KR20240108664A - Pharmaceutical composition comprising fenofibrate having improved bioavailability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising a hydrophilic polymer and saccharides, and comprising fenofibrate as an active ingredient. the fenofibrate is not micronized, and the composition of the present invention has an elution rate equal to or higher than that of a composition comprising micronized fenofibrate.

Description

Pharmaceutical composition comprising fenofibrate having improved bioavailability}

The present invention relates to a pharmaceutical composition containing fenofibrate with improved bioavailability and a method for producing the same. Specifically, the present invention relates to a pharmaceutical composition containing hydrophilic polymers and saccharides and containing fenofibrate as an active ingredient. The fenofibrate is not micronized, and the composition of the present invention is equivalent to the composition containing micronized fenofibrate. It has a dissolution rate of more than

Fenofibrate is a fibric acid derivative, represented by the following formula (1), and is used for primary hyperlipidemia, hypercholesterolemia (type IIa), combined type of hypercholesterolemia and hypertriglyceridemia (type IIb, type III), and hypertriglyceridemia. It is used as a treatment for (Type IV).

[Formula 1]

Fibric acid increases lipolysis by increasing LPL (Lipoprotein lipase) activity and reducing the production of apoprotein C-III, an LPL inhibitor, through activation of PPAR-α (Peroxisome proliferator activated receptor α).

Fenofibrate is a poorly soluble drug that falls under BCS Class 2 and has a problem in that its bioavailability varies depending on the patient's diet. To solve this problem, a method of making fenofibrate into an amorphous solid dispersion using a spray drying method (Korean Registration Publication No. 10-767349, Patent Document 0001) was attempted, but it was not sufficient to solve the problem.

In addition, a method of preparing and using nanoscale fenofibrate particles (International Publication No. W02004/041250, Patent Document 0002) was attempted to solubilize fenofibrate. However, nano-izing fenofibrate involves a complex process, which increases the production cost, and generates heat due to high energy during the grinding process, which may lead to a decrease in stability.

Therefore, the present inventor completed the present invention by developing a pharmaceutical composition containing fenofibrate with high bioavailability by solving the problem of poor solubility without using nanonized or micronized fenofibrate.

Korean Registration Publication No. 10-767349 International Publication W0 2004/041250

In order to solve the problems in the prior art as described above, the purpose of the present invention is to provide an oral pharmaceutical composition with excellent bioavailability regardless of whether it is dietary.

In particular, the object is to provide a fenofibrate composition that has an equivalent or better bioavailability compared to a composition containing micronized fenofibrate, even without going through a micronization or nanoization process of fenofibrate.

Manufacturing nano or micronized fenofibrate particles through pulverization is a complicated manufacturing process, and the heat generated during pulverization may cause a problem in which the stability of fenofibrate is reduced. Therefore, the present inventors attempted to prepare a fenofibrate composition or formulation that exhibits excellent bioavailability without undergoing nanoization/micronization process.

The present inventors completed the present invention by confirming that a composition containing fenofibrate or a pharmaceutically acceptable salt thereof as an active ingredient, a hydrophilic polymer, and saccharides has the effect of improving the dissolution rate and bioavailability of fenofibrate.

The present invention relates to a pharmaceutical composition containing a hydrophilic polymer and a saccharide, and containing fenofibrate or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the fenofibrate is not micronized and the composition contains micronized fenofibrate; In comparison, it has an equal or higher dissolution rate.

The present invention includes the steps of providing a solution in which fenofibrate or a pharmaceutically acceptable salt thereof and a hydrophilic polymer are dissolved, providing a suspension in which saccharides are suspended, and mixing the solution and the suspension to prepare a spray solution. It relates to a method of producing a pharmaceutical composition containing fenofibrate.

When the pharmaceutical composition prepared by the above manufacturing method is subjected to a dissolution test according to the Korean Pharmacopoeia dissolution test method (paddle method) under the conditions of a dissolution solution of pH 1.2, a paddle speed of 50 rpm, and a temperature of 37°C, the dissolution rate of the pharmaceutical composition after 20 minutes is It may be 70% or more, and preferably 75% or more.

The present invention relates to a pharmaceutical composition prepared by the above production method.

The present invention includes the steps of providing a solution in which fenofibrate or a pharmaceutically acceptable salt thereof and a hydrophilic polymer are dissolved, providing a suspension in which saccharides are suspended, mixing the solution and the suspension to prepare a spray solution, It relates to a method for producing a pharmaceutical formulation, comprising the steps of spray-drying a spray liquid to produce a solid dispersion, and compressing the solid dispersion into tablets.

The formulation of the present invention has a dissolution rate equal to or greater than that of a formulation containing micronized fenofibrate. Additionally, the formulation of the present invention may be a tablet for oral administration.

The present invention relates to a composition containing fenofibrate as an active ingredient, a hydrophilic polymer, and saccharides. By including hydrophilic polymers and saccharides, the present invention relates to a composition that contains at least the same level of biological activity as a composition using micronized fenofibrate particles without using micronized fenofibrate particles. A composition having a usability and dissolution rate can be provided. Therefore, by omitting the step of micronizing fenofibrate, the composition of the present invention eliminates problems caused by micronization and simplifies the manufacturing process, providing useful effects for mass production.

Figure 1 shows the results of dissolution tests for the tablets of Examples 1 to 4.
Figure 2 shows the results of the dissolution test for the tablets of Examples 5 to 8.
Figure 3 shows the results of the dissolution test for the tablets of Examples 9 to 11.
Figure 4 shows the results of the dissolution test for the tablets of Examples 12 to 15.

Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present application may be implemented in various forms and is not limited to the embodiments and examples described herein.

Throughout the specification of the present application, when a part "includes" a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.

The present invention relates to a pharmaceutical composition containing a hydrophilic polymer and a saccharide, and containing fenofibrate or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the fenofibrate is not micronized and the composition contains micronized fenofibrate; In comparison, it has an equal or higher dissolution rate.

As used herein, the term “salt” refers to an addition salt of an inorganic, organic, or metal salt of a compound. The salt may be a pharmaceutically acceptable salt. The “pharmaceutically acceptable salt” refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salt is not particularly limited as long as it is pharmaceutically acceptable, and examples include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, and methanesulfonic acid. , benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, etc. can be used.

When the composition of the present invention is tested in accordance with the dissolution test method (paddle method) of the Korean Pharmacopoeia in a dissolution solution of pH 1.2, a paddle speed of 50 rpm, and a temperature of 37°C, the dissolution rate may be more than 70% after 20 minutes. and may preferably be 75% or more.

In the present invention, 'hydrophilic polymer' refers to a substance containing polar or charged functional groups that can interact with or dissolve in water or other polar substances.

The hydrophilic polymer according to the present invention is hypromellose, polyvinylpyrrolidone, polyethylene glycol, vinylpyrrolidone-vinylacetate copolymer, hydroxypropylcellulose, hydroxyethylcellulose, polyvinyl alcohol, or methacrylate copolymer. It may be a polymer, but is not limited thereto, and preferably may be polyethylene glycol.

The hydrophilic polymer according to the present invention may contain 0.05 parts by weight or more, preferably 0.08 parts by weight or more, and more preferably 0.08 to 0.17 parts by weight, based on 1 part by weight of fenofibrate.

The saccharide according to the present invention may be lactose (including lactose hydrate), white sugar, sucrose, mannitol, sorbitol, xylitol, trihalose, maltitol, dulcitol, inositol, dextrin, or cyclodextrin, but is not limited thereto, and is preferably It may be mannitol or sorbitol, and more preferably mannitol.

The sugar according to the present invention may be included in an amount of 0.2 parts by weight or more, preferably 0.2 to 0.5 parts by weight, based on 1 part by weight of fenofibrate.

The present invention includes the steps of providing a solution in which fenofibrate or a pharmaceutically acceptable salt thereof and a hydrophilic polymer are dissolved, providing a suspension in which saccharides are suspended, and mixing the solution and the suspension to prepare a spray solution. It provides a method for producing a pharmaceutical composition containing fenofibrate.

When the pharmaceutical composition prepared by the above manufacturing method is subjected to a dissolution test according to the dissolution test method (paddle method) of the Korean Pharmacopoeia under the conditions of a dissolution solution of pH 1.2, a paddle speed of 50 rpm, and a temperature of 37°C, the dissolution rate of the pharmaceutical composition after 20 minutes is This may be 70% or more, and preferably 75% or more.

The present invention provides a pharmaceutical composition prepared by the above production method.

The present invention includes the steps of providing a solution in which fenofibrate or a pharmaceutically acceptable salt thereof and a hydrophilic polymer are dissolved, providing a suspension in which saccharides are suspended, mixing the solution and the suspension to prepare a spray solution, A method for producing a pharmaceutical formulation is provided, comprising the steps of spray-drying a spray liquid to produce a solid dispersion, and compressing the solid dispersion into tablets.

In particular, the formulation of the present invention has a dissolution rate equal to or greater than that of a formulation containing micronized fenofibrate. Additionally, the formulation of the present invention may be a tablet for oral administration.

The pharmaceutical compositions and preparations of the present invention may additionally contain pharmaceutically acceptable additives. The additives include stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, coagulants, binders, suspending agents, curing agents, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, wetting agents, Wetting agent, filler, anti-foaming agent, freshening agent, masticating agent, anti-static agent, coloring agent, dragee, isotonic agent, softener, emulsifier, adhesive, thickener, foaming agent, pH regulator, excipient, dispersant, disintegrant, water-proofing agent, preservative, preservative. , dissolution aids, solvents, fluidizing agents, etc., but are not limited thereto.

Specifically, the formulation of the present invention may further include a binder. The binder may preferably be copovidone, but is not limited thereto.

The formulation of the present invention may further include a disintegrant. The disintegrant may preferably include crospovidone, croscarmellose sodium, sodium starch glycolate, or a mixture thereof, but is not limited thereto.

The formulation of the present invention may further include a surfactant. The surfactant may preferably include sodium lauryl sulfate, sodium docusate, or a mixture thereof, but is not limited thereto.

The formulation of the present invention may further include a lubricant. The lubricant may preferably include colloidal silicon oxide, magnesium stearate, sodium stearyl fumarate, or a mixture thereof, but is not limited thereto.

The present invention will be described in more detail through examples below. However, the examples below are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Example]

Examples 1 to 4: Preparation of tablets according to types of hydrophilic polymers

Fenofibrate and the hydrophilic polymer were dissolved in methylene chloride, and a binder, disintegrant, and plasticizer were separately added to anhydrous ethanol and mannitol was suspended to prepare a suspension. A spray solution was prepared by mixing the above solution and suspension. Afterwards, a mixture of magnesium aluminometasilicate, crospovidone, and mannitol was placed in a fluidized bed granulator, and the final spray liquid was spray dried to prepare a fenofibrate solid dispersion. The prepared solid dispersion was mixed with colloidal silicon oxide, crospovidone, and sodium stearyl fumarate, and then compressed into tablets to prepare the tablets of Examples 1 to 4. The composition used in this test is shown in Table 1 below.

[Test Example 1]

Fenowell definition dissolution rate

Fenowell tablets containing 145 mg of fenofibrate (micronized) were placed in a dissolution device (manufacturer: Erweka) and tested using the Korean Pharmacopoeia's dissolution test method 2 (paddle method). The eluent was subjected to an elution test at pH 1.2 (0.5% SLS added), paddle speed of 50 rpm, and 37°C, and quantified by HPLC according to liquid chromatography under the following conditions.

<HPLC measurement conditions>

- Detector: Ultraviolet absorptiometry (measurement wavelength: 288nm)

- Column: Column filled with octadecyl silylated silica gel (150mm * 4.6mm, 5㎛) or similar column

- Flow rate: 1ml/min

- Column temperature: 45℃

- Mobile phase: pH 3.0 phosphate buffer: acetonitrile = 30:70 (v/v%)

- Injection amount: 10㎛

The dissolution rate over time is shown in Table 2 below.

As shown in Table 2 above, as a result of conducting a dissolution test of Phenowell tablets, the average dissolution rate at 20 minutes was more than 75%.

[Test Example 2]

Examples 1 to 4: Change in dissolution rate depending on the type of hydrophilic polymer

The tablets of Examples 1 to 4 were subjected to a dissolution test under the same conditions as Test Example 1 and quantified by HPLC, and the results are shown in Table 3 and Figure 1 below.

As shown in Table 3, differences in dissolution rates depending on the hydrophilic polymer used were found.

Specifically, in the case of Example 4, in which the spray liquid did not contain a hydrophilic polymer, the average dissolution rate at 20 minutes was 60.1%, which was significantly lower than the average dissolution rate of 75% for Phenowell tablets. In addition, in the case of Examples 2 and 3, which included polyvinylpyrrolidone as a hydrophilic polymer in the spray liquid, the average dissolution rate for 20 minutes was 66 and 67%, showing an excellent dissolution rate compared to Example 4, which did not contain a hydrophilic polymer. It was confirmed that it represents.

In addition, in the case of Example 1, which included polyethylene glycol as a hydrophilic polymer in the spray solution, it was confirmed that the 20-minute average dissolution rate was similar to the average dissolution rate of Fenowell tablets, 75%, showing the best dissolution rate, and micronized fenofibrate It can be seen that even without use, the dissolution rate is equivalent to that of the micronized fenofibrate preparation.

[Test Example 3]

Examples 5 to 8: Preparation of tablets and changes in dissolution rate according to sugars

Tablets of Examples 5 to 8 were prepared in the same manner as Examples 1 to 4, with the ingredients and compositions shown in Table 4 below.

The tablets of Examples 5 to 8 were subjected to a dissolution test under the same conditions as Test Example 1 and quantified by HPLC, and the results are shown in Table 5 and Figure 2 below.

As shown in Table 5, differences in dissolution rates depending on the sugars used were found. Specifically, in Example 5, which did not contain sugars in the spray liquid, the average dissolution rate at 20 minutes was 49.8%, which was significantly lower than the average dissolution rate of Phenowell tablets.

In addition, in the case of Example 6, which included mannitol as a saccharide in the spray liquid, it was confirmed that the average dissolution rate over 20 minutes was 80.2%, which was higher than the average dissolution rate of Phenowell tablets of 75%. In addition, in the case of Example 7, which included sorbitol as a saccharide in the spray liquid, it was confirmed that the average dissolution rate in 20 minutes was 73.8%, which was similar to the average dissolution rate of Phenowell tablets, which was 75%. In addition, in the case of Example 8, which included lactose hydrate as a saccharide in the spray liquid, it was confirmed that the average dissolution rate over 20 minutes was 58.1%, which was lower than the average dissolution rate of Phenowell tablets of 75%.

Therefore, when saccharides such as mannitol and sorbitol are included, it can be seen that the dissolution rate is equal to or better than that of the micronized fenofibrate preparation, even if micronized fenofibrate is not used.

[Test Example 4]

Examples 9 to 11: Preparation of tablets and change in dissolution rate according to hydrophilic polymer content

Tablets of Examples 9 to 11 were prepared in the same manner as Examples 1 to 4, with the ingredients and compositions shown in Table 6 below.

The tablets of Examples 9 to 11 were subjected to a dissolution test under the same conditions as Test Example 1 and quantified by HPLC, and the results are shown in Table 7 and Figure 3 below.

As shown in Table 7, the difference in dissolution rate depending on the content of the hydrophilic polymer used in the spray liquid can be seen. Specifically, in the case of Example 9 containing about 0.04 parts by weight of hydrophilic polymer based on 1 part by weight of fenofibrate, it was confirmed that the average dissolution rate at 20 minutes was 66.0%.

On the other hand, in the case of Examples 10 and 11, which contain about 0.08 parts by weight and 0.17 parts by weight of hydrophilic polymer, respectively, based on 1 part by weight of fenofibrate, it was confirmed that the 20-minute dissolution rate was more than 80%, showing excellent dissolution rates.

Therefore, when it contains 0.05 parts by weight or more of a hydrophilic polymer based on 1 part by weight of fenofibrate, it can be seen that it exhibits a more excellent dissolution rate than a micronized fenofibrate preparation even if it does not contain micronized fenofibrate.

[Test Example 5]

Examples 12 to 14: Preparation of tablets and changes in dissolution rate according to sugar content

Tablets of Examples 12 to 15 were prepared in the same manner as Examples 1 to 4, with the ingredients and compositions shown in Table 8 below.

The tablets of Examples 12 to 15 were subjected to a dissolution test under the same conditions as Test Example 1 and quantified by HPLC, and the results are shown in Table 9 and Figure 4 below.

As shown in Table 9, the difference in dissolution rate of each hydrophilic polymer can be seen depending on the content of sugars used in the spray liquid.

Specifically, in the case of Example 12 containing 0.10 parts by weight of saccharide per 1 part by weight of fenofibrate, it was confirmed that the average dissolution rate over 20 minutes was low at 66.1%.

On the other hand, in the case of Examples 13 to 15, which contained 0.21, 0.31, and 0.41 parts by weight of sugars per 1 part by weight of fenofibrate, it was confirmed that the 20-minute dissolution rate was more than 75%, which was excellent.

Claims (20)

A pharmaceutical composition containing hydrophilic polymers and saccharides, and containing fenofibrate or a pharmaceutically acceptable salt thereof as an active ingredient,
The fenofibrate or a pharmaceutically acceptable salt thereof is not micronized,
A pharmaceutical composition, characterized in that the composition has a dissolution rate equal to or higher than that of a composition containing micronized fenofibrate.
According to claim 1, when the dissolution test is performed in accordance with the dissolution test method (paddle method) of the Korean Pharmacopoeia under the conditions of a dissolution solution of pH 1.2, a paddle speed of 50 rpm, and a temperature of 37°C, the dissolution rate after 20 minutes is 70% or more. Characterized by pharmaceutical composition.
According to claim 1, when the dissolution test is performed in accordance with the Korean Pharmacopoeia dissolution test method (paddle method) in a dissolution solution of pH 1.2, a paddle speed of 50 rpm, and a temperature of 37°C, the dissolution rate after 20 minutes is 75% or more. Characterized by pharmaceutical composition.
The pharmaceutical composition according to claim 1, wherein the hydrophilic polymer is polyethylene glycol.
The pharmaceutical composition according to claim 1, wherein the saccharide is mannitol or sorbitol.
The pharmaceutical composition according to claim 1, wherein the saccharide is mannitol.
The pharmaceutical composition according to claim 1, comprising 0.05 parts by weight or more of a hydrophilic polymer based on 1 part by weight of fenofibrate.
The pharmaceutical composition according to claim 1, comprising 0.08 parts by weight or more of a hydrophilic polymer based on 1 part by weight of fenofibrate.
The pharmaceutical composition according to claim 1, comprising 0.08 to 0.17 parts by weight of a hydrophilic polymer based on 1 part by weight of fenofibrate.
The pharmaceutical composition according to claim 1, comprising 0.2 parts by weight or more of sugars per 1 part by weight of fenofibrate.
The pharmaceutical composition according to claim 1, comprising 0.2 to 0.5 parts by weight of sugar per 1 part by weight of fenofibrate.
Providing a solution in which fenofibrate or a pharmaceutically acceptable salt thereof and a hydrophilic polymer are dissolved,
providing a suspension in which the sugar is suspended, and
A method of producing a pharmaceutical composition containing fenofibrate, comprising mixing the solution and the suspension to prepare a spray solution.
According to claim 12, when the dissolution test is performed in accordance with the Korean Pharmacopoeia dissolution test method (paddle method) in a dissolution solution of pH 1.2, a paddle speed of 50 rpm, and a temperature of 37°C, the dissolution rate of the pharmaceutical composition is 70% after 20 minutes. How to get more than %.
The method of claim 12, wherein the hydrophilic polymer is polyethylene glycol.
13. The method of claim 12, wherein the saccharide is mannitol or sorbitol.
13. The method of claim 12, wherein the saccharide is mannitol.
A pharmaceutical composition prepared by the method according to any one of claims 12 to 16.
Providing a solution in which fenofibrate or a pharmaceutically acceptable salt thereof and a hydrophilic polymer are dissolved,
providing a suspension in which the sugar is suspended;
Preparing a spray solution by mixing the solution and the suspension,
Preparing a solid dispersion by spray drying the spray liquid, and
A method for producing a pharmaceutical formulation, comprising the step of manufacturing a tablet by compressing the solid dispersion.
The method of claim 18, wherein the formulation has a dissolution rate equal to or greater than that of a formulation containing micronized fenofibrate.
The method of claim 18, wherein the preparation is a tablet for oral administration.