example 1-2 were subjected to a dissolution test under the following conditions.

[069] In order to evaluate the difference in the dissolution rate of the solid particles of Examples 2-1 to 2-3 and the solid particles of Comparative Example 12, the dissolution test was performed using 900 mL of a dissolution medium in which 2% sodium dodecyl sulfate was dissolved in 0.1 N HCl. According to the paddle dissolution method, among the dissolution test methods described in the Korean Pharmacopoeia, the rotation speed was set to 50 rpm and the dissolution medium was sampled after 5 min., 10 min., 15 min., and 30 min. and then filtered using a 0.45 membrane filter, and the resulting filtrate was used as a test solution. High-performance liquid chromatography was used for analysis and the measurement wavelength was 210 nm.

[070] The results of these are shown in Figure 3 and Table 6 below. As shown in Figure 3 and Table 6, the solid particles of Example 2 of the present invention exhibited a final dissolution rate of 88.6 to 94.9%, while the solid particles of Comparative Example 1-2, in which the Petition 870260053808, dated 03 / 06 / 2026, page 32 / 72 23 / 25 quantities of oil and surfactant were smaller than those of the solid particles in Examples 2-1 to 2-3, exhibiting a relatively low final dissolution rate of 81.2%. Table 6 Dissolution Result Example 2-1 Example 2-2 Example 2-3 Comparative Example 1-2 Final Dissolution Rate (%) 88.6 92.0 94.9 81.2 Dissolution Variation (%) 1.0 0.9 1.2 1.4 Experimental Example 5. Comparative evaluation of dutasteride bioavailability.

[071] After oral administration of the tablet (solid preparation) of Example 3 and the commercially available AVODART® soft capsule of Comparative Example 2, a bioavailability comparison test was performed in beagle dogs. A total of 10 beagles were used, comprising 5 beagles per group, and the beagles fasted for 16 hours the day before and received oral administration of the tablet of Example 3 or the commercially available AVODART preparation of Comparative Example 2, such that dutasteride was administered at a dose of 0.5 mg / individual and then they were fed 10 mL of water. Blood was collected and analyzed 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after oral administration to determine the pharmacokinetic parameters of dutasteride. The maximum blood concentration (Cmax) and the time to maximum blood concentration (Tmax) were determined. Petition 870260053808, dated 03 / 06 / 2026, page 33 / 72 24 / 25 were determined directly from the blood concentration graph, and the area under the curve (AUC) of blood concentration up to 72 hours after administration was calculated based on the trapezoidal formula. The results are shown in Table 6 below and in Figure 4. As shown in Table 7 and Figure 4, the tablet from Example 3 exhibited pharmacokinetic parameters equivalent to or superior to the commercially available preparation from Comparative Example 2, and the variation between individuals was small. Table 7 Number AUC Cmax Tmax Example 3 5591.27 ±907.31 143.08 + 24.97 1.8 + 0.81 Comparative example 2 (Commercially available preparation) 4415.07 ± 2357.94 120.12 + 45.85 1.4 + 0.86 AUC: Area under the blood concentration curve up to 72 hours after administration Cmax: maximum blood concentration Tmax: time to maximum blood concentration Industrial Applicability

[072] According to the present invention, the solid preparation comprises, based on 100 parts by weight of the solid preparation, a self-emulsifying composition comprising 0.1 part by weight to 0.5 part by weight of dutasteride, 6 parts by weight to 110 parts by weight of oil and 6 parts by weight to 110 parts by weight of a surfactant and 5 parts by weight to 185 parts by weight of a coated porous excipient that accommodates the self-emulsifying composition formed on a surface thereof. In the present document, a coating agent functions to form a coating film on the surface of a porous excipient, and the coating film controls the Petition 870260053808, dated 03 / 06 / 2026, page 34 / 72 25 / 25 pore depth on the surface of the porous excipient, making the fine surface homogeneous and blocking pores with narrow entrances or very small pores between the pores on the surface of the porous excipient, thus avoiding cases where the self-emulsifying composition introduced into pores with narrow entrances or very small pores is not released from the pores or where the release is delayed. A water-soluble polymer dissolves rapidly in body fluids, helping the self-emulsifying composition to produce emulsions quickly.Therefore, when the dutasteride solid preparation enters the aqueous solution environment of the body after obtaining the dutasteride solid preparation, the coating agent on the surface of the coated porous excipient that accommodates the self-emulsifying composition formed on its surface is dissolved, and thus the self-emulsifying composition accommodated in the pores of the coating excipient can be easily released from the pores, ultimately achieving a high dissolution rate. Furthermore, the solid preparation is released uniformly and rapidly and therefore can exhibit a high dissolution rate and high bioavailability, making it applicable to a formulation such as a tablet or a hard capsule. Petition 870260053808, dated 03 / 06 / 2026, page 35 / 72

Claims

1 / 3 CLAIMS 1. Solid preparation CHARACTERIZED in that it comprises: a self-emulsifying composition comprising 0.5 parts by weight of dutasteride; 30 to 110 parts by weight of oil; and 30 to 110 parts by weight of a surfactant, and 25 to 185 parts by weight of a coated porous excipient, which has pores that accommodate the self-emulsifying composition formed on a surface thereof and which is coated with a coating agent, wherein the coated porous excipient is formed in such a way that the porous excipient is mixed with a coating solution, obtained by mixing an organic solvent and a coating agent, and then dried, in the absence of the self-emulsifying composition, wherein the coating agent is comprised in an amount of 10 to 40 parts by weight based on 83.5 parts by weight of the porous excipient.

2. Solid preparation, according to claim 1, CHARACTERIZED in that the self-emulsifying composition further comprises at least one water-soluble polymer selected from polyethylene glycol, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol graft copolymer.

3. Solid preparation, according to claim 2, CHARACTERIZED in that the self-emulsifying composition is a dutasteride self-emulsifying emulsion composition having an average emulsion particle size of 15 to 180 nm and a size distribution of 15 to 250 nm when dispersed in an aqueous phase.

4. Solid preparation, according to claim 1, CHARACTERIZED in that the oil is at least one selected from glyceryl caprylate / caprate, glyceryl tricaprylate / caprate, glyceryl tricaprylate / tricaprate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol monolaurate and glyceryl monooleate.

5. Solid preparation according to claim 1, CHARACTERIZED in that the surfactant is at least one selected from polyoxyl castor oil, polyoxyethylene-polyoxypropylene block copolymer, Tweens, Macrogol 15 hydroxystearate and sodium dodecyl sulfate.

6. Solid preparation, according to claim 1, CHARACTERIZED in that the porous excipient is at least one selected from magnesium aluminosilicate, calcium silicate, light anhydrous magnesium silicate, powdered cellulose, microcrystalline cellulose, talc, silicon dioxide, lactose and calcium phosphate.

7. Solid preparation, according to claim 1, CHARACTERIZED in that it further comprises at least one stabilizer selected from butylated hydroxyanisole, butylated hydroxytoluene and dibutyl hydroxytoluene.

8. Solid preparation according to claim 1, CHARACTERIZED in that the solid preparation is a tablet.

9. Solid preparation, according to claim 1, CHARACTERIZED in that the coating agent is at least one selected from polyethylene glycol, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol graft copolymer.

10. Method for manufacturing a solid preparation, as defined in any one of claims 1 to 9, CHARACTERIZED in that it comprises: preparing a self-emulsifying composition by mixing dutasteride, oil and a surfactant; obtaining a coating excipient having pores that accommodate the self-emulsifying composition formed on a surface thereof by mixing a Petition 870260053808, dated 03 / 06 / 2026, page.37 / 72 3 / 3 porous excipient, having pores that accommodate the self-emulsifying composition formed on its surface, with a coating solution, obtained by mixing an organic solvent and a coating agent, and then drying; and preparing solid particles in which the self-emulsifying composition is accommodated in the pores of the coating excipient having pores that accommodate the self-emulsifying composition formed on its surface by mixing the self-emulsifying composition and the coating excipient having pores that accommodate the self-emulsifying composition formed on its surface.

11. Method according to claim 10, CHARACTERIZED in that the porous excipient is at least one selected from magnesium aluminosilicate, calcium silicate, light anhydrous magnesium silicate, powdered cellulose, microcrystalline cellulose, talc, silicon dioxide, lactose and calcium phosphate.

12. Method according to claim 10, CHARACTERIZED in that the coating agent is at least one selected from polyethylene glycol, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / polyethylene glycol graft copolymer. Petition 870260053808, dated 03 / 06 / 2026, p. 38 / 72

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