JP2017218432A - Duloxetine enteric pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a duloxetine-containing pharmaceutical composition that attains both an improvement of dissolution property at pH 6.8 and suppression of generation of an analogous substance.SOLUTION: According to the present invention, there is provided an oral pharmaceutical composition comprising a drug layer and an enteric layer. Here, the drug layer comprises duloxetine hydrochloride and a pharmaceutically acceptable additive. The enteric layer comprises carboxymethylethylcellulose as an enteric polymer and a pharmaceutically acceptable additive, and covers the drug layer.SELECTED DRAWING: None

Description

  The present invention relates to an enteric oral pharmaceutical composition containing duloxetine as an active ingredient.

  Duloxetine is one of the antidepressants commonly used as the hydrochloride salt. Duloxetine is unstable in the acidic environment of the stomach because it is easily degraded by acid. Thus, duloxetine is formulated as an enteric pharmaceutical composition.

  For example, Japanese Patent No. 3707831 (Patent Document 1) describes an enteric pellet of duloxetine. US Pat. No. 6,057,059 also shows that duloxetine reacts with many enteric coatings to form a coating that is slow or even insoluble, and does not allow the release of duloxetine in acidic conditions. It is stated that it is particularly difficult to produce enteric preparations at the level. Therefore, in the duloxetine enteric pellet described in Patent Document 1, an enteric layer containing hydroxypropyl methylcellulose acetate succinate as an enteric polymer is used.

  JP-T-2008-543929 (Patent Document 2) includes a homogeneous core containing duloxetine hydrochloride covered with an enteric coating, and the enteric polymer is Eudragit L or Eudragit S, hydroxypropyl methylcellulose. It is described that it is selected from the group comprising phthalates, cellulose acetate phthalates, polyvinyl acetate phthalates and the like, or mixtures thereof.

  JP-T-2009-538315 (Patent Document 3) describes a duloxetine hydrochloride delayed-release preparation containing at least one of methacrylic acid copolymer and hydroxypropyl / methylcellulose / phthalate in an enteric layer. .

  JP-T-2010-530868 (Patent Document 4) describes a duloxetine preparation containing an enteric coating containing hydroxypropylmethylcellulose phthalate.

  JP 2011-510024 A (Patent Document 5) discloses duloxetine containing an enteric coat in which hydroxypropylmethylcellulose phthalate phthalate is used as a preferable enteric polymer selected for layer positive with duloxetine. A pharmaceutical composition comprising is described.

  In Japanese Patent No. 5819329 (Patent Document 6), as an enteric coating agent, aqueous and organic hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, organic cellulose acetate phthalate, and poly (ethyl acrylate-methacrylic acid) are disclosed. ) An alcohol-resistant pharmaceutical composition of duloxetine is described which comprises an enteric coating comprising an enteric component selected from the group consisting of anionic copolymers.

Japanese Patent No. 3707831 Special table 2008-543929 Special table 2009-538315 Special table 2010-530868 Special table 2011-510024 gazette Japanese Patent No. 5819329

  However, the duloxetine-containing pharmaceutical compositions of Patent Documents 1 to 6 have room for improvement in solubility and stability at pH 6.8.

  Accordingly, an object of the present invention is to achieve both improvement in dissolution at pH 6.8 and suppression of production of related substances in a duloxetine-containing pharmaceutical composition.

  As a result of intensive studies, the present inventors have found that duloxetine reacts with the enteric coating and slows dissolution by using carboxymethylethylcellulose as the enteric polymer in the enteric layer in the enteric pharmaceutical composition of duloxetine, or It has been found that the formation of a coating that does not dissolve can be reduced, and at the same time the stability of the enteric pharmaceutical composition can be improved.

  Based on such knowledge, the enteric pharmaceutical composition according to the present invention includes a drug layer and an enteric layer. The drug layer includes duloxetine hydrochloride and a pharmaceutically acceptable additive. The enteric layer contains carboxymethyl ethyl cellulose as an enteric polymer and a pharmaceutically acceptable additive, and covers the drug layer.

It is a figure which shows the time change of the elution rate in pH6.8 of the enteric granule of duloxetine.

  The enteric pharmaceutical composition according to the present invention includes a drug layer and an enteric layer. The drug layer includes duloxetine hydrochloride and a pharmaceutically acceptable additive. The enteric layer contains carboxymethyl ethyl cellulose as an enteric polymer and a pharmaceutically acceptable additive, and covers the drug layer.

  The drug layer and / or enteric layer are known to those skilled in the art as pharmaceutically acceptable additives such as beads made from sugar, vegetable gum, microcrystalline cellulose, wax, and the like. Additives can be included.

  In addition, the enteric pharmaceutical composition according to the present invention preferably includes an intermediate layer between the drug layer and the enteric layer. The intermediate layer is for preventing duloxetine hydrochloride, which is easily decomposed by acid, from coming into contact with the acidic enteric layer coating solution. Materials known as additives to those skilled in the art, such as titanium oxide and fine powder talc, are used. Used.

  In the enteric pharmaceutical composition according to the present invention, the ratio between the thickness of the enteric layer and the particle size of the oral pharmaceutical composition is preferably 1:25 to 1:12. For example, the thickness of the enteric layer: The particle size of the oral pharmaceutical composition is preferably about 40 μm: about 996 μm to about 30 μm: about 347 μm.

  The drug layer, intermediate layer, and enteric layer are each formed by methods known to those skilled in the art.

  The pharmaceutical composition according to the present invention may further have a finishing layer covering the enteric layer. The finishing layer is formed by a known method using materials known to those skilled in the art, for example, to smooth the surface of the pharmaceutical composition.

  The pharmaceutical composition according to the present invention can be manufactured as a powdered or granulated solid composition, tablet, pellet, orally disintegrating tablet, capsule tablet.

  By doing in this way, in the duloxetine-containing pharmaceutical composition, it is possible to achieve both improvement of dissolution at pH 6.8 and suppression of production of related substances.

  Hereinafter, although an example etc. explain the present invention in detail, the present invention is not limited to this.

[Example]
A duloxetine oral pharmaceutical composition according to the present invention was prepared as follows. The amount of each raw material was as shown in Table 1.

(Manufacture of drug layer granules)
D-mannitol was put into a rolling fluidized bed granulator / dryer. Ethanol was mixed with a solution in which povidone was dissolved in purified water. Duloxetine hydrochloride was dispersed in the admixture, and the whole liquid was sprayed and coated. Subsequently, drying and classification were performed to obtain drug layer granules.

(Manufacture of intermediate layer granules)
The drug layer granules obtained as described above were put into a rolling fluidized bed granulator / dryer. Talc was dispersed in a solution in which hypromellose was dissolved in purified water. Titanium oxide was mixed with a liquid dispersed in purified water. The whole liquid was sprayed and coated. Subsequently, it was dried and classified to obtain intermediate layer granules.

(Manufacture of enteric granules)
The intermediate layer granules obtained as described above were put into a rolling fluidized bed granulator / dryer. A solution in which triethyl citrate was dissolved in purified water and a solution in which carboxymethyl ethyl cellulose was dissolved in a mixed solution of ethanol and purified water were mixed. This solution was sprayed onto the intermediate layer granules and coated. Subsequently, the mixture was dried and a mixture of talc was used as an enteric granule.

(Manufacture of tablets)
The enteric granules obtained as described above were sized using a sizing machine to obtain a sized powder. Next, after mixing the sized powder and D-mannitol in a polyethylene bag, magnesium stearate was added and mixed to obtain a tableting powder. Then, the tableting powder was tableted with a tableting machine (VELA5, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets.

[Comparative Example 1]
With the formulation shown in Table 1, tablets were obtained in the same manner as in the Examples. Instead of carboxymethylethyl cellulose used in the production of the enteric granules of Examples, methacrylic acid copolymer LD (Eudragit L30D-55) was used, and only purified water was used for dispersion without using ethanol.

[Comparative Example 2]
As comparative example 2, 30 mg of duloxetine hydrochloride capsule Cymbalta (registered trademark) capsules (sales Japan Eli Lilly Co., Ltd., production and sales Shionogi Pharmaceutical Co., Ltd.) was used.

[Comparison of dissolution]
Each of the enteric granules of Examples, the enteric granules of Comparative Example 1 and the capsules of Comparative Example 2 was taken and tested for comparing dissolution.

The test conditions were as follows.
Detector: UV absorption photometer (Measurement wavelength: 230 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 7.5 cm was packed with 5 μm of octadecylsilylated silica gel for liquid chromatography. (Inertsil C8-3, 3.0 mm × 7.5 cm, 5 μm)
Column temperature: constant temperature around 40 ° C Sample cooler: 25 ° C
Mobile phase: 270 mL of methanol and 90 mL of tetrahydrofuran were mixed with 640 mL of potassium dihydrogen phosphate / triethylamine buffer at pH 5.5.
Flow rate: Adjusted so that the retention time of duloxetine was about 4 minutes.
Analysis time: 6 minutes

  10 mL of the eluate was collected at each sampling time and filtered through a membrane filter having a pore size of 0.45 μm or less. Except for 7 mL of the first filtrate, the next filtrate was used as a sample solution. Separately, about 56 mg of duloxetine hydrochloride (separately measured for moisture in the same manner as standard duloxetine hydrochloride) was accurately weighed, and methanol was added to make exactly 50 mL. 3 mL of this solution was accurately weighed, and the test solution was added to make exactly 100 mL, which was used as a standard solution. The sample solution and 20 μL of the standard solution were tested by liquid chromatography under the following conditions, and the peak areas AT and AS of duloxetine were measured.

  The results of the dissolution test are shown in FIG.

[Stability test]
The stability test was conducted as follows using the tablets of Examples, the tablets of Comparative Example 1 and the capsules of Comparative Example 2 as two preparation samples.

The test conditions were as follows.
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm was packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C. Mobile phase A: pH 5.5 potassium dihydrogen phosphate / triethylamine buffer Mobile phase B: methanol / tetrahydrofuran mixture (3: 1)
Mobile phase feeding: Based on the United States Pharmacopeia (USP), concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B.

  60 mL of a methanol / water mixture (7: 3) was added to each sample, shaken and mixed, then subjected to ultrasonic treatment, and filtered through a membrane filter having a pore size of 0.2 μm or less. The first 3 mL of the filtrate was removed, 3 mL of the next filtrate was weighed, and 3 mL of a methanol / water mixture (7: 3) was added to obtain a sample solution. A 10 μL sample solution was tested by liquid chromatography under the test conditions described above. When each peak area of the sample solution is measured by the automatic integration method and the amount thereof is obtained by the area percentage method, the amount of each peak other than duloxetine is 0.3% or less, and the total amount of peaks other than duloxetine Was 1.0% or less.

  The results are shown in Table 2.

  It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in every respect. The scope of the present invention is defined by the terms of the claims, rather than the description above, and includes all modifications within the scope and meaning equivalent to the terms of the claims.

Claims (3)

A drug layer comprising duloxetine hydrochloride and a pharmaceutically acceptable additive;
An enteric pharmaceutical composition comprising carboxymethyl ethyl cellulose as an enteric polymer and a pharmaceutically acceptable additive, and an enteric layer covering the drug layer.   The enteric pharmaceutical composition according to claim 1, comprising an intermediate layer between the drug layer and the enteric layer.   The enteric pharmaceutical composition according to claim 1 or 2, wherein the ratio between the thickness of the enteric layer and the particle size of the oral pharmaceutical composition is 1:25 to 1:12.

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