JP4993274B2 - Method for producing fenofibrate-containing pharmaceutical composition - Google Patents

Description

  The present invention relates to a method for producing a fenofibrate-containing preparation composition having improved solubility and absorbability without using sodium lauryl sulfate or a nonionic surfactant.

In order to improve the solubility of a poorly soluble drug, methods such as salt formation, solubilization with an organic solvent, formation of a solid dispersion, pulverization, and addition of a surfactant are generally used.
Although fenofibrate is a fibrate hyperlipidemia drug, it is a poorly soluble drug that is extremely insoluble in water, and many techniques for improving the solubility of fenofibrate have been filed.
Japanese Patent Application Laid-Open No. 10-505574 discloses a method of obtaining a solid dispersion by dissolving fenofibrate, a hydrophilic polymer and a surfactant in an organic solvent and then coprecipitation.
JP-T-2003-513904 discloses a method for obtaining a solid dispersion by melting fenofibrate, macrogol 8000, and polyvinylpyrrolidone.
However, in these techniques, preparations with improved solubility can be obtained, but in order to produce a solid dispersion and keep its state stable, it is indispensable to add at least an amount of polymer to fenofibrate. For this reason, preparations with a large single dosage such as fenofibrate lead to significant enlargement of the preparation.
Such an increase in the size of the preparation causes a very large problem in terms of compliance such that it is difficult or impossible to take the preparation.
As a method not using a solid dispersion for improving the solubility, JP-A-9-328427 discloses that fenofibrate is dissolved in a solubilizing agent composed of diethylene glycol monoethyl ether which is a nonionic surfactant, and this solution is used as a solution. A method for filling soft capsules is shown.
JP-T-2003-504331 discloses a method of granulating an aqueous suspension of finely divided fenofibrate, a surfactant and a binding cellulose derivative.
Japanese Patent Publication No. 7-14876 discloses a method for improving solubility by finely pulverizing a mixture of fenofibrate and a solid surfactant.
Furthermore, a method for reducing the size of the conventional preparation by applying this technology is disclosed in International Patent Publications WO2002 / 0699957 and JP-A-2006-274349, and a method for tableting a fenofibrate preparation is disclosed in JP-T-2004-525887. Respectively.
With regard to these technologies, the miniaturization of the formulation and the tableting of capsules that improve the solubility of fenofibrate and further improve the compliance are attempted.
However, in these techniques, addition of sodium lauryl sulfate or a nonionic surfactant is indispensable.
Surfactants improve the solubility of drugs in the gastrointestinal tract and promote the absorption of drugs from the gastrointestinal tract, while they have been pointed out to be damaging to the living body such as irritation and damage to the gastrointestinal mucosa.
In addition, serious side effects such as anaphylactic shock caused by polyoxyethylene hydrogenated castor oil, which is a nonionic surfactant, have been reported. It is desirable to improve.
In addition, since the pulverized product is scattered in the environment in the pulverization process, pulverizing sodium lauryl sulfate having irritation is not preferable in view of the health of the worker.
As described above, there are no examples of techniques for improving solubility and absorbability without adding a surfactant without increasing the size of a fenofibrate formulation.

Japanese National Patent Publication No. 10-505574 Special table 2003-513904 gazette JP-A-9-328427 Special Table 2003-504331 Japanese Patent Publication No. 7-14876 WO2002 / 069957 JP 2006-273449 A Japanese translation of PCT publication No. 2004-525887

  The present invention provides a fenofibrate-containing preparation composition that does not contain sodium lauryl sulfate or a nonionic surfactant, and has a solubility and absorbability equivalent to those of a preparation containing a surfactant. It aims at providing with a simple manufacturing method.

As a result of diligent research to solve the problems inherent in the prior art, the present inventors have produced granules containing finely divided fenofibrate and a water-soluble polymer using a wet granulation method. The surface modification action of fenofibrate improves the wettability of the particle surface of fenofibrate, and without using sodium lauryl sulfate or a nonionic surfactant, a fenofibrate-containing pharmaceutical composition containing these surfactants and It has been found that a fenofibrate-containing preparation composition showing similar solubility and absorbability can be obtained.
In the present invention, micronized fenofibrate can be obtained by pulverizing fenofibrate using an appropriate pulverizer, and those having an average particle size of 15 μm or less are preferred.
Examples of the water-soluble polymer include hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, and hydroxypropylmethylcellulose is particularly preferable.
As described above, in order to improve the solubility and absorbability using the solid dispersion, it is essential to add an amount of a polymer equal to or larger than that of fenofibrate, and an increase in the size of the preparation is inevitable. It is possible to significantly reduce the amount of water-soluble polymer added in comparison with this.
Specifically, it is preferable to use a water-soluble polymer in the range of 2% by mass to 15% by mass with respect to micronized fenofibrate.
When the amount of water-soluble polymer added is less than 2% by mass with respect to micronized fenofibrate, the wettability of the surface of the fenofibrate particles is insufficient, and the dissolution rate is low in the dissolution test. It becomes insufficient.
Further, when the amount of the water-soluble polymer added exceeds 15% by mass with respect to the finely divided fenofibrate, in order to disintegrate the tablet and dissolve the fenofibrate from the tablet when the granules obtained in the present invention are made into tablets. Since a large amount of a disintegrant is required and the preparation becomes large, it is not preferable.
Furthermore, these water-soluble polymers can be dissolved in a solvent or used as a powder.
Examples of the wet granulation method in the present invention include agitation granulation method, kneading granulation method, fluidized bed granulation method, rolling fluidized bed granulation method, extrusion granulation method, etc., preferably the agitation granulation method Is mentioned.
For example, when the agitation granulation method is used, the purpose is to granulate by adding purified water to a powder obtained by mixing micronized fenofibrate and a water-soluble polymer with an appropriate excipient or disintegrant. Granules can be obtained.
It is also possible to obtain the desired granules by adding purified water in which a water-soluble polymer is dissolved to a powder obtained by mixing micronized fenofibrate with appropriate excipients and disintegrants. It is.
The granules containing finely divided fenofibrate obtained in the present invention and a water-soluble polymer are mixed with appropriate additives and compressed into tablets by filling into capsules made of gelatin, hydroxypropylmethylcellulose, etc. It is possible to obtain an agent.
Here, suitable additives are pharmaceutical additives that can be used for oral dosage forms, and have an effect on the solubility of fenofibrate, such as excipients, disintegrants, lubricants, and pigment components. It is possible to mix | blend to such an extent.
Examples of the excipient include lactose, D-mannitol, crystalline cellulose, calcium hydrogen phosphate, corn starch and the like.
Examples of the disintegrant include crospovidone, croscarmellose Na, carboxymethyl starch Na, and low-substituted hydroxypropylcellulose.
Examples of the lubricant include magnesium stearate, light anhydrous silicic acid, talc, hydrogenated oil, calcium stearate, sodium stearyl fumarate and the like.
Examples of the pigment component include iron sesquioxide.

The present invention provides a pharmaceutical composition containing fenofibrate by producing granules containing micronized fenofibrate and a water-soluble polymer by a wet granulation method, and does not contain sodium lauryl sulfate or a nonionic surfactant. In addition, a fenofibrate-containing pharmaceutical composition that maintains bioavailability can be obtained.
The fenofibrate-containing preparation composition obtained by the present invention does not contain sodium lauryl sulfate or nonionic surfactant contained in the conventional fenofibrate-containing preparation composition, and therefore excludes adverse effects on the living body due to the surfactant. It became possible to do.

Examples and comparative examples will be described below in detail.
However, the present invention is not limited to these.
Formulations (Examples 1 to 4, Comparative Example 1) having the formulations shown in the table of FIG. 1 were produced by the stirring granulation method.
Micronized fenofibrate (d50: 6.0 μm), lactose (lactose 200, manufactured by DMV JAPAN), crospovidone (Polyplastidon XL, manufactured by ISP Japan), hydroxypropyl methylcellulose 2910 (TC-5, Shin-Etsu Chemical) Kogyo Co., Ltd.) was weighed and placed in a stirring granulator (High Speed Mixer Mini, Fukae Powtech Co., Ltd.).
After mixing for 1 minute, purified water was added and stirred to obtain a stirred granulated product.
After stirring and granulating the obtained agglomerated product with a fluidized bed dryer (FL-mini, manufactured by Freund Sangyo Co., Ltd.), the stirred granulated product, light anhydrous silicic acid (Adsolida 101, manufactured by Freund Sangyo Co., Ltd.) ) And magnesium stearate (manufactured by Nippon Oil & Fat Co., Ltd.) were weighed and mixed in prescribed amounts to obtain a mixed powder.
A prescribed amount of this mixed powder was weighed and filled into No. 3 capsules to obtain capsules.

(Experimental example 1)
The dissolution test of the capsules prepared in Examples 1 to 4 and Comparative Example 1 and the fenofibrate preparation currently on the market were conducted in accordance with the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (Paddle Method). The test was carried out at 50 rpm with 1% polysorbate 80, 900 mL of the Japanese Pharmacopoeia Test Solution Second Solution (pH 6.8).
The results are shown in FIG.
The dissolution rates after 6 hours of Examples 1 to 4 and the commercial preparation were 70% or more.
On the other hand, the elution rate after 6 hours of Comparative Example 1 was about 50%.

Formulations (Examples 5 to 7) having the formulations shown in the table of FIG. 2 were produced by the stirring granulation method.
Micronized fenofibrate (d50: 6.0 μm), lactose (lactose 200, manufactured by DMV JAPAN), crospovidone (Polyplastidon XL, manufactured by ISP Japan Co., Ltd.) and various water-soluble polymers are weighed and granulated. I put it in the machine (high speed mixer mini).
After mixing for 1 minute, purified water was added and stirred to obtain a stirred granulated product.
Various water-soluble polymers were added in an amount of 4.5% by mass based on finely divided fenofibrate.
The resulting stirred granulated product was dried and sized with a fluidized bed dryer (FL-mini), and then stirred granulated product, light anhydrous silicic acid (ADSOLIDA-101, manufactured by Freund Sangyo Co., Ltd.) and magnesium stearate ( A specified amount was weighed and mixed to obtain a mixed powder.
A prescribed amount of this mixed powder was weighed and filled into No. 3 capsules to obtain capsules.
The mixed powder was tableted to obtain 1 tablet of 150 mg (diameter 7.5 mm).

(Example 8)
Formulations shown in the table of FIG. 3 were produced by the stirring granulation method.
Micronized fenofibrate (d50: 6.0 μm), lactose (lactose 200, manufactured by DMV JAPAN), crospovidone (Polyplastidon XL, manufactured by ASP Japan Co., Ltd.) are weighed and stirred granulator (high speed mixer mini ).
After mixing for 1 minute, purified water in which polyvinylpyrrolidone (Prasidone K30, manufactured by IS Japan Co., Ltd.) was dissolved was added and stirred to obtain a stirred granulated product.
Polyvinylpyrrolidone was added in an amount of 4.5% by mass with respect to finely divided fenofibrate.
The resulting stirred granulated product was dried and sized with a fluidized bed dryer (FL-mini), and then stirred granulated product, light anhydrous silicic acid (ADSOLIDA-101, manufactured by Freund Sangyo Co., Ltd.) and magnesium stearate ( A specified amount was weighed and mixed to obtain a mixed powder.
A prescribed amount of this mixed powder was weighed and filled into No. 3 capsules to obtain capsules.
The mixed powder was tableted to obtain 1 tablet of 150 mg (diameter 7.5 mm).

(Comparative Example 2)
Formulations shown in the table of FIG. 4 were produced by dry granulation.
Micronized fenofibrate (d50: 6.0 μm) and hydroxypropyl methylcellulose 2910 (TC-5, manufactured by Shin-Etsu Chemical Co., Ltd.) are weighed and mixed, and dry-made with a roller compactor (TF-MINI, manufactured by Freund Sangyo Co., Ltd.). Done the grain.
The obtained dry granulated product was pulverized with a granulator, and then lactose (Dilactose S, manufactured by Freund Sangyo Co., Ltd.) and crospovidone (Polyplaston XL, manufactured by IS Japan Co., Ltd.) were weighed and mixed. .
Further, light anhydrous silicic acid (ADSOLIDA-101, manufactured by Freund Sangyo Co., Ltd.) and magnesium stearate (manufactured by Nippon Oil & Fats Co., Ltd.) were weighed and mixed in specified amounts.
A prescribed amount of this mixed powder was weighed and filled into No. 3 capsules to obtain capsules.
The mixed powder was tableted to obtain 1 tablet of 155 mg (diameter 7.5 mm).

(Experimental example 2)
The dissolution test of the capsules, tablets, and commercial preparations prepared in Examples 5 to 8 and Comparative Example 2 was conducted according to the Japanese General Test Method Dissolution Test Method Method 2 (Paddle Method), and the test solution was 1% polysorbate 80. The JP disintegration test liquid second solution (pH 6.8) was used at 50 rpm with 900 mL.
The results are shown in FIGS.
The dissolution rate after 6 hours of the capsules, tablets and commercial preparations of Examples 5 to 8 was 70% or more.
On the other hand, the elution rate after 6 hours of the capsule and tablet of Comparative Example 2 was about 30%.

(Experimental example 3)
The tablet produced in Example 7 and the commercial preparation were administered to beagle dogs, and the plasma concentration transition of fenofibric acid, which is an active metabolite of fenofibrate, was measured.
The results are shown in FIG.
The change in plasma concentration of fenofibric acid was similar between Example 7 and the commercial preparation.

The pharmaceutical formulation of Examples 1-4 and Comparative Example 1 is shown. The pharmaceutical formulation of Examples 5-7 is shown. The preparation formulation of Example 8 is shown. The formulation of Comparative Example 2 is shown. The result of Experimental example 1 is shown. The result of Experimental example 2 when it is set as a capsule is shown. The result of Experimental example 2 when it is set as a tablet is shown. The result of Experimental example 3 is shown.

Claims (3)

  Manufacture of a fenofibrate-containing pharmaceutical composition characterized in that granules containing finely divided fenofibrate and a water-soluble polymer are prepared by wet granulation without containing sodium lauryl sulfate and a nonionic surfactant Method.   The granule containing finely divided fenofibrate and a water-soluble polymer, wherein the amount of the water-soluble polymer is in the range of 2 to 15% by weight with respect to the finely divided fenofibrate. A method for producing a fibrate-containing pharmaceutical composition.   The method for producing a fenofibrate-containing pharmaceutical composition according to claim 1 or 2, wherein the water-soluble polymer is at least one of hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

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