JP6126456B2 - Granules for tableting and production method thereof, orally disintegrating tablets using the granules for tableting - Google Patents

Description

  The present invention generally relates to tableting granules, a method for producing the same, and an orally disintegrating tablet using the tableting granules, and more particularly to a tablet containing candesartan cilexetil.

Candesartan cilexetil is a white or off-white powder and has a structure represented by the following formula (I).

  Candesartan cilexetil is stable to temperature, moisture, and light in a single solid state, but when it is formulated with other ingredients, pressure, friction, heat, etc. are applied to deform the crystal. Decomposes and the purity decreases. Therefore, conventionally, a method of stabilizing candesartan cilexetil so as to maintain the purity of candesartan cilexetil even when pressure or the like is applied during the preparation has been proposed.

  For example, in Japanese Translation of PCT International Publication No. 2010-525066 (Patent Document 1), a compression step is performed by granulating a mixture of a carrier and an oily substance, mixing candesartan cilexetil into the granulated material, and tableting. It has been proposed to prevent or reduce degradation of candesartan cilexetil even after receiving.

  Further, for example, International Publication WO2008 / 045006 pamphlet (Patent Document 2) proposes a stable pharmaceutical composition of candesartan cilexetil containing an antioxidant that acts as a stabilizer. In Patent Document 2, an antioxidant is dissolved in a solvent, a filler is added, granulated using a high shear mixer or a fluidized bed granulator, the granulated product is dried, and then the granulated product is added to the granulated product. In addition, it describes that candesartan cilexetil is coated with a coating agent by a flow method. As the filler, for example, lactose, corn starch, mannitol or the like is used.

  In addition, International Publication WO2009 / 121871 pamphlet (Patent Document 3) describes a combination of polyvinyl alcohol (PVA) and polyethylene glycol (PEG) in order to obtain a chemically or physically stable candesartan cilexetil-containing composition. It has been proposed to add a polymer and optionally at least one other additive. In Patent Document 3, PVA / PEG copolymer and mannitol, carmellose sodium and the like are mixed with a high shear granulator, and the resulting powder mixture is granulated with candesartan cilexetil dispersion, lactose, It describes that a granulated product such as corn starch or carmellose sodium is coated with a dispersion of candesartan cilexetil and mannitol.

  In JP 2012-162467 A (Patent Document 4), in order to suppress and stabilize the decomposition of candesartan cilexetil in the granulated product, a mixture containing candesartan cilexetil and D-mannitol is fluidized bed. It has been proposed to granulate.

Special table 2010-525066 gazette International Publication WO2008 / 045006 Pamphlet International Publication WO2009 / 121871 Pamphlet JP 2012-162467 A

  An object of this invention is to provide the stable candesartan cilexetil containing formulation by which the production | generation of a related substance is suppressed even if it passes through a tableting process.

  In the present invention, a dispersion of candesartan cilexetil (hereinafter sometimes referred to as “the drug substance”) (hereinafter also referred to as “the drug substance dispersion”) is formed in the granule composed of D-mannitol. The drug substance-containing granules (active granules) are produced by spraying and drying. The obtained active granules are used to produce tablets, particularly orally disintegrating tablets, by adding auxiliary components such as excipients, disintegrants, lubricants, etc., and compression molding.

  The granule of D-mannitol is commercially available from Freund Sangyo Co., Ltd. as Nonparel-108. There are three types depending on the particle size, and grade 100 granules having a particle size range of 75 to 150 μm are preferred. This is also because active granules containing granules of D-mannitol having a large particle size range may give a rough feeling in the oral cavity when blended in an orally disintegrating tablet.

  The drug substance dispersion is a dispersion of the drug substance in water or a mixture of water and ethanol, but preferably contains a binder which is a water-soluble cellulose derivative such as hydroxypropylcellulose (HPC), hypromellose, carmellose sodium, methylcellulose and the like. Can be included. As the binder, HPC is particularly preferable, and among them, HPC-M (manufactured by Nippon Soda Co., Ltd.) (viscosity: 150 to 400 mPa · s [20 ° C./2% aqueous solution], molecular weight: about 620,000) is preferable.

  It is known that the drug substance is broken down in crystal form by mechanical stress during tableting and the degradation over time is promoted. This decomposition is known to be suppressed by higher alcohols, fatty acid esters of polyhydric alcohols, macrogol, carrageenan, triethyl citrate and the like. The drug substance dispersion can contain these degradation inhibitors.

  Because the drug substance is poorly soluble in water, the drug substance dispersion can optionally contain a surfactant such as sodium dodecyl sulfate (SDS) that promotes absorption from the gastrointestinal tract.

  The drug substance dispersion is prepared by suspending the drug substance in a solution obtained by dissolving low-substituted hydroxypropyl cellulose, triethyl citrate, and SDS in water-containing ethanol at a weight ratio of 1: 1: 0.2, for example. The

  Active granules are produced by charging D-mannitol granules in a fluid bed granulator, spraying the drug substance dispersion and drying. At that time, a drug substance dispersion containing 1 to 20 parts by weight as the drug substance is sprayed on 100 parts by weight of the core D-mannitol granules.

  D-mannitol is a conventional excipient used for solid preparations such as tablets. In the present invention, D-mannitol is sprayed on granules of D-mannitol having a particle size range of 75 to 150 μm instead of powder. As a result, the stability of the drug substance over time in the preparation is improved compared to granules produced by a conventional method from a mixture of drug substance and powdered D-mannitol. In addition, granules produced from a mixture of the drug substance and powdered D-mannitol must have a large amount of lubricant added due to tableting troubles such as sticking and capping. The lack of obstacles is also a benefit over the prior art.

  The active granules thus obtained are sized, mixed with conventional auxiliary components such as excipients, disintegrants, lubricants, etc., and compressed into a tablet. Among these, an orally disintegrating tablet is particularly preferable. Auxiliary components such as excipients, disintegrants, lubricants and the like and methods for their use are well known to those skilled in the art of pharmaceutical formulation. Instead of individually mixing the excipients and disintegrants, it is convenient to mix the granules obtained by granulating these in advance and the lubricant and tablet them. The tableting pressure for obtaining tablets having the oral disintegration time within 30 seconds and the hardness that can withstand the market distribution using the active granule of the present invention is determined from a mixture of powdered D-mannitol and the drug substance in a conventional manner. It needs to be slightly higher than the granules produced by

It is a figure which shows the time change of the content rate of the related substance (desethyl body) when the solid pharmaceutical composition of an Example and a comparative example is preserve | saved at 70 degreeC. It is a figure which shows the relationship between tableting pressure and disintegration time about the solid pharmaceutical composition of an Example and a comparative example. It is a figure which shows the relationship between tableting pressure and content of a related substance (desethyl body) about the solid pharmaceutical composition of an Example and a comparative example. It is a figure which shows a time change of dissolution property about the solid pharmaceutical composition of an Example and a comparative example.

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to this.

(Example)
As the granules of D-mannitol, “Nonparell-108” (manufactured by Freund Sangyo Co., Ltd.) was used. “Nonparel-108” was a spherical granule having a D-mannitol content of 100% and a particle size range of 75 to 150 μm.

  Triethyl citrate, HPC-M, and SDS were dissolved in a solvent (ethanol concentration 50%) mixed with purified water and absolute ethanol, and candesartan cilexetil was dispersed therein to obtain a dispersion. The concentration of each component in the dispersion was 3.99% triethyl citrate, 0.259% HPC-M, 0.04% SDS, and 3.99% drug substance (candesartan cilexetil).

  “Nonparell-108” was put into a fluidized bed granulator (multiplex MP-01), and the previously prepared dispersion was sprayed and dried to obtain drug particles (active granules).

  Separately from drug particles, fast disintegrating granules were prepared. The rapidly disintegrating granules were prepared by adding 500 g of trehalose to a fluidized bed granulator and spraying and granulating a liquid in which 100 g of corn starch was dispersed in 1250 mL of water.

  The fast disintegrating granules, sweetener, finely powdered ethyl cellulose, and magnesium stearate prepared separately from the drug particles were compressed together with the drug particles using a rotary tableting machine to obtain a solid pharmaceutical composition. As will be described later, in the compression step, solid pharmaceutical compositions compressed with different tableting pressures were prepared.

(Comparative example)
A solid pharmaceutical composition was obtained in the same manner as in Example except that “Pearlitol 50C” (Roquette Freres, Restrem, France) was used as powdered D-mannitol instead of “Nonparel-108”. In the compression step for obtaining the solid pharmaceutical composition of the comparative example, tableting troubles such as capping, which were not seen in the examples, were observed. The average particle diameter of “Pearlitol 50C” was 50 μm.

  The composition ratios of the solid pharmaceutical compositions of Examples and Comparative Examples were as shown in Table 1.

  The following tests were performed using the obtained solid pharmaceutical composition.

The candesartan cilexetil-containing solid pharmaceutical compositions of Examples and Comparative Examples were stored at 70 ° C. and 100% relative humidity for a predetermined time, and the content of related substances in the solid pharmaceutical compositions after storage was measured. As an analogous substance, the content of the desethyl compound represented by the following formula (II) was measured.

  Under the conditions shown in Table 2 below, the solid pharmaceutical composition after being stored for a predetermined time was analyzed by high performance liquid chromatography (HPLC).

  Based on the peak area measured by HPLC, the content in the solid pharmaceutical composition of the desethyl compound represented by the formula (II) was determined. The results are shown in Table 3 and FIG.

  As shown in Table 3 and FIG. 1, in the solid pharmaceutical compositions of the examples, the production of related substances could be suppressed until at least the 9th day as compared with the solid pharmaceutical compositions of the comparative examples.

  Next, the relationship between tableting pressure, disintegration time and stability was investigated. In the compression step of compressing and molding the drug particles, the tableting pressure was changed, and the solid pharmaceutical composition obtained was stored for 6 days at hardness, tablet thickness, oral disintegration time, 70 ° C. and 100% relative humidity. The content of related substances (desethyl body) was examined. The results are shown in FIGS.

  As shown in FIG. 2, it was found that even at a relatively low tableting pressure, the solid pharmaceutical composition of the comparative example tends to have a higher hardness and a longer disintegration time than the solid pharmaceutical composition of the example. In addition, as shown in FIG. 3, the content of desethyl body when stored at 70 ° C. and 100% relative humidity for 6 days is higher than that of the comparative solid pharmaceutical composition in any of the solid pharmaceutical compositions of Examples. Was also suppressed.

  Next, the relationship between tableting pressure and dissolution was investigated. The change over time in the dissolution rate of the solid pharmaceutical composition of Example with a tableting pressure of 100 kg and the solid pharmaceutical composition of Comparative Example with a tableting pressure of 800 kg was examined. The dissolution test was performed based on the paddle method of the JP Test Method (Station 16), with the pH of the test solution being 1.2, the polysorbate 80 concentration being 0.5%, and the paddle rotation speed being 100 rpm. The amount of the test solution was 900 mL, and the test solution temperature was 37 ± 0.5 ° C. The candesartan cilexetil in the solution sampled at each elapsed time shown in Table 4 was measured by high performance liquid chromatography, and the elution rate (area percentage) of candesartan cilexetil was calculated. The results are shown in Table 4 and FIG.

  As shown in FIG. 4, the solid pharmaceutical composition of the example was closer to the zero-order elution than the solid pharmaceutical composition of the comparative example.

  As described above, it was found that the solid pharmaceutical composition of the present invention can be used as a stable orally disintegrating tablet of candesartan cilexetil.

Claims (9)

D-mannitol granules having a particle size range of 75 to 150 μm;
The D- mannitol even spray dried candesartan cilexetil and no less on the granules containing a binder, granules for tableting. The granule for tableting according to claim 1, wherein the spray-dried candesartan cilexetil and at least the binder are those obtained by spray-drying a drug substance dispersion containing candesartan cilexetil and at least the binder.   The tableting granule according to claim 2, wherein the drug substance dispersion further contains triethyl citrate.   The granule for tableting according to claim 3, wherein the drug substance dispersion further contains sodium dodecyl sulfate.   The granule for tableting according to any one of claims 1 to 4, wherein the drug substance dispersion containing 1 to 20 parts by weight of candesartan cilexetil is sprayed per 100 parts by weight of the D-mannitol granules. .   D-mannitol granules having a particle size range of 75 to 150 μm are flowed into a fluidized bed granulator, sprayed with a drug substance dispersion in which candesartan cilexetil is dispersed in water or hydrous ethanol in which at least a binder is dissolved, and dried. The manufacturing method of the granule for tableting including this.   6. The method according to claim 5, wherein the drug substance dispersion corresponding to 1 to 20 parts by weight of candesartan cilexetil is sprayed per 100 parts by weight of D-mannitol granules.   8. A method according to claim 6 or claim 7, wherein the drug substance dispersion further comprises triethyl citrate and optionally sodium dodecyl sulfate.   An orally disintegrating tablet obtained by compression-molding a mixture of the granule according to any one of claims 1 to 5 and at least an excipient, a disintegrant and a lubricant.

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