JP2020002129A - Duloxetine hydrochloride-containing granules with improved photochromic properties - Google Patents

Abstract

To provide technical means for producing granules containing duloxetine hydrochloride with excellent stability to light (such as suppression of color change).SOLUTION: Provided is a granule comprising duloxetine hydrochloride and titanium oxide, characterized by that the titanium oxide is 50.0 parts by weight or more based on 100.0 parts by weight of duloxetine hydrochloride. The granules have a portion containing duloxetine hydrochloride which is first coated with a coating layer containing titanium oxide therearound, and further which is preferably coated with a coating layer containing an enteric coating agent.SELECTED DRAWING: None

Description

  The present invention relates to granules containing duloxetine hydrochloride as a drug substance (drug), and discloses a detailed method for improving light stability (suppression of color change, etc.).

  Duloxetine hydrochloride (generic name) is a serotonin / noradrenaline reuptake whose chemical name is (S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine · hydrochloride It is an inhibitor and is useful for treating depression / depression, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with chronic low back pain (see Non-Patent Document 1, etc.).

  At present, preparations containing duloxetine hydrochloride are provided to medical sites in the form of capsules (see Non-Patent Document 1, etc.). With respect to the preparation containing duloxetine hydrochloride, its formulation and production method are also introduced in the following Patent Documents 1 to 5 and the like. However, there is little suggestion in the prior art about a technique for improving the discoloration of a preparation containing duloxetine hydrochloride.

  Therefore, the present inventors aimed to develop a new technique for improving photostability of granules containing duloxetine hydrochloride.

JP 2018-090510 A JP 2018-016622 A JP 2017-226640 A JP-A-2017-218432 Japanese Patent No. 3707831

"Cymbalta (R) Capsule 20 mg, Cymbalta (R) Capsule 30 mg" Drug Interview Form Revised January 2017 (11th edition)

  An object of the present invention is to provide a technical means for producing granules containing duloxetine hydrochloride having excellent stability to light (such as suppression of color change).

  The present inventors have conducted intensive studies to solve the above problems, and as a result, granules containing duloxetine hydrochloride and titanium oxide, which contain titanium oxide at a certain high content, the color change before and after light irradiation. It was found that it was significantly suppressed. The present inventor has conducted further intensive studies based on the findings, and has completed the present invention described below.

The present invention relates to a granule containing duloxetine hydrochloride and a certain amount or more of titanium oxide or a method for producing the same, and preferred constitutions thereof are described in (1) to (8) below.
(1) A granule containing duloxetine hydrochloride and titanium oxide, wherein the titanium oxide is contained in an amount of 50.0 parts by weight or more based on 100.0 parts by weight of duloxetine hydrochloride.
(2) The granule according to (1), wherein titanium oxide is contained in an amount of 60.0 parts by weight or more based on 100.0 parts by weight of duloxetine hydrochloride.
(3) The granule according to (1) or (2), wherein the periphery of the portion containing duloxetine hydrochloride is covered with a coating layer containing titanium oxide.
(4) The granule according to any one of (1) to (3), wherein the periphery of the portion containing duloxetine hydrochloride and titanium oxide is covered with a coating layer containing an enteric coating agent.
(5) The granule according to any of (1) to (4) above, wherein the periphery of the coating layer containing the enteric coating agent is not covered with a coating layer containing no enteric polymer.
(6) The granule according to any one of (1) to (5), which does not contain a light-shielding agent that is iron oxide.
(7) A capsule containing the granules according to any one of (1) to (6).
(8) Granules (secondary core particles) obtained by coating (primary coating) on an excipient (primary core particles) having a particle size in the range of 50.0 to 350.0 μm are further coated. The method according to any one of the above (1) to (6), further comprising a step of obtaining the granules by further coating (tertiary coating) the granules (tertiary core particles) obtained by (secondary coating). A method for producing granules.

  The present invention provides granules containing duloxetine hydrochloride, which have excellent stability to light (such as suppression of color change).

  Hereinafter, the details of the granules containing duloxetine hydrochloride and a certain amount or more of titanium oxide or a method for producing the same according to the present invention will be described in detail. However, the following description is an exemplification for explaining the present invention, and is not intended to limit the technical scope of the present invention only to this description range.

<Drug salt>
The granules of the present invention contain a drug that is duloxetine hydrochloride. The median diameter (d ₅₀ ) of duloxetine hydrochloride is preferably from 1.0 to 50.0 μm, and more preferably from 1.0 to 10.0 μm. Duloxetine hydrochloride can be adjusted to an arbitrary particle size by appropriately performing dry or wet pulverization as necessary. The particle diameter such as the median diameter in the present specification may be measured under any commonly used measurement conditions and methods, and can be measured, for example, by a laser diffraction / scattering method (dry measurement, volume basis). It is. Duloxetine hydrochloride is contained in the granules of the present invention in the range of 8.0 to 30.0% by weight, preferably 10.0 to 25.0% by weight, based on the total weight of the granules.

<Light shielding agent>
The granules of the present invention contain titanium oxide as a light-shielding agent, and the amount thereof is at least 50.0 parts by weight, preferably at least 55.0 parts by weight, more preferably at least 60.50 parts by weight, based on 100.0 parts by weight of duloxetine hydrochloride. 0 parts by weight or more, and even more preferably 65.0 parts by weight or more. The granules of the present invention do not need to contain a light-shielding agent such as iron oxide (yellow iron sesquioxide, iron sesquioxide, black iron oxide, etc.) (however, it is desirable that the capsule contains iron oxide. ). Titanium oxide is contained in the granules of the present invention in the range of 5.0 to 30.0% by weight, preferably 10.0 to 20.0% by weight, based on the total weight of the granules. The light-shielding agent is preferably contained in a coating layer covering a portion containing duloxetine hydrochloride in the granule of the present invention, and the coating layer is 25.0 to 45% based on the total weight of the granule of the present invention. It is preferably contained in an amount of 0.0 wt%.

<Enteric polymer>
Specific examples of the enteric polymer according to the present invention include methacrylic acid copolymer (methacrylic acid copolymer L, methacrylic acid copolymer LD (solid content), methacrylic acid copolymer S, etc.), cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl Examples include methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose and the like, with hydroxypropylmethylcellulose acetate succinate being preferred. The enteric polymer is contained in the granules of the present invention in an amount of 10.0% by weight or more, preferably 15.0 to 50.0% by weight, based on the total weight of the granules. The enteric polymer is a coating that covers a part containing duloxetine hydrochloride and titanium oxide in the granules of the present invention (preferably, a part containing duloxetine hydrochloride whose inside is covered with a coating layer containing no enteric polymer). Preferably, it is contained in a layer.

<Granules>
The granules of the present invention are desirably coated granules (core particles are coated with a coating layer). In the production of the coated granules, excipients, granules or coated granules can be used as the core particles, but are preferably granules coated one or more times with the excipients or excipients as core particles. Particularly preferred coated granules are those in which an excipient (primary core particles) is coated (primary coating) (secondary core particles) and further coated (secondary coating) (tertiary core particles). (Tertiary coating). The following coating is preferably performed so that the following layers are formed, and the coating is continuously performed at least twice to form a plurality of layers having the following characteristics in common. It is also possible to carry out.
Each coating layer formed by each of the following coatings contains a drug (preferably together with a coating agent that is not an enteric polymer) in the case of the primary coating layer (drug layer), In the case of a secondary coating layer (separating layer), titanium oxide is contained (preferably in combination with a coating agent which is not an enteric polymer), and in the case of a tertiary coating layer (enteric layer), enteric coating is included. It is desirable that a polymer be included. Each of the following coating layers may be composed of a plurality of adjacent layers having different component compositions (provided that the characteristics of the respective following layers are common). It is desirable that the periphery of the coating layer containing the enteric polymer is not covered with the coating layer containing no enteric polymer.
Examples of excipients that become core particles include crystalline cellulose, mannitol, silicon dioxide, calcium silicate and the like, and crystalline cellulose is particularly desirable. The particle diameter of the core particles is desirably less than 500.0 μm, and more desirably in the range of 50.0 to 350.0 μm. Examples of the coating agent that is not an enteric polymer include hydroxypropylcellulose, hypromellose, methylcellulose, ethylcellulose, and talc, and hypromellose (preferably together with talc) is particularly desirable.
In the coated granules, excipients (primary core particles) are 5.0 to 40.0% by weight, preferably 8.0 to 20.0% by weight, and the drug is 8.0 to 8.0% by total weight. 30.0% by weight, preferably 10.0-25.0% by weight, titanium oxide 5.0-30.0% by weight, preferably 10.0-20.0% by weight, coating which is not an enteric polymer The coating agent is 10.0% by weight or more, preferably 15.0-35.0% by weight, and the enteric polymer coating agent is 10.0% by weight or more, preferably 15.0-50.0% by weight. , A coating layer containing titanium oxide is preferably contained in an amount of 25.0% by weight or more, more preferably 30.0 to 45.0% by weight. In the present specification, the coated granules are treated as a kind of granules.

<Other additives>
In order to produce the granules of the present invention, in addition to the above additives, commonly used excipients, binders, disintegrants, lubricants, plasticizers, flavoring agents, coating agents and the like Additives can also be used.

<Capsule>
Capsules can be manufactured by filling the granules (pellets) of the present invention into capsules. One capsule contains, for example, 22.4 mg or 33.7 mg of duloxetine hydrochloride.
Further, it is possible to obtain a PTP sheet product containing the preparation of the present invention by covering and encapsulating the capsule with a packaging sheet and an aluminum foil or the like, followed by heat sealing. Specific materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like. In order to improve the stability of the granules of the present invention against humidity, a PTP sheet product is manufactured using a material having a drying function, the PTP sheet product is packaged in an aluminum pillow, or a desiccant is placed in a bottle. It is possible to perform a known method such as encapsulation.

  Hereinafter, the present invention will be described with reference to examples and the like, but the present invention is not limited to these examples and the like.

(A: primary core particle / drug layer) Crystallized cellulose (Selfia (registered trademark) CP-203 / Asahi Kasei Corporation, particle diameter 150 to 300 μm) is spouted in a fluidized bed granulator (MP-01-SPC type / Pourec). And a solution in which duloxetine hydrochloride was dispersed and suspended in a solution in which hydroxypropyl methylcellulose was dissolved in purified water was sprayed and dried to obtain secondary core particles.
(B: Separation layer) The secondary core particles obtained above are charged into a spouted fluidized bed granulator, and a liquid obtained by dispersing and suspending talc and titanium oxide in a liquid in which hydroxypropylmethylcellulose is dissolved in purified water is used. By spraying and drying, tertiary core particles were obtained.
(C: Enteric layer) The tertiary core particles obtained above are put into a spouted fluidized bed granulator, and hydroxypropyl methylcellulose acetate succinate (AS-LG / manufactured by Shin-Etsu Chemical Co., Ltd.) is dissolved, and talc ( SK-C / Katsumitsusan Mining Co., Ltd.) was dispersed and suspended, and a mixture of purified water and 10% ammonia water was sprayed and dried to obtain coated granules.
In addition, the above-mentioned drug and each additive were used in the above-mentioned production in such amounts as to give the formulations shown in Table 1 below.

[Comparative Examples 1 and 2]
Coated granules were obtained by the same production method as in Example 1.
In addition, the drug and each additive were used in the above-mentioned production in amounts such that the formulations shown in Table 1 below were obtained.

[Test Example 1] Color difference measurement before and after light irradiation For each of the granules obtained in Example 1 and Comparative Examples 1 and 2, before and after light irradiation of 3000 lx incandescent light for 400 hours for a total of 1.2 million lx · hr, lightness (L) was measured. *), And chromaticity (a * and b *) indicating hue and saturation were measured using a spectral colorimeter (SE6000, manufactured by Nippon Denshoku Industries Co., Ltd.). From this result, the color difference (ΔE) of each granule before and after light irradiation was calculated and is shown in Table 2 below. The color difference was calculated using the following formula for ΔE using L * a * b * specified in CIELab 1976 as the chromaticity value. ΔE = ｛(ΔL *) ＾ 2+ (ａa *) ＾ 2 (Δb *) ＾ 2｝ ＾ 1/2 (from Spectrophotometer SE6000, Nippon Denshoku Industries Co., Ltd., instruction manual).

Test Example 2 Measurement of Related Substances Before and After Light Irradiation For each granule obtained in Example 1 and Comparative Examples 1 and 2, after irradiating 3000 lx of incandescent light for 400 hours with a total of 1.2 million lx · hr of light, duloxetine hydrochloride was used. Was measured by HPLC method (quantitative method was area percentage method). The measurement results are shown in Table 2 below.

From Table 2, it was found that the color difference before and after light irradiation of the granules of Example 1 was significantly lower than that of the comparative example. It was also confirmed that the granules of Example 1 and Comparative Examples 1 and 2 had sufficiently low amounts of analogs after light irradiation. Therefore, it was shown that the granules of the present invention had sufficient stability to light.

Claims (6)

A granule comprising duloxetine hydrochloride and titanium oxide, wherein the titanium oxide is contained in an amount of 55.0 parts by weight or more based on 100.0 parts by weight of duloxetine hydrochloride. The granule according to claim 1, wherein titanium oxide is contained in an amount of 60.0 parts by weight or more based on 100.0 parts by weight of duloxetine hydrochloride. The granule according to claim 1 or 2, wherein the periphery of the portion containing duloxetine hydrochloride is covered with a coating layer containing titanium oxide. The granule according to any one of claims 1 to 3, wherein the periphery of the portion containing duloxetine hydrochloride and titanium oxide is covered with a coating layer containing an enteric coating agent. A capsule containing the granules according to claim 1. In an excipient having a particle size in the range of 50.0 to 350.0 μm,
Granules obtained by coating the drug,
Further, granules obtained by coating with a coating agent that is not titanium oxide and an enteric polymer,
The method for producing granules according to any one of claims 1 to 4, wherein the granules are obtained by further coating with an enteric polymer.