Granules containing progerinin 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 granules containing the poorly soluble drug progerinin, capsules or sachets using the same, and methods for producing them. [Background technology]

[0002] Many useful drugs are hydrophobic with low solubility in aqueous media, making them difficult to formulate into suspensions in aqueous vehicles. In particular, due to such characteristics, wetting agents are often required to facilitate the suspension of hydrophobic drug particles in aqueous media. Surface-active wetting agents (i.e., surfactants), such as sodium lauryl sulfate, are known to reduce the interfacial tension between drug particles and the suspension vehicle, allowing the suspension vehicle to penetrate into drug aggregates and / or drug particle pores, at least in part, to increase the suspendability of hydrophobic drugs in aqueous media. However, apart from the beneficial effects of drug-suspension, the use of surfactants in suspensions also leads to the undesirable result of solubilized / dissolved free drug.

[0003] Suspensions containing free drug are chemically unstable because the soluble / dissolved drug is vulnerable to chemical degradation and / or interaction with other components. Yet another undesirable consequence of using a relatively high amount of surfactant to promote the suspension of low-solubility drugs is that air entrained during homogenization or shaking of such suspensions tends to remain trapped, since the surfactant stabilizes air bubbles. Such trapped air changes the volume of the suspension, depending on the stirring force, stirring duration and stirring elapsed time, making it difficult or impossible to administer a uniform dose over time.

[0004] If a drug with low water solubility is administered as a suspension, it is desirable for the suspension to exhibit slow settling to provide adequate dose uniformity. Conversely, if rapid settling occurs, as in the case of a vehicle, the suspension must be shaken before every administration to achieve dose uniformity. Other factors being equal (e.g., drug particle size, uniformity, and density), as the viscosity of a particular suspension vehicle increases, the rate of settling of drug particles decreases. Thus, it is desirable for the suspension to be appropriately viscous to inhibit or slow down the settling of drug particles. However, while such increased viscosity promotes physical stability, it also makes the suspension difficult to pour or administer.

[0005] Meanwhile, progerinin having the structure of the following chemical formula 1 shows excellent progerin expression inhibitory effects and inhibitory effects on the binding of progerin to lamin A, and is a drug having the effect of extending the survival time of an animal model in which progeria is induced, and is used as a pharmaceutical composition for preventing or treating progeria.

[0006] [ka]

[0007] The compound name of the 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 premature aging, and is a BCS class II molecule that exhibits high apparent permeability and low solubility in aqueous media according to the Biopharmaceutical Classification System (BCS) criteria.

[0009] The therapeutic application of progerinin drugs is very limited due to their low water solubility characteristics. To overcome these limitations, numerous methods have been investigated, such as the use of polymeric nanoparticles, solid lipid nanoparticles, self-emulsifying drug delivery systems, nanoemulsions, liposomes, nanosuspensions, and nanofibers. Among them, nanosuspensions refer to colloidal dispersions of drug particles stabilized under conditions of either polymers, surfactants, or both. Nanosuspensions are used to deliver drug substances that exhibit low water solubility and lipid solubility. The small particles of nanosuspensions provide a very large drug surface area, increasing the dissolution rate of insoluble drugs. As a result, BCS class II and IV compounds exhibit improved bioavailability, fast activity, and other desirable biopharmaceutical effects.

[0010] Under such circumstances, the present inventors have realized that although animal experiments could be conducted using a mixture of monoolein and tricaprin, which is an oil-based solution, it is not possible to use a dosage form dissolved in oil when high doses and long-term administration are required due to the characteristics of the disease, and that it is necessary to develop a new dosage form that can be administered for a long period of time. In particular, the above-mentioned progerinin is so poorly soluble in water that its solubility is close to zero, and it also has very low solubility in existing ingestible solvents, so that it is necessary to develop a dosage form that can be administered for a long period of time and absorbed by the human body through the introduction of new technology.

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

[0012] Therefore, there is a need to develop an improved dosage form for oral nanosuspension formulations that is advantageous in terms of storage, transportation, and patient administration. Summary of the Invention [Problem to be solved by the invention]

[0013] An object of the present invention is to provide a granule containing progerinin having excellent bioavailability and a method for producing the same.

[0014] Another object of the present invention is to provide a capsule or sachet formulation using granules containing progerinin, and a method for producing the same, in order to provide an improved dosage form that has excellent bioavailability and is advantageous in terms of storage, transportation and patient administration. [Means for solving the problem]

[0015] In order to achieve the above object, the present invention provides a granule containing progerinin, which comprises: (a) 20-40 wt % of progerinin represented by the following chemical formula 1; (b) 5-15 wt % of hydroxypropylmethylcellulose (HPMC); (c) 1-10 wt % of D-α-tocopherol polyethyleneglycol succinate (TPGS); and (d) the remaining amount of additives, wherein the progerinin is in the form of drug particles having an average particle size (D50) of 100-300 nm formed by wet type ball milling.

[0016] The present invention also provides a capsule or sachet containing the granules.

[0017] The present invention also provides a method for producing granules containing progerinin, which comprises the steps of: (1) mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) in purified water to prepare a vehicle solution, then adding progerinin represented by Chemical Formula 1 and mixing to prepare a suspension; (2) wet ball milling the suspension to prepare a nanosuspension; and (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulating in a fluidized bed granulator, wherein the progerinin in the nanosuspension in step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm. Effect of the Invention

[0018] In order to develop an advantageous dosage form for administering progerinin, a poorly soluble drug effective in treating premature aging, to patients, the present invention has developed progerinin granules containing specific water-soluble polymers, solubility enhancers and excipients in optimal composition ratios, and by using the granules to develop oral solid preparations such as capsules or sachets, it has been possible to not only improve the dispersion stability and bioavailability of progerinin, but also storage, transportation and patient compliance with dosing. [Brief description of the drawings]

[0019] [Figure 1] 1 shows the pharmacokinetic analysis results of progerinin suspension. [Diagram 2] 1 shows the results of measuring the solubility of solid dispersions produced using hot melt extrusion (HMT). [Diagram 3] 1 shows the results of measuring the solubility of solid dispersions prepared using a hot melt extrusion process with polymers at various ratios (1:1). [Figure 4]Pharmacokinetic analysis results for solid dispersions prepared using a hot melt extrusion process. [Diagram 5] The results are the solubility measurements for amorphous solid dispersions using the spray drying process (A: pH 1.2, B: pH 6.8). [Figure 6] Pharmacokinetic analysis results for solid dispersions prepared using a spray drying process. [Figure 7] The shape of the nanosuspension prepared by wet ball milling using beads (top) and the results of measuring the average particle size of the progerinin drug (bottom). [Figure 8] 1 is a diagram showing a process for preparing the dosage forms of progerinin according to the present invention, including granules, capsules, and sachets. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention will now be described in more detail.

[0021] The present inventors have previously prepared a nanosuspension of progerinin in order to improve the bioavailability of progerinin, a poorly soluble drug. However, when actually developing it as a pharmaceutical, the issues of storage and transportation and the patient's compliance with taking the drug must also be taken into consideration. Thus, the present invention has been completed by developing an oral solid dosage form such as a capsule or sachet using the nanosuspension.

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

[0023] [ka]

[0024] The progerinin is a derivative of decursin, and is (7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano[3,2-g]chromen-2-one. In the present invention, progerinin can also be named "SLC-D011".

[0025] Progerinin shows excellent progerin expression inhibitory effects and progerin and lamin A binding inhibitory effects, and is a drug that has the effect of extending the survival time of an animal model in which progerin is induced, and is used as a pharmaceutical composition for preventing or treating progerin, an aging-related disease. Progerinin is poorly soluble in water, with a solubility close to 0, but the present invention provides an oral solid dosage form that improves the solubility, allows long-term administration and absorption by the human body, and takes into consideration storage and transportation issues and patient compliance.

[0026] The hydroxypropyl methylcellulose (HPMC) is a polymeric suspending agent that helps disperse progerinin and other components in the solution, and if the polymeric suspending agent is contained below the range, the settling rate of the suspension becomes poor, and if the polymeric suspending agent is contained above the range, stirring becomes difficult, making production difficult. In particular, if the polymeric suspending agent is contained above the range, stirring is not uniform and the dispersibility of the suspension decreases, which causes an increase in the amount of defective products that do not reach the required content during production.

[0027] The D-α-tocopherol polyethylene glycol succinate (TPGS) is a solubility enhancer, which is a component that improves the solubility of poorly soluble drugs. If the solubility enhancer is contained below the above range, the solubility will be low, and if the solubility enhancer is contained above the above range, the acceptable toxicity limit may be exceeded. Therefore, it is preferable to use the solubility enhancer within the above range.

[0028] The poorly soluble drug progerinin 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, it is most soluble, and the nanoparticles have a larger surface area and are more easily dissolved, so that the bioavailability or bioabsorption efficiency can be maximized. In addition, a nanosuspension having the above average particle size can be prepared by wet ball milling using a wet grinding device such as an agitator bead mill or a dyno mill.

[0029] The nanosuspension of the present invention has a pH of 5.5 to 8.5, preferably 6.0 to 7.0, and a viscosity of 2 to 8.5 mPa·s, preferably 7 to 8.5 mPa·s.

[0030] The nanosuspension of the present invention may further contain additional agents such as a preservative, a pH adjuster, or a colorant.

[0031] The preservative means a pharma- ceutically acceptable substance that prevents decomposition due to microbial growth or undesired chemical changes. Examples of the preservative include, but are not limited to, potassium sorbate.

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

[0033] The colorant is included to give the nanosuspension a different color, and can be used to prepare a nanosuspension having a desired color by being included in the formulation. As long as the colorant is commonly used in the technical field of the present invention, it is not limited and is included in the present invention.

[0034] The additive is one or more additives selected from the group consisting of a filler, a binder, a disintegrant, and a lubricant.

[0035] The excipient means a substance added to give a drug an appropriate hardness or shape, or to give a certain volume or weight to make the drug a manageable size when the amount of the main ingredient is small. The excipient may be 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 thereto.

[0036] The binder means a substance added for the purpose of binding particles of ingredients to a certain size, and is at least one 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 thereto.

[0037] The disintegrant refers to a substance added to promote disintegration in digestive fluids of tablets, capsules, granules, etc. The disintegrant may be one or more selected from the group consisting of croscarmellose sodium, starch, hydroxypropyl starch, methylcellulose, sodium alginate, calcium citrate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, silicic anhydride, sodium lauryl sulfate, carbonates, and dextran, but is not limited thereto.

[0038] The lubricant refers to a substance that improves the fluidity of powder and granules and increases the packing property, and is at least one 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 thereto.

[0039] The present invention also provides a capsule containing the granules.

[0040] The present invention also provides a sachet comprising said granules, a sweetener and a flavouring agent.

[0041] The sweetener refers to a food additive that imparts sweetness but generally has a lower food calorie content, and includes both natural and synthetic sweeteners. The sweetener may be any sweetener commonly used in the food and pharmaceutical fields, including sucralose, without any particular limitation.

[0042] The flavor includes flavoring ingredients or compositions commonly used in the food industry, regardless of whether they are natural or synthetic in origin, and the flavor may be any flavor commonly used in the food and pharmaceutical fields, including grape flavor, without any particular limitation.

[0043] The present invention also provides a method for producing granules containing progerinin, which includes the steps of: (1) mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) with purified water to prepare a vehicle solution, then adding progerinin represented by Chemical Formula 1 and mixing to prepare a suspension; (2) wet ball milling the suspension to prepare a nanosuspension; and (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulating in a fluidized bed granulator; wherein the progerinin in the nanosuspension in step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm.

[0044] The role and amount of each component is the same as that described above, so that redundant description will be omitted.

[0045] FIG. 8 is a flow chart showing the manufacturing process of the dosage forms of progerinin granules, capsules and sachets according to the present invention.

[0046] First, in the present invention, the step (1) is a process of mixing micronized progerinin with a vehicle solution, specifically, a step of mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS), which are polymeric suspending agents, with purified water. In this case, the purified water may have a temperature of 50 to 70°C, and preferably has a temperature of 60°C. The coarse suspension thus mixed is cooled to room temperature, and then the next step is carried out to prepare a nanosuspension.

[0047] Next, in step (2), the suspension of step (1) is subjected to wet ball milling to prepare a nanosuspension. Here, the wet ball milling can be performed using a wet grinding device such as an agitator bead mill or a dyno mill. The ball milling conditions are preferably carried out 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 the highest, and the bioavailability or bioabsorption efficiency of the drug can be maximized.

[0048] The ball milling is a wet ball milling for preparing a nanosuspension, and is an important step in the preparation of a progerinin nanosuspension, in which selection of appropriate bead size, milling media and API ratio in the chamber, temperature control of the mill chamber, etc. can play important roles.

[0049] Specifically, when preparing the nanosuspension, wet ball milling can be performed using the suspension of step (1) and zirconia beads having an average particle size of 0.1-1 mm, preferably 0.02-0.04 mm. The suspension of step (1) and zirconia beads can be used in a volume ratio of 1:1-1:5, but this can be appropriately changed according to the conditions as long as the average particle size (D50) of the drug can be prepared to 200 nm or less.

[0050] Next, in step (3), the nanosuspension prepared in step (2) 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 to prepare granules.

[0051] The present invention also provides a method for producing a capsule containing progerinin, which includes the steps of: (1) mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) in purified water to prepare a vehicle solution, then adding progerinin represented by Chemical Formula 1 and mixing to prepare a suspension; (2) wet ball milling the suspension to prepare a nanosuspension; (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and granulating the mixture in a fluidized bed granulator; and (4) filling the granulated granules into capsules; wherein the progerinin in the nanosuspension in step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm.

[0052] The present invention also provides a method for producing a sachet containing progerinin, which includes the steps of: (1) mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) in purified water to prepare a vehicle solution, and then adding and mixing progerinin represented by Chemical Formula 1 to prepare a suspension; (2) wet ball milling the suspension to prepare a nanosuspension; (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulating the mixture in a fluidized bed granulator; and (4) adding a sweetener and a flavoring to the granulated granules and filling the sachet with the granules; wherein the progerinin in the nanosuspension in step (2) is in the form of particles having 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 help the understanding of the present invention. However, the following examples are provided to more completely explain the present invention to those skilled in the art and to illustrate the contents of the present invention, and the scope of the present invention is not limited to the following examples.

[0054] Example 1: Preparation and limitations of lipid-based progerinin solution In order to overcome the poor bioavailability of the progerinin drug, the present inventors have prepared a progerinin solution using a lipid-based formulation (monoolein:tricaprylin=2:1) ​​in preclinical studies. However, lipid-based formulations were deemed unsuitable for use in a clinical setting due to inadequate drug loading and the high lipid intake expected with the proposed clinical dose. Limited attempts to produce amorphous solid dispersions (ASDs) have shown that ASDs suffer from rapid crystallization when dispersed in aqueous media. Such lipid-based formulations are also deemed unsuitable for use in a clinical setting due to inadequate drug loading and the high lipid intake expected with the proposed clinical dose.

[0055] Therefore, the present inventors intend to prepare a nanosuspension of progerinin, a poorly soluble drug, and to realize a nanosuspension optimized for clinical use by selecting a vehicle composition that improves the stability of the drug.

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

[0057] <1-1> Determination of the average particle size (D50) of progerinin drug As mentioned above, the size of drug particles in a drug is an important factor in determining the bioabsorption efficiency. Therefore, the present inventors analyzed the pharmacokinetics (PK) of the compound using mice in order to design a diameter size that allows smooth bioabsorption of the progerinin drug. Specifically, a microsuspension (D50=1.5mm) containing micro-sized progerinin, a nanosuspension 1 (Nano suspension 1=200nm (D=50)) containing nano-sized progerinin, and a nanosuspension 2 (Nano suspension 2=350nm (D=50)) were prepared. In this case, the microsuspension was prepared using Vivapur power, and the two nanosuspensions were prepared using zirconia beads. The suspensions thus prepared were orally administered to mice at 10mg / kg, 30mg / kg, and 100mg / kg, and the pharmacokinetics (PK) of the suspensions in vivo was analyzed to confirm the results (Figure 1).

[0058] As shown in Figure 1, it was determined that the drug would be smoothly absorbed by the body if the average particle size was 200 nm or less. Therefore, the present inventors decided to develop a suspension formulation containing drug nanoparticles with an average particle size of 200 nm or less.

[0059] In order to devise a manufacturing method that can meet such a dosage form, the inventors carried out a hot melt extrusion process, a spray drying process, a process using an ultra-high pressure homogenizer, and a process using wet ball milling with beads, and tried to select the most suitable manufacturing method for progerinin nanosuspension from among these.

[0060] <1-2> Manufacturing of amorphous solid dispersions using hot melt extrusion (HME) process First, solid dispersions were prepared for various polymers (HPMCAS, HPC, HPMC, PVP VA64, Eudragit EPO, AEA) using hot melt extrusion. In this case, a mixture was prepared with a drug to polymer ratio of 1:3. The solubility of the solid dispersions corresponding to 100 mg of progerinin was tested 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 dissolution medium (Figures 2 to 4). The dissolution 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 improved when HPMCAS was used as the polymer.

[0062] Next, the HPMCAS with the highest solubility was reselected and solid dispersions were prepared in various ratios (1:2, 1:2.5, 1:3, 1:4). A solubility test was carried out for the solid dispersion equivalent 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] As shown in Figure 3, it was confirmed that the solubility is highest when the ratio of drug to HPMCAS is 1:3. However, it was confirmed that the HME method actually produced a light yellow powder form, and the solid form remained amorphous. As shown in Figure 4, the powder obtained using the HME method immediately precipitated when mixed with water, and when bioabsorption was confirmed using mice, there was almost no absorption in the body when orally administered.

[0064] Therefore, it was concluded that it is currently impossible to develop a dosage form of progerinin, the main component of the drug, using the hot melt extrusion process.

[0065] <1-3> Manufacturing of amorphous solid dispersions using the spray drying process Using the polymer of Example <1-2>, amorphous solid dispersions were prepared using a spray drying process. Solid dispersions for various polymers (HPMCAS, HPC, HPMC, PVP VA64, Eudragit EPO, AEA) were prepared using a spray drying process. In this case, a mixture was prepared with a drug to polymer ratio of 1:3. A solubility test was performed for the solid dispersions corresponding to 100 mg of progerinin 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 FIG. 5, when HPMCAS was used as the polymer, as in the solid dispersion prepared by the hot melt extrusion process, the solubility of the polymer was most 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 in the body when orally administered (Figure 6). In addition, when the stability of other polymers was confirmed for two weeks under high temperature and high humidity conditions, recrystallization of progerinin particles was observed, giving unsatisfactory results (Table 1).

[0068] [Table 1]

[0069] Therefore, it was determined that it is currently impossible to develop a dosage form of progerinin, the main component of the drug, using the spray drying method.

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

[0071] [Table 2]

[0072] Table 2 shows the measurement of drug particle size, and it was confirmed that the particle size increased after 3 days. Therefore, the preparation of nanosuspension using ultra-high pressure homogenizer has the limitation that the particles become larger over time. This is also not considered to be a suitable method for preparing progerinin nanosuspension.

[0073] <1-5> Manufacturing nanosuspensions using wet ball milling with beads As another method, the present inventors prepared 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, and then progerinin was weighed and added, and the suspension was stirred for 2 hours to prepare the suspension. The tube containing the beads and the suspension was placed in a DeltaVita (registered trademark) Netzsch (Zentrimix 380R) device to prepare the nanosuspension (speed: 1200 rpm, temperature: -10°C, 6 hours). Figure 7 shows the shape (top) and the average particle size (bottom) of the nanosuspension prepared by the above method.

[0074] As shown in Figure 7, a nanosuspension containing drug nanoparticles with an average particle size of 170 nm was prepared. It was confirmed that when the average particle size of the drug particles is 200 nm or less, the stability of the nanosuspension is the most excellent in solubility, and the nanoparticles have a larger surface area and are more easily dissolved, maximizing bioavailability.

[0075] As a result, the inventors produced nanosuspensions using wet ball milling with beads, and determined that there was a need to select a vehicle composition suitable for producing nanosuspensions in which the average particle size of the drug is 200 nm or less, and attempted to select optimized polymers, surface stabilizers such as surfactants, and preservatives.

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

[0077] b) Nano Milling (Step (2)) The parameters of the mixing and wet grinding equipment, the Agitator Bead Mill, were set appropriately to start the wet ball milling, and the constant pressure pump was adjusted to circulate the suspension. The suspension coming out of the Agitator Bead Mill was recirculated back to the suspension vessel while being kept below the preset value of 35°C. The drug particles continued to proceed through the wet ball milling until the PSD (D50≦200 nm) was reached. Once the target PSD (D50≦200 nm) was reached, the pump was turned off and the milling suspension line was separated from the suspension vessel.

[0078] c) Preparation of nanosuspension with improved stability (Step (3)) The nanomilled suspension was mixed thoroughly with potassium sorbate as a preservative and filled into sterile glass bottles. The bottle filling process was 100% visually inspected and weight-checked, and the bottles were sealed with rubber finish and aluminum flip-off seal after filling.

[0079] <2-2> Selection of an optimized vehicle solution Progerinin nanosuspension for oral use was prepared by the method of Example <2-1>. Specifically, Prototype 1 was composed of 10.0 wt% progerinin, 3.0 wt% HPMC E3, 1.0 wt% surfactant TPGS, and 0.2 wt% potassium sorbate, and TPGS and HPMC solutions were mixed and progerinin was added to prepare a 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 milled. The temperature of the container was closely monitored during the preparation 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 in the same manner. The nanosuspension thus prepared was measured for particle diameter, zeta potential, drug content, flowability, and viscosity by the following methods.

[0080] (1) Particle diameter (D50) measurement: Approximately 2 μL of nanosuspension 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 is a measurement of the electrical charge on the particle surface, which indicates the physical stability of the colloidal 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 nanosuspension was measured.

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

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

[0085] [Table 3]

[0086] From Table 3, it can be seen that the average particle size (D50) of drug particles in Prototype 1 and Prototype 3 is 165.8 nm and 146.3 nm, respectively, both of which satisfy the average particle size of 200 nm or less, and the drug content is higher than 95% without detection of impurities.

[0087] Therefore, it was confirmed that Prototype 1 and Prototype 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 had a tendency to increase in particles over time, making it an unsuitable candidate. In the case of Prototype 5, it was impossible to form a nanosuspension at all.

[0088] Example 3: Selection of optimized excipients To evaluate compatibility with excipients, progerinin was mixed with HPMC E3, TPGS, and potassium sorbate in a ratio of 1:10, and the effectiveness of the API was measured for two weeks at 40℃ / 75% RH. It was confirmed that the addition of HPMC E3, TPGS, and potassium sorbate to the progerinin drug had no effect on the drug. In particular, in the case of preservatives, if they are added before milling, the content decreases, so it is preferable to add them after milling to complete the formulation. This study of the compatibility of pre-excipients suggested that the drug is compatible with the excipients.

[0089] Example 4: Stability confirmation Further stabilization studies of progerinin nanosuspension were conducted for prototype 1 and prototype 3, which showed excellent particle stability during the vehicle solution selection process. Specifically, they were evaluated for 3 weeks at 2-8°C, 40°C / RH 75%, or 1.2M lux exposure. The stabilization studies of progerinin nanosuspension were conducted at room temperature (25±5°C, 60% RH) for 3 weeks. The progerinin nanosuspension was characterized in relation to particle size and 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, it was confirmed that the average particle size was 200 nm or less even at low temperatures or under harsh conditions, and the nano drug particles had stability for more than 3 weeks.

[0093] Example 5: Stability of the optimized progerinin nanosuspension in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF) A nanosuspension of prototype 1 was prepared using the same method as in Example <2-1>, but with the ingredients and contents in Table 6 below. The dispersion stability of the nanosuspension thus prepared in simulated intestinal fluids (SIF) and simulated gastric fluids (SGF) was confirmed. 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 with 250 ml of distilled water, swirled until the ingredients were dissolved, then an additional 700 ml of distilled water was added and the pH was measured. 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, followed by 1000 ml of distilled water, and the ingredients were mixed by swirling. The pH of the solution was adjusted to 1.2.

[0097] c) Preparation of the dispersion An appropriate amount of prototype 1 nanosuspension was added to a translucent HDPE vial (25 ml) with an HDPE lid. It was diluted with 15 ml of simulated gastric or intestinal fluid to a final progenin concentration of 0.5 mg / ml. A dispersant was then added and the prepared dosage form was shaken until it was completely dispersed. The vial was placed in a 37°C oil bath until flocculation was observed. The size of the precipitated particles was measured using a Horiba-LA-910 particle analyzer. The material was then incubated in fasted human gastric fluid for approximately 3 hours.

[0098] d) Average particle size measurement When measuring beads coated with bead cores containing insoluble particles, the weight of the bead cores was calculated in the SIF or SGF experiments and the bead cores were dispersed in the volume as SIF or SGF. 120 gm of distilled water was poured into the Horiba LA-910 chamber and then drained to make the instrument blank. Then, 120 gm of distilled water was poured and the entire volume of the incubated formulation (in 15 ml of SGF or SIF) was poured into the Horiba LA-910 chamber and 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 dispersion stability and bioavailability of the drug were maintained.

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

[0102] [Table 8]

[0103] First, purified water was prepared at 55-60 °C, TPGS was added to the solution preparation vessel while stirring, and the thermostatic water bath was kept heated to 55-60 °C until TPGS was completely dissolved. HPMC E3 was added to the solution preparation vessel while stirring, and then cooled to ambient temperature (15-25 °C) while stirring until the solids were completely dissolved and the HPMC E3 solution was clear. Progerinin (batch formula C19010954-C) was gradually filled into the solution preparation vessel and stirring was continued.

[0104] The parameters of the agitator bead mill, which is a mixing and wet grinding equipment, were set as shown in Table 9 below. The suspension coming out of the agitator bead mill was recycled back to the solution production vessel, 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 250mg and 350mg granules A dosage form of progerinin sachet was prepared with the composition shown in Table 10 below. Mannitol 100SD, Mannitol 200SD and Croscarmellose Sodium SD-711 were added to the container containing the prepared nanosuspension. The mixture was mixed for at least 2 hours to confirm whether the redispersion agent was completely dissolved. After preheating the machine and materials, the granulation solution (nozzle size: 1.0 mm) was sprayed. The inlet air flow, inlet air temperature and spray speed were adjusted to maintain proper fluidization during the entire spray process. After the granulation process was completed, the granules were dried. The LOD (measured at 105°C) was monitored at appropriate times, 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 Progerinin Sachet Sweetener (sucralose), lubricant (magnesium stearate) and flavour (grape flavour) were added to the prepared granules and the R&D sachets were filled manually, while for Human PK batch production a Sachet Filling Machine was used.

[0108] [Table 10]

[0109] Although the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. That is, the substantial scope of the present invention is defined by the claims and their equivalents.

Claims

1. (a) 20 to 40% by weight of progerinin represented by the following chemical formula 1; (b) 5 to 15% by weight of hydroxypropyl methylcellulose (HPMC); (c) 1 to 10 parts by weight of D-α-tocopherol polyethylene glycol succinate (TPGS); (d) the balance of additives, The progerinin-containing granules are characterized in that the progerinin is in the form of drug particles formed by wet ball milling to have an average particle size (D50) of 100 to 300 nm. 【Chemistry 1】

2. The granule according to claim 1, wherein the progerinin has an average particle size (D50) of 100 to 200 nm.

3. The granule according to claim 1, wherein the additive is at least one selected from the group consisting of a filler, a binder, a disintegrant, and a lubricant.

4. The granule according to claim 3, wherein the excipient is at least one selected from the group consisting of mannitol, starch, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, lactose, glucose, fructose, sodium alginate, and hydroxypropyl starch.

5. The granule according to claim 3, wherein the binder is at least one 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.

6. The granule according to claim 3, wherein 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.

7. The granule according to claim 3, wherein the lubricant is at least one selected from the group consisting of calcium stearate, magnesium stearate, sodium stearate, stearic acid, hydrogenated vegetable oil, talc, kaolin, liquid paraffin, and magnesium oxide.

8. A capsule comprising the granules according to any one of claims 1 to 7.

9. A sachet comprising a granule according to any one of claims 1 to 7, a sweetener and a flavouring.

10. (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) with purified water, and then adding and mixing progerinin represented by the following formula 1 to prepare a suspension; (2) wet ball milling the suspension to produce a nanosuspension; (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulating the mixture in a fluidized bed granulator; The method for preparing granules containing progerinin, wherein the progerinin in the nanosuspension in step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm. 【Chemistry 2】

11. The method for preparing granules containing progerinin according to claim 10, wherein the purified water in step (1) is at a temperature of 50 to 70°C.

12. The method for preparing granules containing progerinin according to claim 10, wherein in step (2), the suspension of step (1) and zirconia beads are mixed in a volume ratio of 1:1 to 1:5 during wet ball milling, and then milled to prepare a nanosuspension.

13. (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) with purified water, and then adding and mixing progerinin represented by the following formula 1 to prepare a suspension; (2) wet ball milling the suspension to produce a nanosuspension; (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulating the mixture in a fluidized bed granulator; (4) filling the granulated granules into a capsule, The method for preparing a capsule containing progerinin, wherein the progerinin in the nanosuspension in step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm. 【Chemistry 3】

14. (1) preparing a vehicle solution by mixing hydroxypropyl methylcellulose (HPMC) and D-α-tocopherol polyethylene glycol succinate (TPGS) with purified water, and then adding and mixing progerinin represented by the following formula 1 to prepare a suspension; (2) wet ball milling the suspension to produce a nanosuspension; (3) mixing the nanosuspension with one or more additives selected from the group consisting of excipients, binders, disintegrants, and lubricants, and then granulating the mixture in a fluidized bed granulator; (4) adding sweeteners and flavors to the granulated granules and filling them into sachets, The method for preparing a sachet containing progerinin, wherein the progerinin in the nanosuspension in step (2) is in the form of particles having an average particle size (D50) of 100 to 300 nm. 【Chemistry 4】

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