(19)
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`(12)
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`Europaisches Patentamt
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`European Patent Office
`
`Office europeen des brevets
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`EP1327440A1
`
`(11)
`
`EUROPEAN PATENT APPLICATION
`published in accordance with Art. 158(3) EPC
`
`(43) Date of publication:
`16.07.2003 Bulletin 2003/29
`
`(21) Application number: 01965637.0
`
`(22) Date of filing: 14.09.2001
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES Fl FR GB GR IE IT Ll LU
`MC NL PT SE TR
`Designated Extension States:
`AL LT LV MK RO Sl
`
`(30) Priority: 22.09.2000 JP 2000288234
`
`(51) lnt Cl.7: A61 K 9/16, A61 K 9/20,
`A61 K 9/30, A61 K 31/496,
`A61 K 45/00, A61 K 47/10,
`A61 K 47/26, A61 K 47/30
`
`(86) International application number:
`PCT/JP01/07983
`
`(87) International publication number:
`WO 02/024166 (28.03.2002 Gazette 2002/12)
`
`(71) Applicant: Sumitomo Pharmaceuticals Company,
`Limited
`Osaka·shi, Osaka 541·8510 (JP)
`
`(72) Inventor: FUJIHARA, Kazuyuki
`Takatsuki·shi, Osaka 569-0857 (JP)
`
`(74) Representative: VOSSIUS & PARTNER
`Siebertstrasse 4
`81675 Mi.inchen (DE)
`
`(54) ORAL PREPARATIONS WITH FAVORABLE DISINTEGRATION CHARACTERISTICS
`
`(57)
`The present invention provides oral prepara(cid:173)
`tions with good disintegration containing a slightly wa(cid:173)
`ter-soluble active ingredient, which comprise a mixture
`of a solid formed product (e.g. a granule) and a second
`disintegrant wherein said solid formed product compris(cid:173)
`es a slightly water-soluble active ingredient, a first dis(cid:173)
`integrant and a water-soluble excipient which is formed
`by using a water-soluble polymer binder; or comprises
`a solid formed product prepared from a slightly water(cid:173)
`soluble active ingredient, a disintegrant and a sugar al-
`
`cohol by using a water-soluble polymer binder. When
`orally administered, these oral preparations exhibit ex(cid:173)
`cellent dissolution characteristics of the active ingredi(cid:173)
`ent in the digestive tract, and further, these preparations
`can show equivalent dissolution profile even at different
`amounts of the active ingredient, and thus enable the
`selection of the most suitable medicament for each pa(cid:173)
`tient, which makes these preparations highly useful in
`the clinical field.
`
`,...
`c.
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`Printed by Jouve, 75001 PARIS (FR)
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 001
`
`

`

`EP 1 327 440 A1
`
`Description
`
`TECHNICAL FIELD
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`[0001] The present invention relates to an oral preparation with good disintegration, which comprises a slightly water(cid:173)
`soluble component as an active ingredient. More particularly, the present invention relates to pharmaceutical prepa(cid:173)
`rations for oral administration, especially tablets, containing a slightly water-soluble component as an active ingredient,
`which have equivalent dissolution profile of the active ingredient even at different contents of the active ingredient.
`Further, the present invention relates to a pharmaceutical preparation for oral administration, especially tablets, con-
`taining a slightly water-soluble component as an active ingredient, which show a rapid dissolution of the active ingredient
`even though the amount of the active ingredient therein is varied in the range of several mg to several tens of mg, for
`example, in the range of 5 mg to 20 mg or in the range of 5 mg to 40 mg, and further these preparations show equivalent
`dissolution profile in the same ratio of components.
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`BACKGROUND ART
`
`[0002]
`In order to secure the bioequivalence when a pharmaceutical preparation having different amounts is admin(cid:173)
`istered at the same dose, there was issued "Guideline for Bioequivalence testing of Oral Solid Dosage Forms with
`Different Content" (Notification No. 64 of the Evaluation and Licensing Division, PMSD dated February 14, 2000), by
`which it has been required that a pharmaceutical preparation having different amounts should be equivalent in disso(cid:173)
`lution profile in test solutions such as buffers of pH 1.2, 3.0 to 5.0 and 6.8 (which correspond to the pH values of the
`stomach, the intestine and the oral cavity, respectively), water, and saline solution, etc.
`[0003] For medicaments showing a good solubility in water, it is easy to prepare such a preparation having equivalent
`dissolution profile even in different amounts due to their water solubility. On the contrary, for medicaments containing
`as an active ingredient a slightly water-soluble compound, it has been difficult to prepare a pharmaceutical preparation
`having equivalent dissolution profile even in different amounts, because such an active ingredient shows low affinity
`to water, etc.
`
`DISCLOSURE OF INVENTION
`
`[0004] An object of the present invention is to provide a pharmaceutical preparation for oral administration containing
`as an active ingredient a slightly water-soluble compound, which can rapidly release the active ingredient therefrom
`and can show equivalent dissolution profile even in different amounts of said active ingredient. Especially, the object
`of the present invention is to provide a pharmaceutical preparation for oral administration with increased amount of
`the active ingredient, which can show equivalent dissolution profile to that when multiple tablets having a low content
`of the active ingredient are administered, and can release a slightly water-soluble active ingredient therefrom at a
`desired concentration.
`[0005] The present inventor has intensively studied in order to achieve the above objects, and has found that phar(cid:173)
`maceutical preparations prepared by the following processes showed a good disintegration, and can show a rapid
`dissolution profile regardless of the contents of the active ingredient, by releasing the active ingredient therefrom at a
`desired concentration, and further can show equivalent dissolution profile, and found that such pharmaceutical prep(cid:173)
`arations meet the desired purposes, and finally has accomplished the present invention.
`
`(1) A process of making a preparation comprising a step of preparing a solid formed product (e.g., granule) from
`a slightly water-soluble active ingredient and a mixture of a first disintegrant and a water-soluble excipient with a
`water-soluble polymer binder, and a step of mixing the resultant with a second disintegrant.
`(2) A process of making a preparation comprising a step of preparing a solid formed product from a mixture of a
`slightly water-soluble active ingredient, a first disintegrant and a water-soluble excipient with a water-soluble pol(cid:173)
`ymer binder, and a step of mixing the resultant with a second disintegrant.
`(3) A process of making a preparation comprising a step of preparing a solid formed product from a slightly water(cid:173)
`soluble active ingredient and a mixture of a first disintegrant and a sugar alcohol with a water-soluble polymer
`binder.
`(4) A process of making a preparation comprising a step of preparing a solid formed product from a mixture of a
`slightly water-soluble active ingredient, a first disintegrant and a sugar alcohol with a water-soluble polymer binder.
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`BEST MODE FOR CARRYING OUT THE INVENTION
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`[0006] The present invention will be explained in more detail hereinafter.
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`Par Pharm., Inc.
`Exhibit 1008
`Page 002
`
`

`

`[0007] According to the present invention, oral preparations in the following various embodiments are provided.
`
`EP 1 327 440 A1
`
`(1) An oral preparation with good disintegration, which comprises a mixture of a granule and a second disintegrant,
`said granule being obtained by granulating with spraying an aqueous suspension containing a slightly water-soluble
`active ingredient and a water-soluble polymer binder to a mixture of a water-soluble excipient and a first disinte(cid:173)
`grant.
`(2) The oral preparation with good disintegration according to the above (1 ), which is in the form of a tablet.
`(3) An oral preparation with good disintegration, which comprises a mixture of an active ingredient-containing
`layered composite and a second disintegrant, said layered composite being made by setting a slightly water-soluble
`active ingredient-containing layer onto an internal layer consisting of a water-soluble excipient and a first disinte(cid:173)
`grant via a layer of a water-soluble polymer binder.
`(4) An oral preparation with good disintegration, which comprises a mixture of a granule and a second disintegrant,
`said granule being obtained by granulating with spraying an aqueous solution of a water-soluble polymer binder
`to a mixture of a slightly water-soluble active ingredient, a water-soluble excipient and a first disintegrant.
`(5) The oral preparation with good disintegration according to the above (4), which is in the form of a tablet.
`(6) An oral preparation with good disintegration, which comprises a mixture of an active ingredient-containing
`granule and a second disintegrant, said granule being obtained by combining a slightly water-soluble medicament,
`a water-soluble excipient and a first disintegrant each other by a water-soluble polymer binder.
`(7) An oral preparation with good disintegration, which comprises a granule obtained by granulating with spraying
`an aqueous suspension containing a slightly water-soluble active ingredient and a water-soluble polymer binder
`to a mixture of a sugar alcohol and a first disintegrant.
`(8) The oral preparation with good disintegration according to the above (7), which is in the form of a tablet.
`(9) An oral preparation with good disintegration, which comprises an active ingredient-containing layered compos(cid:173)
`ite, said layered composite being made by setting a slightly water-soluble active ingredient-containing layer onto
`the internal layer consisting of a sugar alcohol and a first disintegrant via a layer of a water-soluble polymer binder.
`(1 0) An oral preparation with good disintegration, which comprises a granule obtained by granulating with spraying
`an aqueous solution of a water-soluble polymer binder to a mixture of a slightly water-soluble active ingredient, a
`sugar alcohol and a first disintegrant.
`(11) The oral preparation with good disintegration according to the above (1 0), which is in the form of a tablet.
`(12) An oral preparation with good disintegration, which comprises an active ingredient-containing granule, said
`granule being obtained by combining a slightly water-soluble medicament, a sugar alcohol and a first disintegrant
`each other by a water-soluble polymer binder.
`(13) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the slightly
`water-soluble active ingredient has a solubility of not more than 0.1 mg/ml at either pH 1.0, 3.0 to 5.0, or 6.8.
`(14) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the
`average particle diameter of the slightly water-soluble active ingredient is in the range of about 0.5 to 5 f-Lm.
`(15) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the water-soluble excipient is a saccharide or a sugar alcohol.
`(16) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the water-soluble excipient is a sugar alcohol.
`(17) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the water-soluble excipient is a saccharide and a sugar alcohol.
`(18) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the water-soluble excipient is one or more members selected from lactose, sucrose, fructo-oligosaccha-
`ride, paratinose, glucose, maltose, hydrogenated maltose, maltotetraose, fructose, isomerized lactose, lactitol,
`honey sugar, D-sorbitol, D-mannitol, maltitol, erythritol, and xylitol.
`(19) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the water-soluble excipient is one or more members selected from D-sorbitol, D-mannitol, erythritol, and
`xylitol.
`(20) The oral preparation with good disintegration according to any one of the above (7), (8), (9), (1 0), (11) and
`(12), wherein the sugar alcohol is one or more members selected from D-sorbitol, D-mannitol, erythritol, and xylitol.
`(21) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`which comprises one or more water-soluble excipients selected from D-sorbitol, D-mannitol, erythritol, and xylitol,
`and further comprises one or more water-soluble excipients selected from lactose, sucrose, fructo-oligosaccharide,
`paratinose, glucose, maltose, hydrogenated maltose, maltotetraose, fructose, lactulose, lactitol and honey sugar.
`(22) The oral preparation with good disintegration according to any one of the above (7), (8), (9), (1 0), (11) and
`(12), which comprises one or more sugar alcohols selected from D-sorbitol, D-mannitol, erythritol, and xylitol, and
`further comprises one or more water-soluble excipients selected from lactose, sucrose, fructo-oligo-saccharide,
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`Par Pharm., Inc.
`Exhibit 1008
`Page 003
`
`

`

`EP 1 327 440 A1
`
`paratinose, glucose, maltose, hydrogenated maltose, maltotetraose, fructose, lactulose, lactitol and honey sugar.
`(23) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the water-soluble excipient has an average particle diameter in the range of about 10 llm to 150 jlm.
`(24) The oral preparation with good disintegration according to any one of the above (7), (8), (9), (1 0), (11) and
`(12), wherein the sugar alcohol has an average particle diameter in the range of about 10 llm to 150 jlm.
`(25) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the first
`disintegrant is selected from corn starch, microcrystalline cellulose, low substituted hydroxypropylcellulose, car(cid:173)
`mellose, carmel lose calcium, carmel lose sodium, croscarmellose sodium, carboxymethyl starch sodium and cross(cid:173)
`povidone.
`(26) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the water(cid:173)
`soluble polymer binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrro(cid:173)
`lidone, polyvinyl alcohol, agar, starch, dextrin and gelatin.
`(27) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the second disintegrant is one or more members selected from lactose, anhydrous dibasic calcium phos-
`phate, dibasic calcium phosphate, microcrystalline cellulose, low substituted hydroxypropylcellulose, carmellose,
`carmel lose calcium, carmel lose sodium, croscarmellose sodium, carboxymethyl starch sodium and crosspovidone.
`(28) The oral preparation with good disintegration according to any one of the above (2), (5), (8) and (11 ), wherein
`the compression hardness is in the range of about 50 to 200 N.
`(29) The oral preparation with good disintegration according to the above (1) or (2), wherein the second disintegrant
`is contained in a ratio of 20 to 1200 w/w% (by weight) to the weight of the granule obtained by granulating with
`spraying an aqueous suspension containing a slightly water-soluble active ingredient and a water-soluble polymer
`binder to a mixture of an excipient and a first disintegrant.
`(30) The oral preparation with good disintegration according to the above (4) or (5), wherein the second disintegrant
`is contained in a ratio of 20 to 1200 w/w (by weight) to the weight of the granule obtained by granulating with
`spraying an aqueous solution of a water-soluble polymer binder to a mixture of a slightly water-soluble active
`ingredient, an excipient and a first disintegrant.
`(31) The oral preparation with good disintegration according to any one of the above (1 ), (2), (3), (4), (5) and (6),
`wherein the amount of the water-soluble excipient is in the range of about 250 to 2000 % by weight (w/w %,
`hereinafer the same) to the weight of the slightly water-soluble active ingredient.
`(32) The oral preparation with good disintegration according to any one of the above (7), (8), (9), (1 0), (11) and
`(12), wherein the amount of the sugar alcohol is in the range of about 250 to 2000% by weight (w/w %, hereinafer
`the same) to the weight of the slightly water-soluble active ingredient.
`(33) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the amount
`of the first disintegrant is in the range of about 5 to 300 % by weight to the weight of the slightly water-soluble
`active ingredient.
`(34) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the amount
`of the water-soluble polymer binder is in the range of about 6 to 80% by weight to the weight of the slightly water(cid:173)
`soluble active ingredient.
`(35) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the amount
`of the water-soluble polymer binder is in the range of about 1 to 10% byweightto the total weight of said preparation.
`(36) The oral preparation with good disintegration according to any one of the above (1) to (12), wherein the amount
`of the water-soluble polymer binder is in the range of about 1 to 5% by weight to the total weight of said preparation.
`(37) A granule, which is obtained by granulating with spraying an aqueous suspension containing a slightly water(cid:173)
`soluble active ingredient and a water-soluble polymer binder to a mixture of a water-soluble excipient and a first
`disintegrant.
`(38) A slightly water-soluble active ingredient-containing granule, which is obtained by adding a water-soluble
`polymer binder to a powdery mixture consisting of a water-soluble excipient, a first excipient and a slightly water(cid:173)
`soluble active ingredient and combining them each other.
`(39) A granule, which is obtained by granulating with spraying an aqueous suspension containing a slightly water-
`soluble active ingredient and a water-soluble polymer binder to a mixture of a sugar alcohol and a first disintegrant.
`(40) A slightly water-soluble active ingredient-containing granule, which is obtained by adding a water-soluble
`polymer binder to a powdery mixture consisting of a sugar alcohol, a first disintegrant and a slightly water-soluble
`active ingredient and combining them each other.
`(41) The oral preparation with good disintegration according to any one of the above (1) to (40), wherein the slightly
`water-soluble active ingredient is N-[4-[4-(1 ,2-benzisothiazol-3-yl)-1-piperazinyi]-(2R,3R)-2,3-tetra-methyleneb(cid:173)
`utyl]-(1 'R,2'S,3'R,4'S)-2,3-bicyclo[2.2.1]-heptanedicarboximide hydrochloride.
`
`[0008] The "slightly water-soluble active ingredient" includes slightly soluble compounds having a low solubility in
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`Par Pharm., Inc.
`Exhibit 1008
`Page 004
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`

`

`EP 1 327 440 A1
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`water, especially compounds having a solubility of not more than about 0.1 mg/ml at pH 1.0, 3.0-5.0 and 6.8, these pH
`values corresponding to the pH values of the stomach, the intestine and the oral cavity, respectively. A concrete example
`thereof is N-[ 4-[4-(1 ,2-benzisoth iazol-3-yl)-1-piperazinyi]-(2R,3R)-2,3-tetramethylenebutyl]-(1' R,2'S,3'R,4'S)-2,3-bicy(cid:173)
`clo[2.2.1]heptanedicarboximide hydrochloride of the following formula:
`
`HCI
`
`(hereinafter, referred to as Compound 1) (cf. Japanese Patent No. 2800953). Compound 1 has been known to exhibit
`a psychotropic effect, and it is useful as an agent for treatment of schizophrenia, etc.
`[0009]
`In addition, these slightly water-soluble active ingredients are preferably finely milled, and the average particle
`diameter thereof is, for example, in the range of about 0.5 to 5 f.lm.
`[0010] The "water-soluble polymer binder" includes, for example, hydroxypropylcellulose, hydroxypropylmethylcel-
`lulose, polyvinylpyrrolidone, polyvinyl alcohol (partially saponificated one), pullulan, starch, dextrin, gelatin, etc., and
`preferable ones are hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol
`(partially saponificated one). These water-soluble polymer binders may be used alone, or two or more thereof may be
`used together.
`[0011] The "first disintegrant" includes, for example, corn starch, microcrystalline cellulose, low substituted hydrox-
`ypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch
`sodium, crosspovidone, etc. These first disintegrants may be used alone or two or more thereof may be used together.
`The average particle diameter of these first disintegrants is, for example, in the range of about 5 to about 75 f.lm, and
`preferable first disintegrant is ones having an average particle diameter in the range of about 5 to about 75 f.lm, wherein
`the ratio of particles having a particle diameter of more than 75 f.lm is not more than 5 % to the total.
`[0012] The "second disintegrant" includes, for example, lactose, anhydrous dibasic calcium phosphate, dibasic cal(cid:173)
`cium phosphate, microcrystalline cellulose, magnesium aluminometasilicate, synthesized hydrotalcite, synthesized
`aluminum silicate, low substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, cro(cid:173)
`scarmellose sodium, carboxymethyl starch sodium, crosspovidone, etc. Preferable second disintegrant is, for example,
`lactose, anhydrous dibasic calcium phosphate, dibasic calcium phosphate, microcrystalline cellulose, low substituted
`hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl
`starch sodium, and crosspovidone. These second disintegrants may be used alone, or two or more thereof may be
`used together.
`[0013] The average particle diameter of the second disintegrant is, for example, in the range of about 5 to about 500
`f.lm, preferably in the range of about 30 to 350 f.lm.
`[0014] The "water-soluble excipient" includes, for example, a sugar alcohol and a saccharide. Specific examples are
`saccharides such as lactose, sucrose, fructo-oligo-saccharide, paratinose, glucose, maltose, hydrogenated maltose,
`maltotetraose, fructose, lactulose, lactitol, honey sugar, and sugar alcohols such as D-sorbitol, D-mannitol, maltitol,
`erythritol, and xylitol. These water-soluble excipients may be used alone, or one or more thereof may be used together.
`[0015] Even when the amount of the slightly water-soluble active ingredient is substantially changed, for example,
`even when it is changed within the range of 5 mg to 40 mg, the oral preparation shall show a rapid dissolution of said
`active ingredient as well as equivalent dissolution profile, and the water-soluble excipients preferable for preparing
`such oral preparation are, for example, sugar alcohols such as D-sorbitol, D-mannitol, erythritol, xylitol, etc. In these
`cases, a saccharide such as lactose, sucrose, fructo-oligosaccharide, paratinose, glucose, maltose, hydrogenated
`maltose, maltotetraose, fructose, lactulose, lactitol, honey sugar, etc. may simultaneously be contained in said oral
`preparation.
`[0016] When orally administered, the oral preparation of the present invention can release a slightly water-soluble
`active ingredient rapidly and can show equivalent dissolution profile regardless of the amounts of the active ingredient
`therein to give a desired serum concentration thereof. The oral preparations of the present invention may include
`various dosage forms such as pills, granules, fine granules, tablets, capsules, etc.
`[0017] The oral preparations of the present invention may be prepared by a conventional method depending on
`desired dosage forms. For instance, the present preparations may be prepared by the following processes.
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`Par Pharm., Inc.
`Exhibit 1008
`Page 005
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`

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`EP 1 327 440 A1
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`Preparation method 1
`
`(1) Preparation of an aqueous solution of a water-soluble polymer binder:
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`[0018] A water-soluble polymer binder is dissolved in purified water, during which the temperature is, for example,
`in the range of about 20°C to 90°C, preferably in the range of about 20°C to 70°C. The amount of the water-soluble
`polymer binder is, for example, in the range of about 1 to 20% by weight, preferably in the range of about 2 to 8% by
`weight, to the weight of the purified water.
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`(2) Preparation of an aqueous suspension containing a water-soluble polymer binder and a slightly water-soluble active
`ingredient:
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`[0019] A slightly water-soluble active ingredient is dispersed and suspended in the aqueous water-soluble polymer
`binder solution obtained in the above (1 ), for example, at a temperature of about 20°C to about 90°C, preferably at a
`temperature of about 20°C to 40°C.
`[0020] The amount of the water-soluble polymer binder is, for example, in the range of about 3 to about 200% by
`weight, preferably about 6 to about 80% by weight, to the weight of the slightly water-soluble active ingredient.
`[0021] The slightly water-soluble active ingredient is preferably finely milled, and the average particle diameter thereof
`is, for example, in the range of about 0.5 to 611m.
`
`(3) Mixing and granulation of the active ingredient-containing aqueous suspension with a first disintegrant:
`
`[0022] A water-soluble excipient and a first disintegrant are charged into a fluid bed granulator, and thereto is sprayed
`the aqueous suspension containing a water-soluble polymer binder and a slightly water-soluble active ingredient ob-
`tained in the above (2), and the mixture is granulated.
`[0023] This granulation step is carried out, for example, at a temperature for supplying air in the range of about 50°C
`to 90°C, preferably about 60°C to 80°C. The granulation is carried out, for example, for about 30 minutes to 180
`minutes, preferably for about 40 minutes to 150 minutes.
`[0024] The apparatus for granulation is, for example, ones classified into fluid bed granulation and roto granulation,
`and preferable one is a fluid bed granulator, a roto fluid bed granulator, etc.
`[0025] The amount of the water-soluble excipient is, for example, in the range of about 200 to about 2000 % by
`weight, preferably in the range of about 250 to about 1200% by weight, to the weight of the slightly water-soluble active
`ingredient.
`[0026] The amount of the first disintegrant is in the range of about 5 to 300 % by weight, preferably in the range of
`about 30 to 150 % by weight, to the weight of the slightly water-soluble active ingredient.
`
`(4) Drying of the granule:
`
`[0027] The above granule containing a slightly water-soluble active ingredient and a first disintegrant is dried either
`under reduced pressure or under atmospheric pressure. The drying is carried out in such a manner that the loss on
`dry measured by infrared moisture meter is, for example, within about 3% by weight, preferably within 2% by weight.
`
`(5) Mixing of the dried granule and a second disintegrant:
`
`[0028] The granule containing a slightly water-soluble active ingredient and a first disintegrant dried in the above (4)
`is then mixed with a second disintegrant. The mixing apparatus is, for example, ones classified into diffusion mixers
`(tumble mixers). If necessary, after mixing with said mixer, the mixture is milled with a mill classified into impact mills.
`The diffusion mixers (tumble mixers) are, for example, tumble blender, V blender, double cone, bin tumbler, etc. The
`impact mills are, for example, a hammer conventional mill, etc.
`[0029] The amount of the second disintegrant is, for example, in the range of 20 to 1200 w/w% (weight ratio) to the
`weight of the granule obtained by granulating with spraying the aqueous suspension of a slightly water-soluble active
`ingredient and a water-soluble polymer binder to a mixture of a first disintegrant and a water-soluble excipient.
`
`(6) Blending of a lubricant:
`
`[0030] The above mixture of the granule and the second disintegrant may be compressed without further compo(cid:173)
`nents, but preferably compressed in admixture with a lubricant.
`[0031] The lubricant may be blended by adding it into the mixture of the above (5). The mixing apparatus is, for
`
`6
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 006
`
`

`

`EP 1 327 440 A1
`
`example, ones classified into diffusion mixers (tumble mixers), such as tumble blender, V blender, double cone, bin
`tumbler, etc.
`[0032] The lubricant is, for example, magnesium stearate, talc, hydrogenated oil, stearic acid, calcium stearate,
`glyceryl behenate, sodium stearylfumarate, etc.
`[0033] The. amount of the lubricant is, for example, in the range of 0.3 to 3% by weight, preferably in the range of
`about 0.5 to 1 .5 % by weight, to the total weight of the tablet.
`
`(7) Compression:
`
`[0034] The above mixture is compressed in a conventional manner to give tablets.
`[0035] The compression apparatus is preferably ones classified into tablet press.
`[0036] The compression hardness is, for example, in the range of about 50 to 200 N.
`
`(8) Film Coating:
`
`[0037] The tablets obtained above may be subjected to film coating, if necessary. The coating apparatus is ones
`classified into coating pans, preferably ones classified into perforated coating system.
`[0038] The coating agent is, for example, a mixture of a base material (e.g., hydroxypropylmethylcellulose, hydro(cid:173)
`propylcellulose, polyvinylpyrrolidone, etc.) and a plasticizer (e.g., polyethylene glycol, propylene glycol, triacetine, tri-
`ethyl citrate, glycerin, glycerin fatty acid ester, polyethylene glycol, etc.). If necessary, an additive such as titanium
`oxide or mannitol may be added therein.
`
`(9) Drying:
`
`[0039] The tablets obtained above are dried. The drying is carried out either under reduced pressure or under at(cid:173)
`mospheric pressure in such a manner that the loss on dry measured by infrared moisture meter is, for example, within
`about 3% by weight, preferably within 2 % by weight.
`
`Preparation method 2
`
`(1) Preparation of an aqueous solution of a water-soluble polymer binder:
`
`[0040] A water-soluble polymer binder is dissolved in purified water, during which the temperature is, for example,
`in the range of about 20°C to 90°C,- preferably in the range of about 20°C to 70°C. The amount of the water-soluble
`polymer binder is, for example, in the range of about 1 to 20% by weight, preferably in the range of about 2 to 8% by
`weight, to the weight of the purified water.
`
`(2) Preparation of an active ingredient-containing granule:
`
`[0041] A slightly water-soluble active ingredient, a water-soluble excipient and a first disintegrant are charged into
`a fluid bed granulator, and thereto is sprayed the aqueous solution of a water-soluble polymer binder obtained in the
`above (1), and the mixture is granulated.
`[0042] The granulation step is carried out, for example, at a temperature for supplying air in the range of about 50°C
`to 90°C, preferably about 60°C to 80°C. The granulation is carried out, for example, for about 30 minutes to 180
`minutes, preferably for about 40 minutes to 150 minutes.
`[0043] The apparatus for granulation is, for example, ones classified into fluid bed granulation and roto granulation,
`and preferable one is a fluid bed granulator, a roto fluid bed granulator, etc.
`[0044] The amount of the water-soluble excipient is, for example, in the range of about 200 to about 2000 % by
`weight, preferably in the range of about 250 to about 1200% by weight, to the weight of the slightly water-soluble active
`ingredient.
`[0045] The slightly water-soluble active ingredient is preferably finely milled, and the average particle diameter thereof
`is, for example, in the range of about 0.5 to 5 flm.
`[0046] The amount of the first disintegrant is, for example, in the range of about 5 to 300% by weight, preferably in
`the range of about 30 to 150 % by weight, to the weight of the slightly water-soluble active ingredient.
`
`(3) Drying of the granule:
`
`[0047] The above granule is dried either under reduced pressure or under atmospheric pressure. The drying is carried
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`20
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`30
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