US007727553B2
`
`(12) United States Patent
`Fujihara
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,727,553 B2
`Jun. 1, 2010
`
`(54) ORAL PREPARATIONS WITH FAVORABLE
`DISINTEGRATION CHARACTERISTICS
`
`(75) Inventor: Kazuyuki Fujihara, Takatsuki (JP)
`
`(73) Assignee: Dainippon Sumitomo Pharma Co.,
`Ltd., Osaka-Shi, Osaka (JP)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 803 days.
`
`(21) Appl. No.:
`
`10/381,036
`
`(22) PCT Filed:
`
`Sep. 14, 2001
`
`(86) PCT No.:
`
`PCT/JP01/07983
`
`§ 371 (0X1)’
`(2), (4) Date:
`
`Mar. 21, 2003
`
`(87) PCT Pub. No.: WO02/24166
`
`PCT Pub. Date: Mar. 28, 2002
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`US 2004/0028741 A1
`
`Feb. 12, 2004
`
`Foreign Application Priority Data
`
`Sep. 22, 2000
`
`(JP)
`
`........................... .. 2000-288234
`
`(51) Int. Cl.
`(2006.01)
`A61K 9/14
`(52) US. Cl. ..................... .. 424/489; 424/452; 424/457;
`424/458; 424/468; 424/470
`(58) Field of Classi?cation Search ............... .. 424/400,
`424/464, 465, 489, 469, 451, 452, 457, 458,
`424/459, 461, 468, 470, 471, 474
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1999 Ohno et a1. ............... .. 424/465
`5,958,453 A *
`5,972,383 A 10/1999 Gibson et 31.
`5,994,348 A 11/1999 Ku et a1.
`6,440,450 B1* 8/2002 Han et a1. ................. .. 424/439
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`JP
`JP
`JP
`JP
`WO
`WO
`WO
`WO
`
`8/1998
`860169
`860169 A2 10/1998
`61-148114 A
`7/1986
`2000016930
`1/2000
`2000-86503 A
`3/2000
`2000-86509 A
`3/2000
`WO-95/17168
`6/1995
`WO-99/32092 A1
`7/1999
`WO-99/47126
`9/1999
`WO-00/64416
`11/2000
`
`* cited by examiner
`
`Primary ExamineriD L Jones
`(74) Attorney, Agent, or FirmiBirch, Stewart, Kolasch &
`Birch, LLP
`
`(57)
`
`ABSTRACT
`
`The present invention provides oral preparations With good
`disintegration containing a slightly Water-soluble active
`ingredient, Which comprise a mixture of a solid formed prod
`uct (eg a granule) and a second disintegrant Wherein said
`solid formed product comprises a slightly Water-soluble
`active ingredient, a ?rst disintegrant 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-soluble active ingredient, a disintegrant and a
`sugar alcohol by using a Water-soluble polymer binder. When
`orally administered, these oral preparations exhibit excellent
`dissolution characteristics of the active ingredient in the
`digestive tract, and further, these preparations can shoW
`equivalent dissolution pro?le even at different amounts of the
`active ingredient, and thus enable the selection of the most
`suitable medicament for each patient, Which makes these
`preparations highly useful in the clinical ?eld.
`
`5,532,372 A *
`5,811,120 A
`
`7/1996 Sajietal. .................. .. 544/368
`9/1998 Gibson et a1.
`
`11 Claims, No Drawings
`
`Par Pharm., Inc.
`Exhibit 1066
`Page 001
`
`

`

`US 7,727,553 B2
`
`1
`ORAL PREPARATIONS WITH FAVORABLE
`DISINTEGRATION CHARACTERISTICS
`
`This application is the national phase under 35 USC §37l
`of PCT International Application No. PCT/ JP0l/ 07983
`Which has an International ?ling date of Sep. 14, 2001, Which
`designated the United States of America.
`
`TECHNICAL FIELD
`
`The present invention relates to an oral preparation With
`good disintegration, Which comprises a slightly Water-soluble
`component as an active ingredient. More particularly, the
`present invention relates to pharmaceutical preparations for
`oral administration, especially tablets, containing a slightly
`Water-soluble component as an active ingredient, Which have
`equivalent dissolution pro?le 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, containing 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 pro?le in the
`same ratio of components.
`
`BACKGROUND ART
`
`In order to secure the bioequivalence When a pharmaceu
`tical preparation having different amounts is administered at
`the same dose, there Was issued “Guideline for Bioequiva
`lence testing of Oral Solid Dosage Forms With Different
`Content” (Noti?cation No. 64 of the Evaluation and Licens
`ing Division, PMSD dated Feb. 14, 2000), by Which it has
`been required that a pharmaceutical preparation having dif
`ferent amounts should be equivalent in dissolution pro?le 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 intes
`tine and the oral cavity, respectively), Water, and saline solu
`tion, etc.
`For medicaments shoWing a good solubility in Water, it is
`easy to prepare such a preparation having equivalent dissolu
`tion pro?le even in different amounts due to their Water solu
`bility. On the contrary, for medicaments containing as an
`active ingredient a slightly Water-soluble compound, it has
`been dif?cult to prepare a pharmaceutical preparation having
`equivalent dissolution pro?le even in different amounts,
`because such an active ingredient shoWs loW a?inity to Water,
`etc.
`
`DISCLOSURE OF INVENTION
`
`An object of the present invention is to provide a pharma
`ceutical 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 pro?le 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 ingredi
`ent, Which can shoW equivalent dissolution pro?le 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 concentra
`tion.
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`The present inventor has intensively studied in order to
`achieve the above objects, and has found that pharmaceutical
`preparations prepared by the folloWing processes shoWed a
`good disintegration, and can shoW a rapid dissolution pro?le
`regardless of the contents of the active ingredient, by releas
`ing the active ingredient therefrom at a desired concentration,
`and further can shoW equivalent dissolution pro?le, and found
`that such pharmaceutical preparations meet the desired pur
`poses, and ?nally 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
`?rst 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 ?rst disintegrant
`and a Water-soluble excipient With a Water- soluble polymer
`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
`soluble active ingredient and a mixture of a ?rst disinte
`grant 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 ?rst disintegrant
`and a sugar alcohol With a Water-soluble polymer binder.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`The present invention Will be explained in more detail
`hereinafter.
`According to the present invention, oral preparations in the
`folloWing various embodiments are provided.
`(1 ) An oral preparation With good disintegration, Which com
`prises 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 ?rst disinte
`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 com
`prises a mixture of an active ingredient-containing layered
`composite and a second disintegrant, said layered compos
`ite being made by setting a slightly Water-soluble active
`ingredient-containing layer onto an internal layer consist
`ing of a Water-soluble excipient and a ?rst disintegrant via
`a layer of a Water-soluble polymer binder.
`(4) An oral preparation With good disintegration, Which com
`prises 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 ?rst 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 com
`prises 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
`
`Par Pharm., Inc.
`Exhibit 1066
`Page 002
`
`

`

`US 7,727,553 B2
`
`3
`soluble excipient and a ?rst disintegrant each other by a
`Water-soluble polymer binder.
`(7) An oral preparation With good disintegration, Which com
`prises 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 ?rst 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 com
`prises an active ingredient-containing layered composite,
`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 ?rst dis
`integrant via a layer of a Water-soluble polymer binder.
`(10) 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 ?rst disintegrant.
`(11) The oral preparation With good disintegration according
`to the above (10), 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 ?rst 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 ingre
`dient is in the range of about 0.5 to 5 um.
`(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 alco
`hol.
`(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-oligosaccharide,
`paratinose, glucose, maltose, hydrogenated maltose, mal
`totetraose, 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 xyli
`tol.
`(20) The oral preparation With good disintegration according
`to any one of the above (7), (8), (9), (10), (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 ofthe 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
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`4
`further comprises one or more Water-soluble excipients
`selected from lactose, sucrose, fructo-oligosaccharide,
`paratinose, glucose, maltose, hydrogenated maltose, mal
`totetraose, fructose, lactulose, lactitol and honey sugar.
`(22) The oral preparation With good disintegration according
`to any one of the above (7), (8), (9), (10), (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, paratinose,
`glucose, maltose, hydrogenated maltose, maltotetraose,
`fructose, lactulose, lactitol and honey sugar.
`(23) The oral preparation With good disintegration according
`to any one ofthe above (1), (2), (3), (4), (5) and (6), Wherein
`the Water-soluble excipient has an average particle diam
`eter in the range of about 10 um to 150 um.
`(24) The oral preparation With good disintegration according
`to any one of the above (7), (8), (9), (10), (11) and (12),
`Wherein the sugar alcohol has an average particle diameter
`in the range of about 10 pm to 150 um.
`(25) The oral preparation With good disintegration according
`to any one of the above (1) to (12), Wherein the ?rst disin
`tegrant is selected from corn starch, micro-crystalline cel
`lulose, loW substituted hydroxypropyl-cellulose, carmel
`lose,
`carmellose
`calcium,
`carmellose
`sodium,
`croscarmellose sodium, carboxymethyl starch sodium and
`crosspovidone.
`(26) The oral preparation With good disintegration according
`to any one of the above (1) to (12), Wherein the Water
`soluble polymer binder is selected from hydroxy-propyl
`cellulose, hydroxypropylmethylcellulose, polyvinyl-pyr
`rolidone, polyvinyl alcohol, agar, starch, dextrin and
`gelatin.
`(27) The oral preparation With good disintegration according
`to any one ofthe above (1), (2), (3), (4), (5) and (6), Wherein
`the second disintegrant is one or more members selected
`from lactose, anhydrous dibasic calcium phosphate, diba
`sic calcium phosphate, microcrystalline cellulose, loW sub
`stituted hydroxypropylcellulose, carmellose, carmellose
`calcium, carmellose sodium, croscarmellose sodium, car
`boxymethyl 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 spray
`ing an aqueous suspension containing a slightly Water
`soluble active ingredient and a Water-soluble polymer
`binder to a mixture of an excipient and a ?rst 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 spray
`ing an aqueous solution of a Water-soluble polymer binder
`to a mixture of a slightly Water-soluble active ingredient, an
`excipient and a ?rst disintegrant.
`(31) The oral preparation With good disintegration according
`to any one ofthe 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 %, hereinafter 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), (10), (11) and (12),
`Wherein the amount of the sugar alcohol is in the range of
`
`Par Pharm., Inc.
`Exhibit 1066
`Page 003
`
`

`

`US 7,727,553 B2
`
`5
`about 250 to 2000% by Weight (W/W %, hereinafter the
`same) to the Weight of the slightly Water-soluble active
`ingredient.
`
`6
`3R)-2,3-tetramethylenebutyl]-(1'R, 2'S, 3'R, 4'S)-2,3-bicyclo
`[2.2.1]heptanedicarboximide hydrochloride of the folloWing
`formula:
`
`(33) The oral preparation With good disintegration according
`to any one of the above (1) to (12), Wherein the amount of
`the ?rst 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
`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% by Weight to 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 spray
`ing 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 ?rst
`disintegrant.
`(38) A slightly Water-soluble active ingredient-containing
`granule, Which is obtained by adding a Water-soluble poly
`mer binder to a poWdery mixture consisting of a Water
`soluble excipient, a ?rst excipient and a slightly Water
`soluble active ingredient and combining them each other.
`(39) A granule, Which is obtained by granulating With spray
`ing 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 ?rst disinte
`grant.
`(40) A slightly Water-soluble active ingredient-containing
`granule, Which is obtained by adding a Water-soluble poly
`mer binder to a poWdery mixture consisting of a sugar
`alcohol, a ?rst 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-ben
`ZisothiaZol-3 -yl)-1-piperaZinyl]-(2R,3R)-2,3 -tetra-meth
`ylenebutyl]-(1'R,2'S,3'R,4'S)-2,3-bicyclo[2.2.1]-hep
`tanedicarboximide hydrochloride.
`The “slightly Water-soluble active ingredient” includes
`slightly soluble compounds having a loW solubility in 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-benZisothiaZol-3-yl)-1-piperaZinyl]-(2R,
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`(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.
`In addition, these slightly Water-soluble active ingredients
`are preferably ?nely milled, and the average particle diameter
`thereof is, for example, in the range of about 0.5 to 5 um.
`The “Water-soluble polymer binder” includes, for
`example, hydroxypropylcellulose, hydroxypropylmethyl
`cellulose, polyvinylpyrrolidone, polyvinyl alcohol (partially
`saponi?cated one), pullulan, starch, dextrin, gelatin, etc., and
`preferable ones are hydroxypropyl-cellulose, hydroxypropy
`lmethylcellulose, polyvinyl-pyrrolidone, and polyvinyl alco
`hol (partially saponi?cated one). These Water-soluble poly
`mer binders may be used alone, or tWo or more thereof may be
`used together.
`The “?rst disintegrant” includes, for example, corn starch,
`microcrystalline cellulose, loW substituted hydroxypropyl
`cellulose, carmellose, carmellose calcium, carmellose
`sodium, croscarmellose sodium, carboxymethyl starch
`sodium, crosspovidone, etc. These ?rst disintegrants may be
`used alone or tWo or more thereof may be used together. The
`average particle diameter of these ?rst disintegrants is, for
`example, in the range of about 5 to about 75 um, and prefer
`able ?rst disintegrant is ones having an average particle diam
`eter in the range of about 5 to about 75 um, Wherein the ratio
`of particles having a particle diameter of more than 75 um is
`not more than 5% to the total.
`The “second disintegrant” includes, for example, lactose,
`anhydrous dibasic calcium phosphate, dibasic calcium phos
`phate, microcrystalline cellulose, magnesium aluminometa
`silicate, synthesiZed hydrotalcite, synthesiZed aluminum sili
`cate, loW substituted hydroxypropyl cellulose, carmellose,
`carmellose calcium, carmellose sodium, cros-carmellose
`sodium, carboxymethyl starch sodium, cross-povidone, etc.
`Preferable second disintegrant is, for example, lactose, anhy
`drous 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.
`The average particle diameter of the second disintegrant is,
`for example, in the range of about 5 to about 500 um, prefer
`ably in the range of about 30 to 350 pm.
`The “Water-soluble excipient” includes, for example, a
`sugar alcohol and a saccharide. Speci?c examples are saccha
`rides such as lactose, sucrose, fructo-oligo-saccharide, para
`tinose, glucose, maltose, hydrogenated maltose, maltotet
`raose, fructose, lactulose, lactitol, honey sugar, and sugar
`
`Par Pharm., Inc.
`Exhibit 1066
`Page 004
`
`

`

`US 7,727,553 B2
`
`7
`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.
`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 ingre
`dient as Well as equivalent dissolution pro?le, and the Water
`soluble excipients preferable for preparing such oral prepa
`ration are, for example, sugar alcohols such as D-sorbitol,
`D-mannitol, erythritol, xylitol, etc. In these cases, a saccha
`ride such as lactose, sucrose, fructo-oligosaccharide, parati
`nose, glucose, maltose, hydrogenated maltose, maltotetraose,
`fructose, lactulose, lactitol, honey sugar, etc. may simulta
`neously be contained in said oral preparation.
`When orally administered, the oral preparation of the
`present invention can release a slightly Water-soluble active
`ingredient rapidly and can shoW equivalent dissolution pro?le
`regardless of the amounts of the active ingredient therein to
`give a desired serum concentration thereof. The oral prepa
`rations of the present invention may include various dosage
`forms such as pills, granules, ?ne granules, tablets, capsules,
`etc.
`The oral preparations of the present invention may be pre
`pared by a conventional method depending on desired dosage
`forms. For instance, the present preparations may be prepared
`by the folloWing processes.
`
`Preparation Method 1
`(1) Preparation of an aqueous solution of a Water-soluble
`polymer binder:
`A Water-soluble polymer binder is dissolved in puri?ed
`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 puri?ed Water.
`(2) Preparation of an aqueous suspension containing a Water
`soluble polymer binder and a slightly Water-soluble active
`ingredient:
`A slightly Water-soluble active ingredient is dispersed and
`suspended in the aqueous Water-soluble polymer binder solu
`tion 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.
`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.
`The slightly Water-soluble active ingredient is preferably
`?nely milled, and the average particle diameter thereof is, for
`example, in the range of about 0.5 to 5 um.
`(3) Mixing and granulation of the active ingredient-contain
`ing aqueous suspension With a ?rst disintegrant:
`A Water-soluble excipient and a ?rst disintegrant are
`charged into a ?uid bed granulator, and thereto is sprayed the
`aqueous suspension containing a Water-soluble polymer
`binder and a slightly Water-soluble active ingredient obtained
`in the above (2), and the mixture is granulated.
`This granulation step is carried out, for example, at a tem
`perature 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.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`The apparatus for granulation is, for example, ones classi
`?ed into ?uid bed granulation and roto granulation, and pref
`erable one is a ?uidbed granulator, a roto ?uid bed granulator,
`etc.
`The amount of the Water-soluble excipient is, for example,
`in the range of about 200 to about 2000% by Weight, prefer
`ably in the range of about 250 to about 1200% by Weight, to
`the Weight of the slightly Water-soluble active ingredient.
`The amount of the ?rst 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:
`The above granule containing a slightly Water-soluble
`active ingredient and a ?rst 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:
`The granule containing a slightly Water-soluble active
`ingredient and a ?rst disintegrant dried in the above (4) is then
`mixed With a second disintegrant. The mixing apparatus is,
`for example, ones classi?ed into diffusion mixers (tumble
`mixers). If necessary, after mixing With said mixer, the mix
`ture is milled With a mill classi?ed 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.
`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 aque
`ous suspension of a slightly Water-soluble active ingredient
`and a Water-soluble polymer binder to a mixture of a ?rst
`disintegrant and a Water-soluble excipient.
`(6) Blending of a lubricant:
`The above mixture of the granule and the second disinte
`grant may be compressed Without further components, but
`preferably compressed in admixture With a lubricant.
`The lubricant may be blended by adding it into the mixture
`of the above (5). The mixing apparatus is, for example, ones
`classi?ed into diffusion mixers (tumble mixers), such as
`tumble blender, V blender, double cone, bin tumbler, etc.
`The lubricant is, for example, magnesium stearate, talc,
`hydrogenated oil, stearic acid, calcium stearate, glyceryl
`behenate, sodium stearylfumarate, etc.
`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:
`The above mixture is compressed in a conventional manner
`to give tablets.
`The compression apparatus is preferably ones classi?ed
`into tablet press.
`The compression hardness is, for example, in the range of
`about 50 to 200 N.
`(8) Film Coating:
`The tablets obtained above may be subjected to ?lm coat
`ing, if necessary. The coating apparatus is ones classi?ed into
`coating pans, preferably ones classi?ed into perforated coat
`ing system.
`The coating agent is, for example, a mixture of a base
`material (e.g., hydroxypropylmethylcellulose, hydropropyl
`cellulose, polyvinylpyrrolidone, etc.) and a plasticiZer (e.g.,
`polyethylene glycol, propylene glycol, triacetine, triethyl cit
`
`Par Pharm., Inc.
`Exhibit 1066
`Page 005
`
`

`

`US 7,727,553 B2
`
`1 0
`
`rate, glycerin, glycerin fatty acid ester, polyethylene glycol,
`etc.). If necessary, an additive such as titanium oxide or man
`nitol may be added therein.
`(9) Drying:
`The tablets obtained above are dried. The drying is carried
`out either under reduced pressure or under atmospheric pres
`sure 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:
`A Water-soluble polymer binder is dissolved in puri?ed
`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 puri?ed Water.
`(2) Preparation of an active ingredient-containing granule:
`A slightly Water-soluble active ingredient, a Water-soluble
`excipient and a ?rst disintegrant are charged into a ?uid 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.
`The granulation step is carried out, for example, at a tem
`perature 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.
`The apparatus for granulation is, for example, ones classi
`?ed into ?uid bed granulation and roto granulation, and pref
`erable one is a ?uid bed granulator, a roto ?uid bed granulator,
`etc.
`The amount of the Water-soluble excipient is, for example,
`in the range of about 200 to about 2000% by Weight, prefer
`ably in the range of about 250 to about 1200% by Weight, to
`the Weight of the slightly Water-soluble active ingredient.
`The slightly Water-soluble active ingredient is preferably
`?nely milled, and the average particle d