KR101925590B1 - Formulation of fenofibric acid with improved bioavailability - Google Patents

Abstract

The present invention relates to a penofibric acid-containing preparation having improved bioavailability, particularly a release-controlled composition comprising a phenobicyclic acid or a pharmaceutically acceptable salt thereof and a release-controlling agent; And
A pharmaceutical formulation comprising a quick release composition comprising phenobic acid or a pharmaceutically acceptable salt thereof and a diluent.

Description

[0002] Formulations of fenofibric acid with improved bioavailability have improved bioavailability,

The present invention relates to phenobipric acid preparations having improved bioavailability.

2-yl 2-4 - [(4-chlorophenyl) carbonyl] fenofibrate or propan-2-yl 2-4 - [(4- chlorophenyl) carbonyl] phenoxy- ] phenoxy-2-methylpropanoate) is a lipid modulating agent used in the treatment of endogenous hyperlipidemia, hypercholesterolemia and hypertriglyceridemia in adults. It is known that administration of phenobibrate reduces 20 to 25% of hypercholesterolemia and 40 to 50% of hypertriglyceridemia.

Fenofibrate is absorbed in the gastrointestinal tract after the duodenum after oral administration and is metabolized in the body after absorption and the metabolites fenofibric acid or 2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid. Phenopricic acid is an active metabolite of fenofibrate, and fenofibrate is a prodrug that is converted into an active form in vivo.

In general, most orally administered drugs are absorbed through the digestive tract. In the digestive tract, which is directly absorbed by the drug, the most important factor is the intake of food. In particular, phenobibrate is a poorly soluble drug, which varies widely depending on the condition of the gastrointestinal tract.

Fenofibrate is a hydrophobic drug that is very poorly soluble in water, and absorption is further increased in the fasting state when the food is consumed rather than in the fasting state. Therefore, in order to increase the bioavailability, it is necessary to take the phenobarbate together with the food. Accordingly, there have been many studies to improve the solubility of the phenobibrate.

International Patent Publication No. WO 2000-072825 discloses an amorphous state in which fenofibrate is dissolved or dispersed in a hydrophilic, amorphous polymer.

United States Patent Publication No. 4895726 discloses a composition in which both of the phenobibrate and the solid surfactant are micronized.

In addition, there are examples in which an alkalizing agent or a polyhydric alcohol excipient is added to increase the solubility of the phenobibrate.

Phenobrate must be dissolved within 4 hours in the small intestine region to maximize bioavailability since the absorption rate decreases if the drug is not sufficiently released within 4 hours, which is the retention time from the preparation.

However, since penovalate is mainly absorbed in the upper part of the small intestine, it may cause a safety problem due to an abrupt increase in absorption when it is released and disintegrated from above. It is therefore desirable to minimize the release and disintegration of the drug in the gastrointestinal tract.

On the other hand, the effective blood concentration of phenobic acid, which is an active metabolite in humans, is preferably 5 to 35 μg / mL, preferably not exceeding 10 μg / mL (Current Therapeutic Research, 1979, Vol. -362). Therefore, it is necessary to improve the solubility of phenobicyclic acid by the solubilization technique, and to solve the safety problem due to the increase of the absorption rate and the absorption rate.

International Patent Publication WO2000-072825 U.S. Patent No. 4,895,726

It is an object of the present invention to provide a pharmaceutical formulation comprising a phenobiphilic acid or a pharmaceutically acceptable salt thereof having improved bioavailability and minimized drug absorption deviation.

The present invention also provides a method for producing a pharmaceutical preparation comprising a phenobiphilic acid or a pharmaceutically acceptable salt thereof with improved safety and stability.

One aspect of the present invention is a controlled release pharmaceutical composition comprising a phenobicyclic acid or a pharmaceutically acceptable salt thereof and a release-controlling agent; And

There is provided a pharmaceutical formulation comprising a spontaneous composition comprising phenobic acid or a pharmaceutically acceptable salt thereof and a diluent.

The controlled release composition in the pharmaceutical formulation of the present invention comprises a phenobicyclic acid or a pharmaceutically acceptable salt thereof and a release-controlling agent. The release-controlling composition may include a hydrophilic polymer that swells and / or gels as a release-controlling agent, and may further include a pharmaceutically acceptable additive if necessary.

The immediate-release composition of the pharmaceutical preparation of the present invention comprises a phenobicyclic acid or a pharmaceutically acceptable salt thereof and a diluent, and may further comprise a pharmaceutically acceptable additive if necessary.

The release-controlled composition in the pharmaceutical preparation of the present invention means a controlled release part of phenobic acid, and the immediate release composition is prepared by dissolving the drug in a general release part of phenobicyclic acid, i.e., a release controlling agent such as a hydrophilic polymer. Means that the emission is not controlled.

Specific components of the pharmaceutical composition of the present invention will be described below.

(1) a phenobicyclic acid or a pharmaceutically acceptable salt thereof

The phenobicyclic acid or a pharmaceutically acceptable salt thereof provides phenobicyclic acid as a pharmacologically active ingredient. The pharmaceutically acceptable salt of phenobic acid refers to a substance that is metabolized in the body to produce a phenolic active substance, phenobic acid.

The pharmaceutically acceptable salt of the phenopyrric acid may include any salt selected from the group consisting of choline, ethanolamine, diethanolamine, piperazine and tromethamine. For example, the pharmaceutically acceptable salt of phenobicric acid may specifically be the choline salt of phenoprivic acid (choline phenobibrate).

The pharmaceutically acceptable salt of the phenobicyclic acid may be included in about 20 to 80 parts by weight, preferably about 40 to 70 parts by weight, based on 100 parts by weight of the total weight of the preparation. In addition, when the phenobiphilic acid or its pharmaceutically acceptable salt is 100 parts by weight, the phenobicyclic acid or a pharmaceutically acceptable salt thereof is contained in about 15 to 85 parts by weight of the release-controlling composition And may be included in the immediate release composition at about 15 to 85 parts by weight.

(2) Release control mechanism

In the present invention, the release control agent may comprise a hydrophilic polymer which swells and / or forms a gel as an additive or medium used to control the release of the drug. The release-controlling agent may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, methylhydroxyethylcellulose, polyethylene oxide, natural gum, carbomer, Vinyl acetate, a methacrylate copolymer, and a mixture thereof. The natural black acacia gum, carrageenan gum, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, tara gum, galactomannan gum, agar gum, guti gum, karaya gum, cardaya gum or rhamsan gum.

The release-controlling agent may be contained in an amount of about 1 to 80 parts by weight, preferably 1 to 75 parts by weight, more preferably about 6 to 60 parts by weight per 100 parts by weight of the total weight of the preparation ≪ / RTI > If it is used in an amount of less than 1 part by weight, release control can not be performed. If it is used in an amount of more than 80 parts by weight, the total weight may exceed 700 mg.

 (3) Thinner

In the present invention, the diluent may be a saccharide including lactose, glucose, sucrose, fructose and maltose as an additive used for increasing the volume of the preparation; Sugar alcohols including mannitol, sorbitol, erythritol, xylitol, lactitol and maltitol; Cellulases including microcrystalline cellulose, Ludipress and Cellactose; Wheat starch, rice starch, corn starch and potato starch; And at least one selected from the group consisting of pregelatinized starch, partially pregelatinized starch, and hydroxypropyl starch.

Specifically, the diluent may be at least one selected from the group consisting of lactose, mannitol, sorbitol, microcrystalline cellulose, ruddy press, cellulose and starch.

The diluent may be contained in an amount of about 1 to 80 parts by weight, preferably 1 to 75 parts by weight, more preferably 5 to 60 parts by weight based on 100 parts by weight of the total weight of the preparation. have. If it is used in an amount of less than 1 part by weight, it can not be released into the body. If it is used in an amount of more than 80 parts by weight, the total weight may exceed 700 mg.

In one embodiment, 10 to 50 parts by weight of the release-controlling agent may be included, and 10 to 50 parts by weight of the diluent may be included per 100 parts by weight of the phenobicyclic acid or its pharmaceutically acceptable salt in the preparation. In addition, when the phenobiphilic acid or its pharmaceutically acceptable salt is 100 parts by weight, the phenobicyclic acid or a pharmaceutically acceptable salt thereof is contained in about 15 to 85 parts by weight of the release-controlling composition And may be included in the immediate release composition at about 15 to 85 parts by weight.

(4) Delayed release coatings

The pharmaceutical preparations of the present invention may be coated with a delayed release coating agent, if necessary, outside the release-controlling composition and / or the immediate release composition. In the present invention, the delayed release coating agent is used to delay the release of the formulation until it reaches the small intestine. The delayed release coating may protect the drug from gastric juice, reduce gastric irritation, and promote gastrointestinal transit of the small intestine absorbed drug. The delayed release coating agent may be an enteric coating agent.

The delayed release coating may be a pH sensitive polymer. For example, at a pH of 2 to 4, a stable hydrophobic coating is formed to inhibit drug release, and at least partially soluble at a pH of 5 to 9, specifically at a pH of 6 to 8, more specifically at a pH of 6.5 to 7.5, So that it can swell. The delayed-release coating material may be a material that is at least partially disintegrated by the penetration of water at a pH of at least 5.8, more specifically at a pH of at least 6.8.

The delayed release coating agent may be at least one selected from the group consisting of methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate (hydroxypropylmethylcellulose phthalate), hydroxypropylmethylcellulose acetate succinate (hydroxypropylmethylcellulose acetate succinate), cellulose acetate phthalate, cellulose acetate, polyvinyl Alcohol phthalate, shellac, and mixtures thereof. The methacrylic acid copolymer includes a methacrylic acid-methyl methacrylic acid copolymer, a methyl acrylate-methyl methacrylate-methacrylate copolymer, and a methacrylic acid-ethyl acrylate copolymer. For example, as the methacrylic acid copolymer, EUDRAGIT L type, for example, Eudragit L 30D-55 may be used.

The delayed release coating agent may be included in an amount of about 5 to 30 parts by weight based on 100 parts by weight of the total weight of the formulation. If the amount is less than 5 parts by weight, the effect of enteric coating is not sufficient. If the amount is more than 30 parts by weight, the productivity may decrease due to an increase in the working time.

(5) Other additives

In the pharmaceutical preparation of the present invention, each of the release-controlling composition and the immediate release composition may contain other additives as needed as a pharmaceutically acceptable carrier. The additive may be at least one selected from the group consisting of a binder, a lubricant, a coating, a colorant, a disintegrant, and a mixture thereof.

The binder is used to bind the raw material of the preparation, and examples thereof include hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copovidone, macrogol, light silicic anhydride, synthetic aluminum silicate, calcium silicate, Silicate derivatives such as silicate aluminates, phosphates such as calcium hydrogen phosphate, calcium carbonate, and the like.

The lubricant is used to improve the smoothness of the tableting process and the formability of the preparation. Examples thereof include magnesium stearate, silica (SiO ₂ ), colloidal silicon dioxide, and talc.

In the present invention, the pharmaceutical preparation may further include a coating agent, a coloring agent, and the like for increasing stability, controlling degradation and appearance, and optionally adding a disintegrant capable of accelerating the disintegration of the agent and drug elution As shown in FIG.

The solvent to be used in the present invention may be selected from the group consisting of water (cold water, hot water), alcohol, anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, alcohol, propanol, butanol), a mixed solvent of the lower alcohol and water Can be used. An example of the alcohol is a fermented alcohol of 95% ethanol. In one embodiment, purified water may be used as a solvent for the immediate release composition, and a spirit may be used as a solvent for the release-controlled composition.

The form of the pharmaceutical preparation of the present invention will be described in detail as follows.

The pharmaceutical preparations of the present invention comprise a release-controlling composition comprising a phenobicyclic acid or a pharmaceutically acceptable salt thereof and a release-controlling agent; And

0.0 > 1, < / RTI > or a pharmaceutically acceptable salt thereof, and a diluent,

The immediate release composition and the release-controlled composition may be in the form of particles, granules, pellets, and tablets.

The pharmaceutical preparations comprising the immediate release composition and the release-controlled composition may be formulated in the form of an oral preparation. For example, the pharmaceutical preparations can be formulated in the form of granules, tablets, capsules, etc., and can be preferably tablets or capsules. The tablet may be a multi-layered tablet or a triple tablet containing multi-layer tablet or triple tablet. In addition, the capsule may be a hard capsule or a soft capsule.

In embodiments, the release-controlling composition and the immediate release composition may each be included in the same tablet in the form of granules or pellets. For example, the pharmaceutical preparations of the present invention may be in the form of a pellet wherein the release-controlling composition and the immediate release composition are in a granular form, respectively, and the granules are contained in different layers of the tablet.

In another embodiment, the pharmaceutical preparation of the present invention may be in the form of a core-shell composed of a release-controlling composition and a core-shell composition consisting of a rapid composition surrounding the outer surface of the inner core.

The pharmaceutical preparations of the present invention can be provided in a loose state without any additional coating, and can be formed in the form of a coated tablet, which further comprises a coating layer, if necessary, forming a coating layer on the outside of the formulation. It is possible to provide a preparation capable of further securing the stability of the active ingredient by forming a coating layer.

The pharmaceutical preparations of the present invention may additionally form a coating layer on the outside of the release-controlling composition and / or the immediate release composition. For example, coatings can be applied to the surface of particles, granules, pellets, tablets or capsules made of the release-controlling composition and / or the immediate release composition for delayed release or stabilization of the formulation.

The method for preparing the pharmaceutical preparation according to the present invention will be described in detail as follows. The pharmaceutical preparations of the present invention can be produced by a method known in the art such as a wet granulation method, a direct method, a dry granulation method and the like, and can be produced in tablets, capsules and the like. For example, the pharmaceutical preparations of the present invention can be prepared by the wet granulation method.

The pharmaceutical preparation according to the present invention

(I) mixing a phenobicyclic acid or a pharmaceutically acceptable salt thereof with a release-controlling agent and a pharmaceutically acceptable carrier to prepare a release-controlling composition; And

(Ii) mixing the phenobicyclic acid or a pharmaceutically acceptable salt thereof with a diluent and a pharmaceutically acceptable carrier to prepare an immediate release composition,

(Iii) co-formulating the composition in steps (i) and (ii) above.

Accordingly, one aspect of the present invention is

(I) preparing a mixture by mixing (a) a phenobicyclic acid or a pharmaceutically acceptable salt thereof with a release-controlling agent; (b) combining the mixture with a binder to produce a conjugate; (c) granulating and drying the associated material; (d) drying the dried material, and then adding a lubricant to prepare a controlled release composition; And

(Ii) (e) mixing a phenobiphilic acid or a pharmaceutically acceptable salt thereof with a diluent to prepare a mixture; (f) combining the mixture with a binder to produce a conjugate; (g) granulating and drying the association product; (h) sizing the dried material, and then adding a lubricant to prepare an immediate release composition,

(Iii) co-formulating the composition in steps (i) and (ii) above.

The preparation of the release-controlling composition or the immediate release composition may further comprise a pharmaceutically acceptable additive, for example, a binder. The steps (a) to (d) for preparing the release-controlling composition and the steps (e) to (h) for preparing the immediate release composition may be carried out in advance of any one of the steps It may also proceed at the same time.

The pharmaceutical preparations of the present invention can be prepared into multi-layered tablets by tableting the release-controlling composition and the immediate release composition. For example, a double-layer tablet can be prepared from the release-controlling composition and the immediate release composition using a multilayer tablet press.

In addition, triple or more multi-layered tablets can be prepared by adding a release design or, if desired, a release aid layer. Each of the layers constituting the multilayer tablet may be in a parallel state. The formulations may have different release rates for each layer and may be formulated to allow for controlled and controlled release in embodiments, such as formulation (s) such that prior release (immediate release) and post-release (delayed release) .

The pharmaceutical preparation of the present invention may be prepared by directly or additionally coating the immediate release granules obtained from the immediate release composition and drying and then tableting the granules in a predetermined amount or by further coating them into the inner core, The tablet can be prepared by coating or tableting with a tablet press tablet to prepare or coat a press-coated tablet with a release-controlled granule surface surrounding the immediate-release granule surface.

In the present invention, the coating layer may be formed by a conventional method of forming a film-like coating layer on the surface of granules or tablets. Examples thereof include a fan coating method, a fluidized bed coating method and a compression coating method.

The preparation method of the present invention provides a pharmaceutical preparation containing the release-controlled composition and the immediate release composition capable of controlled release and general release at different release rates, respectively, in one preparation, so that the preparation having improved stability in the gastrointestinal tract can be easily Thereby providing an economical method of manufacturing.

The dissolution profile of the pharmaceutical preparation of the present invention will be described below.

The pharmaceutical preparation of the present invention was prepared by dissolving 80 mL of an artificial intestinal fluid (USP, USP) having a pH of 6.8 at 37 ± 0.5 ° C and 50 rpm at 80 rpm according to the KP elution method (paddle method) Or more. In embodiments, the dissolution rate may be from 86.8% to 99.9% after 4 hours.

The above pharmaceutical preparations were subjected to the dissolution test according to the following (1) and (2) according to the KP elution test method 2 (paddle method) to obtain a dissolution profile, and the USP 39 <1090> The similarity factor (f ₂ ) was calculated using the equation to compare the dissolution profile according to Drug Product Performance.

Specifically, when the similarity factor (f ₂ ) of the elution profile obtained in the above conditions (1) and ( ₂ ) is evaluated according to the following formula (A), it may have a range of 50? F ₂ ? For example, the f ₂ value may be 50 to 100.

 Condition (1): elution test at 900 rpm for 240 minutes in an artificial intestinal fluid (USP, USP) of 37 占 0.5 占 폚, pH 6.8

Condition (2): elution test at 900 rpm for 40 minutes at 37 ± 0.5 ° C, 900 mL of artificial intestinal fluid (USP, USP) of pH 6.8

Formula (A):

(In the above formula (A), R _t and T _t denote the cumulative percentage of drug eluted at the time of elution at the time of elution under the conditions (1) and (2), n denotes the number of time points, And n may be an integer of 1 to 20)

The present invention provides pharmaceutical preparations containing phenobicyclic acid useful for the treatment of hyperlipidemia and hypertriglyceridemia by having excellent bioavailability and minimized drug absorption deviation.

The present invention provides a pharmaceutical formulation containing penoficic acid which exhibits improved safety by reducing rapid release and disintegration in the stomach and maximizing bioavailability in the small intestine.

The present invention provides a pharmaceutical preparation containing phenobic acid which exhibits a minimized drug absorption deviation without being affected by ingestion of food.

The present invention provides a pharmaceutical preparation containing phenobicyclic acid which can be taken irrespective of the diet and can increase the patient's compliance with the medication.

The present invention provides a pharmaceutical preparation containing phenobiphilic acid exhibiting a minimized drug absorption deviation that is not affected by the ingestion of food and the mobility deviation of the individual gastrointestinal tract.

1 shows the dissolution test results in Test Examples 3 and 4 for Comparative Examples 7 and 8.
Fig. 2 shows the blood drug concentration in the body in Test Example 8. Fig.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example  1 to 11: Accelerated  Granules and Emission controllability  Manufacture of dual definition containing granules

Example 1

35.8 mg of choline phenobibrate, 21.8 mg of microcrystalline cellulose and 1.8 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. The dried material was set in 18 mesh, and 0.6 mg of magnesium stearate was added thereto to prepare an immediate release granule.

143.0 mg of choline phenobibrate, 87.2 mg of hydroxypropylmethylcellulose and 7.2 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was set in 18 mesh, and 2.6 mg of magnesium stearate was added to prepare release-controlled granules. The biodegradable granules and release-controlling granules were tableted together using a multi-layer tablet machine (Ichihashiseiki (japan), AutoTab-200TR) to prepare a solid tablet of a bimodal shape.

Example 2

53.6 mg of choline phenobibrate, 32.7 mg of microcrystalline cellulose and 2.7 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was set as 18 mesh, and 1.0 mg of magnesium stearate was added thereto to prepare an immediate release granule.

125.2 mg of choline phenobibrate, 76.3 mg of hydroxypropylmethylcellulose and 6.3 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was set in 18 mesh, and 2.2 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 3

71.5 mg of choline phenobibrate, 43.6 mg of microcrystalline cellulose, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, and fed, granulated and dried according to a conventional wet granulation method. Then, the dried material was set as 18 mesh, and 1.3 mg of magnesium stearate was added to prepare an immediate release granule.

107.3 mg of choline phenobibrate, 65.4 mg of hydroxypropylmethylcellulose and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. After drying the dried material to 18 mesh, 1.9 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 4

89.4 mg of choline phenobibrate, 54.5 mg of microcrystalline cellulose and 4.5 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. The dried material was set as 18 mesh, and 1.6 mg of magnesium stearate was added thereto to prepare an immediate release granule.

89.4 mg of choline phenobibrate, 54.5 mg of hydroxypropylmethylcellulose and 4.5 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was set in 18 mesh, and 1.6 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 5

107.3 mg of choline phenobibrate, 65.4 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

71.5 mg of choline phenobibrate, 43.6 mg of hydroxypropylmethylcellulose and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 6

125.2 mg of choline phenobibrate, 76.3 mg of microcrystalline cellulose and 6.3 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 2.2 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of hydroxypropylmethylcellulose and 2.7 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was set in 18 mesh, and 1.0 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 7

143.0 mg of choline phenobibrate, 87.2 mg of microcrystalline cellulose, and 7.2 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 2.6 mg of magnesium stearate was added thereto to prepare an immediate release granule.

35.8 mg of choline phenobibrate, 21.8 mg of hydroxypropylmethylcellulose and 1.8 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. After the dried material was set in 18 mesh, 0.6 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 8

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of hydroxypropylmethylcellulose and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 9

125.2 mg of choline phenobibrate, 76.3 mg of starch, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of hydroxyethylcellulose and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 10

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of hydroxypropylcellulose and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 11

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of xanthan gum and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example  12: Accelerated  Granules and Emission controllability  Manufacture of triple wells containing granules

125.2 mg of choline phenobibrate, 76.3 mg of starch, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of polyethylene oxide, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules.

A three-packed solid preparation was prepared by layering together the layers in the order of immediate release granules-release controlled granules-immediate release granules using a multi-layer tablet machine.

Example  13: Accelerated  Granules and Emission controllability Pellet  Preparation of tablets containing

125.2 mg of choline phenobibrate, 76.3 mg of starch, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of carbomer, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and then the mixture was added with a solvent to prepare a conventional wet granule. The resulting allied material was extruded into 2 meshes and then spheronized and dried to prepare release-controlled pellets. After mixing the immediate release granules with the release-controlled pellets, tablets were prepared by tabletting using a tablet machine.

Example  14 to 17: Accelerated  Granules and Emission controllability  Manufacture of dual definition containing granules

Example 14

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. After the dried material was set in 18 mesh, 32.7 mg of collidon sul and 1.3 mg of magnesium stearate were added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 15

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of ethylcellulose, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 16

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of polyvinyl acetate, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Example 17

125.2 mg of choline phenobibrate, 38.1 mg of lactose, 38.2 mg of microcrystalline cellulose, and 5.4 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was formed into 18 mesh, and 1.9 mg of magnesium stearate was added thereto to prepare an immediate release granule.

53.6 mg of choline phenobibrate, 32.7 mg of methacrylate copolymer, and 3.6 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying according to a conventional wet granulation method. Then, the dried material was set in 18 mesh, and 1.3 mg of magnesium stearate was added to prepare release-controlled granules. The solid preparation of the present invention was prepared by tableting the immediate release granules and the release-controlled granules using a multi-layer tablet machine.

Comparative Example  1 to 6: Emission controllability  Preparation of tablets containing only granules

Comparative Example 1

178.8 mg of choline phenobibrate, 109.0 mg of hydroxyethylcellulose, and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying according to a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 2

178.8 mg of choline phenobibrate, 109.0 mg of hydroxypropylmethylcellulose and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying according to a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 3

178.8 mg of choline phenobibrate, 109.0 mg of hydroxypropylcellulose, and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 4

178.8 mg of choline phenobibrate, 109.0 mg of polyethylene oxide and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 5

178.8 mg of choline phenobibrate, 109.0 mg of xanthan gum and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 6

178.8 mg of choline phenobibrate, 109.0 mg of carbomer, and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and the resulting mixture was subjected to coalescence, granulation and drying in accordance with a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example  7 to 9: Accelerated  Preparation of tablets containing only granules

Comparative Example 7

178.8 mg of choline phenobibrate, 109.0 mg of lactose and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 8

178.8 mg of choline phenobibrate, 109.0 mg of microcrystalline cellulose and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Comparative Example 9

178.8 mg of choline phenobibrate, 109.0 mg of starch and 9.0 mg of hydroxypropylcellulose were weighed and mixed, respectively, and purified water was added thereto, followed by coalescence, granulation and drying according to a conventional wet granulation method. The dried material was formulated into 18 meshes, and 3.2 mg of magnesium stearate was added thereto to prepare a lubricant, which was then tableted to prepare a solid preparation.

Example  18 to 20: Accelerated  Granules and Emission controllability  Delayed release containing granules Coating definition  Produce

Example 18

The Eudragit® L30D-55: ethyl cellulose: talc (62: 6: 31) mixture was dissolved in 80% ethanol at a concentration of 10% to provide a delayed-coated substrate. The nail prepared in Example 8 was coated by the conventional pan coating method using the retard coating base material to prepare a delayed release coated tablet having a total weight of 330 mg.

Example 19

Hydroxypropylmethylcellulose phthalate was dissolved in 80% ethanol at a concentration of 10% to prepare a delayed-coating substrate. The nail prepared in Example 8 was coated by the conventional pan coating method using the retard coating base material to prepare a delayed release coated tablet having a total weight of 330 mg.

Example 20

The hydroxypropyl methylcellulose acetate succinate: triethyl citrate: talc (63:16:22) mixture was dissolved in 80% ethanol at a concentration of 10% to form a delayed-coating substrate. The nail prepared in Example 8 was coated by the conventional pan coating method using the retard coating base material to prepare a delayed release coated tablet having a total weight of 330 mg.

Comparative Example  10 to 12: Accelerated  Granules and Emission controllability  General containing granules Coating definition  Produce

Comparative Example 10

Hydroxypropylmethylcellulose was dissolved in 80% ethanol at a concentration of 10% to prepare a retard coating base. The nail prepared in Example 8 was coated by the conventional pan coating method using the retard coating base material to prepare a delayed release coated tablet having a total weight of 330 mg.

Comparative Example 11

Polyvinyl alcohol was dissolved in 80% alcohol at a concentration of 10% to prepare a delayed-coated substrate. The nail prepared in Example 8 was coated by the conventional pan coating method using the retard coating base material to prepare a delayed release coated tablet having a total weight of 330 mg.

Comparative Example 12

A mixture of ethylcellulose: polyethylglycol: titanium oxide (68:20:12) was dissolved in 80% ethanol at a concentration of 10% to form a retarded coating base. The nail prepared in Example 8 was coated by the conventional pan coating method using the retard coating base material to prepare a delayed release coated tablet having a total weight of 330 mg.

Test Example  1: Measurement of solubility

The amount (mg) of phenobiphenyl acid and choline phenobibrate dissolved in 100 mL of water at room temperature was measured. The results of comparative solubilities of phenobic acid and choline phenobibrate are shown in Table 1.

[Table 1]

As a result, it was confirmed that the solubility of choline phenobibrate was about 100 times higher than that of phenobicyclic acid. Choline-phenobibrate-containing preparations can improve the problems due to low solubility of phenobicyclic acid, but can cause safety problems due to rapid increase in solubility.

In addition, since phenobic acid is mainly absorbed from the upper part of the small intestine, when it is released and disintegrated from above, rapid increase in absorption at the upper part of the small intestine may cause gastrointestinal disorders such as abdominal pain, nausea, diarrhea and abdominal distension and acute hepatitis.

Thus, there is a need to minimize drug release and disintegration in the stomach. In addition, since phenobic acid is a drug absorbed in the small intestine, it must be released sufficiently within 4 hours of its retention time in order to maximize bioavailability.

In addition, in order to increase the adherence of phenobicyclic acid, it is necessary not only to be able to take the food regardless of the diet, but also to minimize the influence of the food intake.

Test Example  2: dissolution test in small intestine area (1)

The tablets of Comparative Examples 1 to 6 were subjected to a dissolution test in a small area. The tablets of Comparative Examples 1 to 6 show tablets containing only release-controlled granules.

Table 2 shows the results of dissolution test in 900 mL of artificial intestinal fluid (pH 6.8, USP) at 50 rpm for 4 hours according to Korean Pharmacopoeia Method 2 (paddle method).

[Table 2]

As shown in Table 2, Comparative Examples 1 to 6 did not reach 80% in the elution test using artificial intestinal fluid as a medium for 4 hours, and showed less than 60% elution.

Considering that the phenobic acid which is mainly absorbed in the small intestine can increase the bioavailability by sufficient elution of the tablet for 2 to 4 hours, which is the retention time in the small intestine, in the preparations of Comparative Examples 1 to 6, It can not be done.

Test Example  3: dissolution test in small intestine area (2)

The tablets of Comparative Examples 7 to 9 were subjected to a dissolution test in a small area. The tablets of Comparative Examples 7 to 9 show tablets containing only immediate-release granules.

In order to predict the change of release of drugs in the preparation due to the presence of food and the mobility of the gastrointestinal tract according to the individual, the paddle rotation speed was set to 50 rpm and 100 rpm, and the artificial intestinal fluid (pH 6.8, USP) at 50 rpm and 100 rpm for 4 hours. The results are shown in Table 2 (unit:%).

In order to compare the results of the dissolution test according to the USP 39 <1090> Assessment of Drug Product Performance, the similarity factor (f ₂ ) was calculated using the equation. If the similarity factor (f ₂ ) value is 50 or more, the two dissolution profiles to be compared (Test, Reference) are guaranteed to be equivalent or similar. The equation for obtaining the similarity factor (f ₂ ) is as follows. The results are shown in Table 3.

(In the above formula (A), R _t and T _t refer to the cumulative percentage of the drug eluted at the time of elution at the time of elution under conditions (1) and (2), respectively, 3, n is an integer of 1 to 6)

[Table 3]

In Table 3, in Comparative Examples 7 to 9, the dissolution rate of phenobiphilic acid reached 80% within 2 hours after the start of elution, so that the drug absorption was not lowered, so that the bioavailability was no problem. However, since the value of the similarity factor (f ₂ ) is much less than 50 in Comparative Examples 7 to 9, it can be seen that there is no similarity between the result of elution at 50 rpm and the result of elution at 100 rpm.

Therefore, it can be confirmed that Comparative Examples 7 to 9 including only the inert granules are greatly influenced by the ingestion of food.

Test Example  4: dissolution test in small intestine area (3)

EXAMPLES 1 TO 20 The dissolution test in the small intestine region for tablets was carried out. (Paddle method) was applied to 900 mL of artificial intestinal fluid (pH 6.8, USP). The paddle rotation speed was set to 50 rpm and 100 rpm in order to predict the release of drug in the formulation due to the presence of food and the deviation of motility of the gastrointestinal tract by individual. The results are shown in Table 4.

[Table 4]

As shown in Table 4, the pharmaceutical preparations of Examples 1 to 20 according to the present invention show that the dissolution rate satisfies the condition that the dissolution rate is 80% within 4 hours and the similarity factor (f ₂ ) is 50 or more.

Phenopricic acid, which is mainly absorbed in the small intestine, must elute the tablets within 2 to 4 hours, which is the retention time in the small intestine, to increase bioavailability in vivo. Therefore, Examples 1 to 20 according to the present invention can be said to be an optimal formulation for absorption of drug because the elution test using artificial intestinal fluid as a medium has reached 80% in 4 hours.

Further, in Examples 1 to 16 prepared in the multi-release preparation in Table 4, the value of the similarity factor (f ₂ ) was 50 or more, and it was confirmed that there was a similarity between the result of elution at 50 rpm and the result of elution at 100 rpm have. From these results, it can be confirmed that the multi-release preparation is equivalent in vivo.

1 also shows the dissolution test result of Test Example 3 for Comparative Example 7 and the dissolution test result of Test Example 4 for Example 8 together. In FIG. 1, in Comparative Example 7, when the rotational speeds of the paddles were changed at 50 rpm and 100 rpm, the elution curves of Example 8 showed similar elution curves, especially when compared with those showing a large difference within 2 hours from the start of elution.

As a result, it can be seen that the preparation according to the present invention is not affected physically in the gastrointestinal tract caused by food, and is not affected by variations in motility of the individual gastrointestinal tract.

Test Example  5: dissolution test in small intestine area (4)

The coated tablets prepared in Examples 18 to 20 and Comparative Examples 10 to 12 were continuously subjected to a dissolution test at pH 3.5 and pH 6.8 by applying the second weak electric field method (paddle method). Specifically, the elution test was carried out at pH 3.5 and 500 mL of sodium hydrogen phosphate for 2 hours, followed by the addition of 400 mL of phosphate buffer to adjust the pH to the same level as that of artificial intestinal fluid (pH 6.8, USP), and then the elution test was continued. The results are shown in Table 5.

[Table 5]

 From Table 5, it can be seen that Comparative Examples 10 to 12 show that most of the drug is released 30 minutes after the transfer from the stomach to the small intestine (150 minutes after the dissolution test).

On the contrary, Examples 18 to 20 according to the present invention not only did not elute in the stomach area but also exhibited a dissolution rate of less than 20% even after 150 minutes from the dissolution test, so that excessive rapid elution within 30 minutes after moving from the stomach to the small intestine It can be seen that it does not happen.

In Examples 18 to 20, the dissolution rate was 7 to 42 times less than those of Comparative Examples 10 to 12 within 30 minutes after the transfer from the stomach to the small intestine, and the abdominal pain, area, diarrhea and abdominal distension due to abrupt absorption Gastrointestinal disorders and acute hepatitis can be reduced very effectively.

Further, in Examples 18 to 20, the elution progressed slowly for 4 hours (360 minutes after the elution test) after moving to the small intestine region, and finally eluted more than 96%. Thus, it can be expected that most of the drug can be eluted within the small intestine retention time in the small intestine where the main absorption is performed, thereby maximizing the bioavailability and maintaining a stable blood concentration of the drug in the body.

Test Example  6: dissolution test in small intestine area (5)

With respect to the tablets of Examples 18 to 20 and Comparative Examples 10 to 12, the dissolution test was carried out at pH 1.6, which is the fasting state, and at pH 3.5 and 5.0, which is the post-food intake pH. The Korean Pharmacopoeia second method (paddle method) was applied.

The dissolution test was carried out in 900 mL of Fed-State Simulated Gastric Fluid (FaSSGF), sodium hydrogenphosphate pH 3.5, and pH 5.0 solution in 900 mL of Fed-State Simulated Gastric Fluid (FeSSGF) as pH 1.6 solution.

The results are shown in Table 6 (see Simulated Biological Fluids with Possible Application in Dissolution Testing, Marques et al., 2011).

[Table 6]

As shown in Table 6, when the release of the preparation was evaluated according to changes in composition of gastric pH and gastric juice after the meal, Comparative Examples 10 to 12, to which the delayed release technique was not applied, showed a difference of about 47 to 82 times . On the other hand, in Examples 18 to 20 in which the delayed release technique was applied, it can be confirmed that the release of the drug is not affected by the change in the stomach environment.

Test Example  7: dissolution test in small intestine area (6)

Fasted-State Simulated Intestinal Fluid (FaSSIF) and Fed-State Simulated Intestinal Fluid (FeSSIF), which are commonly used to confirm the effect of diet on the tablets of Comparative Example 7, Example 8, Example 14 and Example 18 The elution test was carried out by applying the second assay method (paddle method) according to Kagaku Kogyo Co., Ltd. (900 mL). The results are shown in Table 7.

[Table 7]

In Table 7, it can be confirmed that the dissolution rate in the fasting condition (FaSSIF) and the eating condition (FeSSIF) is equal to that of the similarity factor (f ₂ ) of 50 or more in Examples 8, 14 and 18.

In Comparative Example 7, the dissolution rate of Example 8, Example 14, and Example 18 showed similar dissolution rates, compared to a comparison of fasting conditions (FaSSIF) and eating conditions (FeSSIF). From this, it can be confirmed that the drug release is not affected by the ingestion of food in the preparation of the present invention.

Test Example  8: Evaluation of pharmacokinetic parameters

The pharmacokinetic parameters were measured in 40 healthy subjects when the tablets of Examples 18 to 20 were taken before and after meals. Specifically, the tablets of Examples 18 to 20 were taken before and after the meal, and the drug blood concentrations of the phenobiphilic acid in the body were measured for 24 hours. In addition, pharmacokinetic parameters of blood concentration-time curve subscale (AUC) and peak blood concentration ( _Cmax ) were calculated statistically from the above measurement results and used as an index for evaluating bioequivalence.

The tablets of Examples 18 to 20 showed an average AUC of 160.55 · h / mL (CV 30.39%) and a C _{max of} 8.98 / / mL (CV 26.37%) at the time of pre-meal administration, AUC 170.36 · h / mL (CV 27.25%) and C _max 9.02 / / mL (CV 25.92%). In addition, when the pharmacokinetic parameters before and after the meal were statistically processed, the AUC average value ratio was 1.06 and the C _max average value ratio was 1.00, and the results after pre-meal / post-meal were very similar, and the pre / post-meal bioavailability was statistically equivalent Respectively.

Compared to this, the pharmacokinetic parameters were measured after taking the pre-existing and post-meal Triglide Tablets (NDA 21-350) in 20 healthy subjects, and the AUC was 131.350 · · h / mL C _{max was} 6.932 μg / mL, and AUC was 157.334 μg · h / mL and C _{max was} 10.380 μg / mL after the meal. In addition, when the pharmacokinetic parameters before and after the meal were statistically processed, it was known that the AUC average value ratio was 1.20 and the C _max average value ratio was 1.50, and the pharmacokinetic parameters after the pre / post meal were about 20 to 50%. In addition, the 90% confidence interval of the log-transformed mean differences did not meet the requirements of log AUC between log 1.07 and log 1.34 and C _max between log 1.34 and log 1.72, within log 0.8 to log 1.25 on the drug equivalency criteria Ref. Application number: 21-350 Clinical pharmacology and biopharmaceutics review (s)).

From the above results, it can be seen that the conventional bioavailability of phenobarbital is not equal to the bioavailability after meal, and the absorption of the drug in the body is significantly influenced by the presence or absence of the meal.

In addition, the blood plasma concentrations of phenobiphilic acid in the body for 24 hours after taking the tablets of Examples 18 to 20 before and after the meal were shown in FIG.

As shown in FIG. 2, the tablets of Examples 18 to 20 can maintain an optimal blood concentration of phenobiphic acid of 5 to 10 占 퐂 / mL in the body for 6 hours or more in both pre- and postmeal tests, and do not exceed 10 占 퐂 / It is possible to take safe treatment and it is possible to absorb certain drugs in the body regardless of whether or not they eat.

Claims (12)

A release-controlling composition comprising choline phenobibrate and a release-controlling agent; And
&Lt; RTI ID = 0.0 &gt; choline &lt; / RTI &gt; phenobibrate and a diluent,
The release control agent may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, xanthan gum, carbomer, collidon searl, ethylcellulose, polyvinylacetate, methacrylate copolymer, And at least one selected from the group consisting of
Wherein the diluent is at least one selected from the group consisting of lactose, microcrystalline cellulose, starch and a mixture thereof,
(KP) Elution Test According to the second method (paddle method), elution test was carried out under the following conditions (1) and (2) to obtain a dissolution profile,
When formula (A) hayeoteul evaluate the similarity factor (f ₂₎ of the elution profile obtained in the above condition (1) and (2) according to, tablets having a range of 50≤f ₂ ≤100.
Condition (1): elution at 900 rpm in an artificial intestinal fluid (US Pharmacopoeia, USP) at 37 ± 0.5 ° C and pH 6.8 for 240 minutes at 100 rpm
Condition (2): elution at 900 rpm in an artificial intestinal fluid (US Pharmacopoeia, USP) at 37 ± 0.5 ° C, pH 6.8, at 50 rpm for 240 minutes
Formula (A):

(In the above formula (A), R _t and T _t mean the cumulative percentage of the drug eluted at the time of elution in the conditions (1) and (2), respectively, where n is an integer of 1 to 20) delete delete The tablet according to claim 1, comprising 20 to 80 parts by weight of choline phenobibrate, 1 to 80 parts by weight of a release-controlling agent and 1 to 80 parts by weight of a diluent. The tablet according to claim 1, wherein the release-controlling composition and the immediate release composition are in the form of particles, granules, pellets and tablets. delete The tablet according to claim 1, wherein the tablet is a multi-layer tablet or a press-formed tablet. The tablet of claim 1, wherein the tablet is coated with a delayed release coating. [8] The composition of claim 8, wherein the delayed release coating is selected from the group consisting of methacrylic acid copolymer, hypromellose phthalate (hydroxypropylmethylcellulose phthalate) and hypromellose acetate succinate (hydroxypropylmethylcellulose acetate succinate) At least one of the tablets. The tablet according to claim 1, wherein said tablet is eluted at 900 rpm in an artificial intestinal fluid (USP, USP) at 37 ± 0.5 ° C and pH 6.8 according to Method 2 (paddle method) of KP elution for 4 hours &Lt; / RTI &gt; delete (I) mixing choline phenobibrate with a release-controlling agent and a pharmaceutically acceptable carrier to produce a release-controlling composition; And
(Ii) mixing the choline phenobibrate with a diluent and a pharmaceutically acceptable carrier to prepare an immediate release composition,
(Iii) co-formulating the composition in steps (i) and (ii) above,
The release control agent may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, xanthan gum, carbomer, collidon searl, ethylcellulose, polyvinylacetate, methacrylate copolymer, And at least one selected from the group consisting of
Wherein the diluent is at least one selected from the group consisting of lactose, microcrystalline cellulose, starch, and mixtures thereof. &Lt; Desc / Clms Page number 19 &gt;

Images