WO2022071768A1 - A pharmaceutical composition comprising fenofibrate particles with improved bioavailability - Google Patents

Abstract

Provided is a pharmaceutical composition comprising finely pulverized fenofibrate particles, a surfactant, and a hydrophilic polymer. According to the present invention, by selecting an appropriate fenofibrate particle size and an appropriate hydrophilic polymer content, it is possible to provide a fenofibrate composition having bioavailability independent of dietary intake although using micrometer-sized fenofibrate particles.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING FENOFIBRATE PARTICLES WITH IMPROVED BIOAVAILABILITY

The present invention relates to a pharmaceutical composition comprising fenofibrate particles.

Fenofibrate, which is a fibric acid derivative, is used for the treatment of primary hyperlipidemia: hypercholesterolemia (Type IIa), combined types of hypercholesterolemia and hypertriglyceridemia (Types IIb and III), and hypertriglyceridemia (Type IV). Fibric acid acts as an agonist on peroxisome proliferator-activated receptor alpha (PPAR-α) and thereby inhibits triglyceride synthesis in the liver, and promotes triglyceride metabolism by accelerating the oxidation of triglycerides.

Fibrate-based materials such as fenofibrate are poorly soluble materials classified as Biopharmaceutics Classification System (BCS) class II drugs, so their bioavailability greatly varies depending on the patient's diet, and the bioavailability decreases when administered before meals. In order to solve these problems, methods such as adding a solubilizing agent to fenofibrate to prepare wet granules or dissolving fenofibrate into an amorphous state and forming a solid dispersion therewith (Korean Patent Publication No. 10-767349; Patent Document 1) were tried, but the above problems were not sufficiently solved.

In order to solubilize a fibrate, a formulation was also prepared by finely pulverizing fibrate particles into micrometer-sized particles, but the problems related to dietary intake were not sufficiently solved, so attempts have been made to achieve equivalent levels of bioavailability before and after dietary intake by making smaller fibrate nanoparticles having an average particle size of less than 500 nm (International Publication No. WO2004/041250; Patent Document 2).

However, pulverizing particles into smaller nanoscale particles requires a large amount of energy, and when a lot of energy is applied, there is a possibility that an active ingredient may be melted due to heat generated during the pulverization process and the crystal form may be partially changed, and in general, when a particle size decreases, the surface area of the active ingredient increases, so the probability of crystal form deformation may increase. In addition, as the particle size of the drug becomes smaller, surface free energy increases, and when the drug is administered, the nanometer-sized drug particles tend to agglomerate with one another in order to reduce the surface free energy, so bioavailability may be lowered.

[Related Art Documents]

[Patent Documents]

(Patent Document 1) Korean Patent Publication No. 10-767349

(Patent Document 2) International Publication No. WO2004/041250

The present invention is directed to providing finely pulverized fenofibrate particles for preparing an oral pharmaceutical composition having bioavailability independent of dietary intake although having a micrometer-scale particle size, a pharmaceutical composition comprising the fenofibrate particles, and a method of preparing the pharmaceutical composition.

In general, attempts have been made to reduce a particle size to improve the bioavailability of poorly soluble drugs, but the decrease in the particle size of poorly soluble drugs and increase in bioavailability do not always show a correlation.

Tricor^TM tablets commercially available in the United States use nanometer-sized fenofibrate particles, as disclosed in WO2004/041250. However, the fabrication of nanometer-sized fenofibrate particles requires high energy, and the stability of the active ingredient may be degraded by heat, and the particles may easily form particle agglomerations due to high free energy. Therefore, the present inventors have made efforts to prepare fenofibrate particles which are prepared by finely pulverizing fenofibrate although not in nanometer size, but exhibit an excellent dissolution rate and excellent bioavailability.

As a result, the present inventors confirmed, through the Examples described below, that it is very important to select an appropriate fenofibrate particle size and, at the same time, use an appropriate amount of hydrophilic polymer in order to achieve the desired fenofibrate dissolution rate and bioavailability.

In Experimental Example 1, an experiment was conducted to observe a change in dissolution rate according to a particle size, and considering that the dissolution rate is 75% or more up to 60 minutes in Preparation Examples 2 and 3 having a fenofibrate particle size in which d(90) is 1 to 3 μm, it can be seen that the dissolution rate is similar to that of the Tricor^TM tablets.

In Experimental Example 2, a dissolution rate test for tablets of Preparation Examples 4 and 5 having different compositions from Preparation Examples 1 to 3 was performed, and considering that the dissolution rate of the tablet of Preparation Example 4 having a fenofibrate particle size in which d(90) is more than 3 μm is too low, it can be seen that tablets having a d(90) of more than 3 μm are not appropriate.

On the other hand, in the case of Preparation Example 5 having a fenofibrate particle size in which d(90) is 1 to 3 μm, although a dissolution rate is 70% or more up to 60 minutes, the maximum dissolution rate does not exceed 75%, which is probably because the content of a hydrophilic polymer is lower than that of the tablets of Preparation Examples 2 and 3.

Therefore, even when a fenofibrate have a particle size in which d(90) is 1 to 3 μm, when a hydrophilic polymer is not used, a dissolution rate is not sufficiently high, so it was determined that in order to improve the dissolution rate, it is necessary to use a specific amount of hydrophilic polymer or more.

Accordingly, the present inventors have found, through Preparation Examples 6 to 8 in which the content of the hydrophilic polymer was increased, that the hydrophilic polymer content condition resulting in a maximum dissolution rate of 75% or more was 0.25 to 0.8 parts by weight relative to 1 part by weight of the fenofibrate.

Accordingly, one aspect of the present invention provides a pharmaceutical composition comprising finely pulverized fenofibrate particles, a surfactant, and a hydrophilic polymer, wherein (a) the fenofibrate particles have a d(90) of 1 to 3 μm, and (b) the hydrophilic polymer is comprised in an amount of 0.25 to 0.8 parts by weight based on 1 part by weight of the fenofibrate.

In the pharmaceutical composition of the present invention, the d(90) of the fenofibrate particles may be 1 to 3 μm, for example, 1.1 to 2.9 μm, 1.2 to 2.8 μm, 1.3 to 2.7 μm, 1.4 to 2.6 μm, or 1.5 to 2.5 μm.

In another embodiment, the fenofibrate particles may have a d(50) of 0.5 μm or more. As described above, when the particle size of the fenofibrate particles is lowered to a nanometer level, since the stability of the active ingredient may be negatively affected, it is preferable that the fenofibrate particles used in the pharmaceutical composition of the present invention preferably have a d(50) of 0.5 μm or more. Although not limited thereto, the fenofibrate particles may have a d(50) of 0.5 to 1.2 μm. For example, the fenofibrate particles may have a d(50) of 0.6 to 1.1 μm.

For the same reason, the fenofibrate particles may have an average particle sizee of 0.7 to 1.4 μm. For example, the fenofibrate particles may have an average particle size of 0.8 to 1.3 μm. In the present specification, the average particle size is a volume- or mass-based average and refers to a volume weighted Mean D[4,3] value in each distribution plotted versus volume or mass.

In an embodiment of the present invention, the fenofibrate particles may have a d(90) of 1 μm to 3 μm, and at the same time have a d(50) of 0.5 μm to 1.2 μm or an average particle size of 0.7 μm to 1.4 μm, and the hydrophilic polymer may be comprised in an amount of 0.25 parts by weight to 0.8 parts by weight based on 1 part by weight of the fenofibrate.

Even though not specified as a specific example, when fenofibrate particles having d(90), d(50), and/or average particle size values within the above-exemplified ranges are used, a pharmaceutical composition desired in the present invention can be obtained.

Methods for finely pulverizing drug particles are well known in the art. For example, the particles can be pulverized using a conventional mill capable of pulverizing particles, such as a Z-mill, a hammer mill, a ball mill, or a fluid energy mill. In addition, a sieving method performed using a sieve or a size classification method such as an air current classification method may be used to further subdivide the size of drug particles. Methods for adjusting to a desired particle size are well known in the art. See, for example, the document: Pharmaceutical Dosage Forms:Volume 2, 2nd edition (Ed.): H. A. Lieberman, L. Lachman, J. B. Schwartz (Chapter 3: Size Reduction).

In this specification, a particle size of a drug may be represented based on a particle size distribution such as d(X) = Y (here, X and Y are positive numbers). d(X) = Y refers to the fact that, when a particle size distribution of a drug obtained by measuring a particle diameter of a certain drug in a formulation is represented as a cumulative curve, a point at which particle sizes accumulate in ascending order and the result reaches X% (% is calculated based on a number, a volume or a weight) has a particle diameter of Y. For example, d(10) represents a diameter of a particle at a point at which particle sizes of a drug accumulate in ascending order and the result reaches 10%. d(50) represents a diameter of a particle at a point at which particle sizes of a drug accumulate in ascending order and the result reaches 50%. d(90) represents a diameter of a particle at a point at which particle sizes of a drug accumulate in ascending order and the result reaches 90%.

In the present specification, d(X) can also be expressed as d(0.X), and d(X) and d(0.X) are used interchangeably. For example, d(50) is also expressed as d(0.5), and d(10) and d(90) are also expressed as d(0.1) and d(0.9), respectively.

Whether the cumulative percentage in d(X) in the particle size distribution is based on the number, volume, or weight of particles depends on a method used for measuring the particle size distribution. Methods for measuring the particle size distribution and types of % associated therewith are known in the art. For example, when the particle size distribution is measured by a well-known laser diffraction method, the value of X in d(X) represents a percentage calculated based on a volume-based average. A person skilled in the art is well aware, based on routine experimental experience, that the particle size distribution measurement results obtained by one method may be correlated with results obtained by other methods. For example, the laser diffraction method gives a volume-based average particle size because it is sensitive to the volume of particles, and the volume-based average particle size is equivalent to a weight-based average particle size when density is uniform.

In the present invention, the average particle size and particle size distribution of fenofibrate particles may be measured using a commercially available instrument according to a laser diffraction/scattering method based on the Mie theory. For example, the average particle size and particle size distribution are measured using a commercially available instrument such as a Mastersizer laser diffraction instrument manufactured by Malvern Panalytical Ltd. This instrument measures a particle diameter distribution as follows. When particles are irradiated with a helium-neon laser beam and light from a blue light-emitting diode, scattering occurs and a light scattering pattern appears on a detector, and by analyzing the light scattering pattern according to the Mie theory, the particle diameter distribution is obtained. The measurement method may be either a dry method or a wet method, but in the Examples described below, results measured by the wet method will be described.

In a pharmaceutical composition of the present invention, a hydrophilic polymer and a surfactant are essentially used to stabilize the finely pulverized fenofibrate.

In the present invention, the hydrophilic polymer serves to help the pulverization of fenofibrate and the redispersion of finely pulverized fenofibrate, and serves as a solubilizer capable of improving the dissolution rate of fenofibrate.

In one embodiment of the present invention, the hydrophilic polymer may be one or more selected from the group consisting of hypromellose, polyvinylpyrrolidone, polyethylene glycol, a vinylpyrrolidone/vinyl acetate copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, and a methacrylate copolymer.

Although not limited thereto, in one exemplary embodiment of the present invention, the hydrophilic polymer may be hypromellose, polyvinylpyrrolidone, or a vinylpyrrolidone/vinyl acetate copolymer. In one exemplary embodiment of the present invention, the hydrophilic polymer may be hypromellose.

The surfactant serves to inhibit the agglomeration of finely pulverized fenofibrate and help redispersion. Increasing the surfactant content may be advantageous in terms of increasing the redispersion rate of fenofibrate pulverized to a micrometer or nanometer size, but since the increased use of surfactant may be harmful to the human body, it is better to use less surfactant.

In one embodiment of the present invention, the surfactant may be comprised in an amount of 0.02 to 0.12 parts by weight based on 1 part by weight of the fenofibrate. Compared to the previously reported fenofibrate compositions, the above surfactant content is significantly lower, which is advantageous in terms of safety for the human body.

In one embodiment of the present invention, the surfactant may be one or more selected from the group consisting of a docusate salt, a lauryl sulfate salt, sucrose, a stearate salt, a cetyltrimethylammonium salt, a fatty alcohol ethoxylate, a poloxamer, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, and polyoxyethylene monooleate.

In one embodiment of the present invention, the surfactant may be sodium docusate and sodium lauryl sulfate. In one embodiment of the present invention, the surfactant may be sodium docusate, sodium lauryl sulfate and sucrose.

In one embodiment of the present invention, the fenofibrate dissolution rate of a pharmaceutical composition of the present invention up to, for example, 60 minutes may be 75% or more, for example, 80% or more.

The fenofibrate dissolution rate of a pharmaceutical composition of the present invention is approximately equivalent to the fenofibrate dissolution rate of a nanoparticulate fibrate formulation. Here, the nanoparticulate fibrate formulation is a product approved by a drug approval institution such as the FDA and the Ministry of Food and Drug Safety of Korea. For example, the fenofibrate dissolution rate of a pharmaceutical composition of the present invention is approximately equivalent to the fenofibrate dissolution rate of Tricor^TM.

In addition, the present invention provides a pharmaceutical composition, the fenofibrate of which has a biologically equivalent total integrated area under the plasma drug concentration-time curve (AUC) and peak plasma concentration (C_max) to those of finely pulverized fenofibrate formulations having the same active ingredient content. In one embodiment, the present invention provides a pharmaceutical composition, the fenofibrate of which has a biologically equivalent AUC and C_max to those of Tricor^TM tablets having the same active ingredient content.

Here, drug equivalence criteria may be used to determine whether the area under the concentration-time curve (AUC) and the maximum observed plasma concentration (C　_max) show a bioequivalence level. For example, when the area under the concentration-time curve (AUC) and the maximum observed plasma concentration (C　_max) of a reference drug and a test drug are log-transformed and statistically processed according to a bioequivalence test of drug equivalence test criteria of drug-related law, if two items are within log 0.8 to log 1.25 in a confidence interval of 90% of a difference of log-transformed average values, it is determined that the drug equivalence test is equivalent. However, as the guidelines for bioequivalence exception, it was determined as equivalent when both conditions are satisfied, 1) when a difference of log-transformed average values of comparison evaluation item values of the reference drug and the test drug is within log 0.9 to log 1.11, and 2) when a comparison dissolution test is performed according to drug equivalence test criteria, the results are equivalent under all defined conditions.

In the pharmaceutical composition of the present invention, no particular limitation is imposed on the fenofibrate content. For example, the pharmaceutical composition of the present invention may be formulated to contain fenofibrate in various amounts, for example, 48 mg, 120 mg, 130 mg, 145 mg, 160 mg, or the like per unit dose.

In one embodiment of the present invention, the pharmaceutical composition may contain 145 mg of fenofibrate.

In another embodiment of the present invention, the pharmaceutical composition may be in form of a tablet, a mini-tablet- and/or pellet-containing capsule.

The pharmaceutical composition of the present invention which comprises fenofibrate may be used for the treatment of primary hyperlipidemia: hypercholesterolemia (Type IIa), combined types of hypercholesterolemia and hypertriglyceridemia (Types IIb and III), and hypertriglyceridemia (Type IV).

In addition to the active ingredient, the pharmaceutical composition of the present invention comprises one or more additives.

A diluent increases the volume of a solid pharmaceutical composition so that patients and caregivers can easily handle a pharmaceutical formulation comprising the composition. Examples of diluents for solid compositions include microcrystalline cellulose, microfine cellulose, lactose, lactose hydrate, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., Eudragit^®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

A solid pharmaceutical composition compressed into dosage forms such as tablets may include an additive that serves to help bind an active ingredient with excipients after compression. Examples of binders for solid pharmaceutical compositions include acacia, alginic acid, a carbomer (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel^®), hydroxypropylmethyl cellulose (e.g., Methocel^®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g., Kollidon^®, Plasdone^®), pregelatinized starch, sodium alginate, and starch.

A disintegrant may be added to the composition to increase the dissolution rate of the compressed solid pharmaceutical composition in the patient's stomach. Examples of disintegrants include hydroxypropyl cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., Ac-Di-Sol^®, Primellose^®), microcrystalline cellulose, methyl cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon^®, Polyplasdone^®), guar gum, magnesium aluminum silicate, polacrilin potassium, pregelatinized starch, alginic acid, sodium alginate, sodium starch glycolate (e.g., Explotab^®), and starch.

When compressing a powder composition to form a dosage form such as a tablet, the composition is pressed with a punch and a die. In this case, some excipients and active ingredients tend to adhere to a surface of the punch or die, and this may cause pitting and miscellaneous surface irregularities in the product. A lubricant may be added to the composition to reduce tackiness and facilitate the ejection of a product from a die. Examples of lubricants include stearate salts such as magnesium stearate, calcium stearate, aluminum stearate, and zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc, and the like.

In order to improve storage stability, preservative and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added in amounts that are safe for consumption.

The pharmaceutical composition of the present invention may be formulated as a tablet, and in this case, the composition may be coated with a coating agent when necessary.

Another aspect of the present invention provides a method of treating hyperlipidemia including administering the above-described pharmaceutical composition to a subject in need thereof, and a use of the composition for the manufacture of a medicament for treating hyperlipidemia.

In the present invention, the hyperlipidemia includes primary hyperlipidemia such as hypercholesterolemia (Type IIa), combined types of hypercholesterolemia and hypertriglyceridemia (Types IIb and III), and hypertriglyceridemia (Type IV), but the present invention is not limited thereto.

In the present invention, "subject" refers to a warm-blooded animal such as a mammal (e.g., human, orangutan, chimpanzee, mouse, rat, dog, cow, chicken, pig, goat, sheep) suffering from a specific disease or disorder, but the present invention is not limited to these examples.

In the present invention, "treatment" includes alleviating symptoms, temporarily or permanently eliminating the cause of symptoms, or preventing or slowing the onset of symptoms and the progression of a disease or a disorder, but the present invention is not limited thereto.

An "effective amount" of an active ingredient of the pharmaceutical composition of the present invention refers to an amount required to achieve the treatment of a disease. Therefore, the effective amount may be adjusted according to various factors including the type of disease, the severity of disease, the types and amounts of active ingredients and other ingredients comprised in the composition, the type of formulation, the age, weight, general health condition, and sex of the patient, diet, administration time, administration route, and the secretion rate of composition, duration of treatment, and concurrently used drugs. For example, the pharmaceutical composition of the present invention may be administered one to three times a day, and may be taken in an amount per dosage unit exemplified above, but the present invention is not limited thereto.

According to the present invention, by selecting an appropriate fenofibrate particle size and an appropriate hydrophilic polymer content, it is possible to provide a fenofibrate composition having bioavailability independent of dietary intake although using micrometer-sized fenofibrate particles.

FIG. 1 is a fenofibrate dissolution graph of tablets of Preparation Examples 1 to 3.

FIG. 2 is a fenofibrate dissolution graph of tablets of Preparation Examples 4 and 5.

FIG. 3 is a fenofibrate dissolution graph of tablets of Preparation Examples 5 to 8.

FIG. 4 is a graph showing pharmacokinetics (PK) test results of a commercially available formulation and a tablet of Preparation Example 8.

FIG. 5 is a fenofibrate dissolution graph of tablets of Preparation Examples 6, 9 to 10.

FIG. 6 is a fenofibrate dissolution graph of tablets of Preparation Examples 7, 11 to 12.

FIG. 7 is a fenofibrate dissolution graph of tablets of Preparation Examples 13 to 14.

Advantages and features of the present invention and methods for achieving the same will become apparent with reference to the exemplary embodiments described below in detail. However, the present invention is not limited to the embodiments described below but can be implemented in a variety of different forms, and the embodiments are only provided so that the disclosure of the present invention is complete and to fully inform those of ordinary skill in the art to which the present invention belongs of the scope of the invention, and the present invention is only defined by the scope of the claims.

[Examples]

Preparation Examples 1 to 3: Preparation of tablets having different fenofibrate particle sizes

Preparation of fenofibrate composition (units: mg)

Classification	Ingredient name	Preparation Example 1	Preparation Example 2	Preparation Example 3
Binder solution 1	Fenofibrate	145	145	145
	Hypromellose	30	30	30
	Sodium docusate	2	2	2
	Sodium lauryl sulfate	1.5	1.5	1.5
	Purified water	300	300	300
Binder solution 2	Hypromellose	30	30	30
	Purified water	210	210	210
Carrier	Lactose hydrate	150	150	150
	D-mannitol	50	50	50
Blend/ Lubrication	Crospovidone	120	120	120
	Microcrystalline cellulose	20	20	20
	Aerosil	5	5	5
	Magnesium stearate	3	3	3

Tablets of Preparation Examples 1 to 3 were prepared according to compositions shown in the above Table 1. The compositions of Preparation Examples 1 to 3 were completely the same.

First, materials used forBinder solution 1 in the compositions of Table 1 were mixed and then pulverized under high-energy milling conditions using a high-pressure particle pulverizer (Microfluidics International Corporation), and by varying the number of pulverization cycles applied to Preparation Examples 1 to 3, finely pulverized fenofibrate particles having different particle sizes were prepared.

The size of the finely pulverized fenofibrate particles according to Preparation Examples 1 to 3 was measured using a laser scattering particle size analyzer (Mastersizer 2000; manufacturer: Malvern Panalytical Ltd.), in which case, purified water was used as a medium. A suspension was prepared by adding finely pulverized fenofibrate particles and a solvent to a beaker (1,000 ml) and then stirred at 1,500 rpm, and the dispersion phase in which the finely pulverized particles to be analyzed were homogeneously suspended was analyzed, and the results are shown in Table 2.

<Particle size measurement conditions>

- Instrument: Malvern Mastersizer 2000/Hydro 2000MU

- Usage amount of sample: 0.5 g

- Refractive index of sample: 1.520

- Analysis model: General purpose

- Sensitivity: Normal

- Sample measurement time: 10 seconds

- Analysis range: 0.020 to 2,000.0 μm

Classification	Particle size (μm)			Average particle size (μm)
	d(10)	d(50)	d(90)
Preparation Example 1	0.577	1.354	3.348	1.693
Preparation Example 2	0.221	0.832	2.324	1.084
Preparation Example 3	0.199	0.669	1.836	0.860

In Preparation Examples 1 to 3, materials used forBinder solution 2 were mixed together and then with the finely pulverized fenofibrate particles, and thus a final binder solution was obtained.

Subsequently, granules were prepared using a fluid bed granulator while spraying the final binder solution onto a mixture of lactose hydrate and D-mannitol used as a carrier. The granules were prepared under the conditions of an injection temperature of 70 to 85 ℃, a chamber temperature of 35 to 45 ℃, and an injection rate of 8 to 25 g/min. The prepared granules were mixed well with crospovidone, microcrystalline cellulose, Aerosil, and magnesium stearate and then compressed into tablets.

Reference Example: Dissolution rate of Tricor^TM tablet

Tricor^TM tablets containing 145 mg fenofibrate(Reference drug) were tested by the dissolution test method II (paddle method) of the Korean Pharmacopoeia using a dissolution tester (manufacturer: Teledyne Hanson). The dissolution test was carried out under the conditions of a deionized water (DW; containing 0.4% sodium lauryl sulfate (SLS)) eluent, a paddle speed of 50 rpm, and a temperature of 37 ℃, and quantification was performed using high performance liquid chromatography (HPLC; manufacturer: Agilent), which is a liquid chromatography method, under the following conditions, and the results are shown in Table 3.

<HPLC measurement conditions>

- Detector: Ultraviolet absorbance spectrometer (measurement wavelength: 286 nm)

- Column: Column (250 mmХ4.0 mm, 5 μm) filled with octadecyl silylated silica gel or similar column

- Flow rate: 2.5 mL/min

- Column temperature: 35 ℃

- Mobile phase: acetonitrile: pH 2.5 phosphoric acid solution=85:15 v/v%

- Injection volume: 10 μL

Dissolution rate (%)
0minutes	5minutes	10 minutes	15minutes	30minutes	60 minutes
0.0	5.9	25.4	45.5	78.7	77.8

According to the dissolution rest results for Tricor^TM tablets, the average dissolution rate at 60 minutes was 75% or more.

Experimental Example 1: Change in dissolution rate according to particle size

The tablets of Preparation Examples 1 to 3 were tested by the dissolution test method II (paddle method) of the Korean Pharmacopoeia. The dissolution test was carried out under the conditions of a DW (with 0.4% SLS added) eluent, a paddle speed of 50 rpm, and a temperature of 37 ℃, and quantification was carried out using HPLC, and the results are shown in Table 4 and FIG. 1. The results show that the dissolution rates are different for different fenofibrate particle sizes.

Classification / Time (minutes)	Dissolution rate (%)
	0minutes	5minutes	10 minutes	15minutes	30minutes	60 minutes
Preparation Example 1	0.0	35.6	72.6	70.5	71.1	70.3
Preparation Example 2	0.0	34.9	60.3	73.9	83.9	85.5
Preparation Example 3	0.0	29.2	72.0	76.8	80.6	82.3

As can be seen in Table 4 and FIG. 1, in the case of Preparation Example 1(#1), a dissolution rate of 70% or more was reached within 10 minutes, but the dissolution rate did not increase any more thereafter. In the case of Preparation Example 2(#2) and Preparation Example 3(#3) having a fenofibrate particle size d(90) of 1 to 3 μm, an average dissolution rate up to 60 minutes was greater than or equal to 75% which is the average dissolution rate of Tricor^TM, so Preparation Examples 2 and 3 are considered appropriate.

Preparation Examples 4 and 5: Preparation of tablets having different fenofibrate particle sizes

In order to confirm whether the tendency that different fenofibrate particle sizes result in different dissolution rates will be similarly seen in the case of compositions different from Preparation Examples 1 to 3, Preparation Examples 4 and 5 having compositions shown in the following Table 5 were additionally prepared. Unlike in Preparation Examples 1 to 3, components ofBinder solution 2 were not used in Preparation Examples 4 and 5.

Preparation of fenofibrate composition (units: mg)

Classification	Ingredient name	Preparation Example 4	Preparation Example 5
Binder solution 1	Fenofibrate	145	145
	Hypromellose	30	30
	Sodium docusate	2	2
	Sodium lauryl sulfate	1.5	1.5
	Purified water	300	300
Binder solution 2	Hypromellose	-	-
	Purified water	-	-
Carrier	Lactose hydrate	150	150
	D-mannitol	50	50
Blend/Lubrication	Crospovidone		100	100
	Microcrystalline cellulose	30	30
	Aerosil	5	5
	Magnesium stearate	3	3

First, materials used forBinder solution 1 in the compositions of Table 5 were mixed and then pulverized under high-energy milling conditions using a high-pressure particle pulverizer (Microfluidics International Corporation), and by varying the number of pulverization cycles applied to Preparation Examples 4 and 5, finely pulverized fenofibrate particles having different particle sizes were prepared.

The size of the finely pulverized fenofibrate particles according to Preparation Examples 4 and 5 was measured using a Mastersizer 2000 laser scattering particle size analyzer (manufacturer: Malvern Panalytical Ltd.), and the results are shown in Table 6.

Classification	Particle size (μm)			Average particle size (μm)
	d(10)	d(50)	d(90)
Preparation Example 4	0.342	1.276	3.135	1.540
Preparation Example 5	0.303	1.052	2.344	1.204

In Preparation Examples 4 and 5,Binder solution 2 was not used, andBinder solution 1 was used as a final binder solution.

Granules were prepared using a fluid bed granulator while spraying the final binder solution onto a mixture of lactose hydrate and D-mannitol used as a carrier. The granules were prepared under the conditions of an injection temperature of 70 to 85 ℃, a chamber temperature of 35 to 45 ℃, and an injection rate of 8 to 25 g/min. The prepared granules were mixed well with crospovidone, microcrystalline cellulose, Aerosil, and magnesium stearate and then compressed into tablets.

Experimental Example 2: Change in dissolution rate according to particle size

As in Experimental Example 1, the tablets of Preparation Examples 4 and 5 were tested by the dissolution test method II (paddle method) of the Korean Pharmacopoeia. The dissolution was carried out under the conditions of a DW (with 0.4% SLS added) eluent, a paddle speed of 50 rpm, and a temperature of 37 ℃, and quantification was carried out using HPLC, and the results are shown in Table 7 and FIG. 2. The results show that the dissolution rates are different for different fenofibrate particle sizes.

Classification / Time (minutes)	Dissolution rate (%)
	0minutes	5minutes	10 minutes	15minutes	30minutes	60 minutes
Preparation Example 4	0.0	38.1	58.0	57.7	55.0	54.2
Preparation Example 5	0.0	38.2	63.6	68.6	71.7	74.4

As can be seen in Table 7 and FIG. 2, in the case of Preparation Example 4(#4) in which a fenofibrate particle size d(90) was greater than 3 μm andBinder solution 2 including a hydrophilic polymer was not used, a dissolution rate of 58% was exhibited after 10 minutes, but the dissolution rate did not increase any more thereafter.

In the case of Preparation Example 5(#5) having a fenofibrate particle size d(90) of 1 to 3 μm, it can be seen that a dissolution rate was about 74% up to 60 minutes, but this was lower than the dissolution rates of tablets of Preparation Examples 2 and 3 in whichBinder solution 2 including a hydrophilic polymer was used.

Therefore, even though a fenofibrate particle diameter d(90) was in the range of 1 to 3 μm, since a low dissolution rate was exhibited whenBinder solution 2 additionally including a hydrophilic polymer was not used, it was found that the additional use of a hydrophilic polymer was necessary to improve the dissolution rate.

Preparation Examples 6 to 8: Preparation of fenofibrate tablets having various hydrophilic polymer contents

Preparation of fenofibrate composition (units: mg)

Classification	Ingredient name	Preparation Example 5	Preparation Example 6	Preparation Example 7	Preparation Example 8
Binder solution 1	Fenofibrate	145.00	145.00	145.00	145.00
	Hypromellose	30	30	30	30
	Sodium docusate	2	2	2	2
	Sodium lauryl sulfate	1.5	1.5	1.5	1.5
	Purified water	300	300	300	300
Binder solution 2	Hypromellose	-	10	30	80
	Purified water	-	70	210	560
Carrier	Lactose hydrate	150	150	150	150
	D-mannitol	50	50	50	50
Blend/Lubrication	Crospovidone		100	100	100	100
	Microcrystalline cellulose	30	30	30	30
	Aerosil	5	5	5	5
	Magnesium stearate	3	3	3	3

Tablets of Preparation Examples 6 to 8 were configured with compositions shown in the above Table 8. First, in the preparation of tablets of Preparation Examples 6 to 8, the finely pulverized fenofibrate particles of Preparation Example 5, that is,Binder solution 1 of Preparation Example 5, was used, andBinder solution 2 was additionally used unlike in Preparation Example 5, and tablets were formed while varying the amount of hydrophilic polymer (hypromellose) comprised inBinder solution 2.

Experimental Example 3: Change in dissolution rate according to hydrophilic polymer content

The tablets of Preparation Example 5 and Preparation Examples 6 to 8 were tested by the dissolution test method II (paddle method) of the Korean Pharmacopoeia. The dissolution test was carried out under the conditions of a DW (with 0.4% SLS added) eluent, a paddle speed of 50 rpm, and a temperature of 37 ℃, and quantification was carried out using HPLC, and the results are shown in Table 9 and FIG. 3. The results show that the dissolution rates are different for different hydrophilic polymer contents under the same fenofibrate particle size conditions.

Classification / Time (minutes)	Dissolution rate (%)
	0minutes	5minutes	10 minutes	15minutes	30minutes	60 minutes
Preparation Example 5	0.0	38.2	63.6	68.6	71.7	74.4
Preparation Example 6	0.0	33.3	70.4	77.8	80.9	82.6
Preparation Example 7	0.0	36.0	62.5	72.4	78.8	80.7
Preparation Example 8	0.0	37.3	72.3	79.4	81.9	83.0

As can be seen in Table 9 and FIG. 3, in the case of Preparation Example 5 in whichBinder solution 2 comprising a hydrophilic polymer was not used, as confirmed above, the dissolution rate was not sufficiently high as compared to cases whereBinder solution 2 including a hydrophilic polymer was used. On the other hand, in the case of all of Preparation Examples 6 to 8(#6 to #8) in which the total content of hydrophilic polymer in a composition was increased usingBinder solution 2 including a hydrophilic polymer, a dissolution rate of 80% or more was exhibited, and it can be seen that Preparation Examples 6 to 8 are suitable for use as a fenofibrate formulation.

Experimental Example 4: Plasma concentration comparison test

The formulation of Preparation Example 8 in which a fenofibrate particle size d(90) was 3 μm or less and a dissolution profile showing a dissolution rate of 80% or more was selected as a test drug, and Tricor^TM tablets which include 145 mg fenofibrate were selected as a reference drug, and the bioavailabilities thereof were compared and evaluated.

When the area under the concentration-time curve (AUC) and the maximum observed plasma concentration (C_max) of a reference drug and a test drug are log-transformed and statistically processed according to a bioequivalence test of drug equivalence test criteria of drug-related law, if two items are within log 0.8 to log 1.25 in a confidence interval of 90% of a difference of log-transformed average values, it is determined that the drug equivalence test is equivalent. However, as the guidelines for bioequivalence exception, it was determined as equivalent when both conditions are satisfied, 1) when a difference of log-transformed average values of comparison evaluation item values of the reference drug and the test drug is within log 0.9 to log 1.11, and 2) when a comparison dissolution test is performed according to drug equivalence test criteria, the results are equivalent under all defined conditions.

After orally administrating the test drug and the reference drug to 10 male beagle dogs before meals, the plasma concentration of materials according to time was compared and analyzed. A total of two groups, a test group and a control group, were set up for the experiment. After orally administering to each group of five animals, blood was collected from each individual at regular time intervals, and plasma was separated. The analysis of biological samples was performed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), where fenofibric acid in plasma was quantitatively analyzed.

The results of analyzing fenofibric acid of the test drug and the reference drug in plasma are shown in Table 10 and FIG. 4. As shown in Table 10 and FIG. 4, as a result of performing an animal test on beagle dogs before meals when bioavailability is low, it was found that the plasma concentrations of a commercially available nanoparticle fenofibrate formulation and a microparticle test formulation were equivalent.

Plasma concentration of reference drug (TricorTM) and test drug (Preparation Example 8) in fasting state
Parameters	Units	N	LSMean		% Ratio (T/R)
			Reference drug	Test drug
Cmax	ng/mL	10	6163.027	5474.151	88.82
AUClast	hr*ng/mL	10	23604.711	22446.020	95.00
AUCinf	hr*ng/mL	10	27409.995	26596.385	97.03
t1/2	hr	10	3.507	4.354	124.15

In conclusion, the pharmaceutical composition of the present invention, which comprises finely pulverized fenofibrate, can provide dissolution and pharmacokinetic profiles equivalent to those of a reference drug even though the fenofibrate particles are not nanometer-sized, since the fenofibrate particles have been adjusted to an appropriate size and are combined with a specific amount of hydrophilic polymer.

Preparation Examples 9 to 12: Preparation of fenofibrate tablets using various hydrophilic polymers

Preparation of fenofibrate composition (units: mg)

Classification	Ingredient name	Preparation Example 6	Preparation Example 9	Preparation Example 10
Binder solution 1	Fenofibrate	145	145	145
	Hypromellose	30	-	-
	polyvinylpyrrolidone	-	30	-
	vinylpyrrolidone/vinyl acetate copolymer	-	-	30
	Sodium docusate	2	2	2
	Sodium lauryl sulfate	1.5	1.5	1.5
	Purified water	300	300	300
Binder solution 2	Hypromellose	10	-	-
	polyvinylpyrrolidone	-	10	-
	vinylpyrrolidone/vinyl acetate copolymer	-	-	10
	Purified water	70	70	70
Carrier	Lactose hydrate	150	150	150
	D-mannitol	50	50	50
Blend/Lubrication	Crospovidone		100	100	100
	Microcrystalline cellulose	30	30	30
	Aerosil	5	5	5
	Magnesium stearate	3	3	3

Tablets of Preparation Example 9 or Preparation Example 10 were prepared in the same manner as in Preparation Example 6 using polyvinylpyrrolidone or a vinylpyrrolidone-vinylacetate copolymer instead of hypromellose, which is the hydrophilic polymer of Preparation Example 6.

Preparation of fenofibrate composition (units: mg)

Classification	Ingredient name	Preparation Example 7	Preparation Example 11	Preparation Example 12
Binder solution 1	Fenofibrate	145	145	145
	Hypromellose	30	-	-
	polyvinylpyrrolidone	-	30	-
	vinylpyrrolidone/vinyl acetate copolymer	-	-	30
	Sodium docusate	2	2	2
	Sodium lauryl sulfate	1.5	1.5	1.5
	Purified water	300	300	300
Binder solution 2	Hypromellose	30	-	-
	polyvinylpyrrolidone	-	30	-
	vinylpyrrolidone/vinyl acetate copolymer	-	-	30
	Purified water	210	210	210
Carrier	Lactose hydrate	150	150	150
	D-mannitol	50	50	50
Blend/Lubrication	Crospovidone		100	100	100
	Microcrystalline cellulose	30	30	30
	Aerosil	5	5	5
	Magnesium stearate	3	3	3

Similarly, the tablets of Preparation Examples 11 and 12 were prepared in the same manner as in Preparation Example 7 using polyvinylpyrrolidone or vinylpyrrolidone-vinylacetate copolymer instead of hypromellose of Preparation Example 7, respectively.

Experimental Example 5: Change in dissolution rate according to the type of hydrophilic polymer

The tablets of Preparation Example 6 and Preparation Examples 9 to 10 were tested by the dissolution test method II (paddle method) of the Korean Pharmacopoeia. The dissolution test was carried out under the conditions of a DW (with 0.4% SLS added) eluent, a paddle speed of 50 rpm, and a temperature of 37 ℃ and quantification was carried out using HPLC, and the results are shown in [Table 13] and [FIG. 5].

Time (minutes)	Preparation Example 6	Preparation Example 9	Preparation Example 10
0	0.0	0.0	0.0
5	33.3	22.7	19.2
10	70.4	64.2	62.1
15	77.8	72.6	70.4
30	80.9	80.6	78.5
60	82.6	81.7	80.0

As can be seen from Table 13 and FIG. 5, Preparation Example 9(#9) and Preparation Example 10(#10) were prepared in spite of using polyvinylpyrrolidone or vinylpyrrolidone-vinylacetate copolymer instead of hypromellose of Preparation Example 6(#6), Preparation Examples 9 and 10 showed an average dissolution rate similar to that of Preparation Example 6, indicating that the change in the type of the hydrophilic polymer does not affect the realization of the effect of the present invention under the conditions in which the fenofibrate particle size and the content of the hydrophilic polymer are the same.

The dissolution test was performed in the same manner for the tablets of Preparation Example 7 and Preparation Examples 11 to 12.

Time (minutes)	Preparation Example 7	Preparation Example 11	Preparation Example 12
0	0.0	0.0	0.0
5	36.0	20.5	16.4
10	62.5	66.3	60.2
15	72.4	75.2	69.8
30	78.8	80.9	77.5
60	80.7	81.2	79.7

Similarly, as can be seen from Table 14 and Fig. 6, Preparation Examples 11 and 12 were prepared in spite of using polyvinylpyrrolidone or vinylpyrrolidone-vinylacetate copolymer instead of hypromellose of Preparation Example 7, Preparation Examples 11 and 12 showed an average dissolution rate similar to that of Preparation Example 7, indicating that the change in the type of the hydrophilic polymer does not affect the realization of the effect of the present invention.

Preparation Examples 13 to 14: Preparation of fenofibrate tablets using additional surfactants

Tablets of Preparation Examples 13 and 14 were prepared in the same manner as in Preparation Examples using sucrose as an additional surfactant in addition to sodium docusate and Sodium lauryl sulfate used in Preparation Examples.

The particle size of the finely pulverized fenofibrate particles and the fenofibrate composition used to prepare the tablets of Preparation Examples 13 and 14 are as shown in Tables 15 and 16.

Classification	particle size			average particle size (um)
	d(0.1)	d(0.5)	d(0.9)
Preparation Example 13, 14	0.427	1.126	2.585	1.344

Preparation of fenofibrate composition (units: mg)

Classification	Ingredient name	Preparation Example 13	Preparation Example 14
Binder solution 1	Fenofibrate	145	145
	Hypromellose	40	40
	Sodium docusate	2	2
	Sucrose	1	1
	Sodium lauryl sulfate	1	1
	Purified water	300	300
Binder solution 2	Hypromellose	40	40
	Sodium lauryl sulfate	10	10
	Purified water	500	500
Carrier	Lactose hydrate	140	140
	D-mannitol	60	60
Blend/Lubrication	Crospovidone		100	100
	Microcrystalline cellulose	30	30
	Sodium lauryl sulfate	-	20
	Aerosil	5	5
	Magnesium stearate	3	3

Experimental Example 6: Change in dissolution rate according to the use of additional surfactant

A dissolution test was performed on the tablets of Preparation Example 13 (#13) and Preparation Example 14(#14) in the same manner as in Experimental Example 5, and the results are shown in Table 17 and FIG. 7.

Classification / Time (minutes)	Dissolution rate (%)
	0minutes	5minutes	10 minutes	15minutes	30minutes	60 minutes
Preparation Example 13	0.0	57.6	76.6	82.7	84.4	84.6
Preparation Example 14	0.0	15.2	43.3	64.2	81.8	86.1

As can be seen in Table 17 and FIG. 7, it was confirmed that there was no problem in reaching the average dissolution rate up to 60 minutes to be achieved in the present invention even if the type of surfactant was changed.

Claims (14)

1. A pharmaceutical composition comprising finely pulverized fenofibrate particles, a surfactant, and a hydrophilic polymer,

   wherein:

   (a) the fenofibrate particles have a d(90) of 1 μm to 3 μm, and

   (b) the hydrophilic polymer is comprised in an amount of 0.25 parts by weight to 0.8 parts by weight based on 1 part by weight of the fenofibrate.
2. The pharmaceutical composition of claim 1, wherein the fenofibrate particles have a d(50) of 0.5 μm or more.
3. The pharmaceutical composition of claim 1, wherein the fenofibrate particles have a d(50) of 0.5 μm to 1.2 μm.
4. The pharmaceutical composition of claim 1, wherein the fenofibrate particles have an average particle size of 0.7 μm to 1.4 μm.
5. The pharmaceutical composition of claim 1, wherein the fenofibrate particles have a d(90) of 1 μm to 3 μm, and at the same time have a d(50) of 0.5 μm to 1.2 μm or an average particle size of 0.7 μm to 1.4 μm, and

   the hydrophilic polymer is comprised in an amount of 0.25 parts by weight to 0.8 parts by weight based on 1 part by weight of the fenofibrate.
6. The pharmaceutical composition of claim 1, wherein the hydrophilic polymer is one or more selected from the group consisting of hypromellose, polyvinylpyrrolidone, polyethylene glycol, a vinylpyrrolidone/vinyl acetate copolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, and a methacrylate copolymer.
7. The pharmaceutical composition of claim 1, wherein the hydrophilic polymer is hypromellose, polyvinylpyrrolidone, or a vinylpyrrolidone/vinyl acetate copolymer.
8. The pharmaceutical composition of claim 1, wherein the surfactant is comprised in an amount of 0.02 parts by weight to 0.12 parts by weight based on 1 part by weight of the fenofibrate.
9. The pharmaceutical composition of claim 1, wherein the surfactant is one or more selected from the group consisting of a docusate salt, a lauryl sulfate salt, sucrose, a stearate salt, a cetyltrimethylammonium salt, a fatty alcohol ethoxylate, a poloxamer, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, and polyoxyethylene monooleate.
10. The pharmaceutical composition of claim 1, wherein the surfactant is sodium docusate and sodium lauryl sulfate.
11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains 145 mg of the fenofibrate.
12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated in the form of a tablet.
13. A method of treating hyperlipidemia comprising administering the pharmaceutical composition of any one of claim 1 to 12 to a subject in need thereof.
14. Use of the composition of any one of claim 1 to 12 for the manufacture of a medicament for treating hyperlipidemia.

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