Granules containing progerin and sachets using the same

Abstract

The present invention relates to granules containing progerinin, capsules or sachets using the same, and methods for manufacturing the same. More specifically, in order to develop an advantageous dosage form for administering progerinin, a poorly soluble drug having a therapeutic effect on premature aging, to patients, progerinin granules containing specific water-soluble polymers, solubility enhancers and excipients in optimal composition ratios have been developed, and oral solid preparations such as capsules or sachets have been developed using the granules, thereby improving not only the dispersion stability and bioavailability of progerinin, but also storage, transportation, and patient compliance with dosing.

Description

Technical Field

[0001] The present invention relates to a granule containing Progerinin, which is a poorly soluble drug, a capsule or sachet using the same, and a method for producing the same.

Background Art

[0002] Many useful drugs are hydrophobic and have low solubility in aqueous media, and it is difficult to formulate them into suspensions in aqueous vehicles. In particular, due to such characteristics, wetting agents are often required to promote the suspension of hydrophobic drug particles in aqueous media. A surface-active wetting agent (i.e., a surfactant), for example, sodium lauryl sulfate, reduces the interfacial tension between drug particles and the suspension vehicle, allowing the suspension vehicle to penetrate into drug aggregates and / or drug particle pores, and is known to increase the suspension property of hydrophobic drugs in an aqueous medium at least partially. However, in addition to the beneficial effects of drug-suspension, the use of surfactants in suspensions also leads to undesirable results for soluble / dissolved free drugs.

[0003] Soluble / dissolved drugs are vulnerable to chemical decomposition and / or interaction with other components, so suspensions containing free drugs are chemically unstable. Another undesirable result of using a relatively high amount of surfactant to promote the suspension of poorly soluble drugs is that the air involved during the homogenization or shaking of such suspensions tends to remain trapped because the surfactant stabilizes the bubbles. Since such trapped air varies depending on the stirring force, stirring period, and stirring elapsed time, it makes it difficult or impossible to administer the suspension in a uniform dose over time due to changes in the volume of the suspension.

[0004] If a poorly water-soluble drug is administered as a suspension, it is desirable that the suspension exhibits a slow settling to provide uniformity in appropriate dosage. Conversely, if rapid settling occurs, the suspension must be shaken before each dose to ensure uniformity in dosage, as is the case with the vehicle. Assuming other factors (e.g., drug particle size, uniformity, and density) are equal, the settling rate of drug particles decreases as the viscosity of a particular suspension vehicle increases. Therefore, it is desirable that the suspension be appropriately viscous to inhibit or slow the settling of drug particles. However, while such increased viscosity promotes physical stability, it also makes pouring or administering the suspension more difficult.

[0005] On the other hand, progerin having the structure of chemical formula 1 below exhibits excellent progerin expression inhibitory effects and progerin-lamin A binding inhibitory effects, and is a drug that has the effect of extending the survival period of animal models in which progeria is induced, and is used as a pharmaceutical composition for the prevention or treatment of progeria.

[0006] [ka]

[0007] The compound name of the aforementioned progerinin is (7S)-(+)-8,8-dimethyl-7-(3-phenylallyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one (which is named "SLC-D011").

[0008] Progerinin is a drug that has been shown to be effective against progeria, and is a BCS (Biopharmaceutical Classification System) class II molecule that exhibits high apparent permeability and low solubility in aqueous media according to the BCS criteria.

[0009] The therapeutic applications of progerin drugs are severely limited by their low water solubility. To overcome these limitations, numerous methods have been studied, such as the use of polymer nanoparticles, solid lipid nanoparticles, self-emulsifying drug delivery systems, nanoemulsions, liposomes, nanosuspensions, and nanofibers. Among these, nanosuspensions refer to colloidal dispersions of drug particles stabilized under certain conditions by polymers, surfactants, or both. Nanosuspensions are used for the delivery of drug substances exhibiting low water and lipid solubility. The small particles in nanosuspensions provide a very large drug surface area, increasing the solubility ratio of insoluble drugs. As a result, BCS class II and IV compounds exhibit improved bioavailability, rapid activity, and other desirable biopharmaceutical effects.

[0010] Against this backdrop, the inventors were able to conduct animal experiments using a mixture of monoolein and tricaprin, which are oil-based solutions. However, due to the characteristics of the disease, it became clear that the use of oil-soluble dosage forms was not feasible when high doses and long-term administration were required. Therefore, they recognized the need to develop a new dosage form that would allow for long-term administration. In particular, progerinin, as mentioned above, is extremely insoluble in water, with a solubility close to zero. Even with existing ingestible solvents, its solubility is very low, necessitating the development of a dosage form that allows for long-term administration and absorption by the human body through the introduction of new technologies.

[0011] Furthermore, in Korean Patent Application No. 10-2020-0113071 (filed on September 4, 2020), the inventors optimized the particle size of a progerinin drug with excellent bioavailability and selected water-soluble polymers, excipients, etc., for the production of nanosuspensions to provide an oral nanosuspension formulation containing progerin with excellent dispersibility or uniformity and improved bioavailability and improved stability. However, there were inconveniences in terms of storage, transportation, and patient administration.

[0012] Therefore, there is a need to develop improved dosage forms of oral nano-suspension formulations that offer advantages in terms of storage, transportation, and patient administration. [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] The object of the present invention is to provide a granular preparation containing progerin with excellent bioavailability and a method for producing the same.

[0014] Another object of the present invention is to provide capsules or sachets utilizing granules containing progerin, and methods for producing the same, in order to provide improved dosage forms that offer superior bioavailability and advantages in terms of storage, transport, and patient administration. [Means for solving the problem]

[0015] To achieve the above objective, the present invention provides a granular preparation containing progerin, comprising (a) 20-40% by weight of progerin represented by the following chemical formula 1; (b) 5-15% by weight of hydroxypropyl methylcellulose (HPMC); (c) 1-10% by weight of D-α-tocopherol polyethyleneglycol succinate (TPGS); and (d) the remainder of an additive, wherein the progerin is a drug particle formed by wet ball milling with an average particle size (D50) of 100-300 nm.

[0016] Furthermore, the present invention provides a capsule or sachet containing granules.

[0017] Furthermore, the present invention provides a method for producing a granular preparation containing progerin, comprising the steps of (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) in purified water, then adding progerin represented by chemical formula 1 and mixing to produce a suspension; (2) preparing a nanosuspension by wet ball milling the suspension; and (3) mixing one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants into the nanosuspension, and then granulating it in a fluidized bed granulator, wherein the progerin in the nanosuspension in step (2) is in the form of particles with an average particle size (D50) of 100 to 300 nm. [Effects of the Invention]

[0018] This invention aims to develop a favorable dosage form for the patient administration of progerinin, a poorly soluble drug with therapeutic effects on progeria. It involves developing a progerinin granule formulation containing specific water-soluble polymers, solubility enhancers, and excipients in optimal compositional ratios. By using this granule formulation to develop oral solid dosage forms such as capsules or sachets, the invention not only improves the dispersion stability and bioavailability of progerin but also enhances storage, transportation, and patient adaptation to administration. [Brief explanation of the drawing]

[0019] [Figure 1] This is the result of the pharmacokinetic analysis of progerin suspension. [Figure 2] This shows the solubility measurement results of a solid dispersion manufactured using the hot-melt extrusion (HMT) method. [Figure 3] This shows the solubility measurements of solid dispersions produced using a hot melt extrusion process with polymers in various ratios (1:1). [Figure 4]Results of pharmacokinetic analysis of the solid dispersion produced using the hot melt extrusion process. [Figure 5] Results of solubility measurement of the amorphous solid dispersion using the spray drying process (A: pH 1.2, B: pH 6.8). [Figure 6] Results of pharmacokinetic analysis of the solid dispersion produced using the spray drying process. [Figure 7] Results of measuring the shape (upper) and the average particle size of the progeline drug (lower) of the nano-suspension produced using wet ball milling with beads. [Figure 8] It is a drawing showing the manufacturing process of the granule, capsule and sachet dosage forms of progeline according to the present invention.

Mode for Carrying Out the Invention

[0020] Hereinafter, the present invention will be described in more detail.

[0021] The present inventor has produced a nano-suspension of progeline in order to improve the bioavailability of progeline, which is a poorly soluble drug. However, in actuality, when developing it as a pharmaceutical product, problems of storage and transportation and aspects of patient compliance must also be considered. Therefore, in the present invention, the present invention has been completed by developing an oral solid dosage form such as a capsule or sachet using the nano-suspension.

[0022] The present invention provides a granule containing progeline, which comprises (a) 20 to 40% by weight of progeline represented by the following chemical formula 1; (b) 5 to 15% by weight of hydroxypropylmethylcellulose (HPMC); (c) 1 to 10% by weight of D-α-tocopherol polyethylene glycol succinate (TPGS); and (d) the balance of additives, wherein the progeline is drug particles formed by wet ball milling to have an average particle size (D50) of 100 to 300 nm.

[0023]

Chemical formula

[0024] The aforementioned progerinin is a declusin derivative, specifically (7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one. In this invention, progerinin may also be named "SLC-D011".

[0025] Progerinin is a drug that exhibits excellent progerin expression inhibitory effects and progerin and lamin A binding inhibitory effects, and has the effect of extending the survival period in animal models in which progeria is induced, and is used as a pharmaceutical composition for the prevention or treatment of progeria, an age-related disease. Progerinin is poorly soluble in water, with a solubility close to zero, but the present invention provides an oral solid dosage form that improves solubility, enables long-term administration and absorption by the human body, and takes into account the issues of storage and transportation as well as aspects of patient adaptation to administration.

[0026] The hydroxypropyl methylcellulose (HPMC) is a polymeric suspending agent that helps disperse progerin and other components in the solution. If the amount of polymeric suspending agent is below the specified content range, the settling rate of the suspension will be poor. If the amount of polymeric suspending agent exceeds the specified range, stirring will be difficult, making manufacturing difficult. In particular, if the amount of polymeric suspending agent exceeds the specified range, stirring will not be uniform, resulting in poor dispersibility of the suspension. This leads to a problem where the amount of defective products with insufficient content increases during product production.

[0027] The D-α-tocopherol polyethylene glycol succinic acid (TPGS) is a solubility enhancer, an ingredient that improves the solubility of poorly soluble drugs. If the amount of solubility enhancer is below the range, the solubility will be low, and if the amount of solubility enhancer exceeds the range, the toxicity limit may be exceeded. It is desirable to use it within the range.

[0028] The progerinin, a poorly soluble drug in the suspension, preferably has an average particle size (D50) of 100 to 300 nm. More preferably, the average particle size is 100 to 200 nm. When the average particle size is within this range, the solubility is best, and since nanoparticles have an even larger surface area, they dissolve even more easily, thus maximizing bioavailability or bioabsorption efficiency. Furthermore, the nano-suspension having the above average particle size can be manufactured by wet ball milling using a wet grinding device such as an agitator bead mill or a dyno-mill.

[0029] Furthermore, the pH of the nano-suspension of the present invention is 5.5 to 8.5, preferably 6.0 to 7.0, and the viscosity of the nano-suspension is 2 to 8.5 mPa·s, preferably 7 to 8.5 mPa·s.

[0030] Furthermore, the nano-suspension of the present invention may additionally contain preservatives, pH adjusters, or colorants.

[0031] The aforementioned preservative means a pharmaceutically acceptable substance that prevents the growth of microorganisms or degradation due to undesirable chemical changes. Potassium sorbate may be used as the preservative, but is not limited to this.

[0032] The aforementioned pH adjusting agent refers to a substance used to adjust the pH of a suspension to a desired value, and is, but is not limited to, citric acid, sodium citrate, or ascorbic acid.

[0033] The colorants are included to give the nano-suspensions different colors and can be included in the dosage form to produce nano-suspensions with a desired color. They are included in the present invention, but are not limited to those commonly used in the art of the present invention.

[0034] The aforementioned additive is one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants.

[0035] The aforementioned excipient refers to a substance added to a drug to give it an appropriate hardness and shape, or to give it a certain volume and weight when the amount of the main component is small, in order to make it a size that is easy to handle. The aforementioned excipient is one or more selected from the group consisting of mannitol, starch, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, lactose, glucose, fructose, sodium alginate, and hydroxypropyl starch, but is not limited to these.

[0036] The aforementioned binder refers to a substance added for the purpose of binding the particles of the components together to form a certain size. The aforementioned binder is one or more selected from the group consisting of gelatin, gum arabic, glucose, ethanol, purified water, dextrin, glycerin, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and calcium carboxymethylcellulose, but is not limited to these.

[0037] The disintegrant refers to a substance added to tablets, capsules, granules, etc., for the purpose of promoting their disintegration in digestive fluid. The disintegrant is one or more selected from the group consisting of croscarmellose sodium, starch, hydroxypropyl starch, methylcellulose, sodium alginate, calcium citrate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, anhydrous silicic acid, sodium lauryl sulfate, carbonate, and dextran, but is not limited to these.

[0038] The lubricant refers to a substance that improves the fluidity of powders and granules and increases their packing efficiency. The lubricant is one or more selected from the group consisting of calcium stearate, magnesium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, talc, kaolin, liquid paraffin, and magnesium oxide, but is not limited to these.

[0039] Furthermore, the present invention provides a capsule containing the granular preparation within a capsule.

[0040] Furthermore, the present invention provides a sachet containing the aforementioned granules, sweetener, and flavoring agent.

[0041] The aforementioned sweeteners refer to food additives that provide sweetness but generally have a lower calorific value, and include both natural and synthetic sweeteners. The aforementioned sweeteners include sucralose and other substances commonly used in the food and pharmaceutical fields, and are not particularly limited to those mentioned above.

[0042] The aforementioned flavoring agents (flavor, flavor) include flavoring components or compositions commonly used in the food industry, whether of natural or synthetic origin, and the flavoring agents are not particularly limited as long as they include grape flavor and are commonly used in the food and pharmaceutical fields.

[0043] Furthermore, the present invention provides a method for producing a granular preparation containing progerin, comprising the steps of (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) in purified water, then adding progerin represented by chemical formula 1 and mixing to produce a suspension; (2) preparing a nanosuspension by wet ball milling the suspension; and (3) mixing one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants into the nanosuspension, and then granulating it in a fluidized bed granulator, wherein the progerin in the nanosuspension in step (2) is in the form of particles with an average particle size (D50) of 100 to 300 nm.

[0044] The roles and amounts used for each component are the same as described above, so additional explanations that would be redundant will be omitted.

[0045] Figure 8 is a flowchart showing the manufacturing process for the granular, capsule, and sachet formulations of progerin according to the present invention.

[0046] First, in the present invention, step (1) is a process of mixing micronized progerinin into a vehicle solution, specifically a step of mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS), which are polymeric suspension agents, with purified water. In this case, purified water having a temperature of 50 to 70°C can be used, preferably having a temperature of 60°C. After the suspension thus mixed (coarse suspension) is cooled to room temperature, the following steps are taken to produce a nanosuspension.

[0047] Next, step (2) is a step in which the suspension from (1) is wet-ball-milled to produce a nano-suspension. Here, wet-ball-milling can be performed using a wet-milling device such as an agitator bead mill or a dyno-mill. The ball-milling conditions should preferably proceed until the average particle size of the drug particles reaches 100 to 300 nm. More preferably, the average particle size is 100 to 200 nm. When the average particle size is within the above range, the solubility is best, and the bioavailability or bioabsorption efficiency of the drug can be maximized.

[0048] The aforementioned ball milling is a wet ball milling for the production of nanosuspensions, and is an important step in the production of progerinin nanosuspensions. In this process, the selection of appropriate bead size, grinding medium and API ratio, and temperature control of the grinder chamber can play important roles.

[0049] Specifically, when manufacturing nanosuspensions, wet ball milling can use (1) the suspension and zirconia beads with an average particle size of 0.1 to 1 mm, preferably 0.02 to 0.04 mm. Furthermore, the suspension and zirconia beads can be used in a volume ratio of 1:1 to 1:5, but this can be appropriately changed according to the conditions, as long as it is possible to manufacture the drug with an average particle size (D50) of 200 nm or less.

[0050] Next, step (3) is a step in which one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants are mixed with the nanosuspension produced in step (2), and then granulated in a fluidized bed granulator to produce a granular material.

[0051] Furthermore, the present invention provides a method for producing capsules containing progerin, comprising the steps of (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) in purified water, then adding progerin represented by chemical formula 1 and mixing to produce a suspension; (2) preparing a nanosuspension by wet ball milling the suspension; (3) mixing one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants into the nanosuspension, and then granulating it in a fluid bed granulator; and (4) filling capsules with the granulated granules, wherein the progerin in the nanosuspension in step (2) is in the form of particles with an average particle size (D50) of 100 to 300 nm.

[0052] Furthermore, the present invention provides a method for producing a sachet containing progerin, comprising the steps of (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) in purified water, then adding progerin represented by chemical formula 1 and mixing to produce a suspension; (2) preparing a nanosuspension by wet ball milling the suspension; (3) mixing one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants into the nanosuspension, and then granulating it in a fluid bed granulator; and (4) adding sweeteners and flavorings to the granulated granules and filling a sachet; wherein the progerin in the nanosuspension in step (2) is in the form of particles with an average particle size (D50) of 100 to 300 nm.

[0053] The present invention will be described in detail below with reference to examples to aid in understanding the present invention. However, the following examples are provided to give a more complete explanation of the present invention to those skilled in the art and are illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples.

[0054] <Example 1> Production and limitation of lipid-based progerin solution To overcome the poor bioavailability of progerin drugs, the inventors prepared a progerin solution using a lipid-based formulation (monoolein:tricaprylin = 2:1) in preclinical studies. However, the lipid-based formulation was deemed unsuitable for use in a clinical setting due to inappropriate drug loading and the large amount of lipid intake expected from the proposed clinical dose. Limited attempts to produce amorphous solid dispersions (ASDs) have shown that when dispersed in an aqueous medium, ASDs experience difficulties due to rapid crystallization. Furthermore, such lipid-based formulations are considered unsuitable for use in a clinical setting due to inappropriate drug loading and the large amount of lipid intake expected from the proposed clinical dose.

[0055] Therefore, the inventors aim to produce progerinin, a poorly soluble drug, in nano-suspension form, select a vehicle composition that improves drug stability, and realize a nano-suspension optimized for clinical use.

[0056] Therefore, the inventors determined that the selection of polymers, stabilizers such as surfactants, and particle size within the suspension are important factors in the production of poorly soluble drug nanosuspensions. First, since the size of drug particles within the drug is an important factor in determining bioavailability, the inventors selected the average particle size of progerinin (SLC-D011), which exhibits excellent bioavailability, as shown in the following experiment, and optimized the polymers, surfactants, preservatives, etc., for the production of the nanosuspension.

[0057] <1-1> Determination of the average particle size (D50) of progerin drugs As mentioned above, the size of drug particles within a drug is an important factor in determining the bioavailability of the drug. Therefore, the inventors conducted pharmacokinetic (PK) analysis of the progerin drug using mice to design a diameter size that facilitates bioavailability. Specifically, they prepared a micro-suspension containing micro-sized progerin (D50=1.5mm), nano-suspension 1 containing nano-sized progerin (Nano suspension 1=200nm (D=50)), and nano-suspension 2 (Nano suspension 2=350nm (D=50)). The micro-suspension was prepared using Vivapur power, while the two nano-suspensions were prepared using zirconia beads. The prepared suspensions were orally administered to mice at doses of 10 mg / kg, 30 mg / kg, and 100 mg / kg, and the results were confirmed by pharmacokinetic (PK) analysis of the suspensions in vivo (Figure 1).

[0058] As shown in Figure 1, it was determined that when the average particle size is 200 nm or less, the drug is smoothly absorbed by the body. Based on this, the inventors decided to develop a dosage form of a suspension containing drug nanoparticles with an average particle size of 200 nm or less.

[0059] In order to devise a manufacturing method that can satisfy such dosage forms, the inventors attempted to select the most suitable method for producing progerinin nanosuspensions from among a thermal melt extrusion process, a spray drying process, a process using an ultra-high pressure homogenizer, and a process using wet ball milling with beads.

[0060] <1-2> Production of amorphous solid dispersions using the fused thermal extrusion (HME) process First, solid dispersions were prepared for various polymers (HPMCAS, HPC, HPMC, PVP VA64, Eudragit EPO, AEA) using a fused thermal extrusion method. The drug-to-polymer ratio was 1:3 for the preparation of the mixture. Solubility tests were conducted for solid dispersions corresponding to 100 mg of progerinin, using 300 mL of pH 1.2 buffer (Eudragit EPO, AEA) or 300 mL of pH 6.8 buffer (HPMCAS, HPC, HPMC, PVP VA64) as the eluent (Figures 2 to 4). The elution conditions were as follows: paddle method, temperature: 37°C, rotation speed: 150 rpm.

[0061] As shown in Figure 2, it was confirmed that the solubility was most significantly improved when HPMCAS was used as the polymer.

[0062] Next, HPMCAS, which showed the best solubility, was re-selected, and solid dispersions were prepared in various ratios (1:2, 1:2.5, 1:3, 1:4). Solubility tests were conducted for solid dispersions corresponding to 100 mg of progerinin using 300 mL of pH 6.8 buffer as the eluent (Figure 3). The elution conditions were as follows: paddle method, temperature: 37°C, rotation speed: 150 rpm.

[0063] Figure 3 shows that the highest solubility was observed when the ratio of drug to HPMCAS was 1:3. However, the HME method actually yielded a light yellow powder (light yellow power), confirming that it retained an amorphous solid form. Furthermore, Figure 4 shows that the powder obtained by the HME method immediately precipitated when mixed with water, and when bioabsorption was confirmed using mice, there was almost no absorption into the body after oral administration.

[0064] Therefore, we were able to conclude that it is currently impossible to develop a dosage form for progerinin, the main component of the drug, using the thermal melting and extrusion process.

[0065] <1-3> Production of amorphous solid dispersions using a spray drying process Using the polymers from the above-mentioned Examples <1-2>, amorphous solid dispersions were produced using a spray-drying process. Solid dispersions were produced for various polymers (HPMCAS, HPC, HPMC, PVP VA64, Eudragit EPO, AEA) using the spray-drying process. In this process, the drug-to-polymer ratio was 1:3 to produce the mixture. Solubility tests were conducted for solid dispersions corresponding to 100 mg of progerin using 300 mL of pH 1.2 buffer (Eudragit EPO, AEA) and 300 mL of pH 6.8 buffer (HPMCAS, HPC, HPMC, PVP VA64) as eluents (Figure 5). The elution conditions were as follows: paddle method, temperature: 37°C, rotation speed: 150 rpm.

[0066] As shown in Figure 5, when HPMCAS was used as the polymer, similar to the solid dispersion produced by the thermal melt extrusion process, the solubility of the polymer was highest and improved at pH 1.2 and pH 6.8.

[0067] However, when bioabsorption (PK analysis) was confirmed using mice, it was found that, similar to HME, there was almost no absorption into the body after oral administration (Figure 6). Furthermore, when the stability of other polymers was confirmed for two weeks under high temperature and high humidity conditions, recrystallization of progerinin particles was observed, resulting in unsatisfactory results (Table 1).

[0068] [Table 1]

[0069] Therefore, we were able to conclude that it is currently impossible to develop a dosage form for progerinin, the main component of the drug, using the spray-drying method.

[0070] <1-4> Production of nanosuspensions using an ultra-high pressure homogenizer The inventors have produced a nanosuspension using an ultra-high pressure homogenizer as another method for producing nanosuspensions. Specifically, a polymer (HPMC 3cp) and a surfactant (TPGS) were dissolved in a 100 mL beaker containing distilled water, and then a drug (SLC-D011) was weighed and added. The mixture was then stirred for 2 hours to produce a suspension. The suspension was then placed in an ultra-high pressure homogenizer to produce a nanosuspension (pressure: 40,000 psi, 1 hour).

[0071] [Table 2]

[0072] Table 2 above shows the measured drug particle size, confirming that the particle size increased after 3 days. Therefore, the production of nanosuspensions using an ultra-high pressure homogenizer had a limitation in that the particles grew larger over time. This also makes it difficult to consider this method suitable for the production of progerinin nanosuspensions.

[0073] <1-5> Production of nanosuspensions using wet ball milling with beads As an alternative method, the inventors manufactured a nanosuspension using wet ball milling with beads. Specifically, a polymer (HPMC 3cp) and a surfactant (TPGS) were dissolved in a 100 mL beaker containing distilled water, then progerinin was weighed and added, and the mixture was stirred for 2 hours to produce a suspension. The tube containing the beads and the suspension was mounted on a DeltaVita® Netzsch (Zentrimix 380R) apparatus to manufacture the nanosuspension (speed: 1200 rpm, temperature: -10°C, 6 hours). Figure 7 shows the shape (top) and the results of measuring the average particle size (bottom) of the nanosuspension manufactured by the above manufacturing method.

[0074] As shown in Figure 7, we were able to produce a nanosuspension containing drug nanoparticles with an average particle size of 170 nm. We confirmed that when the average particle size of the drug particles is 200 nm or less, the nanosuspension exhibits the best solubility, and since nanoparticles have an even larger surface area, they dissolve even more easily, thus maximizing bioavailability.

[0075] As a result, the inventors determined that while they produce nanosuspensions using wet ball milling with beads, it is necessary to select a vehicle composition suitable for producing nanosuspensions with an average particle size of 200 nm or less of drugs, and attempted to select an optimized polymer, a surface stabilizer such as a surfactant, and a preservative.

[0076] <Example 2> Selection of optimized vehicle solution <2-1> Preparation of progerinin nanosuspension a) Suspension Preparation (Step 1) The TPGS solution is prepared by dissolving TGPS in 60°C water and allowing it to cool to room temperature. The HPMC E3 solution is prepared by dissolving HPMC E3 in 60°C water and allowing it to cool to room temperature. The two solutions are then stirred until completely mixed. To prepare the suspension, progerinin is gradually added to the mixed solution as the API (Active Pharmaceutical Ingredient) while continuing to stir.

[0077] b) Nano Milling (2-step process) The parameters of the mixing and wet grinding equipment, the Agitator Bead Mill, were appropriately set to initiate wet ball milling, and the constant-pressure pump was adjusted to ensure the suspension was circulated. The suspension exiting the Agitator Bead Mill was recirculated back into the suspension container while maintaining a temperature below the predetermined value of 35°C. Wet ball milling continued until the drug particles reached a PSD (D50 ≤ 200 nm). Once the target PSD (D50 ≤ 200 nm) was reached, the pump was switched off and the milling suspension line was separated from the suspension container.

[0078] c) Manufacturing of nanosuspensions with improved stability (3 steps) The suspension obtained by nanomilling was thoroughly mixed with potassium sorbate as a preservative. This was then filled into sterile glass bottles. The bottle filling process was 100% visually inspected and by weight, and after filling, the bottles were sealed with rubber finishes and aluminum flip-off seals.

[0079] <2-2> Selection of optimized vehicle solutions Oral progerinin nanosuspensions were prepared using the method described in Example <2-1> above. Specifically, Prototype 1 consisted of 10.0 wt% progerinin, 3.0 wt% HPMC E3, 1.0 wt% surfactant TPGS, and 0.2 wt% potassium sorbate. The TPGS and HPMC solutions were mixed, and progerin was added to prepare the suspension. The mixture thus prepared was mixed with 0.3 mm VHD ZrO beads in a volume ratio of 1:1 to 5 and ball milling was performed. The temperature of the container was carefully monitored during the manufacturing process. In addition, the particle size distribution was monitored during milling until the target average particle size D50 ≤ 200 nm was reached. Prototypes 2 to 5 were also prepared using the same method. The particle diameter, zeta potential, drug content, dispersibility (flowability), and viscosity (viscosity) of the nanosuspensions thus prepared were measured using the method described below.

[0080] (1) Particle diameter (D50) measurement: Approximately 2 μL of nano-suspension was dispersed in 1 mL of water, then placed in a sample tube and measured using a Zeta Potential & Particle Sizer (ZPPS) (Nicomp 380 / ZLS, Nicomp) used for aqueous suspensions.

[0081] (2) Zeta potential measurement: This measures the electrical charge on the particle surface and indicates the physical stability of the colloid system. The zeta potential was measured using the laser-Doppler method.

[0082] (3) Drug content measurement: The content of progerinin relative to the total weight of the nano-suspension was measured.

[0083] (4) Dispersibility measurement: Dispersibility was evaluated by visual observation of the presence or absence of precipitation in the suspension.

[0084] (5) Viscosity measurement: Using a BROOKFIELD viscometer (TC-550MX-230) with a torsional moment of 32.9%, a temperature of 25°C, and a probe rotation speed of 200 rpm, the measured viscosity was 13.03 dyne / cm². 2 Shear force, 264.0 S -1 The shear rate was measured for 1 minute.

[0085] [Table 3]

[0086] Through Table 3, it was confirmed that the average particle size (D50) of drug particles in prototype 1 and prototype 3 was 165.8 nm and 146.3 nm, respectively, satisfying the requirement of an average particle size of 200 nm or less, and that the drug content was higher than 95% without the detection of impurities.

[0087] Therefore, we were able to confirm that prototypes 1 and 3 were the most suitable vehicle compositions in terms of dispersibility, stability, and drug efficacy. On the other hand, prototype 4 had limitations in terms of drug efficacy and could not be selected as a suitable vehicle composition. Prototype 2 tended to increase in particles over time and was therefore unsuitable as a candidate. In the case of prototype 5, the formation of the nano-suspension itself was impossible.

[0088] <Example 3> Selection of Optimized Excipients To evaluate compatibility with excipients, progerinin was mixed with HPMC E3, TPGS, and potassium sorbate in a 1:10 ratio, and the effectiveness of the drug (API) component was measured over two weeks at 40°C / 75% RH. The results confirmed that adding HPMC E3, TPGS, and potassium sorbate to progerinin did not affect the drug. In particular, in the case of preservatives, if they are added before milling, the content decreases, so it is desirable to add them after milling. Such studies on the compatibility of pre-excipients suggest that the drug is compatible with the excipients.

[0089] <Example 4> Confirmation of Stability Further studies were conducted on the stabilization of progerinin nanosuspensions using prototypes 1 and 3, which showed excellent particle stability during the vehicle solution selection process. Specifically, evaluations were performed over 3 weeks under conditions of 2–8°C, 40°C / RH 75%, or 1.2M lux exposure. The stabilization study of progerinin nanosuspensions was conducted at room temperature (25±5°C, 60% RH) for 3 weeks. The particle size of the progerinin nanosuspensions was characterized in relation to the drug content. The results are shown in Tables 4 and 5.

[0090] [Table 4]

[0091] [Table 5]

[0092] As shown in Tables 4 and 5, we were able to confirm that even under low temperature or harsh conditions, the average particle size was 200 nm or less and the nano-drug particles maintained stability for 3 weeks or more.

[0093] <Example 5> Confirmation of the stability of the optimized progerinin nanosuspension in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). The nano-suspension of prototype 1 was prepared using the same method as in Example <2-1>, but with the components and concentrations shown in Table 6 below. The dispersion stability of the nano-suspension prepared in this way was confirmed in simulated intestinal fluids (SIF) and simulated gastric fluids (SGF). The specific experimental method is as follows.

[0094] [Table 6]

[0095] a) Simulated intestinal fluid (SIF) Monobasic potassium phosphate (6.8 gm) and sodium hydroxide (0.616 gm) were added to a 1000 ml volumetric flask along with 250 ml of distilled water. The mixture was then stirred until the components dissolved, and another 700 ml of distilled water was added to measure the pH. The pH was adjusted to pH 6.8 + / - 0.1 by adding 0.2 N sodium hydroxide or 0.2 N hydrochloric acid.

[0096] b) Simulated gastric fluid (SGF) Sodium chloride (2 gm), 750 ml of distilled water, and 7.0 ml of concentrated hydrochloric acid were added to a 1000 ml volumetric flask, and then 1000 ml of distilled water was added. The components were then mixed by stirring. The pH of this solution was adjusted to 1.2.

[0097] c) Preparation of dispersion An appropriate amount of the nano-suspension of Prototype 1 was added to a translucent HDPE vial (25 ml) with an HDPE lid. At this time, it was diluted with 15 ml of simulated gastric or intestinal fluid to a final progenin concentration of 0.5 mg / ml. Next, a dispersant was added, and the vial was shaken until the prepared dosage form was completely dispersed. This vial was placed in an oil bath at 37°C until flocculation occurred. The size of the precipitated particles was measured using a Horiba-LA-910 particle analyzer. The substance was then cultured in fasting human gastric juice for approximately 3 hours.

[0098] d) Particle size measurement When measuring beads coated with bead cores containing insoluble particles, the weight of the bead core was calculated using SIF or SGF experiments, and the bead core was dispersed in a volume similar to SIF or SGF. After pouring 120 gm of distilled water into the HoribaLA-910 chamber, the chamber was drained to empty the instrument. Then, 120 gm of distilled water was poured in, and the total volume of the cultured dosage form (in 15 ml of SGF or SIF) was poured into the HoribaLA-910 chamber, after which the average particle size was measured.

[0099] [Table 7]

[0100] As shown in Table 7, the progenin drug (prototype 1) with an average particle size (D50) of 200 nm or less maintained an average particle size (D50) of 190-220 nm even in simulated intestinal fluid or simulated gastric fluid, confirming that the stability of dispersion and the bioavailability of the drug were maintained.

[0101] <Example 6> Manufacturing of capsules or sachets <6-1> Preparation of nano-suspension (10%, w / w) A progerinin nanosuspension (10%, w / w) was prepared with the composition shown in the following table.

[0102] [Table 8]

[0103] First, purified water was prepared at 55-60°C, and TPGS was added to the solution preparation container while stirring. The constant temperature water bath was maintained at 55-60°C until the TPGS was completely dissolved. HPMC E3 was added to the solution preparation container while stirring, and then cooled to ambient temperature (15-25°C) while stirring until the solid was completely dissolved and the HPMC E3 solution became clear. Progerinin (batch formula C19010954-C) was gradually added to the solution preparation container, and stirring was continued.

[0104] The parameters for the mixing and wet grinding equipment, the agitator bead mill, were set as shown in Table 9. The suspension from the agitator bead mill was recycled back into the solution preparation container, which was then placed in a cooler, and milling was continued until the PSD result was D50 ≤ 200 nm.

[0105] [Table 9]

[0106] <6-2> Manufacturing of 250 mg and 350 mg granules Progerin sachet dosage forms were prepared with the compositions shown in Table 10 below. Mannitol 100SD, mannitol 200SD, and croscarmellose sodium SD-711 were added to a container containing the prepared nano-suspension. The mixture was mixed for at least 2 hours to confirm that the redispersant was completely dissolved. After preheating the machine and materials, the granulation solution (nozzle size: 1.0 mm) was sprayed. The inlet airflow, inlet air temperature, and spray speed were adjusted to maintain proper fluidity throughout the spray process. After the granulation process was complete, the granules were dried. The LOD (measured at 105°C) was monitored at appropriate intervals, and drying was stopped until the LOD was 2.00% or less. After drying, the inlet air temperature was set to 25.0°C (20.0~30.0°C), and cooling was started until the product temperature was below 35.0°C.

[0107] <6-3> Packaging of Progerin Sachets Sweetener (sucralose), lubricant (magnesium stearate), and flavoring (grape flavor) were added to the prepared granules, and R&D sachets were filled manually. In human PK batch production, a sachet filling machine was used.

[0108] [Table 10]

[0109] Having described in detail certain aspects of the present invention, it will be clear to those skilled in the art that such specific descriptions are merely desirable embodiments and do not limit the scope of the invention. In other words, the substantial scope of the invention is defined by the claims and their equivalents.

Claims

1. (1) A step in which a vehicle solution is prepared by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) with purified water, and then progerin represented by the following chemical formula 1 is added and mixed to prepare a suspension, (2) A step of producing a nanosuspension by wet ball milling the suspension, (3) The nanosuspension is mixed with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulated in a fluidized bed granulator, 10% by weight of progerin represented by the following chemical formula 1, Hydroxypropyl methylcellulose (HPMC) 3% by weight, D-α-tocopherol polyethylene glycol succinic acid (TPGS) 1% by weight, Includes the remaining amount of additives, A method for producing a granular preparation containing progerin, characterized in that the progerin in the nano-suspension of step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm. 【Chemistry 1】

2. A method for producing a granular preparation containing progerin according to claim 1, characterized in that the purified water in step (1) is at a temperature of 50 to 70°C.

3. A method for producing a granular preparation containing progerin according to claim 1, characterized in that, in step (2), during wet ball milling, the suspension from step (1) and zirconia beads are mixed in a volume ratio of 1:1 to 1:5 and milled to produce a nanosuspension.

4. (1) A step in which a vehicle solution is prepared by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) with purified water, and then progerin represented by the following chemical formula 1 is added and mixed to prepare a suspension, (2) A step of producing a nanosuspension by wet ball milling the suspension, (3) The step of mixing one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants into the nanosuspension, and then granulating it in a fluid bed granulator, (4) The step of filling capsules with the granulated granules, 10% by weight of progerin represented by the following chemical formula 1, Hydroxypropyl methylcellulose (HPMC) 3% by weight, D-α-tocopherol polyethylene glycol succinic acid (TPGS) 1% by weight, Includes the remaining amount of additives, A method for producing a capsule containing progerin, characterized in that the progerin in the nano-suspension of step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm. 【Chemistry 2】

5. (1) A step in which a vehicle solution is prepared by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinic acid (TPGS) with purified water, and then progerin represented by the following chemical formula 1 is added and mixed to prepare a suspension, (2) A step of producing a nanosuspension by wet ball milling the suspension, (3) The step of mixing one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants into the nanosuspension, and then granulating it in a fluid bed granulator, (4) The step of adding a sweetener and a flavoring to the granulated granules and filling a sachet with them, 10% by weight of progerin represented by the following chemical formula 1, Hydroxypropyl methylcellulose (HPMC) 3% by weight, D-α-tocopherol polyethylene glycol succinic acid (TPGS) 1% by weight, Includes the remaining amount of additives, A method for producing a sachet containing progerin, characterized in that the progerin in the nano-suspension of step (2) is in the form of particles with an average particle size (D50) of 100 to 300 nm. 【Transformation 3】

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