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(21)Application Number: KElP/ 2009/ 000946       
               
(22) Filing Date: 30/01/2008       
               
(30) Priority data: 2007-023594  01/02/2007  JP
               
(86) PCT data    PCT/JP08/051900    30/01/2008 W0/2008/093882    07/08/2008

(73) Owner: TAKEDA PHARMACEUTICAL COMPANY LIMITED of 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 541-0045, Japan

(72) Inventors: NAKAMURA, Kenji of c/o TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, Jusohonmachi 2-chome, Y odogawa-ku, Osaka-shi, Osaka 5328686, Japan; KIYOSHIMA, Kenichiro of c/o TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka-shi, Osaka 5328686, Japan and NOMURA, Junya of c/o TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, Jusohonmachi 2-chome, Y odogawa-ku, Osaka-shi, Osaka 5328686, Japan

(74) Agent/address for correspondence: Hamilton Harrison & Mathews, ICEA Building, Kenyatta Avenue, P.O. Box 30333-00100, Nairobi

(54) Title: SOLID PREPARATION COMPRJSING ALOGLIPTIN AND PIOGLITAZONE

(57) Abstract: A solid preparation containing compound (1), wherein the definition of compound (I) is as defined in the description, and pioglitazone, which is useful as a therapeutic drug for diabetes and the like and superior in the dissolution property, chemical stability and dissolution stability, is provided. A solid preparation containing the following first and second parts: (1) the first part containing compound (I) or a salt thereof and, as the first excipient, sugar or sugar alcohol; and (2) the second part containing pioglitazone or a salt thereof and, as the second excipient, sugar or sugar alcohol.
 DESCRIPTION

SOLID  PREPARATION  COMPRISING  ALOGLIPTIN  ~OP.~TAZONE

TECHNICAL  FIELD  OF  THE  INVENTI~

The  present  invention  relates  to  a  solid  pr~•~-

5    comprising 2-[ [6-[ (3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile

(general name: Alogliptin; hereinafter sometimes to be referred to as compound (I)) or a salt thereof, and pioglitazone or a salt thereof, which is useful as a

10    therapeutic  drug  for  diabetes  and  the  like.

BACKGROUND  OF  THE  INVENTION

Compound (I) to be used in the present invention is reported as an inhibitor of dipeptidyl peptidase (DPP-IV), which is an enzyme that decomposes glucagon-like peptide-1

15    (GLP-1), which is a hormone enhancing insulin secretion (patent reference 1).

However, a preparation comprising compound (I) or a salt thereof and pioglitazone or a salt thereof has not been reported.

20    [patent  reference  1]  US-B-2005/0261271

DISCLOSURE  OF  THE  INVENTION

Compound (I), which is a DPP-IV inhibitor, and pioglitazone are both effective for the treatment of diabetes and the like, and provision of a preparation (combination

25    agent) containing them as active ingredients provides extremely high usefulness from the clinical aspect. However, practicalization of a preparation containing plural active

ingredients  is  not  easy  as  compared  to  a  preparation

containing  a  single  active  ingredient.    For  example,   since  the

30    dissolution rate of an active ingredient from a preparation can influence the time-course drug efficacy profile after administration, practicalization of a preparation requires

control of the preparation formulation to optimize the dissolution rate of the active ingredient. In the case of a

35    combination  agent,   however,   it  is  associated  with  high

difficulty from the aspect of pharmaceutical technology since the dissolution rate of each active ingredient needs to be optimized. Moreover, it is also necessary to suppress an adverse influence (degraded storage or chemical stability such

5    as time-course decomposition of active ingredients, decreased activity and the like, degraded dissolution stability such as time-course changes in the active ingredient dissolution

pattern and the like, and the like) caused by the interaction of plural active ingredients contained in a combination agent.

10 The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that, by individually preparing the first part containing compound (I) or a salt thereof and, as the first excipient, sugar or sugar alcohol, and the second part containing


15    pioglitazone or a salt thereof and, as the. second excipient, sugar or sugar alcohol, and forming a solid preparation containing these two parts, the dissolution rate of each

active    ingredient  can  be  controlled,   and  an  adverse  influence

caused  by  the  interaction  of  the  respective  active  ingredients

20    can be suppressed, and further study has resulted in the completion of the present invention.
Accordingly,   the  present  invention  relates  to

[1]    a  solid  preparation  comprising  the  following  first  and

second  parts:

25 (1) the first part comprising compound (I) or a salt thereof and, as the first excipient, sugar or sugar alcohol; and

(2) the second part comprising pioglitazone or a salt thereof and, as the second excipient, sugar or sugar alcohol,

[2]    the  solid  preparation  of  the  above-mentioned   [1],   wherein

E    the sugar or sugar alcohol is lactose, sucrose, erythritol or mannitol,

[3]    the solid preparation of the above-mentioned [2], wherein the first and the second excipients are mannitol,

[4]    the  solid  preparation  of  the  above-mentioned   [3],   which  is

35    a  coated  tablet  comprising  an  inner  core  made  of  the  first
 
part,    and  an  outer  layer  made  of  the  second  part,

[5] the solid preparation of the above-mentioned [2], wherein the first excipient is mannitol and the second excipient is lactose,

s [6] the solid preparation of the above-mentioned [5], which is a coated tablet comprising an inner core made of the second part, and an outer layer made of the first part,

[7] the solid preparation of the above-mentioned [5], which is a multi-layer tablet comprising the first layer made of the

10    first part, and the second layer made of the second part, and the like.

The solid preparation of the present invention is useful as a therapeutic drug for diabetes and the like, can optimize the dissolution rate of the active ingredient contained in the

15    preparation and can suppress an adverse influence (degraded storage or chemical stability such as time-course

decomposition of active ingredients, decreased activity and the like, degraded dissolution stability such as time-course changes in the active ingredient dissolution pattern and the

20 like, and the like) caused by the interaction of active ingredients contained in the preparation.

DETAILED  DESCRIPTION  OF  THE  INVENTION

The solid preparation of the present invention is explained in detail in the following.

25 The first and the second parts in the solid preparation of the present invention mean compositions or constituent components each capable of existing as an independent composition.


(1)    First  part

30 The first part in the present invention is a part (composition) containing compound (I) or a salt thereof and, as the first excipient, sugar or sugar alcohol.

In the present specification, the "sugar or sugar alcohol" to be used as the first excipient is sometimes to be

35    abbreviated  simply  as  "the  first  excipient".

Examples of the salt of compound (I) include a pharmacologically acceptable salt, such as a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like.

5 Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts with benzoic acid, formic acid, acetic acid,

10 trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.


Preferable  examples  of  the  salt  with  basic  amino  acid

15    include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid

include salts with aspartic acid, glutamic acid and the like. Preferable examples of the salt of compound (I) include

salts    with  benzoic  acid,   trifluoroacetic  acid,   p-

20    toluenesulfonic acid and the like, more preferably a salt with benzoic acid.

Compound   (I)   or  a  salt  thereof  is  preferably  benzoate  of

compound (I), trifluoroacetate of compound (I), or p-toluenesulfonate of compound (I), more preferably benzoate of

25 compound (I) (sometimes to be abbreviated as compound (IA) in the present specification) .

The content of compound (I) or a salt thereof is preferably 0.1 - 90 parts by weight, more preferably 0.5 - 80 parts by weight, still more preferably 1 - 70 parts by weight,

~    relative to 100 parts by weight of the first part in the present invention.

Examples of the sugar in the first excipient include lactose, sucrose, fructose, glucose and the like, preferably,

lactose  or  sucrose.
35    Examples  of  the  sugar  alcohol  in  the  first  excipient

include erythritol, mannitol, sorbitol, xylitol, maltitol and the like, preferably, erythritol or mannitol, more preferably mannitol.

These    sugar  and  sugar  alcohol  may  be  used  alone,   or  two

5    or  more  kinds  thereof  may  be  used  in  combination.

The first excipient is preferably lactose, sucrose, erythritol or mannitol, more preferably mannitol.

The amount of the first excipient to be used in the present invention is preferably 5 - 99 parts by weight, more

10    preferably 10 - 95 parts by weight, still more preferably 20 - 90 parts by weight, relative to 100 parts by weight of the above-mentioned first part.

The weight ratio of compound (I) or a salt thereof relative to the first excipient (compound (I) or a salt

15    thereof : first excipient) is preferably 0. 001 - 15 : 1, more preferably 0.005- 10 : 1, still more preferably 0 . 01 - 5 : 1.

The above-mentioned first part may have any shape or size as long as it can form a solid preparation together with the below-mentioned second part, and can be administered

20 (preferably orally administered) to living organisms. In addition, the first part may have any inside structure, and the inside may be uniform or nonuniform.

The above-mentioned first part may further contain an additive conventionally used in the field of pharmaceutical

25    preparation. Examples of the additive include excipients other than sugar or sugar alcohol, disintegrant, binder, lubricant, colorant, pH adjusting agent, surfactant, stabilizer, acidulant, flavor, glidant, coating base, coating additive and the like. Unless particularly indicated, these additives are

30    used in an amount conventionally employed in the field of pharmaceutical preparation.

The above-mentioned first part can be produced by mixing compound (I) or a salt thereof and the first excipient and, where necessary, the above-mentioned additive according to a

35    method  known  per  se  and  then,   according  to  a  dosage  form,

compression  molding  or  covering  the  second  part.

Preferable examples of the excipient other than sugar or sugar alcohol include starches such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized

s starch, pregelatinized starch, porous starch and the like; anhydrous calcium phosphate, crystalline cellulose (e.g., microcrystalline cellulose), precipitated calcium carbonate, calcium silicate and the like. Of these, crystalline cellulose is preferable.


10 The amount of the excipient other than sugar or sugar alcohol is preferably 1 - 40 parts by weight, more preferably 5 - 30 parts by weight, still more preferably 10 - 20 parts by weight, relative to 100 parts by weight of the above-mentioned first part.


15 Preferable examples of the disintegrant include carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, croscarmellose sodium, croscarmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch and the like. Of these, croscarmellose

20    sodium  is  preferable.

The amount of the disintegrant to be used is preferably 0 . 1 - 30 parts by weight, more preferably 1 - 20 parts by weight, still more preferably 2 - 10 parts by weight, relative to 100 parts by weight of the above-mentioned first part.

25 Preferable examples of the binder include crystalline cellulose (e.g., microcrystalline cellulose), hydroxypropylcellulose [e.g., grades: L, SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropylmethylcellulose

[e.g.,   TC-5   (grades:  MW,   E,   EW,  R,   RW)   (trade  name);   Shin-Etsu

30    Chemical Co., Ltd.], polyvinylpyrrolidone, gum arabic and the like. Of these, hydroxypropylcellulose is preferable.

The amount of the binder to be used is preferably 0 . 1 - 40 parts by weight, more preferably 0.5 - 30 parts by weight, still more preferably l - 20 parts by weight, relative to 100

35    parts  by  weight  of  the  above-mentioned  first  part.


Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate and the like. Of these, magnesium stearate is pref~rable.

5    The  amount  of  the  lubricant  to  be  used  is  preferably  0.01

-    5 parts by weight, more preferably 0.05 - 3 parts by weight, still more preferably 0.1 - 2 parts by weight, relative to 100 parts by weight of the above-mentioned first part.

Preferable  examples  of  the  colorant  include  food  colors

10    such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 and the like, food lake colors, red ferric oxide (diiron trioxide), yellow ferric oxide and the like.

Preferable  examples  of  the  pH  adjusting  agent  include

citric  acid  or  a  salt  thereof,   phosphoric  acid  or  a  salt

15    thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, fumaric acid or a salt thereof, acetic acid or salt thereof, amino acid or a salt thereof and the like.

Preferable  examples  of  the  surfactant  include  sodium

lauryl    sulfate,   polysorbate  80,

20 polyoxyethylene(160)polyoxypropylene(30)glycol and the like. Preferable examples of the stabilizer include tocopherol,

tetrasodium edetate, nicotinic acid amide, cyclodextrins and the like.

Preferable  examples  of  the  acidulant  include  ascorbic

25 acid, citric acid, tartaric acid, malic acid and the like. Preferable examples of the flavor include menthol,

peppermint oil, lemon oil, vanillin and the like. Preferable examples of the glidant include light

anhydrous    silicic  acid,   hydrated  silicon  dioxide,   talc  and  the

30    like.

Preferable examples of the coating base include sugar coating base, aqueous film coating base, enteric film coating base, sustained-release film coating base and the like.

As    the  sugar  coating  base,   sucrose  is  used.    Furthermore,

35    one  or  more  kinds  selected  from  talc,   precipitated  calcium

carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

Examples of the aqueous film coating base include cellulose polymers such as hydroxypropylcellulose [e.g.,

5    grades: L, SL, SL-T, SSL (trade name); Nippon Soda Co., Ltd.], hydroxypropylmethylcellulose [e.g., TC-5 (grades: MW, E, EW, R, RW) (trade name); Shin-Etsu Chemical Co., Ltd.]], hydroxyethylcellulose, methylhydroxyethylcellulose and the

like;    synthetic  polymers  such  as  polyvinyl  acetal

10 diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone and the like; polysaccharides such as pullulan and the like, and the like.

Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose

15    phthalate, hydroxypropylmethylcellulose acetatesuccinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid

copolymer  L  [Eudragit  L  (trade  name)],  methacrylic  acid

copolymer  LD   [Eudragit  L-30055   (trade  name)],   methacrylic  acid

20    copolymerS [Eudragit S (trade name)] and the like; naturally occurring substances such as shellac and the like; and the

like.

Examples of the sustained-release film coating base include cellulose polymers such as ethylcellulose and the

25 like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate• methacrylic acid methyl copolymer suspension [Eudragit NE (trade name)] and the like; and the like.

Preferable  examples  of  the  coating  additive  include  light

Jo shielding agents such as titanium dioxide and the like, fluidizers such as talc and the like, and/or colorants such as red ferric oxide (diiron trioxide), yellow ferric oxide and the like; plasticizers such as polyethylene glycol [e.g., macrogol 6000 (trade name)], triethyl citrate, castor oil, polysorbates

35    and  the  like;   organic  acids  such  as  citric  acid,   tartaric  acid,

malic  acid,   ascorbic  acid  and  the  like;   and  the  like.

The above-mentioned additive may be a mixture of two or more kinds at an appropriate ratio.

The    above-mentioned  first  part  preferably  contains

5    compound (I) or a salt thereof (preferably benzoate of compound (I)); the first excipient (preferably mannitol); an

excipient  other  than  sugar  and  sugar  alcohol   (preferably

crystalline  cellulose);  a  disintegrant   (preferably

croscarmellose    sodium);  a  binder   (preferably

10    hydroxypropylcellulose); and a lubricant (preferably magnesium stearate).

( 2)   Second  part

The  second  part  in  the  present  invention  is  a  part

(composition)    containing  pioglitazone  or  a  salt  thereof  and,

15    as  the  second  excipient,   sugar  or  sugar  alcohol.

In the present specification, the "sugar or sugar alcohol" to be used as the second excipient is sometimes to be simply abbreviated as "the second excipient".

Examples    of  the  salt  of  pioglitazone  include

20    pharmacologically acceptable salts such as salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like. As such salt, those recited as the examples of the salt of the above-mentioned compound

(I)    can  be  used.

25 Preferable examples of the salt of pioglitazone include salts with hydrochloric acid.

As pioglitazone or a salt thereof, pioglitazone hydrochloride is preferable.

The  content  of  the  pioglitazone  or  a  salt  thereof  is

30    preferably 0.1 - 60 parts by weight, more preferably l - 50 parts by weight, more preferably 2 - 40 parts by weight, relative to 100 parts by weight of the above-mentioned second

part.

As    the  sugar  and  sugar  alcohol  in  the  second  excipient,

35    those  recited  as  the  examples  of  the  sugar  and  sugar  alcohol

of the above-mentioned first excipient can be used respectively.

The second excipient is preferably lactose, sucrose, erythritol or mannitol, more preferably lactose or mannitol.

5 The amount of the second excipient to be used in the present invention is preferably 5 - 99 parts by weight, more preferably 10 - 95 parts by weight, still more preferably 20 - 90 parts by weight, relative to 100 parts by weight of the above-mentioned second part.


10 The weight ratio of the pioglitazone or a salt thereof relative to the second excipient (pioglitazone or a salt thereof: second excipient) is preferably 0.001 - 30 1, more preferably 0.005 - 10 : 1, still more preferably 0.01 - 1 : 1.

The  above-mentioned  second  part  may  have  any  shape  or

15    size as long as it can form a solid preparation together with the aforementioned first part, and can be administered (preferably orally administered) to living organisms. In

addition, the second part may have any inside structure, and the inside may be uniform or nonuniform.

20 The above-mentioned second part may further contain an additive conventionally used in the field of pharmaceutical preparation, and can be produced according to a known method. Examples of the additive include those recited in the above-mentioned first part (e.g., excipients other than sugar and

25 sugar alcohol, disintegrant, binder, lubricant, colorant, pH adjusting agent, surfactant, stabilizer, acidulant, flavor, fluidizer, coating base, coating additive and the like). Unless particularly indicated, these additives are used in an amount conventionally employed in the field of pharmaceutical

30    preparation.

The above-mentioned second part can be produced by mixing pioglitazone or a salt thereof and the second excipient and, where necessary, the above-mentioned additive according to a method known per se and then, according to a dosage form,

35    compression  molding  or  covering  the  first  part.

The amount of the excipient other than sugar and sugar alcohol to be used in the second part is preferably 0.1 - 40 parts by weight, more preferably 0.1 - 30 parts by weight, still more preferably 0.1 - 20 parts by weight, relative to

5    100  parts  by  weight  of  the  above-mentioned  second  part.

The amount of the disintegrant to be used in the second part is preferably 0.1 - 30 parts by weight, more preferably 1 - 20 parts by weight, still more preferably 2 - 10 parts by weight, relative to 100 parts by weight of the above-mentioned

10    second  part.

The amount of the binder to be used in the second part is preferably 0.1 - 30 parts by weight, more preferably 0.5 - 20 parts by weight, still more preferably 1 - 10 parts by weight, relative to 100 parts by weight of the above-mentioned second

15    part.

The amount of the lubricant to be used in the second part is preferably 0.01 - 5 parts by weight, more preferably 0.05

1 parts by weight, still more preferably 0.1 - 0.5 parts by weight, relative to 100 parts by weight of the above-mentioned

20    second  part.

The amount of other additives to be used in the second part is the amount conventionally used in the field of pharmaceutical preparation.

The  above-mentioned  second  part  preferably  contains

25    pioglitazone or a salt thereof (preferably pioglitazone hydrochloride) ; the second excipient (preferably lactose or mannitol); and a binder (preferably hydroxypropylcellulose).

The  weight  ratio  of  the  second  part  relative  to  the  first

part  of  the  solid  preparation  of  the  present  invention   (second

30    part : first part) is preferably 0.01 - 100 : 1, more preferably 0.05 - 10 : 1, still more preferably 0.1 - 5 : 1.

The compound (I) and pioglitazone may be solvates (e.g., hydrates) or non-solvates.

In  addition,   compound   (I)   may  be  labeled  with  an  isotope
35    (e.g.,   3H,   14C,   35S,   12si).
 

Furthermore, it may be a deuterium converter wherein 1 H is converted to 2H(D).

The solid preparation of the present invention is not particularly limited as long as it is a preparation wherein

5    the first part and the second part are integrally formed, and can be produced by mixing these parts together with, where necessary, the above-mentioned additives according to a method known per se, followed by compression molding, or covering one part with the other part.


10 In addition, the solid preparation of the present invention may have an inactive intermediate layer between the first part and the second part.

When the solid preparation of the present invention has an intermediate layer, the intermediate layer is formed at the

15    ratio of preferably 0.1 - 1000 parts by weight, more preferably 0.5 - 500 parts by weight, still more preferably 1

-    200 parts by weight, relative to 100 parts by weight of the first part.

When  the  solid  preparation  of  the  present  invention  has

20    such an intermediate layer, an adverse influence (degraded storage or chemical stability such as time-course decomposition of active ingredients, decreased activity and

the    like,   degraded  dissolution  stability  such  as  time-course

changes    in  the  active  ingredient  dissolution  pattern  and  the

25    like, and the like) caused by the interaction of active ingredients can be suppressed more effectively.

Specific  examples  of  the  solid  preparation  of  the  present

invention include [1] a coated tablet containing the inner core made of the first part and the outer layer made of the

30 second part (sometimes to be abbreviated as "coated tablet (A)" in the present specification); [2] a coated tablet containing the inner core made of the second part and the outer layer made of the first part (sometimes to be abbreviated as "coated tablet (B)" in the present


35    specification";   and   [3]   a  multi-layer  tablet  containing  the

first layer made of the first part and the second layer made of the second part (sometimes to be abbreviated as "multi-layer tablet (A)" in the present specification)

In  the  above-mentioned  coated  tablet   (A) ,   the  first  and

5    the  second  excipients  are  both  preferably  mannitol.

The coated tablet (A) of the present invention can be produced, for example, by the following production steps.

The inner core made of the first part can be produced, for example, by granulating compound (I) or a salt thereof and

10 the first excipient together with, where necessary, an additive. After granulation, an operation such as drying, sizing, and the like may be performed as necessary.

The additive preferably includes excipients other than sugar and sugar alcohol (preferably crystalline cellulose);

15 disintegrants (preferably croscarmellose sodium); binders (preferably hydroxypropylcellulose); and lubricants (preferably magnesium stearate) and the like.

The inner core made of the above-mentioned first part can be preferably produced by the following production steps.

20    1) compound (I) or a salt thereof (preferably benzoate of compound (I)); the first excipient (preferably mannitol); and excipients other than sugar and sugar alcohol (preferably crystalline cellulose) are granulated using a dispersion

liquid  of  a  binder   (preferably  hydroxypropylcellulose)   in  a

25    solvent (e.g., water, acetone, ethyl alcohol, propyl alcohol, and a mixture of these at an appropriate ratio; preferably water) .

Here, the dispersion liquid may be any of solution and suspension, and the "dispersion liquid" in the present

~    specification  includes  both  solution  and  suspension.

2) The obtained granules are dried, sized and the obtained milled granule, a disintegrant (preferably croscarmellose sodium), a lubricant (preferably magnesium stearate) and, where necessary, an excipient other than sugar and sugar

35    alcohol   (preferably  crystalline  cellulose)   are  mixed.
 
3) The obtained mixture is compression molded (preferably tableted) .

On the other hand, the outer layer made of the second part can be produced, for example, by applying pioglitazone or

5    a salt thereof and the second excipient together with, where necessary, an additive to the above-mentioned first part.

The  applying  can  be  performed,   for  example,   by

compression ~olding, coating and the like. The additive is preferably a binder (preferably hydroxypropylcellulose) and

10    the  like.

The above-mentioned outer layer made of the second part can be preferably produced according to the following production steps.

1)    The  inner  core  made  of  the  first  part  is  coated  with  a

15    dispersion liquid of pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), the second excipient

(preferably mannitol) and a binder (preferably hydroxypropylcellulose) in a solvent (e.g., water, acetone, ethyl alcohol, propyl alcohol, and a mixture of these at an

~    appropriate  ratio;   preferably  water)  .

During production of coated tablet (A), it is preferable to form an inactive intermediate layer between an inner core and an outer layer to avoid a direct contact of them. The intermediate layer contains, for example, the above-mentioned

25    coating base and a coating additive. The intermediate layer preferably contains an aqueous film coating base (preferably

hydroxypropylmethylcellulose) and a glidant (preferably talc) In the above-mentioned coated tablet (A), the outer layer

is    formed  in  a  proportion  of  preferably  0.1  -   1000  parts  by

JO    weight, more preferably 1 - 300 parts by weight, still more preferably 10 - 100 parts by weight, relative to 100 parts by weight of the inner core.

In the above-mentioned coated tablet (A), moreover, the intermediate layer is formed in a proportion of preferably 0.1

35    -    30  parts  by  weight,   more  preferably  0.5  -   20  parts  by  weight,
 
still more preferably 1 - 10 parts by weight, relative to 100 parts by weight of the inner core.

In the above-mentioned coated tablet (B), the first excipient is preferably mannitol and the second excipient is

5    preferably  lactose.

The above-mentioned coated tablet (B) can be produced in the same manner as coated tablet (A) except that the second part is used as the inner core and the first part is used as the outer layer.

10 In the above-mentioned coated tablet (B), the outer layer is formed in a proportion of preferably 1 - 300 parts by weight, more preferably 5 - 200 parts by weight, still more preferably 10 - 80 parts by weight, relative to 100 parts by weight of the inner core.


15 In the above-mentioned multi-layer tablet (A), the first excipient is preferably mannitol and the second excipient is preferably lactose.

Multi-layer tablet (A) can be produced, for example, according to the following production steps.

20 The first layer is produced by mixing compound (I) or a salt thereof and the first excipient and, where necessary, an additive, and granulating the obtained mixture. After granulation, an operation such as drying, sizing, and the like may be performed as necessary.


25 Then, pioglitazone or a salt thereof and the second excipient are mixed with an additive as necessary, and the obtained mixture is superimposed to form a layer on the above-mentioned first layer, which is followed by compression molding (preferably tableting) .


30 In this case, an inactive intermediate layer may be formed between respective layers to avoid a direct contact of them. The intermediate layer contains, for example, the above-mentioned binder.


Multi-layer  tablet   (A)   can  be  produced,   for  example,

35    according  to  the  following  production  steps.
 

1) Compound (I) or a salt thereof (preferably benzoate of compound (I)); the first excipient (preferably mannitol); and an excipient other than sugar and sugar alcohol (preferably crystalline cellulose) are granulated with a dispersion liquid

5 of a binder (preferably hydroxypropylcellulose) in a solvent (e.g., water, acetone, ethyl alcohol, propyl alcohol, and a mixture of these at an appropriate ratio; preferably water) . 2) The obtained granules are dried, sized, and the obtained milled granule and a disintegrant (preferably croscarmellose

10 sodium), a lubricant (preferably magnesium stearate) and, as necessary, an excipient other than sugar and sugar alcohol (preferably crystalline cellulose) are mixed to give granules. 3-1) Pioglitazone or a salt thereof (preferably pioglitazone hydrochloride); the second excipient (preferably lactose); and

15 a disintegrant (preferably croscarmellose sodium) are granulated with a dispersion liquid of a binder (preferably hydroxypropylcellulose) in a solvent (e.g., water, acetone, ethyl alcohol, propyl alcohol, and a mixture of these at an appropriate ratio; preferably water) .


20    3-2) The obtained granules are further granulated with a dispersion liquid of a binder (preferably hydroxypropylcellulose) and the second excipient (preferably

lactose)    in  a  solvent   (e.g.,   water,   acetone,   ethyl  alcohol,

propyl  alcohol,   and  a  mixture  of  these  at  an  appropriate

25    ratio;   preferably  water).

4)    The obtained granules are dried, sized, and the obtained milled granule and a disintegrant (preferably croscarmellose sodium) and a lubricant (preferably magnesium stearate) are

mixed  to  give  granules.

30    5) The granules obtained in the above-mentioned 4) and the granules in the above-mentioned 2) are superimposed on each other in layers, followed by compression molding (preferably

tableting)  .

The  dispersion  in  the  above-mentioned  steps  may  be  any  of

~    solution  and  suspension.
 

The step of the above-mentioned 3-2) is particularly important to control the dissolution rate of each active ingredient and suppress an adverse influence caused by an interaction of the active ingredients.

5 In the above-mentioned multi-layer tablet (A), the second layer is formed in a proportion of preferably l - 1000 parts

by weight, more preferably 5 - 500 parts by weight, still more preferably 10 - 300 parts by weight, relative to 100 parts by weight of the first layer.

10 In the above-mentioned multi-layer tablet (A), moreover, the intermediate layer is formed in a proportion of preferably 0 . 1 - 1000 parts by weight, more preferably 0.5 - 500 parts by weight, still more preferably 1 - 200 parts by weight,

relative  to  100  parts  by  weight  of  the  first  layer.

15 A capsule produced by filling the above-mentioned coated tablet (A) or (B) or multi-layer tablet (A) in a capsule (e.g., gelatin capsule) is also encompassed in the solid preparation

of  the  present  invention.

The  solid  preparation  of  the  present  invention  is

20    preferably coated tablet (A) or multi-layer tablet (A), more preferably multi-layer tablet (A).

In  addition,   a  film  coating  preparation  produced  by  film

coating  the  above-mentioned  coated  tablet   (A),   (B)   or  multi-

layer  tablet   (A)   with  the  above-mentioned  coating  agent  and

25    coating additive is also encompassed in the solid preparation of the present invention.

In  addition,   the  solid  preparation  of  the  present

invention may be stamped or printed with letters for discrimination, or have a separating line for dividing the

~    tablet.

From the aspects of easy administration, preparation strength and the like, the solid preparation of the present invention is preferably film-coated.

The  operations  such  as  mixing,   compression  molding,

35    coating  and  the  like  in  the  aforementioned  production  step  are
 

performed according to a method conventionally used in the technical field of pharmaceutical preparations.

The mixing is performed, for example, using a mixer such as a V-type mixer, a tumbler mixer and the like; and a

5    granulation machine such as a high speed mixer granulator, a fluid bed granulator, an extrusion granulator, a roller compactor and the like.

Compression molding is performed, for example, using a single punch tableting machine, a rotary tableting machine and

10    the  like.

When a single punch tableting machine, a rotary tableting machine and the like are used, a tableting pressure of generally 1 - 35 kN/cm2 (preferably 5 - 35 kN/cm2 ) is

preferably  employed.    Furthermore,   to  prevent  capping,   a

15    tapered  die  is  preferably  used.

The coating is performed, for example, using a film coating apparatus and the like.

The solid preparation of the present invention can be safely administered orally or parenterally to a mammal (e.g.,

20 mouse, rat, rabbit, cat, dog, bovine, horse, monkey, human). The solid preparation of the present invention and each

active ingredient contained in the solid preparation are useful for the prophylaxis or treatment of, for example, diabetes [e.g., type 1 diabetes, type 2 diabetes, type 1.5

25 diabetes (LADA (Latent Autoimmune Diabetes in Adults)), gestational diabetes, diabetes with impaired insulin secretion, obese diabetes, impaired glucose tolerance (IGT), IFG

(Impaired Fasting Glucose), IFG (Impaired Fasting Glycaemia)], diabetic complications [e.g., neuropathy, nephropathy,

30 retinopathy, cataract, macroangiopathy, arteriosclerosis, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia

35    hypacusis,   cerebrovascular  disorder,   peripheral  blood
 
circulation disorder], obesity, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypoHDL-emia, postprandial hyperlipemia), arteriosclerosis (e.g., atherosclerosis), hypertension, myocardial infarction, angina

5    pectoris, cerebrovascular disorder (e.g., cerebral infarction, cerebral apoplexy), insulin resistance syndrome, syndrome X, dysmetabolic syndrome and the like. In addition, the solid preparation of the present invention is also useful for

secondary  prevention  of  the  above-mentioned  various  diseases

10 (e.g., secondary prevention of cardiovascular event such as myocardial infarction and the like) or suppression of progression [e.g., suppression of progression from impaired glucose tolerance to diabetes; suppression of progression from diabetes to diabetic complications (preferably diabetic


15 neuropathy, diabetic nephropathy, diabetic retinopathy, arteriosclerosis)] .

The dose of the solid preparation of the present invention only needs to be an effective amount of compound

(I)    or  pioglitazone  contained  in  the  solid  preparation.

20 Here, the effective amount of compound (I) or a salt thereof is, for example, generally 1 - 1000 mg/day, preferably 1 - 100 mg/day, more preferably 10 - 30 mg/day, even more preferably 12.5 - 25 mg/day, as compound (I) (free form) for one adult (body weight 60 kg).


25 In the case of pioglitazone or a salt thereof, the effective amount thereof is generally 5 - 100 mg/day, preferably 7 . 5 - 60 mg/day, more preferably 15 - 60 mg/day, as pioglitazone (free form) for one adult (body weight 60 kg).

The  solid  preparation  of  the  present  invention  is

JO preferably administered to the aforementioned mammal 1 to 3 times, more preferably once, relative to day. Particularly, the solid preparation of the present invention is preferably administered once before breakfast to a mammal.

Particularly  preferable  specific  examples  of  the  solid

~    preparation  of  the  present  invention  include
 

"coated tablet containing pioglitazone hydrochloride (outer layer) 16.53 mg (15 mg as pioglitazone) and benzoate of compound (I) (inner core) 17 mg ( 12.5 mg as compound (I) ) per one tablet";

5    "coated tablet containing pioglitazone hydrochloride (outer layer) 33.06 mg (30 mg as pioglitazone) and benzoate of

compound (I) (inner core) 17 mg (12.5 mg as compound (I)) per one tablet";

"coated  tablet  containing  pioglitazone  hydrochloride   (outer

10    layer) 49.59 mg (45 mg as pioglitazone) and benzoate of compound (I) (inner core) 17 mg ( 12. 5 mg as compound (I) ) per one tablet";

"coated tablet containing pioglitazone hydrochloride (outer layer) 16.53 mg (15 mg as pioglitazone) and benzoate of

15    compound (I) (inner core) 34 mg (25 mg as compound (I)) per one tablet";

"coated tablet containing pioglitazone hydrochloride (outer layer) 33.06 mg (30 mg as pioglitazone) and benzoate of compound (I) (inner core) 34 mg (25 mg as compound (I)) per

20    one  tablet";

"coated tablet containing pioglitazone hydrochloride (outer layer) 49.59 mg (45 mg as pioglitazone) and benzoate of

compound    (I)   (inner  core)   34  mg   (25  mg  as  compound   (I))   per

one  tablet";

25    "coated tablet containing pioglitazone hydrochloride (inner core) 49.59 mg (45 mg as pioglitazone) and benzoate of

compound (I) (outer layer) 68 mg (50 mg as compound (I)) per one tablet";

"multi-layer  tablet  containing  pioglitazone  hydrochloride

30    16.53 mg (15 mg as piog1itazcne) and benzoate of compound (I) 17 mg (12.5 mg as compound (I)) per one tablet";

"multi-layer tablet containing pioglitazone hydrochloride 33.6 mg (30 mg as pioglitazone) and benzoate of compound (I) 17 mg (12.5 mg as compound (I)) per one tablet";

35    "multi-layer  tablet  containing  pioglitazone  hydrochloride
 


49.59 rng (45 rng as pioglitazone) and benzoate of compound (I) 17 rng (12.5 mg as compound (I)) per one tablet";

"multi-layer  tablet  containing  pioglitazone  hydrochloride

16.53  mg   (15  mg  as  pioglitazone)   and  benzoate  of  compound   (I)

5    34  mg   (25  mg  as  compound   (I))   per  one  tablet";

"multi-layer  tablet  containing  pioglitazone  hydrochloride

33.06 mg (30 mg as pioglitazone) and benzoate of compound (I) 34 mg (25 mg as compound (:.::,) per one tablet"; and

"multi-layer  tablet  containing  pioglitazone  hydrochloride

10    49.59  rng   (45  mg  as  pioglitazone)   and  benzoate  of  compound   (I)

34  mg   (25  mg  as  compound   (I))   per  one  tablet".

The solid preparation of the present invention is advantageous in the design of preparation since the dissolution rate of pioglitazone or a salt thereof from a

15 solid preparation can be controlled by changing the kind, amount and the like of the second excipient (sugar or sugar alcohol), and/or changing the content of pioglitazone or a salt thereof.

Each  of  the  solid  preparation  of  the  present  invention

20 and the active ingredients contained in the solid preparation can be used in combination with one or more pharmaceutical agents selected from a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an

25    antiobesitic agent, a diuretic, an antithrombotic agent and the like (hereinafter sometlmes to be abbreviated as concomitant drug).

Examples  of  the  therapeutic  agent  for  diabetes  include

insulin  preparations   (e.g.,   animal  insulin  preparation

30    extracted from the pancreas of bovine or swine; human insulin preparation synthesized by genetic engineering using

Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1), oral insulin preparation), insulin sensitizers except for

35    pioglitazone   (e.g.,   rosiglitazone  or  a  salt  thereof
 



(preferably maleate), tesaglitazar, ragaglitazar, muraglitazar, edaglitazone, metaglidasen, naveglitazar, AMG-131, THR-0921),

a-glucosidase inhibitors (e.]., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., metformin, buformin or salts

5    thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogue [sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole),

repaglinide,    nateglinide,  mitiglinide  or  calcium  salt  hydrate

10    thereof], dipeptidyl peptidase IV inhibitors other than compound (I) (e.g., vildagliptin, sitagliptin, saxagliptin, T-

6666, TS-021), ~3 agonists (e.g., AJ-9677), GPR40 agonists, GLP-1 receptor agonists (e.g., GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib(8,35)hGLP-1(7,37)NH 2 , CJC-

15    1131], amylin agonists (e.g., pramlintide), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon

antagonist),    SGLUT   (sodium-glucose  cotransporter)   inhibitors

20    (e.g., T-1095), 11~-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498), adiponectiil or agonist thereof, IKK

inhibitors    (e.g.,   AS-2868)  1     leptin  resistance   improving  drugs,

somatostatin receptor agonists, glucokinase activators (e.g., Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide)

25    and  the  like.

Examples of the therapeutic agents for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophic factors and increasing drugs

30    thereof (e.g., NGF, NT-3, BDNF, neurotrophin production/secretion promoting agent described in W001/14372 (e.g., 4-(4-ch1oropheny1)-2-(2-methy1-1-imidazoly1)-5-[3-(2-

methy1phenoxy)propy1]oxazo1e) ), nerve regeneration promoters (e.g., Y-128), PKC inhibitors (e.g., ruboxistaurin mesylate),

35    AGE  inhibitors   (e.g.,  ALT946,   pimagedine,   N-phenacy1thiazo1ium
 


cetilistat), ~3 agonists (e.g., AJ-9677), anorectic peptides (e.g., leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (e.g., lintitript, FPL-15849), feeding deterrents (e.g., P-57) and the like.

Examples of the diuretic include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide,

10 polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), chlorobenzenesulfonamide

agents (e.g., chlortalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide,

15    furosemide  and  the  like.

Examples of the antithrombotic agent include heparins (e.g., heparin sodium, heparin calcium, dalteparin sodium), warfarins (e.g., warfarin potassium), anti-thrombin drugs (e.g., aragatroban), thrombolytic agents (e.g., urokinase,

20 tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.

Of  the  above-mentioned  combination  drugs,   insulin

25    preparation, a-glucosidase inhibitors (preferably voglibose, acarbose), biguanides (preferably metformin hydrochloride), sulfonylureas (preferably glimepiride) are preferable.

When  the  solid  preparation  of  the  present  invention  and  a

concomitant  drug  are  used  in  combination,   the  administration

30    time of these is not limited, and the solid preparation of the present invention and the combination drug can be administered simultaneously to an administration subject, or may be administered in a staggered manner.

In  addition,   the  solid  preparation  of  the  present

35    invention  and  the  concomitant  drug  may  be  administered  as
 


separate preparations to an administration subject, or the solid preparation of the present invention and the concomitant drug may be administered to an administration subject as a single preparation containing the solid preparation of the

5    present  invention  and  the  concomitant  drug.

The dose of the concomitant drug can be appropriately determined based on the clinically employed dose of each drug. In addition, the mixing ratio of the solid preparation of the present invention and the concomitant drug can be

10    appropriately determined according to the administration subject, administration route, target disease, condition,

combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of

15    the  solid  preparation  of  the  present  invention.

Use of the concomitant drug in this way provides superior effects such as 1) enhanced action of the solid preparation of the present invention or the concomitant drug (synergistic effect of the actions of the pharmaceutical agents), 2)

20    reduced dose of the solid preparation of the present invention or the combination drug (effect of reduction of dose of pharmaceutical agents as compared to single drug

administration), 3) reduced secondary action of the solid preparation of the present irvention or the concomitant drug,

25    and  the  like.

The present invention is explained in more detail in the following by referring to Example, Comparative Example and Experimental Examples, which are not to be construed as limitative.

30 As additives for pharmaceutical preparations in the following Examples and Comparative Examples, the Japanese Pharmacopoeia 15th edition, the Japanese Pharmacopoeia Japanese Pharmaceutical Codex or Japanese Pharmaceutical Excipients 2003 compatible products were used.

35


EXAMPLES

Example  1

According to the formulation shown in Table l, multi-layer tablet (A) of the present invention was produced.

5 (l) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2190 g) was dissolved in purified water (34310g) to give a binding solution (I). Compound (IA) (benzoate of compound (I); 26520 g), mannitol (32370 g) and microcrystalline cellulose (3900 g) were uniformly mixed in a fluid bed granulator (WSG-

10    60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (32500 g) and dried to give a granule. A part of the obtained granule was pulverized with a

screening  mi~l  (P-7S,   Showa  Chemical  Machinery)   and  a  1.5  mm$

punching  screen  to  give  a  milled  granule.    To  a  part   (60180  g)

15    of the obtained milled granule were added microcrystalline cellulose (7250 g), croscarmellose sodium (4350 g) and magnesium stearate (725 g), and the mixture was mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give

granule    (I).

20 (2) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1802 g) was dissolved in purified water (34290 g) to give a binding solution (II). Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give

25    suspension   (I) .    Pioglitazone  hydrochloride   (20330  g),   lactose

(30520 g) and croscarmellose sodium (2706 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding

solution    (II)   (27920  g),   sprayed  with  suspension   (I)    (74130  g),

30    and then dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa

Chemical Machinery) and a 1.5 mm$ punching screen to give a milled granule. To a part (66050 g) of the obtained milled granule were added croscarmellose sodium (2075 g) and

35    magnesium  stearate   (273.6  g),   and  they  were  mixed  in  a  tumbler
 

26
 






mixer    (TM-400S,   Showa  Chemical  Machinery)   to  give   granule   (II).

(3) Granule (I) (100 mg) and granule (II) (180 mg) were formed into a multi-layered by a rotary tableting machine (AQUA 08242L2JI, Kikusui Seisakusho) using a 8.5 mm~ punch to give a

5    plain  tablet .

(4)    Hydroxypropylmethylcellulose (TC-5 RW, Shin-Etsu Chemical Co., Ltd.; 390 g) and talc (60 g) were dispersed in purified

water (3500 g) to give dispersion (I). Titanium dioxide (35 g) and red ferric oxide (15 g) were dispersed in purified water

10 (750 g) to give dispersion (II). Dispersion (II) and purified water (250 g) were added to dispersion (I), and they were mixed by stirring in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (DRC-650, POWREX CORPORATION)

15    on the plain tablet obtained in (3) until the weight of the plain tablet increased by 10 mg per one tablet to give multi-layer tablet (A) containing compound (I) ( 2 5 mg) and pioglitazone (45 mg) per one tablet .
 

(l                                       
    Table  1                                       
                                                           
                                    component    formulation   
                                                        amount   
                                                                   
                                                                   
                                compound   (IA)    34        mg   
                                                                   
    layer        mannitol    41    .5    mg   
            microcrystalline                cellulose    15        mg   
    containing                                   
                                       
        hydroxypropylcellulose    2.5    mg   
    compound   (I)                   
            croscarmellose  sodium    6        mg   
                                               
                                                                   
                                magnesium  stearate    1        mg   
                                                       
                                pioglitazone  hydrochloride    49.59    mg   
                                                                   
    layer    lactose    110.43    mg   
                                   
    containing    hydroxypropylcellulose    7    .2    mg   
                           
    pioglitazone    croscarmellose  sodium    12.0 6    mg   
                                               
                                magnesium  stearate    0.72    mg   
                                                   
                                hydroxypropylmethylcellulose    7    .8    mg   
                                                   
    film  coating            talc    1    .2    mg   
            titanium  dioxide    0    .7    mg   
                                               
                                                   
                                red  ferric  oxide    0    .3    mg   
                                                                   
                                                                   

Example  2

According to the formulation shown in Table 2, the coated tablet (A) of the present invention was produced.

5 (1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2460 g) was dissolved in purified water (38540 g) to give a binding solution (I). Compound (IA) (7480 g), mannitol (50600 g) and microcrystalline cellulose (11550 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION),

10    and the mixture was granulated while spraying a binding solution (I) (33000 g) and dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-

73, Showa Chemical Machinery) and a 1.5 mm¢ punching screen to give a milled granule. To a part (67380 g) of the obtained

15 milled granule were added croscarmellose sodium (4347 g) and magnesium stearate (724.5 g), and they were mixed in a tumbler mixer (TM-4003, Showa Chemical Machinery) to give granules.


The obtained granules were tableted by a rotary tableting machine (AQUARIUS 0836SS2JII, Kikusui Seisakusho) using a 9.5 mm~ punch at a weight of 350 mg to give plain tablet containing compound (I) (25 mg) per one tablet.

(2) HydroxypropylmethylceJl•1lose (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5771 g) and talc (641.3 g) were dissolved or suspended in purified water (36340 g) to give coating solution

(I). The coating solution (I) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the plain tablet obtained

10    in (1) until the weight of the plain tablet increased by 15 mg per one tablet to give coated tablet (I).

(3)    Pioglitazone hydrochloride (6360 g), hydroxypropylcellulose (grade SL-T, Nlppon Soda Co., Ltd.;

384.8  g)   and  mannitol   (12490  g)   were  dissolved  or  suspended  in

15 purified water (128200 g) to give coating solution (II). The coating solution (II) was sprayed in a coating machine (DRC-1200, POWREX CORPORATION) on the coated tablet (I) obtained in

(2) until the weight of the coated tablet increased by 150 mg per one tablet to give coated tablet (II).

20 (4) Hydroxypropylmethylcellulose (HPMC) (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5131 g) and macrogol 6000 (1026 g) were dissolved in purified water (30550 g) to give HPMC solution

(I). Titanium dioxide (478.8 g) and red ferric oxide (205.2 g) were dispersed in purified water (8208 g) to give dispersion

25 (I). Dispersion (I) was added to the HPMC solution (I), and they were mixed by stirring in a stirrer (MXD-2302, Satake Chemical Equipment Mfg Ltd.) to give coating solution (III) The coating solution (III) was sprayed in a coating machine (DRC-1200, POWREX CORPORATION) on the coated tablet (II)

30    obtained in (3) until the weight of the coated tablet increased by 15 mg per one tablet to give coated tablet (A) containing compound (I) (25 mg) and pioglitazone (45 mg) per one tablet.
 

    Table    2                                               
                                               
                component    formulation   
                            amount   
                                                       
                compound   (IA)    34                    mg   
                                                       
    plain    tablet    mannitol    230                    mg   
            microcrystalline  cellulose    52.5            mg   
    containing                       
        hydroxypropylcellulose    9                mg   
    compound   (I)                           
        croscarmellose  sodium    21                    mg   
                                           
                                                       
                magnesium  stearate    3    .5            mg   
                                                   
    intermediate    hydroxypropylmethylcellulose    13    .5            mg   
                                                   
    layer            talc    1    .5            mg   
                                       
    layer            pioglitazone  hydrochloride    49.59            mg   
                                   
    containing    mannitol    97.41            mg   
    pioglitazone                                   
        hydroxypropylcellulose    3                    mg   
                                       
                hydroxypropylmethylcellulose    11.25            mg   
                                       
    film    coating    macrogol  6000    2.25            mg   
            titanium  dioxide    1. 05            mg   
                                   
                                       
                red  ferric  oxide    0.45            mg   
                                                       

Example  3

According to the formulation shown in Table 3, the coated tablet (B) of the present invention was produced.

(1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 450 g) was dissolved in purified water (7050 g) to give a binding solution (I). Pioglitazone hydrochloride (4959 g), lactose (11451 g) and carmellose calcium (540 g) were uniformly mixed in a fluid bed granulator (FD-82, POWREX

10    CORPORATION), and the mixture was granulated while spraying a binding solution (!), and dried to give a granule containing pioglitazone. A part of the obtained granule (3 batches) was pulverized with a screening mill (P-3, Showa Chemical

Machinery)    and  a  1.5  mm$  punching  screen  to  give  a  milled

15    granule. To a part (46980 g) of the obtained milled granule were added carmellose calcium (1458 g) and magnesium stearate (162 g), and they were mixei in a tumbler mixer (TM20-0-0,
 

30
 





Suehiro Kakouki) to give granules. The obtained granules were tableted by a rotary tableting machine (Correct 19K, Kikusui Seisakusho) using a 7.5 mm~ punch at a weight of 180 mg to give plain tablet containing piog1itazone (45 mg) per one tablet.

5 (2) Hydroxypropylmethylcellulose (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 45 g) and macrogol 6000 (5 g) were dissolved in purified water (450 g) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (HC-LABO, Freund Corporation) on the plain tablet obtained in (1) until

10    the weight of the plain tablet increased by 10 mg per one tablet to give coated tablet (I).

(3)    Compound   (IA)   (272  g),   hydroxypropylcellulose   (grade  SL-T,

Nippon Soda Co., Ltd.; 24 g) and mannitol (104 g) were dissolved or suspended in purified water (2000 g) to give

15    coating solution (II). The coating solution (II) was sprayed in a coating machine (HC-LABO, Freund Corporation) on the coated tablet (I) obtained in (2) until the weight of the

coated tablet increased by 100 mg per one tablet to give coated tablet (B) containing compound (I) (50 mg) and

20    pioglitazone (45 mg) per one tablet. Table 3

                component    formulation
                    amount
                       
            pioglitazone  hydrochloride    49.59        mg
                       
plain  tablet    lactose        114.51        mg
                       
containing    hydroxypropylcellulose    4    .5        mg
                       
pioglitazone    carmel lose  calcium    10    .8        mg
                           
            magnesium  stearate    0    .6        mg
                       
intermediate    hydroxypropylmethylcellulose    9            mg
                           
layer    macrogol    6000    1            mg
                       
layer    compound    (IA)    68            mg
                       
containing    mannitol        26            mg
                   
compound   (I)    hydroxypropylcellulose    6            mg
                               

Example  4
 

31
 





According to the formulation shown in Table 4, the coated tablet (A) of the present invention was produced.

(1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2460 g) was dissolved in purified water (38540 g) to give a

5 binding solution (I). Compound (IA) (3740 g), mannitol (54340 g) and microcrystalline cellulose (3850 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (33000 g) and dried to give a granule. A part of

10    the  obtained  granule  was  pulverized  with  a  screening  mill   (P-

7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (60130 g) of the obtained

milled  granule  were  added  microcrystalline  cellulose   (7245  g),

croscarmellose    sodium  (4347  g)   and  magnesium  stearate   (724.5

15    g) , and they were mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granules. The obtained granules were tableted by a rotary tableting machine (AQUARIUS

0836SS2JII,    Kikusui  Seisakusho)   using  a   9.5  mm~ punch  at  a

weight  of  350  mg  to  give  plain  tablet  containing  compound   (I)

20    (12.5  mg)   per  one  tablet.

(2)    Hydroxypropylmethylcellulose (TC~5 EW, Shin-Etsu Chemical Co., Ltd.; 5771 g) and talc (641.3 g) were dissolved or

suspended  in  purified  water   (36340  g)   to  give  coating  solution

(I).    The  coating  solution   (I)   was  sprayed  in  a  coating  machine

25 (DRC-1200DS, POWREX CORPORATION) on the plain tablet obtained in (1) until the weight of the plain tablet increased by 15 mg per one tablet to give coated tablet (I).

(3) Pioglitazone hydrochloride (2069 g), hydroxypropylcellulose (grade SL-T, Nippon Soda Co., Ltd.;

30    375.5 g) and mannitol (15580 g) were dissolved or suspended in purified water (106400 g) to give coating solution (II). The coating solution (II) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (I) obtained in (2) until the weight of the coated tablet increased by 150

35    mg  per  one  tablet  to  give  coated  tablet   (II).
 

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(4) Hydroxypropylmethylcellulose (HPMC) (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5131 g) and macrogol 6000 (1026 g) were dissolved in purified water (29640 g) to give HPMC solution

(I).    Titanium  dioxide   (663.5  g)   and  yellow  ferric  oxide   (20.52

5    g) were dispersed in purified water (9120 g) to give dispersion (I). Dispersion (I) was added to HPMC solution (I), and they were mixed by stirring in a stirrer (MXD-2302, Satake Chemical Equipment Mfg Ltd.) to give coating solution (III). The coating solution (III) was sprayed in a coating machine

10 (DRC-1200DS, POWREX CORPORATION) on the coated tablet (II) obtained in (3) until the weight of the coated tablet increased by 15 mg per one tablet to give coated tablet (III).

(5) Macrogol 6000 (1848 g) was dissolved in purified water (16630 g) to give coating solution (IV). The coating solution

15 (IV) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (III) obtained in (4) until the weight of the coated tablet increased by 0.25 mg per one tablet to give coated tablet (A) containing compound (I) (12.5 mg) and piog1itazone (15 mg) per one tablet.
 

Table    4            ...                                                               
                                                                                   
                    component            t;f'lXl!ll,l..l.i=!t io!.l~: /   
                                                                                    -'~':       
                                        ..    t!..QA.E~}S:"           
                                                       
                                                       
                compound    (IA)                17                        mg   
                                                                                           
plain        tablet        mannitol                                        247                        mg   
                                                                                   
                microcrystalline  cellulose                    52.5                    mg       
containing                                           
                                           
        hydroxypropylcellulose                    9                    mg       
compound   (I)                                           
        croscarmellose  sodium                    21                        mg       
                                                           
                                                       
                                                                                   
                magnesium    stearate        3    .5                    mg       
                                                                       
intermediate    hydroxypropylmethylcellulose        13    .5                    mg       
                                                                                       
layer                talc                            1    .5                    mg       
                                                               
layer                pioglitazone  hydrochloride        16.53                    mg       
                                                                   
containing    mannitol                            130.47                    mg       
pioglitazone                                                   
    hydroxypropylcellulose        3                        mg       
                                                       
                hydroxypropylmethylcellulose        11.25                    mg       
                                                                       
                macrogol    6000                        2.25                    mg       
                                           
film    coating    titanium  dioxide        1. 455                mg       
                                               
                yellow  ferric  oxide                    0.045                mg       
                                                                       
                macrogol    6000                                    0.25                    mg       
                                                                                               

Example  5

According to the formulation shown in Table 5, the coated tablet (A) of the present invention was produced.

s (1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2460 g) was dissolved in purified water (38540 g) to give a binding solution (I). Compound (IA) (3740 g), mannitol (54340 g) and microcrystalline cellulose (3850 g) were uniformly mixed in a f:uid bed granulator (WSG-60, POWREX CORPORATION),

10    and the mixture was granulated while spraying a binding solution (I) (33000 g) and dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (60130 g) of the obtained

15    milled granule were added microcrystalline cellulose (7245 g), croscarmellose sodium (4347 g) and magnesium stearate (724.5
 

34
 





g), and they were mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granules. The obtained granules were tableted by a rotary tableting machine (AQUARIUS 0836SS2JII, Kikusui Seisakusho) using a 9.5 mm~ punch at a

5    weight of 350 mg to give plain tablet containing compound (I) (12.5 mg) per one tablet.

(2)    Hydroxypropylmethylcellulose (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5771 g) and talc (641.3 g) were dissolved or suspended in purified water (36340 g) to give coating solution

10    (I). The coating solution (I) was sprayed in a coating machine (DRC-l200DS, POWREX CORPORATION) on the plain tablet obtained

in (l) until the weight of the plain tablet increased by 15 mg per one tablet to give coated tablet (I).

(3)    Pioglitazone  hydrochloride   (4139  g),

15    hydroxypropylcellulose   (grade  SL-T,   Nippon  Soda  Co.,   Ltd.;

375.5 g) and mannitol (13510 g) were dissolved or suspended in purified water (106400 g) to give coating solution (II). The

coating solution (II) was sprayed in a coating machine (DRC-l200DS, POWREX CORPORATION) on the coated tablet (I) obtained

20    in (2) until the weight of the coated tablet increased by 150 mg per one tablet to give coated tablet (II).

(4)    Hydroxypropylmethylcellulose (HPMC) (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5131 g) and macrogol 6000 (1026 g) were

dissolved  in  purified  water   (29640  g)   to  give  HPMC  solution

25 (I). Titanium dioxide (663.5 g), yellow ferric oxide (14.36 g) and red ferric oxide (6.156 g) were dispersed in purified water (9120 g) to give dispersion (I). Dispersion (I) was added to the HPMC solution (I), and they were mixed by stirring in a stirrer (MXD-2302, Satake Chemical Equipment Mfg

~    Ltd.)   to  give  coating  solution   (III).    The  coating  solution

(III)    was  sprayed  in  a  coating  machine   (DRC-l200DS,   POWREX

CORPORATION) on the coated tablet (II) obtained in (3) until the weight of the coated tablet increased by 15 mg per one tablet to give coated tablet (III).

35    (5)   Macrogol  6000   (1848  g)   was  dissolved  in  purified  water
 

35
 





(16630 g) to give coating solution (IV). The coating solution (IV) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (III) obtained in (4) until the weight of the coated tablet increased by 0.25 mg per one

5    tablet to give coated tablet (A) containing compound (I) (12.5 mg) and pioglitazone (30 mg) per one tablet.

Table  5

                                    component    formulation       
                                                        amount       
                                                                           
                    compound    (IA)    17        mg       
                                                                           
    plain  tablet        mannitol                        247        mg       
                                                                       
                    microcrystalline  cellulose    52.5        mg       
    containing                               
                                   
                                                                   
            hydroxypropylcellulose    9        mg       
    compound   (I)                                   
                croscarmellose  sodium    21        mg       
                                       
                                                       
                magnesium    stearate    3.5        mg       
                                                   
    intermediate        hydroxypropylmethylcellulose    13.5        mg       
                                                                   
    layer        talc                        1.5        mg       
                                                   
    layer        pioglitazone  hydrochloride    33.06        mg       
                                                               
    containing    mannitol                        113.94        mg       
                                                       
    pioglitazone        hydroxypropylcellulose    3        mg       
                                                       
                    hydroxypropylmethylcellulose    11.25        mg       
                                                               
                macrogol    6000                2.25        mg       
                                                       
                    titanium        dioxide    1.455        mg       
                                                       
    film  coating                        •-                    0.0315        mg       
                    yellow  ferric  oxide                   
                                               
                    red  ferric  oxide    0.0135        mg       
                                                       
                macrogol    6000                0.25        mg       
                                                                           
                                                                           

Example  6

According  to  the  formulation  shown  in  Table  6,   and  by  a

10 method similar to that in Example 4, coated tablet (A) containing compound (I) (12.5 mg) and pioglitazone (45 mg) per one tablet was obtained.
 


        Table    6                    -                       
                                                                       
                                                component    ~ci~il;ii;liih   
                                            """" .. _..    . '    ..._,._       ....   
                                                    amount   
                                                           
                                                ~~1~.'.{7' /'>    mg -• .   
                                            compound   (IA)           
    plain        tablet            mannitol    24T    mg   
                        microcrystalline  cellulose        52.5    mg   
    containing                   
                                   
        hydroxypropylcellulose        9    mg   
    compound   (I)                           
                croscarmellose  sodium        21    mg   
                                                           
                                                           
                                            magnesium  stearate        3.5    mg   
                                   
    intermediate    hydroxypropylmethylcellulose        13.5    mg   
                                                   
    layer                        talc        1.5    mg   
                                                   
    layer                        pioglitazone  hydrochloride        49.59    mg   
                                                                       
    containing    mannitol        97.41    mg   
                           
    pioglitazone    hydroxypropylcellulose        3    mg   
                                                           
                                            hydroxypropylmethylcellulose        11.25    mg   
                                                           
                                            macrogol  6000        2.25    mg   
                                   
    film    coating    titanium  dioxide        l. 35    mg   
                           
                                                           
                                            red  ferric  oxide        0.15    mg   
                                            .                0.25       
                                            macrogol  6000            mg   
                                                                       
                                                                       

Example  7

According to the formulation shown in Table 7, and by a method similar to that in Example 4, coated tablet (A)

s    containing compound (I) (25 mg) and pioglitazone (15 mg) per one tablet was obtained.
 


    Table    7                                           
                                               
                                component    formulation   
                                        amount   
                                                   
                        compound   (IA)    34    mg   
                                                   
    plain    tablet            mannitol    230        mg   
                            microcrystalline  cellulose    52.5        mg   
    containing                           
                               
                                   
        hydroxypropylcellulose    9    mg   
    compound   (I)                       
                croscarmellose  sodium    21    mg   
                                   
                                           
                        magnesium  stearate    3.5        mg   
                           
    intermediate    hydroxypropylmethylcellulose    13.5        mg   
                                           
    layer                    talc    1.5    mg   
                                           
    layer                    pioglitazone  hydrochloride    16.53    mg   
                                                   
    containing    mannitol    130.47        mg   
                           
    pioglitazone    hydroxypropylcellulose    3        mg   
                                           
                        hydroxypropylmethylcellulose    11.25        mg   
                                           
                        macrogol  6000    2.25        mg   
                                   
    film    coating    titanium  dioxide    1. 35        mg   
                                           
                        yellow  ferric  oxide    0.15        mg   
                                           
                        macrogol  6000    0.25        mg   
                                                   

Example  8

According  to  the  formulation  shown  in  Table  8,   the  coated

tablet    (A)   of  the  present  invention  was  produced.

5 (1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2460 g) was dissolved in purified water (38540 g) to give a binding solution (I). Compound (IA) (7480 g), mannitol (50600 g) and microcrystalline cellulose (3850 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION),

10    and the mixture was granulated while spraying a binding solution (I) (33000 g) and dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-

7S, Showa Chemical Machiner~•) and a 1. 5 mm$ punching screen to give a milled granule. To a part (60130 g) of the obtained

15 milled granule were added microcrystalline cellulose (7245 g), croscarmellose sodium (4347 g) and magnesium stearate (724.5


g), and they were mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granules. The obtained granules were tableted by a rotary tableting machine (AQUARIUS 0836SS2JII, Kikusui Seisakusho) using a 9.5 mm~ punch at a

5    weight  of  350  mg  to  give  a  plain  tablet  containing  compound

(I)    (25  mg)   per  one  tablet.

(2)    Hydroxypropylmethylcellulose (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5771 g) and talc (641.3 g) were dissolved or

suspended  in  purified  water   (36340  g)   to  give  coating  solution

10    (I). The coating solution (1) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the plain tablet obtained

in (1) until the weight of the plain tablet increased by 15 mg per one tablet to give coated tablet (I).
(3)    Pioglitazone  hydrochloride   (4139  g),

15    hydroxypropylcellulose   (grade  SL-T,   Nippon  Soda  Co.,   Ltd.;

375.5 g) and mannitol (13510 g) were dissolved or suspended in purified water (106400 g) to give coating solution (II). The

coating solution (II) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (I) obtained

20    in (2) until the weight of the coated tablet increased by 150 mg per one tablet to give coated tablet (II).

(4)    Hydroxypropylmethylcellulose   (HPMC)   (TC-5  EW,   Shin-Etsu

chemical Co., Ltd.; 5131 g) and macrogol 6000 (1026 g) were dissolved in purified water (29640 g) to give HPMC solution

25 (I). Titanium dioxide (615.6 g), yellow ferric oxide (47.88 g) and red ferric oxide (20.52 g) were dispersed in purified water (9120 g) to give dispersion (I). Dispersion (I) was added to the HPMC solution (1), and they were mixed by stirring in a stirrer (MXD-2302, Satake Chemical Equipment Mfg

30    Ltd.)   to  give  coating  solution   (III).    The  coating  solution

(III)    was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (II) obtained in (3) until the weight of the coated tablet increased by 15 mg per one

tablet  to  give  co a ted  tablet   (I I I)  .

35    (5)   Macrogol  6000   (1848  g)   was  dissolved  in  purified  water


(16630 g) to give coating solution (IV). The coating solution (IV) was sprayed in a coating machine (DRC-120003, POWREX CORPORATION) on the coated tablet (III) obtained in (4) until the weight of the coated tablet increased by 0.25 mg per one

5 tablet to give coated tablet (A) containing compound (I) (25 mg) and pioglitazone (30 mg) per one tablet.

Table    8

                    component    formulation   
                                amount   
                                                           
                compound    (IA)    34                mg   
                                           
                                                           
plain  tablet        mannitol                230                mg   
                                           
        microcrystalline  cellulose    52.5            mg   
containing                           
        hydroxypropylcellulose    9                mg   
compound   (I)                               
        croscarmellose  sodium    21                mg   
                                       
                                                   
                magnesium  stearate    3.5            mg   
                                               
intermediate    hydroxypropylmethylcellulose    13.5            mg   
                                                       
layer    talc                1.5            mg   
                                           
layer    pioglitazone  hydrochloride    33.06        mg   
                                                   
containing    mannitol                113. 94        mg   
                                           
pioglitazone    hydroxypropylcellulose    3                mg   
                                       
                hydroxypropylmethylcellulose    11.25        mg   
                                               
                macrogol    6000            2.25        mg   
                                       
film  coating        titanium  dioxide    1. 35        mg   
        yellow  ferric  oxide    0.105        mg   
                               
                                   
                red  ferric  oxide    0.045        mg   
                                               
                macrogol    6000            0.25        mg   
                                                           

Example  9

According  to  the  formulation  shown  in  Table  9,   and  by  a

10 method similar to that in Example 4, coated tablet (A) containing compound (I) (25 mg) and pioglitazone (45 mg) per one tablet was obtained.
 


Table    9                           
                               
            component        formulation   
                        amount   
                           
                               
            compound   (IA)        34    mg   
                               
plain    tablet        mannitol        230    mg   
            microcrystalline  cellulose        52.5    mg   
containing                       
        hydroxypropylcellulose        9    mg   
compound   (I)                       
        croscarmellose  sodium            21    mg   
                           
                               
            magnesium  stearate        3.5    mg   
                               
intermediate    hydroxypropylmethylcellulose        13.5    mg   
                           
layer            talc        1.5    mg   
                           
layer            pioglitazone  hydrochloride        49.59    mg   
                       
containing    mannitol        97.41    mg   
pioglitazone                   
    hydroxypropylcellulose        3    mg   
                           
            hydroxypropy1methylcellulose        11.25    mg   
                           
            macrogol  6000        2.25    mg   
                       
film    coating    titanium  dioxide        1. 05    mg   
                       
                           
            red  ferric  oxide        0.45    mg   
                           
            macrogol  6000        0.25    mg   
                               

Example  10

According    to  the  formulation  shown  in  Table  10,   multi-

layer  tablet   (A)   of  the  present  invention  was  produced.

5 (1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2250 g) was dissolved in purified water (35250 g) to give a binding solution (I). Compound (IA) (benzoate of compound (I); 13260 g), mannitol (45630 g) and microcrystalline cellulose (3900 g) were uniformly mixed in a fluid bed granulator (WSG-

10    60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (32500 g) and dried to give a granule. A part of the obtained granule was pulverized with a

screening  mill   (P-7S,   Showa  Chemical  Machinery)   and  a  1.5  mm~

punching  screen  to  give  a  milled  granule.    To  a  part   (60180  g)

15    of the obtained milled granule were added microcrystalline cellulose (7250 g), croscari".ellose sodium (4350 g) and
 

magnesium stearate (725 g), and the mixture was mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (I) .

(2) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; s 1802 g) was dissolved in purified water (34290 g) to give a

binding solution (II). Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give suspension (I). Pioglitazone hydrochloride (6777 g), lactose

10 (44070 g) and croscarmellose sodium (2706 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding

solution (II) (27920 g), sprayed with suspension (I) (74130 g), and then dried to give a granule. A part of the obtained

15    granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (66050 g) of the obtained milled granule were added croscarmellose sodium (2075 g) and

magnesium  stearate   (273.6  g),   and  they  were  mixed  in  a  tumbler

20    mixer   (TM-400S,   Showa  Chemical  Machinery)   to  give  granule   (II).

(3)    Granule (I) (100 mg) and granule (II) ( 180 mg) were formed into a multi-layer by a rotary tableting machine (AQUA

08242L2JI, Kikusui Seisakusho) using a 8.5 mm~ punch to give a plain tablet.

25 (4) Hydroxypropylmethylcellulose (TC-5 RW, Shin-Etsu Chemical Co., Ltd.; 1365 g) and talc (210 g) were dispersed in purified water (12250 g) to give dispersion (I). Titanium dioxide

(169.8 g) and yellow ferric oxide (5.25 g) were dispersed in purified water (2625 g) to give dispersion (II). Dispersion

30 (II) and purified water (875 g) were added to dispersion (I), and they were mixed by stirring in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (HCF(S)-lOON, Freund Corporation) on the plain tablet obtained in (3)

35    until  the  weight  of  the  plain  tablet  increased  by  10  mg  per
 

one    tablet  to  give  multi-layer  tablet   (I).

(5)    Macrogol  6000   (90  g)   was  dissolved  in  purified  water   (1710

g)    to  give  coating  solution   (II).    The  coating  solution   (II)

was    sprayed  in  a  coating  machine   (HCF(S)-100N,   Freund

5    Corporation) on the multi-layer tablet (I) obtained in (4) until the weight of the multi-layer tablet increased by 0.15 mg per one tablet to give multi-layer tablet (A) containing

compound (I) (12.5 mg) and pioglitazone (15 mg) per one tablet. Table 10

        component    formulation   
                amount   
                                       
        compound   (IA)    17        mg   
                                       
layer        mannitol    58.5        mg   
        microcrystalline  cellulose    15        mg   
containing                       
        hydroxypropylcellulose    2.5        mg   
compound   (I)                       
        croscarmellose  sodium    6        mg       
                           
        magnesium  stearate    1        mg       
                                       
        pioglitazone  hydrochloride    16.53        mg       
                                   
layer    lactose    143.49        mg       
                                   
containing    hydroxypropylcellulose    7.2        mg       
                               
pioglitazone    croscarmellose  sodium    12.06        mg       
                               
        magnesium  stearate    0. 72        mg       
                               
        hydroxypropylmethylcellulose    7.8        mg       
                           
        talc    1.2        mg       
                       
film  coating    titanium  cEo xi de    0. 97        mg       
        •-                               
        yellow  ferric  oxide    0.03        mg       
                           
        macrogol  6000    0.15        mg       
                                       

10    Example  11

According to the formulation shown in Table 11, multi-layer tablet (A) of the present invention was produced.

(1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2250 g) was dissolved in purified water (35250 g) to give a

15    binding  solution   (I) .    Compound   (IA)   (benzoate  of  compound   (I);

13260  g),   mannitol   (45630  g)   and  microcrystalline  cellulose
 


(3900 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (32500 g) and dried to give a granule. A part of the obt2~ned granule was pulverized with a

5    screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (60180 g) of the obtained milled granule were added microcrystalline cellulose (7250 g), croscarmellose sodium (4350 g) and magnesium stearate (725 g), and the mixture was mixed in a

10    tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (I).

(2)    Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1802 g) was dissolved in purified water (34290 g) to give a

binding  solution   (II).    Hydroxypropylcellulose   (grade  L,   Nippon

15    Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give suspension (I). Pioglitazone hydrochloride (13550 g), lactose (37290 g) and croscarmellose sodium (2706 g) were uniformly

mixed  in  a  fluid  bed  granulator   (WSG-60,   POWREX  CORPORATION),

20    and  the  mixture  was  granulated  while  spraying  a  binding

solution (II) (27920 g), spu.yed with suspension (I) (74130 g), and then dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a

25 milled granule. To a part (66050 g) of the obtained milled granule were added croscarmellose sodium (2075 g) and magnesium stearate (273.6 g), and they were mixed in a tumbler

mixer    (TM-400S,   Showa  Chemical  Machinery)   to  give  granule   (II).

(3)    Granule   (I)   (100  mg)   and  granule   (II)   (180  mg)   were  formed

30    into a multi-layer by a rotary tableting machine (AQUA 08242L2JI, Kikusui Seisakusho) using a 8.5 mm~ punch to give a plain tablet.

(4)    Hydroxypropylmethylcellulose   (TC-5  RW,   Shin-Etsu  Chemical

co.,   Ltd.;   1365  g)   and  talc   (210  g)   were  dispersed  in  purified

35    water   (12250  g)   to  give  dispersion   (I).    Titanium  dioxide
 


(169.8 g), yellow ferric oxide (3.675 g) and red ferric oxide (1.575 g) were dispersed in purified water (2625 g) to give dispersion (II). Dispersion (II) and purified water (875 g) were added to dispersion (I), and they were mixed by stirring

5    in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (HCF(S)-lOON, Freund Corporation) on the plain tablet obtained in (3) until the weight of the plain tablet increased by 10 mg per one tablet to give multi-layer

10    tablet   (I).

(5)    Macrogol  6000   (90  g)   was  dissolved  in  purified  water   (1710

g)    to give coating solution (II). The coating solution (II) was sprayed in a coating machine (HCF(S)-lOON, Freund

Corporation)    on  the  multi-layer  tablet   (I)   obtained  in   (4)

15    until the weight of the multi-layer tablet increased by 0.15 mg per one tablet to give multi-layer tablet (A) containing

compound   (I)   (12.5  mg)   and  pioglitazone   (30  mg)   per  one  tablet.
 



Table    11

                        component    formulation   
                                amount   
                                                       
                compound   (IA)    17                    mg   
                                                       
    layer    mannitol    58.5                mg   
                microcrystalline  cellulose    15                    mg   
    containing                                       
                                           
                                                   
            hydroxypropylcellulose    2.5                mg   
    compound   (I)                               
            croscamellose  sodium    6                    mg   
                                           
                                               
            magnesium  stearate    1                    mg   
                                                   
                pioglitazone  hydrochloride    33.06                mg   
                                               
    layer        lactose    12 6. 96                mg   
                                               
    containing        hydroxypropylcellulose    7.2                    mg   
                                           
    pioglitazone        croscarmellose  sodium    12.06                mg   
                                           
            magnesium  stearate    0. 72                mg   
                                               
                hydroxypropylmethylcellulose    7.8                mg   
                                               
                talc    1.2                mg   
                                           
    film  coating        titanium  dioxide    0.97                mg   
            yellow  ferric  oxide    0.021        mg   
                               
                               
                red  ferric  oxide    0.009        mg   
                                   
            macrogol  6000    0.15                mg   
                                                       

Example  12

According to the formulation shown in Table 12, multi-layer tablet (A) of the present invention was produced.

5 (1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2250 g) was dissolved in purified water (35250 g) to give a binding solution (I). Compound (IA) (benzoate of compound (I); 13260 g), mannitol (45630 g) and microcrystalline cellulose (3900 g) were uniformly mixed in a fluid bed granulator (WSG-

10    60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (32500 g) and dried to give a granule. A part of the obtained granule was pulverized with a

screening mill (P-7S, Showa Chemical Machinery) and a 1.5 rnrn~ punching screen to give a milled granule. To a part (60180 g)

15    of  the  obtained  milled  granule  were  added  microcrystalline
 


cellulose (7250 g), croscarmellose sodium (4350 g) and magnesium stearate (725 g), and the mixture was mixed in a tumbler mixer (TM-4003, Showa Chemical Machinery) to give granule (I).

5 (2) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1802 g) was dissolved in purified water (34290 g) to give a binding solution (II). Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give

10    suspension   (I).    Pioglitazone  hydrochloride   (20330  g),   lactose

(30520 g) and croscarmellose sodium (2706 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding

solution    (II)   (27920  g),   sprayed  with  suspension   (I)    (74130  g),

15    and then dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa

Chemical Machinery) and a 1.5 mm$ punching screen to give a milled granule. To a part (66050 g) of the obtained milled granule were added croscarmellose sodium (2075 g) and

20    magnesium stearate (273.6 g), and they were mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (II).

(3)    Granule (I) (100 mg) and granule (II) (180 mg) were formed into a multi-layer by a rotary tableting machine (AQUA

08242L2JI,    Kikusui  Seisakusho)   using  a  8.5  mm$  punch  to  give  a

25    plain  tablet.

Hydroxypropylmethylcellulose (TC-5 RW, Shin-Etsu Chemical Co., Ltd.; 1365 g) and talc (210 g) were dispersed in purified water (12250 g) to give dispersion (I). Titanium dioxide

(157.5  g)   and  red  ferric  oxide   (17.50  g)   were  dispersed  in

30    purified  water   (2625  g)   to  give  dispersion   (II). Dispersion

(II)    and purified water (875 g) were added to dispersion (I), and they were mixed by stirring in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The

coating  solution   (I)   was  sprayed  in  a  coating  machine   (HCF(S)-

35    lOON,   Freund  Corporation)   on  the  plain  tablet  obtained  in   (3)

until the weight of the plain tablet increased by 10 mg per one tablet to give multi-layer tablet (I).

(5)    Macrogol  6000   (90  g)   was  dissolved  in  purified  water   (1710

g)    to  give  coating  solution   (II).    The  coating  solution   (II)

5    was sprayed in a coating machine (HCF(S)-100N, Freund Corporation) on the multi-layer tablet (I) obtained in (4) until the weight of the multi-layer tablet increased by 0.15 mg per one tablet to give multi-layer tablet (A) containing

compound   (I)   (12.5  mg)   and  pioglitazone   (45  mg)   per  one  tablet.

10    Table  12

                                component    formulation   
                                    amount   
                                                   
                                compound   (IA)    17            mg   
                                                   
    layer            mannitol    58    .5        mg   
                microcrystalline  cellulose    15            mg   
    containing                               
                hydroxypropylcellulose    2    .5        mg   
    compound   (I)                               
                croscarmellose  sodium    6            mg   
                                                   
                                                   
                                magnesium  stearate    1            mg   
                                                   
                                pioglitazone  hydrochloride    49.59        mg   
                                   
    layer    lactose    110.43        mg   
                                   
    containing    hydroxypropylcellulose    7.2        mg   
                                                   
    pioglitazone    croscarmellose  sodium    12.06        mg   
                                               
                                magnesium  stearate    0. 72        mg   
                                                   
                                hydroxypropylmethylcellulose    7    .8        mg   
                                                   
                                talc    1    .2        mg   
                               
    film  coating    titanium  dioxide    0    .9        mg   
                           
                                                   
                                red  ferric  oxide    0    .1        mg   
                                               
                                macrogol  6000    0.15        mg   
                                                   
                                                   

Example  13

According to the formulation shown in Table 13, multi-layer tablet (A) of the present invention was produced.

(1)    Hydroxypropylcellulose   (grade  L,   Nippon  Soda  Co.,   Ltd.;

15    2250 g) was dissolved in purified water (35250 g) to give a binding solution (I). Compound (IA) (benzoate of compound (I);


26520 g), mannitol (32370 g) and microcrystalline cellulose (3900 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (32500 g) and dried to give a

5    granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (60180 g) of the obtained milled granule were added microcrystalline

cellulose    (7250  g),   croscarmellose  sodium   (4350  g)   and

10 magnesium stearate (725 g), and the mixture was mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (I).

(2) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1802 g) was dissolved in purified water (34290 g) to give a

15    binding solution (II). Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give suspension (I). Pioglitazone hydrochloride (6777 g), lactose

(44070  g)   and  croscarmellose  sodium  (2706  g)   were  uniformly

20    mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding

solution (II) (27920 g), sprayed with suspension (I) (74130 g), and then dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa

25    Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (66050 g) of the obtained milled granule were added croscarmellose sodium (2075 g) and

magnesium stearate (273.6 g), and they were mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (II) .

30 (3) Granule (I) (100 mg) and granule (II) (180 mg) were formed into a multi-layer by a rotary tableting machine (AQUA 08242L2JI, Kikusui Seisakusho) using a 8.5 mm~ punch to give a plain tablet.

(4)    Hydroxypropylmethylcellulose   (TC-5  RW,   Shin-Etsu  Chemical

35    co.,   Ltd.;   1365  g)   and  talc   (210  g)   were  dispersed  in  purified
 

49
 





water (12250 g) to give dispersion (I). Titanium dioxide (157.5 g) and yellow ferric oxide (17.5 g) were dispersed in purified water (2625 g) to give dispersion (II). Dispersion (II) and purified water (875 g) were added to dispersion (I),

5    and they were mixed by stirring in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (HCF(S)-

lOON, Freund Corporation) on the plain tablet obtained in (3) until the weight of the plain tablet increased by 10 mg per

10    one  tablet  to  give  multi-layer  tablet   (I).

(5)    Macrogol  6000   (90  g)   was  dissolved  in  purified  water   (1710

g)    to give coating solution (II). The coating solution (II) was sprayed in a coating machine (HCF(S)-lOON, Freund

Corporation)    on  the  multi-layer  tablet   (I)   obtained  in   (4)

15    until the weight of the multi-layer tablet increased by 0.15 mg per one tablet to give multi-layer tablet (A) containing compound (I) (25 mg) and pioglitazone (15 mg) per one tablet.
 
Table    13

            component    formulation       
                amount       
                                       
        compound   (IA)    34                mg       
                                   
layer        mannitol    41.5        mg       
        microcrystalline  cellulose    15                mg       
containing                                   
        hydroxypropylcellulose    2.5        mg       
compound   (I)                           
        croscarmellose  sodium    6            mg       
                               
                                       
        magnesium  stearate    1                mg       
                                   
        pioglitazone  hydrochloride    16.53        mg       
                                   
layer    lactose    143    .49        mg       
                                       
containing    hydroxypropylcellulose    7    .2        mg       
                                   
pioglitazone    croscarmellose  sodium    12.06        mg       
                               
        magnesium  stearate    0. 72        mg       
                                   
        hydroxypropylmethylcellulose    7    .8        mg       
                                   
        talc    1    .2        mg       
                           
film  coating    titanium  dioxide    0    .9        mg       
                               
        yellow  ferric  oxide    0    .1        mg       
                           
        macrogol  6000    0.15        mg       
                                       

Example  14

According to the formulation shown in Table 14, multi-layer tablet (A) of the present invention was produced.

5 (1) Hydroxypropylcellulose (grade 1, Nippon Soda Co., Ltd.; 2250 g) was dissolved in purified water (35250 g) to give a binding solution (I). Compound (IA) (benzoate of compound (I);

26520 g), mannitol (32370 g) and microcrystalline cellulose (3900 g) were uniformly mixed in a fluid bed granulator (WSG-

10    60, POWREX CORPORATION), and the mixture was granulated while spraying a binding solution (I) (32500 g) and dried to give a granule. A part of the obt~ined granule was pulverized with a

screening  mill   (P-73,   Showa  Chemical  Machinery)   and  a  1.5  mm~

punching  screen  to  give  a  milled  granule.    To  a  part   (60180  g)

15    of the obtained milled granule were added microcrystalline cellulose (7250 g), croscarmellose sodium (4350 g) and
 

51
 





magnesium stearate (725 g), ~nd the mixture was mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (I).

(2) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; s 1802 g) was dissolved in purified water (34290 g) to give a

binding solution (II). Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give suspension (I). Pioglitazone hydrochloride (13550 g), lactose

10 (37290 g) and croscarmellose sodium (2706 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding

solution (II) (27920 g), sprayed with suspension (I) (74130 g), and then dried to give a granule. A part of the obtained

15 granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (66050 g) of the obtained milled granule were added croscarmellose sodium (2075 g) and magnesium stearate (273.6 g), and they were mixed in a tumbler

20    mixer   (TM-400S,   Showa  Chemical  Machinery)   to  give  granule   (II).

(3)    Granule (I) (100 mg) and granule (II) (180 mg) were formed into a multi-layer by a rotary tableting machine (AQUA

08242L2JI, Kikusui Seisakusho) using a 8.5 mm~ punch to give a plain tablet.

25 (4) Hydroxypropylmethylcellulose (TC-5 RW, Shin-Etsu Chemical co., Ltd.; 1365 g) and talc (210 g) were dispersed in purified water (12250 g) to give dispersion (I). Titanium dioxide

(157.5 g), yellow ferric oxide (12.25 g) and red ferric oxide (5.25 g) were dispersed in purified water (2625 g) to give

30 dispersion (II). Dispersion (II) and purified water (875 g) were added to dispersion (I), and they were mixed by stirring in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (HCF(S)-lOON, Freund Corporation) on the

35    plain  tablet  obtained  in   (3)   until  the  weight  of  the  plain
 


tablet increased by 10 mg per one tablet to give multi-layer tablet (I).

(5)    Macrogol  6000   (90  g)   was  dissolved  in  purified  water   (1710

g)    to  give  coating  solution   (II).    The  coating  solution   (II)

5    was sprayed in a coating machine (HCF(S)-lOON, Freund Corporation) on the multi-layer tablet (I) obtained in (4) until the weight of the multi-layer tablet increased by 0.15 mg per one tablet to give multi-layer tablet (A) containing compound (I) (25 mg) and pioglitazone (30 mg) per one tablet.

10    Table  14

                            component        formulation   
                                        amount   
                                                       
                    compound   (IA)        34            mg   
                                                       
    layer            mannitol        41    .5        mg   
                        microcrystalline  cellulose        15            mg   
    containing                                   
                                           
        hydroxypropylcellulose        2    .5        mg   
    compound   (I)                                   
                croscarmellose  sodium        6            mg   
                                           
                                           
                    magnesium  stearate        1            mg   
                                       
                    pioglitazone  hydrochloride        33.06        mg   
                               
    layer    lactose        12 6. 96        mg   
                           
    containing    hydroxypropylcellulose        7.2        mg   
                               
    pioglitazone    croscarmellose  sodium        12.06        mg   
                                       
                    magnesium  stearate        0.72        mg   
                                       
                    hydroxypropylmethylcellulose        7.8        mg   
                                       
                    talc        1.2        mg   
                                           
    film  coating            titanium  dioxide        0    .9        mg   
            yellow  ferric  oxide        0.07        mg   
                                       
                                       
                    red  ferric  oxide        0.03        mg   
                                       
                    macrogol  6000        0.15        mg   
                                                       
                                                       

Example  15

According to the formulation shown in Table 15, multi-layer tablet (A) of the present invention was produced.
(1)    Hydroxypropylcellulose   (grade  L,   Nippon  Soda  Co.,   Ltd.;

15    2250  g)   was  dissolved  in  purified  water   (35250  g)   to  give  a
 


binding solution (I). Compound (IA) (benzoate of compound (I); 26520 g), mannitol (32370 g) and crystalline cellulose (3900

g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while

5    spraying a binding solution (I) (32500 g) and dried to give a granule. A part of the obtained granule was pulverized with a

screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (60180 g) of the obtained milled granule were added crystalline

10 cellulose (7250 g), croscarmellose sodium (4350 g) and magnesium stearate (725 g), and the mixture was mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granule (I).

(2)    Hydroxypropylcellulose   (grade  L,   Nippon  Soda  Co.,   Ltd.;

15    1802 g) was dissolved in purified water (34290 g) to give a binding solution (II). Hydroxypropylcellulose (grade L, Nippon

Soda Co., Ltd.; 1976 g) was dissolved in purified water (73320 g), and lactose (18720 g) was dispersed therein to give suspension (I). Pioglitazone hydrochloride (20330 g), lactose

20 (30520 g) and croscarmellose sodium (2706 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION), and the mixture was granulated while spraying a binding

solution (II) (27920 g), sprayed with suspension (I) (74130 g), and then dried to give a granule. A part of the obtained

25    granule  was  pulverized  with  a  screening  mill   (P-7S,   Showa

Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (66050 g) of the obtained milled

granule were added croscarmellose sodium (2075 g) and magnesium stearate (273.6 g), and they were mixed in a tumbler

30    mixer   (TM-400S,   Showa  Chemical  Machinery)   to  give  granule   (II).

(3)    Granule (I) (100 mg) and granule (II) (180 mg) were formed into a multi-layer by a rotary tableting machine (AQUA

08242L2JI, Kikusui Seisakusho) using a 8.5 mm~ punch to give a plain tablet.

35    (4)   Hydroxypropylmethylcellulose   (TC-5  RW,   Shin-Etsu  Chemical
 

54
 





Co., Ltd.; 1365 g) and talc (210 g) were dispersed in purified water (12250 g) to give dispersion (I}. Titanium dioxide

(122.5 g) and red ferric oxide (52.5 g) were dispersed in purified water (2625 g) to give dispersion (II). Dispersion

5 (II) and purified water (875 g) were added to dispersion (I), and they were mixed by stirring in a stirrer (LR400D, Yamato Scientific Co., Ltd.) to give coating solution (I). The coating solution (I) was sprayed in a coating machine (HCF(S)-lOON, Freund Corporation) on the plain tablet obtained in (3)

10    until the weight of the plain tablet increased by 10 mg per one tablet to give multi-layer tablet (I).

(5)    Macrogol  6000   (90  g)   was  dissolved  in  purified  water   (1710

g)    to give coating solution (II) . The coating solution (II) was sprayed in a coating machine (HCF(S)-100N, Freund

15    Corporation) on the multi-layer tablet (I) obtained in (4) until the weight of the multi-layer tablet increased by 0.15 mg per one tablet to give multi-layer tablet (A) containing compound (I) (25 mg) and pioglitazone (45 mg) per one tablet.
 

Table    15

                            component    formulation       
                                    amount       
                                               
                compound    (IA)    34    mg       
                                               
layer        mannitol            41.5    mg       
                microcrystalline  cellulose    15    mg       
containing                           
                                   
    hydroxypropylcellulose    2.5    mg       
compound   (I)                       
        croscarmellose  sodium    6    mg       
                               
                                   
                magnesium    stearate    l    mg       
                               
                pioglitazone  hydrochloride    49.59    mg       
                           
layer    lactose            ll0.43  mg       
                           
containing        hydroxypropylcellulose    7.2    mg       
pioglitazone    croscarmellose  sodium    12.06    mg       
                                   
                magnesium    stearate    0. 72    mg       
                               
                hydroxypropylmethylcellulose    7.8    mg       
                                       
                talc            1.2    mg       
                       
film  coating    titanium  dioxide    0.7    mg       
                               
                red  ferric  oxide    0.3    mg       
                                       
                macrogol    6000        0.15    mg       
                                               

Example  16

According to the formulation shown in Table 16, the coated tablet (A) of the present invention was produced.

5 (1) Hydroxypropylcellulose (grade L, Nippon Soda Co., Ltd.; 2460 g) was dissolved in purified water (38540 g) to give a binding solution (I). Compound (IA) (3740 g), mannitol (54340 g) and microcrystalline cellulose (3850 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION),

10    and the mixture was granulated while spraying a binding solution (I) (33000 g) and dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm~ punching screen to give a milled granule. To a part (60130 g) of the obtained

15    milled granule were added microcrystalline cellulose (7245 g), croscarmellose sodium (4347 g) and magnesium stearate (724.5
 

g), and they were mixed in a tumbler mixer (TM-400S, Showa Chemical Machinery) to give granules. The obtained granules were tableted by a rotary tableting machine (AQUARIUS 0836SS2JII, Kikusui Seisakusho) using a 9.5 rnrn~ punch at a

5    weight of 350 mg to give plain tablet containing compound (I) (12.5 mg) per one tablet.

(2)    Hydroxypropylmethylcellulose   (TC-5  EW,   Shin-Etsu  Chemical

Co., Ltd.; 5805 g) and talc (645.0 g) were dissolved or suspended in purified water (36550 g) to give coating solution

10    (I). The coating solution (I) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the plain tablet obtained

in (1) until the weight of the plain tablet increased by 15 mg per one tablet to give coated tablet (I).

(3)    Pioglitazone  hydrochloride   (5290  g),

15    hydroxypropylcellulose   (grade  SL-T,   Nippon  Soda  Co.,   Ltd.;

480.0 g) and mannitol (17270 g) were dissolved or suspended in purified water (136000 g) to give coating solution (II). The

coating solution (II) was sprayed in a coating machine (DRC-120003, POWREX CORPORATION) on the coated tablet (I) obtained

20 in (2) until the weight of the coated tablet increased by 75 mg per one tablet to give coated tablet (II).

(4) Hydroxypropylmethylcellulose (HPMC) (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5760 g) and macrogol 6000 (1152 g) were dissolved in purified water (35200 g) to give HPMC solution

25    (I).    Titanium  dioxide   (745.0  g)   and  yellow  ferric  oxide   (23.04

g)    were dispersed in purified water (8320 g) to give dispersion (I). Dispersion (I) was added to the HPMC solution (I), and they were mixed by stirring in a stirrer (MXD-2302, Satake Chemical Equipment Mfg Ltd.) to give coating solution

30 (III). The coating solution (III) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (II) obtained in (3) until the weight of the coated tablet increased by 12 mg per one tablet to give coated tablet (A) containing compound (I) (12.5 mg) and pioglitazone (15 mg) per

35    one  tablet.
 

Table    16
<.
                                    component  /}'!/"'"",_ •"    •            fi   ''llj,,~   
                                                       
                                        ~ ~    •)    Jl                ,,  ,C\r¥.1}:\. C!~~    \,   
                                        I,~. ..        ...    '            JUl-nt.   I'   
                                        l~i        "'Z.           
                                                                               
                            compound    (IA)    t~\    1'.0.~    ~< -~        <   
                                                           
                            mannitol        ~~                ~~j.."'               
    plain  tablet                                               
                                                       
                            microcrystalline  cellula"'                        g       
    containing                                                ~   
            hydroxypro0ylcellulose                               
    compound   (I)                                    9    mg       
            croscarmellose  sodium                            21    mg       
                                                                   
                            magnesium    stearate                            3.5    mg       
                                           
        intermediate    hydroxypropylmethylcellulose            13.5    mg       
                                                                   
        layer    talc                                    1.5    mg       
        layer    pioglitazone    hydrochloride                    16.53    mg       
                                                                   
        containing    mannitol                                    56.97    mg       
                                                           
        pioglitazone    hydroxypropylcellulose                            1.5    mg       
                                                   
                                                       
                            hydroxypropylmethylcellulose            9    mg       
                                                                               
        film  coating        macrogol    6000                                1.8    mg       
                titanium  dioxide                            1.164    mg       
                                                                   
                                                                           
                            yellow  ferric    oxide                            0.036    mg       
                                                                               
                                                                               

Example  17

Using a method similar to that of Example 16, and according to the formulation of Table 17, coated tablet (A)

s    containing compound (I) (25 mg) and pioglitazone (15 mg) per one tablet can be obtained.
 


    Table    17                                                           
                                                               
                                        ::e>mponent    formulation   
                                                    amount   
                                                                       
                                compound   (IA)    34            mg   
                                                                       
    plain        tablet                mannitol        230            mg   
                                                   
                            microcrystalline  cellulose    52.5        mg   
    containing                               
                                   
                                                       
                hydroxypropylcellulose    9            mg   
    compound   (I)                                       
                                           
                        croscarmellose  sodium    21            mg   
                                           
                                                   
                                               
                        magnesium  stearate    3    .5        mg   
                                   
    intermediate        hydroxypropylmethylcellulose    13.5        mg   
                                                       
    layer                            talc    1    .5        mg   
                                                   
    layer                            pioglitazone  hydrochloride    16.53        mg   
                               
    containing    mannitol    56.97        mg   
    pioglitazone                               
            hydroxypropylcellulose    1    .5        mg   
                                                   
                            hydroxypropylmethylcellulose    9            mg   
                                               
    film    coating            macrogol  6000    1    .8        mg   
                        titanium  dioxide    1. 08        mg   
                                               
                                                   
                                yellow  ferric  oxide    0.12        mg   
                                                                       
                                                                       

Example  18

According to the formulation shown in Table 18, the coated tablet (A) of the present invention was produced.

5 (l) Hydroxypropylcellulose (grade 1, Nippon Soda Co., Ltd.; 2460 g) was dissolved in purified water (38540 g) to give a binding solution (I). Compound (IA) (7480 g), mannitol (50600 g) and microcrystalline cellulose (3850 g) were uniformly mixed in a fluid bed granulator (WSG-60, POWREX CORPORATION),

10    and the mixture was granulated while spraying a binding solution (I) (33000 g) and dried to give a granule. A part of the obtained granule was pulverized with a screening mill (P-7S, Showa Chemical Machinery) and a 1.5 mm$ punching screen to give a milled granule. To a part (60130 g) of the obtained

15    milled granule were added microcrystalline cellulose (7245 g), croscarmellose sodium (4347 g) and magnesium stearate (724.5 g), and they were mixed in a tumbler mixer (TM-400S, Showa
 


Chemical Machinery) to give granules. The obtained granules were tableted by a rotary tableting machine (AQUARIUS 0836SS2JII, Kikusui Seisakusho) using a 9.5 mm~ punch at a weight of 350 mg to give plain tablet containing compound (I)

5    (25  mg)   per  one  tablet.

(2)    Hydroxypropylmethylcellulose   (TC-5  EW,   Shin-Etsu  Chemical

Co., Ltd.; 5805 g) and talc (645.0 g) were dissolved or suspended in purified water (36550 g) to give coating solution

(I).    The  coating  solution   (I)   was  sprayed  in  a  coating  machine

10 (DRC-1200DS, POWREX CORPORATION) on the plain tablet obtained in (1) until the weight of the plain tablet increased by 15 mg per one tablet to give coated tablet (I).

(3) Pioglitazone hydrochloride (12950 g), hydroxypropylcellulose (grade SL-T, Nippon Soda Co., Ltd.;

15    1175 g) and mannitol (42790 g) were dissolved or suspended in purified water (235000 g) to give coating solution (II) The coating solution (II) was sprayed in a coating machine (DRC-1200DS, POWREX CORPORATION) on the coated tablet (I) obtained

in    (2)   until  the  weight  of  the  coated  tablet  increased  by  225

20    mg  per  one  tablet  to  give  coated  tablet   (II).

(4)    Hydroxypropylmethylcellulose (HPMC) (TC-5 EW, Shin-Etsu Chemical Co., Ltd.; 5940 g) and macrogol 6000 (1188 g) were dissolved in purified water (36080 g) to give HPMC solution

(I).    Titanium  dioxide   (554.4  g)   and  red  ferric  oxide   (237.6  g)

25    were  dispersed  in  purified  water   (8800  g)   to  give  dispersion

(I)    . Dispersion (I) was added to the HPMC solution (I), and they were mixed by stirring in a stirrer (MXD-2302, Satake Chemical Equipment Mfg Ltd.) to give coating solution (III). The coating solution (III) was sprayed in a coating machine

30 (DRC-1200DS, POWREX CORPORATION) on the coated tablet (II) obtained in (3) until the weight of the coated tablet increased by 18 mg per one tablet to give coated tablet (A) containing compound (I) (25 wg) and pioglitazone (45 mg) per one tablet.
 

Table    18                                       
                                       
                component    formulation   
                        amount   
                                           
            compound    (IA)    34                mg   
                                           
plain    tablet        mannitol            230                mg   
            microcrystalline  cellulose    52.5        mg   
containing                       
        hydroxypropylcellulose    9                mg   
compound   (I)                               
        croscarmellose  sodium    21                mg   
                                   
                                           
            magnesium    stearate    3    .5        mg   
                               
intermediate    hydroxypropylmethylcellulose    13    .5        mg   
                                           
layer            talc            1    .5        mg   
                               
layer            pioglitazone  hydrochloride    49.59        mg   
                                   
containing    mannitol            170.91        mg   
pioglitazone                           
    hydroxypropylcellulose    4    .5        mg   
                               
            hydroxypropylmethylcellulose    13.5        mg   
                                       
film    coating        macrogol    6000        2.7        mg   
            titanium  dioxide    1. 2 6        mg   
                           
                               
            red  ferric  oxide    0.54        mg   
                                           

Example  19

Using a method similar to that of Example 18 and according to the formulation of Table 19, coated tablet (A)

5    containing compound (I) (12.5 mg) and pioglitazone (45 mg) per one tablet can be obtained.
 



    Table    19                                               
                            component    formulation       
                                        amount       
                                                       
                            compound   (IA)    17        mg       
                                                       
    plain    tablet            mannitol    247        mg       
                    microcrystalline  cellulose    52.5        mg       
    containing                           
                                       
            hydroxypropylcellulose    9        mg       
    Compound   (I)                               
                croscarmellose  sodium    21        mg       
                                               
                                                   
                            magnesium  stearate    3.5        mg       
                                       
    intermediate        hydroxypropylmethylcellulose    13.5        mg       
                                                   
    layer                        talc    1.5        mg       
                                                   
    layer                        pioglitazone  hydrochloride    49.59        mg       
                                           
    containing        mannitol    170.91        mg       
                                                       
    pioglitazone        hydroxypropylcellulose    4.5        mg       
                                                   
                            hydroxypropylmethylcellulose    13.5        mg       
                                                   
    film    coating            macrogol  6000    2.7        mg       
                    titanium  dioxide    1. 62        mg       
                                               
                                                   
                            red  ferric  oxide    0.18        mg       
                                                       
                                                       

    Comparative  Example    1   
    Compound   (IA)   (50  mg)   was  weighed.
5    Comparative  Example    2   
    Compound    ( IA)    ( 8 00  mg)    and  piogli tazone  hydrochloride
    (793.44  mg)   were  uniformly  mixed  with  a  pestle  in  a  mortar  to
    give  a  compound   (IA)/pioglitazone  hydrochloride   (1:1)   mixture.
    Comparative  Example    3   
10    Compound    (IA)    (1200  mg)    and  lactose   (6000  mg)   were
    uniformly  mixed  with  a  pestle  in  a  mortar  to  give  a  compound
    (IA)/lactose   (1:5)    mixture.   
    Comparative  Example  4   
    According  to  the  formulation  shown  in  Table  20,   a  single

15 layer tablet (A) containing compound (I) and pioglitazone was produced.

Hydroxypropylcellulose    (grade  L,   Nippon  Soda  Co.,   Ltd.;


Table    21

component    formulation    amount   
               
compound   (IA)    68        mg   
           
pioglitazone  hydrochloride    49.59    mg   
           
mannitol    75.61    mg   
               
microcrystalline  cellulose    24        mg   
               
hydroxypropylcellulose    6        mg   
               
croscarmellose  sodium    14    .4    mg   
           
magnesium  stearate    2.4    mg   
               

Experimental  Example  1

Compound    (IA)   (50  mg)   of  Comparative  Example  1,   the

5    mixture (99.59 mg) of Compar~tive Example 2, and tablets of Example 1 and Example 2 were preserved in glass bottles at 40°C, 75% RH with opened cap or at 60°C with closed cap and the

amount of benzoic acid remaining as compound (IA) was measured to evaluate the chemical stability. The results are shown in

10    Table 22. Table 22
                conditions    residual  benzoic       
                                    acid       
        Initial                        99.8%       
Comparative    40°C,    75%RH,    opened  bottle,           
    2  week    storage    product    99.2%       
Example    1                       
        60°C,    closed    bottle,           
                           
        2  week    storage    product    99.0%       
        Initial                        101.0%       
Comparative    40°C,    75%RH,    opened  bottle,           
    2  week    storage    product    89.4%       
Example    2                       
        60°C,    closed    bottle,           
                           
        2  week    storage    product    80.0%       
        Initial                        99.3%       
        40°C,    75%RH,    1    month  storage           
Example    1    product                        99.0%       
        60°C,    closed    bl)ttle,           
        1  month    storage  product    99.3%       
        Initial                        99.2%       
        40°C,   75%RH,   1  month  storage           
Example    2    product                        100.9%       
        60°C,    closed    bottle,           
        1  month    storage  product    100.9%       


As    shown  in  Table  22,   it  has  been  shown  that  the  tablet

of    the  present  invention  is  superior  in  the  chemical  stability.

Experimental  Example  2

The  mixture   (408  mg)   of  Comparative  Example  3,   and

5 tablets of Comparative Example 4, Example 1 and Example 2 were each preserved in a glass bottle at 60°C with closed cap, and the amount of all related substances derived from compound (I) (desmethyl form, dibenzyl form, dimer and the like of compound (I)) was measured. The results are shown in Table 23.

10    Table  23

                            conditions    all  related   
                                substances  derived   
                                from  compound   (I)   
Comparative        Initial        0.15%   
        60°C,    closed  bottle,       
Example    3                   
            2  week    storage  product    0.58%   
                               
Comparative        Initial        0.16%   
        60°C,    closed  bottle,       
Example    4                   
            2  week    storaqe  product    1.15%   
                               
                    Initial        <0.04%   
Example    1        60°C,    closed  bottle,       
                    1  month    storaqe  product    <0.04%   
                    Initial        <0.04%   
Example    2        60°C,    closed  bottle,       
                    1  month    storaqe  product    0.20%   

As    shown  in  Table  23,   it  has  been  shown  that  the  tablet

of    the  present  invention  is  superior  in  the  chemical  stability.

Experimental  Example  3

The  dissolution  property  of  pioglitazone  hydrochloride  in

15    the tablets of Comparative Example 5, Example 1, Example 2 and Example 3 was evaluated by che Paddle Method (50 rpm) using

0.3 M hydrochloric acid-potassium chloride buffer (37°C, pH 2.0, 900 mL). The results are shown in Table 24. In the Table,

each  value  shows  an  average  value  of  the  dissolution  rate  of  3

20    -    6  tablets.
 

Table  24

                    10  min    15  min    20  min    30  min   
                                       
Comparative    Initial            87.6    95.4    96.7        99.0   
                                   
    4 0°C  closed                       
Example    5        60.2    70.3    77.8        87.2   
        bottle    1    month                       
                                       
                                       
        Initial            98.4    101.5    102.7        103.8   
Example    1                           
        4 0°C  closed    95.8    100.5    102.3        103.8   
        bottle    1    month                       
                                       
                                       
        Initial            83.6    101.0    103.8        104.0   
Example    2                           
        40°C  closed    84.0    98.4    103.3        104.5   
        bottle    1    month                       
                                       
                                       
        Initial            51.9    92.1    96.4        99.1   
Example    3                           
        40°C  closed    58.3    94.3    96.8        98.8   
        bottle    1    month                       
                                       
                                       

As shown in Table 24, it has been shown that the tablet of the present invention is superior in the dissolution property pioglitazone both before and after storage.

s    Experimental  Example  4

The dissolution property of compound (I) in the tablets of Example 1, Example 2 and Example 3 was evaluated by the Paddle Method (50 rpm) using 0.3 M hydrochloric acid-potassium chloride buffer (37°C, pH 2.0, 900 mL). The results are shown

10    in Table 25. In the Table, each value shows an average value of the dissolution rate of 3 tablets.
 


Table  25
                                                    ~Jll ..                           
                        f'.        •);\~    ~;o.~r    Ir,.iii    J5 min    20  min    30  min   
                                                       
                Inl    ~tial    .:>    '    .••~98,~    ~            98.7    98.8        98.9       
                                    ',f.",                                           
Example    1    40"'  closed    .-   •    ~    102.4    102    .5        102.6       
                bottl  •.    ,IDQri~                               
                                                                               
                Initial            85.5                        100.8    101    .3        101. 4       
Example    2                                                                       
        40°C  closed        79.3                        99.1    99.    8        100.6       
                bottle    1  month                                                   
                                                                               
                                                                               
                Initial            81.8                            92.2    97.3        99.5       
Example    3                                                                       
        40°C  closed        87.3                        94.4    97.    7        99.6       
                bottle    1  month                                                   
                                                                               
                                                                                           

As shown in Table 25, it has been shown that the tablet of the present invention is superior in the dissolution property of compound (I) both before and after storage.


INDUSTRIAL  APPLICABILITY

The solid preparation of the present invention is useful as a therapeutic drug for diabetes and the like and simultaneously has superior dissolution property, chemical

10    stability  and  dissolution  stability.

This application is based on application No. 2007-023594 filed in Japan, the contents of which are incorporated hereinto by reference.

15
 

1.  A  solid  preparation  comprisin~~;t9wip.g ~and

second  parts:

5 (1) the first part comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile or a salt thereof and, as the first excipient, sugar or sugar alcohol; and

(2)    the  second  part  comprising  pioglitazone  or  a  salt  thereof

10    and,   as  the  second  excipient,   sugar  or  sugar  alcohol.

2. The solid preparation of claim 1, wherein the sugar or sugar alcohol is lactose, sucrose, erythritol or mannitol.

15    3. The solid preparation of claim 2, wherein the first and second excipients are mannitol.



    4.   The  solid  preparation  of  claim  3,   which  is  a  coated  tablet
    comprising  an  inner  core  made  of  the  first  part,   and  an  outer
20    layer  made  of  the  second  part.
    5.   The  solid  preparation  of  claim  2,   wherein  the  first
    excipient  is  mannitol  and  the  second  excipient  is  lactose.
25    6.   The  solid  preparation  of  claim  5,   which  is  a  coated  tablet
    comprising  an  inner  core  made  of  the  second  part,   and  an  outer
    layer  made  of  the  first  part.

7.   The  solid  preparation  of  claim  5,   which  is  a  multi-layer

30    tablet comprising the first layer made of the first part, and the second layer made of the second part.
 

ABSTRACT

A solid preparation containing coJili~d '11•) \:ih~_!:-"'-j-n definition of compound (I) is as definElit:-tn tht'Y de'!i;:.ripi,i.p.n~ If

and  pioglitazone,   which  is  useful  as  a  w~eut.-:ii{:;,mi:h!~ ~•-  '
5    diabetes   and  the  like  and  superior  in  the~~Ji!J_,i:~i.b:.~rty,
---; --~...:r

chemical stability and dissolution stability, is provided. A solid preparation containing the following first and second parts:

(1)    the  first  part  containing  compound   (I)   or  a  salt  thereof

10    and,   as  the  first  excipient,   sugar  or  sugar  alcohol;   and

(2) the second part containing pioglitazone or a salt thereof and, as the second excipient, sugar or sugar alcohol.


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