JP5424571B2 - Topiramate-containing solid preparation - Google Patents

Description

  The present invention relates to a solid preparation containing topiramate having an antiepileptic effect or the like.

Topiramate is known as a compound useful for the treatment of diseases and symptoms such as epilepsy (see Patent Documents 1 and 2). In addition, solid preparations containing topiramate are subject to degradation of topiramate by humidity and heat, resulting in a change in physical appearance (such as brown or blackening of the appearance of the tablet) and standard methods known to those skilled in the art (for example, high speed It is known that sulfate ions that can be easily detected by liquid chromatography are generated, and a method of stabilizing by removing water in the preparation as much as possible is known (see Patent Document 3). .
However, since topiramate requires a relatively high dose for treatment and the content of topiramate in the topiramate-containing solid preparation is high, it has been difficult to suppress changes in the physical appearance of the solid preparation.
JP-A-60-109558 Special Table 2002-515875 Special table 2003-534051 gazette

  An object of the present invention is to provide a stable topiramate-containing solid preparation while suppressing changes in the physical appearance of the topiramate-containing solid preparation.

The present invention relates to the following (1) to (20).
(1) A topiramate-containing solid preparation comprising topiramate crystals, wherein the crystals have a volume average particle diameter of 1.0 to 100.0 μm.
(2) The topiramate-containing solid preparation according to the above (1), wherein the volume average particle diameter of the topiramate crystals is 30.0 to 80.0 μm.
(3) The topiramate-containing solid preparation according to (1) or (2), further comprising an additive which is a carboxylate.
(4) The additive which is a carboxylate is at least one selected from croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, sodium carboxymethyl starch, sodium glutamate, sodium aspartate and sodium alginate (3) Topiramate-containing solid preparation.
(5) Further, any one of (1) to (4), further comprising one or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate and magnesium aluminate metasilicate Topiramate-containing solid preparation.
(6) The topiramate-containing solid preparation according to any one of (1) to (5), wherein the solid preparation is selected from tablets, fine granules, granules, capsules and dry syrups.

(7) A method for producing a topiramate-containing solid preparation, comprising a step of selecting a topiramate crystal having a volume average particle size of 1.0 to 100.0 μm in the method for producing a solid preparation containing topiramate.
(8) The method according to (7), wherein the step of selecting topiramate crystals is a step of selecting topiramate crystals having a volume average particle diameter of 30.0 to 80.0 μm.
(9) The production method of the above (7) or (8), comprising a step of mixing a topiramate crystal and an additive which is a carboxylate.
(10) The additive which is a carboxylate is at least one selected from croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, sodium carboxymethyl starch, sodium glutamate, sodium aspartate and sodium alginate (9) The production method of (9).
(11) comprising the step of mixing topiramate crystals and one or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate and magnesium aluminate metasilicate (7) to The production method according to any one of (10).
(12) The production method of any one of (7) to (11), wherein the solid preparation is a tablet, fine granule, granule, capsule or dry syrup.
(13) The topiramate crystal having a volume average particle diameter of 1.0 to 100.0 μm is a crystal obtained by pulverizing a crude crystal using a pulverizer classified as a high-speed rotary mill (7 ) To (12).

(14) A method for stabilizing a topiramate-containing solid preparation, wherein topiramate crystals having a volume average particle diameter of 1.0 to 100.0 μm are used as the topiramate used in the production of a solid preparation containing topiramate.
(15) The stabilization method of (14), wherein the topiramate crystal used is a topiramate crystal having a volume average particle diameter of 30.0 to 80.0 μm.
(16) The method according to the above (14) or (15), wherein an additive which is a carboxylate is allowed to coexist in a preparation together with a topiramate crystal.
(17) The additive which is a carboxylate is at least one selected from croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, carboxymethyl starch sodium, sodium glutamate, sodium aspartate and sodium alginate The stabilization method of (16) above.
(18) One or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, and magnesium aluminate metasilicate are allowed to coexist in the preparation (14) The stabilization method in any one of (17).
(19) The stabilization method according to any one of (14) to (18), wherein the solid preparation is a tablet, fine granule, granule, capsule or dry syrup.
(20) The stable form according to any one of (14) to (19), wherein the topiramate crystal is a crystal obtained by pulverizing a crude crystal using a pulverizer classified as a high-speed rotary mill. Method.

  According to the present invention, it is possible to provide a stable topiramate-containing solid preparation and the like by suppressing changes in the physical appearance of the topiramate-containing solid preparation.

  The topiramate-containing solid preparation of the present invention contains topiramate as an active ingredient, and the shape thereof is not particularly limited, but is preferably in the form of a tablet, fine granule, granule, capsule or dry syrup. In addition, the topiramate-containing solid preparation of the present invention is preferably a solid preparation comprising a raw preparation containing topiramate and a film covering the raw preparation. For example, a coating composition containing a compound exhibiting light-shielding properties is coated. It is more preferable that it is a solid preparation containing the film formed in this way.

  Topiramate in the present invention has the formula (I)

2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate represented by
The topiramate-containing solid preparation of the present invention preferably contains topiramate crystals having a volume average particle diameter of 1.0 to 100.0 μm, and more preferably contains topiramate crystals having a volume average particle diameter of 30.0 to 80.0 μm.

  The topiramate-containing solid preparation of the present invention preferably contains an additive that is a carboxylate, and examples of the additive that is a carboxylate in the present invention include croscarmellose sodium, carmellose sodium, carmellose potassium, Polymers such as carmellose calcium, sodium carboxymethyl starch, sodium alginate, sodium citrate, sodium dihydrogen citrate, sodium fumarate, sodium propionate, sodium acetate, calcium lactate, sodium tartrate, sodium oleate, sodium glutamate, Organic acid salts such as sodium aspartate and the like, and more preferably croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, Carboxymethyl starch sodium, sodium alginate, one or more can be mentioned selected from sodium glutamate and sodium aspartate, more preferably croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium and the like. Further, calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate and the like may be contained.

  The blending amount of the additive which is a carboxylate is not particularly limited, but is preferably 0.01 to 50%, more preferably 0.1 to 20%, and further preferably 1 to 10% in a blending ratio in the tablet. The additives that are carboxylates include those used in general solid preparations such as excipients, disintegrants, binders, lubricants, etc., and also in the topiramate-containing solid preparations of the present invention. , For example, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch as a disintegrating agent, carmellose sodium, carmellose potassium, sodium alginate and the like as a binder, Sodium glutamate, sodium aspartate and the like may be contained as excipients. Further, calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate and the like may be contained as an excipient or a lubricant.

The topiramate-containing solid preparation of the present invention may contain other active ingredients and / or other additives in addition to the additive which is topiramate crystals and carboxylate.
Examples of other additives include those used in general solid preparations such as excipients, disintegrants, binders and lubricants.

  Excipients as other additives include, for example, sugar (for example, lactose, sucrose, maltose, etc.), sugar alcohol (for example, mannitol, maltitol, erythritol, etc.), starch (for example, corn starch, rice starch, wheat starch, etc.), Cellulose (e.g., crystalline cellulose, powdered cellulose, etc.), sparingly water-soluble inorganic salts (e.g., talc, light anhydrous silicic acid, sodium metasilicate sodium phosphate, calcium phosphate, etc.) and the like are included, and these may be used alone or in combination of two or more. One or more substances selected from sugar, starch, cellulose and the like are preferably used, and one or more substances selected from lactose, corn starch and crystalline cellulose are more preferable. Further, the topiramate-containing solid preparation of the present invention contains one or more substances selected from sugar, starch, cellulose and the like as an excipient in order to exhibit good manufacturability and / or rapid drug dissolution. It is preferable to contain one or more substances selected from lactose, corn starch, and crystalline cellulose.

Disintegrants as other additives include, for example, cellulose derivatives (for example, low-substituted hydroxypropyl cellulose, carmellose, etc.), starch (for example, pregelatinized starch, partially pregelatinized starch, etc.), starch derivatives (hydroxypropyl starch, etc.), crospovidone And bentonite. These may be used alone or in combination of two or more.
Examples of binders as other additives include cellulose derivatives (e.g., methylcellulose, carmellose, carboxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), cellulose (e.g., crystalline cellulose), starch (e.g., pregelatinized starch), Examples thereof include polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, dextrin, gum arabic, and gelatin. These may be used alone or in combination of two or more.

  Examples of lubricants as other additives include magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester, polyethylene glycol and the like, and these may be used alone or in combination of two or more.

  When the topiramate-containing solid preparation of the present invention contains a film, the film is preferably a film containing a compound having a light-shielding property. Examples of the compound include a metal compound, a silicon compound, an organic compound, and a complex having a light-shielding property. Examples thereof include titanium oxide, iron oxide (specifically, yellow iron sesquioxide, iron sesquioxide, yellow iron oxide, black iron oxide, etc.), zinc oxide, silicon oxide, etc., more preferably An example is titanium oxide. The titanium oxide in the present invention may be in the rutile type or anatase type crystal form, and the particle diameter is not particularly limited. These titanium oxides may be used in combination of two or more having different crystal forms and particle sizes.

The film in the topiramate-containing solid preparation of the present invention may contain a pigment, a light-shielding agent, a lubricant or a dispersing agent in addition to the compound exhibiting the light-shielding property. For example, Bengala, carbon black, medicinal Examples include charcoal, barium sulfate, edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, and copper chlorofin.
The film in the topiramate-containing solid preparation of the present invention may further contain, for example, a coating base, a plasticizer, other coating agents, etc., and may be used in a mixture of two or more.

  Examples of the coating base include gastric film coating agents, enteric film coating agents, sustained-release film coating agents, and the like. Examples of gastric film coating bases include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy Cellulose polymers such as ethyl cellulose and methyl hydroxyethyl cellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, synthetic polymers such as polyvinylpyrrolidone, polysaccharides such as pullulan, etc., and enteric film coating bases include: For example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cell Cellulose polymers such as cellulose acetate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, acrylic acid polymers such as methacrylic acid copolymer S, natural products such as shellac, etc. Examples of the coating base include cellulose polymers such as ethyl cellulose, and acrylic acid polymers such as aminoalkyl methacrylate copolymer RS and ethyl acrylate / methyl methacrylate copolymer.

Examples of the plasticizer include triethyl citrate, medium chain fatty acid triglyceride, diethyl phthalate, dibutyl phthalate, triacetin, butyl phthalyl butyl glycolate, glyceryl caprylate ester, etc .; alcohols such as glycerin, propylene glycol, polyethylene glycol, etc. Etc.
Examples of other coating agents include lactose, sucrose, talc, calcium carbonate, gelatin, gum arabic, and carnauba wax.

The production method of the solid preparation containing the topiramate of the present invention may be any known solid preparation production method, and includes a step of selecting topiramate crystals having a volume average particle size of 1.0 to 100.0 μm, It is preferable to select a topiramate crystal having a volume average particle diameter of 30.0 to 80.0 μm.
A topiramate crystal having a volume average particle diameter of 1.0 to 100.0 μm is obtained by classifying a topiramate crystal (crude crystal) produced according to the production method described in JP-A-3-230011, for example, with a sieve to obtain a volume average particle diameter. May be obtained in a range of 1.0 to 100.0 μm. For example, a pulverizer classified as a high-speed rotary mill, a roller mill, a jet mill, a ball mill, or the like, preferably a pulverizer classified as a high-speed rotary mill, may be used. It is preferable to obtain a powder having a volume average particle size of 1.0 to 100.0 μm by pulverization. Examples of the pulverizer classified as a high-speed rotating mill include a hammer mill, a cage mill, a shearing mill, an impact mill, an aerofall mill, and the like, and preferably a hammer mill.

Further, the method for producing a solid preparation containing topiramate of the present invention preferably includes a step of mixing topiramate crystals and an additive (as defined above) that is a carboxylate. Further, in the method for producing a solid preparation containing topiramate of the present invention, topiramate crystals are mixed with calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate, etc. It is preferable that the process to include is included.
In addition, in the method for producing a solid preparation containing topiramate of the present invention, in addition to the additive that is topiramate crystal and carboxylate, other active ingredients and / or other additives (as defined above) are added to topiramate crystals. It is preferable to include the process of mixing with.

  In any mixing step, there is no limitation on the mixer to be used. For example, a V-type mixer, a cone-type mixer, a horizontal cylindrical mixer, a ribbon-type mixer, a high-speed stirring type, an air-flow stirring type, etc. Or may be mixed with a granulator such as a fluidized bed granulator / dryer or a high-speed stirring granulator.

  The mixture obtained in the mixing step may be used as it is in powders or capsules filled into capsules, or may be granulated to form fine granules or granules. Further, the mixture obtained in the mixing step may be directly compressed by a tableting method, or may be granulated by adding water or the like and then tableted (indirect tableting method) to form tablets. In the present invention, as a method for producing a solid preparation containing topiramate, it is most preferable that the mixture obtained in the mixing step is granulated by adding water or the like and then compressed into tablets.

(1) Granulation step The granulated product can be produced, for example, by a wet granulation method, a dry granulation method or the like. Examples of wet granulation methods include extrusion granulation (by screw extrusion granulation apparatus, roll extrusion granulation apparatus, etc.), rolling granulation method (rotary drum type granulation apparatus, centrifugal rolling granulation apparatus, etc.) ), Fluidized bed granulation method (by fluidized bed granulator, rolling fluidized bed granulator, etc.), stirring granulation method (by stirring granulator, etc.), etc., preferably fluidized bed granulation The law is raised. As the dry granulation method, for example, flakes are produced using a commercially available dry granulator, or slug tablets are produced using a tableting machine, and the obtained flakes or slug tablets are crushed with a commercially available crusher or granulator. The crushing granulation method etc. which obtain a granulated material by doing are mention | raise | lifted. Preferably, each granulated product has a desired particle size by appropriate pulverization and / or sieving.

(2) Tableting process After the granulated product obtained in the above (1) is dried, a lubricant is added and mixed and compression molded. At this time, an additive which is a carboxylate (as defined above), another active ingredient and / or another additive (as defined above) may be added.
The tableting machine used for compression molding is not particularly limited, but a rotary tableting machine is preferably used, and the compression molding pressure is preferably 300 kgf to 2000 kgf.

  Further, when the topiramate-containing solid preparation of the present invention contains a film, the film contains a coating agent containing a light-shielding compound (as defined above) in a suitable solvent such as water, methanol, ethanol, 2-propanol, ethyl acetate. , Ethyl lactate, acetone, methylene chloride, 1,1,1-trichloroethane, etc. or a mixed solvent thereof or the like can be obtained by spraying and coating the raw material with a coating solution. The coating apparatus at this time is not particularly limited, but the coating apparatus for coating fine granules or granules is preferably a fluidized bed coating drying apparatus, a centrifugal fluidized granulator, a rolling fluidized coating drying apparatus. Etc. are used. The coating apparatus for coating tablets is not particularly limited, but a drum type film coating drying apparatus or a fluidized bed coating apparatus is preferably used.

  The method for producing a topiramate-containing solid preparation of the present invention can contain a high content of drug. For example, in the case of a tablet, a preparation having a practically sufficient tablet hardness and a rapid dissolution rate can be obtained. The amount of topiramate used in the topiramate-containing solid preparation of the present invention is, for example, preferably 30 to 200 mg in one tablet, preferably 5 to 80% by mass, more preferably 10 to 60% by mass in the tablet.

The method for stabilizing a solid preparation containing topiramate according to the present invention comprises using a topiramate crystal having a volume average particle size of 1.0 to 100.0 μm as the topiramate used in the method for producing a solid preparation containing topiramate. More preferably, topiramate crystals having a volume average particle diameter of 30.0 to 80.0 μm are used.
In general, it is known that if the particle diameter of the crystal is reduced, the specific surface area is increased, and hydrolysis and the like are likely to proceed. It has been found that a solid preparation containing topiramate can be stabilized by reducing the diameter.

  In addition, the present inventors blended an additive (as defined above) which is a carboxylate, calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate, etc. It has also been found that the stability of the topiramate-containing solid preparation can be further improved. The inventors of the present application paid attention to the decomposition mechanism of topiramate and tried to suppress the promotion of the decomposition reaction. That is, when topiramate is stored under warm and humid conditions, acid is generated by hydrolysis of sulfamine. The presence of the acid further promotes hydrolysis, resulting in autocatalytic and accelerated degradation. Therefore, in the present invention, when various additives were blended and an attempt was made to suppress the decomposition of topiramate, the additive as a carboxylate (as defined above), calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate , Magnesium silicate, magnesium aluminate, dipotassium phosphate, etc., preferably a carboxylate additive coexisting in the formulation, it was found that the blackening caused by the decomposition of topiramate can be further suppressed .

  The inventors of the present invention also provide a coating composition containing a compound exhibiting light-shielding properties, wherein the topiramate-containing solid preparation of the present invention is a solid preparation containing a topiramate-containing raw preparation and a film covering the raw preparation. It has also been found that the stability of a topiramate formulation can be further improved by being a solid formulation containing a film formed by coating. In this case, the additive containing the carboxylate (as defined above), calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate Etc. (preferably, an additive which is a carboxylate (as defined above)) is more preferably blended.

  Hereinafter, the present invention will be described in more detail based on examples and test examples, but the present invention is not limited to these examples and test examples.

Reference example 1
The topiramate before pulverization obtained by the conventional method was pulverized using a hammer mill (sample mill / Fuji powder) at a screen hole diameter of 1 mm and a screw rotation speed of 18 rpm. Using an image analyzer (TMN-1528-01; Olympus Optical Co., Ltd.), the particle diameter (volume average diameter, ferret diameter) of topiramate before and after pulverization was measured. The results are shown in Table 1.

  Using each of the pulverized topiramate crystals obtained in Reference Example 1, a preparation was produced by the following procedure. The amount of topiramate, lactose, crystalline cellulose and croscarmellose sodium according to the composition shown in Table 2 is mixed in a fluid bed granulator (FLO-5EX; Freund Sangyo) and sprayed with an aqueous hydroxypropylcellulose solution. And granulated. The resulting granulated product was sized (Landel mill; Tokuju Seisakusho) and then mixed with magnesium stearate (V-type mixer; Tokusu Seisakusho). This mixture was tableted (Collect 12; Kikusui Seisakusho) to obtain a preparation.

Comparative Example 1
As a comparative example, a preparation was obtained in the same manner as in Example 1 using each of the topiramate crystals before pulverization obtained in Reference Example 1.

Test example 1
In Example 1 and Comparative Example 1, the preparations produced using the APIs of lots B and C were placed in a glass container, and visually observed over time at 40 ° C./75% RH in an open state. The color difference was measured by (SQ-2000 / Nippon Denshoku Industries Co., Ltd.). The results are shown in Table 3. Example 1 (using crushed crystals) was clearly less colored than Comparative Example 1 (using crystals before pulverization).

Test example 2
The preparations produced in Example 1 and Comparative Example 1 using the APIs of lots D and E were placed in a glass container and color difference meter (SQ-2000 / Japan) over time at 60 ° C / 75% RH in an open state. The color difference was measured by Denshi Kogyo). As shown in Table 4, Example 1 (using crushed crystals) was clearly less colored than Comparative Example 1 (using crushed crystals).

Test example 3
The tablet hardness of the preparation produced in Example 1 was measured using a hardness meter (PTB-311 / Japan Machinery). The results are shown in Table 5.

Test example 4
A dissolution test was performed on the formulations produced in Example 1 using lots C and E. The test solution was 900 mL of water, sampled with time at 50 paddles per minute, and quantified by HPLC. The results are shown in FIGS.

A pulverized topiramate crystal obtained in the same manner as in Reference Example 1 was produced by the following procedure. According to the composition shown in Table 6, topiramate crystals 100 g, lactose 52 g, crystalline cellulose 18 g, magnesium stearate 1 g and croscarmellose sodium as disintegrant, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose or Carmellose 9 g was mixed in a plastic bag, weighed 180 mg, and compressed with a hydraulic press at 50 kg / cm ² to obtain tablets.

Test Example 5
The tablet obtained in Example 2 was placed in a glass container, stored in an open state at 40 ° C./75% RH for 4 months, and then the color difference was measured using a color difference meter (SQ-2000 / Nippon Denshoku Industries). The results are shown in Table 7.

  A pulverized topiramate crystal obtained in the same manner as in Reference Example 1 was produced by the following procedure. According to the composition shown in Table 8, topiramate, lactose, crystalline cellulose and croscarmellose sodium or low-substituted hydroxypropylcellulose are mixed in a fluid bed granulator (FLO-5EX; Freund Sangyo) The aqueous solution was sprayed and granulated. The resulting granulated product was sized (Landel mill; Tokuju Seisakusho) and then mixed with magnesium stearate (V-type mixer; Tokusu Seisakusho). This mixture was tableted (Collect 12; Kikusui Seisakusho) to obtain a preparation.

  The tablets obtained in Example 3 were coated by spraying a film coating agent containing hydroxypropylmethylcellulose, titanium oxide, and light silicic acid anhydride using a coating machine (Hicoater; Freund Industries). Tablets were obtained (hereinafter, preparations coated with Examples 3-1, 3-2, 3-3 and 3-4 in Table 8 were prepared in Examples 4-1, 4-2, 4-3 and 4-, respectively. 4).

Test Example 6
The preparations obtained in Examples 3 and 4 were placed in a glass container and visually observed over time at 40 ° C./75% RH in an open state, and color difference was measured with a color difference meter (SQ-2000 / Nippon Denshoku Industries Co., Ltd.). Was measured.
The results are shown in Table 9.

FIG. 2 shows the results of a dissolution test of a preparation produced using the lot C drug substance in Example 1. FIG. 2 shows the results of a dissolution test of a preparation produced using the drug substance of lot E in Example 1.

Claims (4)

A topiramate-containing tablet containing 10 to 60% by mass of topiramate crystals and having a volume average particle diameter of 30.0 to 80.0 μm (except when a solubilizer is contained). Topiramate containing tablets according to claim 1, further comprising an additive is a carboxylic acid salt. Additive is a carboxylic acid salt, croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, sodium carboxymethyl starch, sodium glutamate, claim 2 is one or more selected from sodium aspartate and sodium alginate The topiramate-containing tablet as described. The topiramate-containing tablet according to any one of claims 1 to 3 , comprising one or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate and magnesium aluminate metasilicate.

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