111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20040028741Al
`
`(19) United States
`(12) Patent Application Publication
`Fujihara
`
`(10) Pub. No.: US 2004/0028741 A1
`Feb. 12, 2004
`(43) Pub. Date:
`
`(54) ORAL PREPARATIONS WITH FAVORABLE
`DISINTEGRATION CHARACTERISTICS
`
`(52) U.S. Cl. .............................................................. 424/486
`
`(76)
`
`Inventor: Kazuyuki Fujihara, Osaka-fu (JP)
`
`(57)
`
`ABSTRACT
`
`Correspondence Address:
`BIRCH STEWART KOLASCH & BIRCH
`PO BOX 747
`FALLS CHURCH, VA 22040-0747 (US)
`
`(21) Appl. No.:
`
`10/381,036
`
`(22) PCT Filed:
`
`Sep. 14,2001
`
`(86) PCT No.:
`
`PCT/JPOl/07983
`
`(30)
`
`Foreign Application Priority Data
`
`Sep. 22, 2000
`
`(JP) ........................................ 2000288234
`
`Publication Classification
`
`(51)
`
`Int. CI? ....................................................... A61K 9/14
`
`The present invention provides oral preparations with good
`disintegration containing a slightly water-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 comprises a slightly water-soluble
`active ingredient, a first 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 profile even at different
`amounts of the active ingredient, and thus enable the selec(cid:173)
`tion of the most suitable medicament for each patient, which
`makes these preparations highly useful in the clinical field.
`
`Par Pharm., Inc.
`Exhibit 1039
`Page 001
`
`

`

`US 2004/00287 41 A1
`
`Feb. 12,2004
`
`1
`
`ORAL PREPARATIONS WITH FAVORABLE
`DISINTEGRATION CHARACTERISTICS
`
`TECHNICAL FIELD
`
`[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 particu(cid:173)
`larly, the present invention relates to pharmaceutical prep a(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(cid:173)
`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 compo(cid:173)
`nents.
`
`BACKGROUND ART
`
`[0002]
`In order to secure the bioequivalence when a
`pharmaceutical preparation having different amounts is
`administered 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 Feb. 14, 2000), by
`which it has been required that a pharmaceutical preparation
`having different amounts should be equivalent in dissolution
`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 contain(cid:173)
`ing as an active ingredient a slightly water-soluble com(cid:173)
`pound, 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 pharmaceu(cid:173)
`tical 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.
`
`pharmaceutical preparations prepared by the following pro(cid:173)
`cesses 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 dis(cid:173)
`solution profile, and found that such pharmaceutical prepa(cid:173)
`rations meet the desired purposes, and finally has accom(cid:173)
`plished the present invention.
`
`[0006]
`(1) A process of making a preparation com(cid:173)
`prising 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 poly(cid:173)
`mer binder, and a step of mixing the resultant with a
`second disintegrant.
`
`[0007]
`(2) A process of making a preparation com(cid:173)
`prising 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 polymer binder, and a
`step of mixing the resultant with a second disinte(cid:173)
`grant.
`
`[0008]
`(3) A process of making a preparation com(cid:173)
`prising a step of preparing a solid formed product
`from a slightly water-soluble active ingredient and a
`mixture of a first disintegrant and a sugar alcohol
`with a water-soluble polymer binder.
`
`[0009]
`(4) A process of making a preparation com(cid:173)
`prising 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.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`[0010] The present invention will be explained in more
`detail hereinafter.
`
`[0011] According to the present invention, oral prepara(cid:173)
`tions in the following various embodiments are provided.
`
`[0012]
`(1) An oral preparation with good disintegra(cid:173)
`tion, 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 disintegrant.
`
`[0013]
`(2) The oral preparation with good disintegra(cid:173)
`tion according to the above (1), which is in the form
`of a tablet.
`
`[0014]
`(3) An oral preparation with good disintegra(cid:173)
`tion, which comprises a mixture of an active ingre(cid:173)
`dient-containing layered composite and a second
`disintegrant, said layered composite being made by
`setting a slightly water-soluble active ingredient(cid:173)
`containing layer onto an internal layer consisting of
`a water-soluble excipient and a first disintegrant via
`a layer of a water-soluble polymer binder.
`
`[0005] The present inventor has intensively studied in
`order to achieve the above objects, and has found that
`
`[0015]
`( 4) An oral preparation with good disintegration,
`which comprises a mixture of a granule and a second
`
`Par Pharm., Inc.
`Exhibit 1039
`Page 002
`
`

`

`US 2004/00287 41 A1
`
`Feb. 12,2004
`
`2
`
`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 ingre(cid:173)
`dient, a water-soluble excipient and a first disintegrant.
`
`[0016]
`(5) The oral preparation with good disintegra(cid:173)
`tion according to the above (4), which is in the form
`of a tablet.
`( 6) An oral preparation with good disintegra(cid:173)
`[0017]
`tion, which comprises a mixture of an active ingre(cid:173)
`dient-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.
`
`[0018]
`(7) An oral preparation with good disintegra(cid:173)
`tion, which comprises a granule obtained by granu(cid:173)
`lating with spraying an aqueous suspension contain(cid:173)
`ing a slightly water-soluble active ingredient and a
`water-soluble polymer binder to a mixture of a sugar
`alcohol and a first disintegrant.
`
`[0019]
`(8) The oral preparation with good disintegra(cid:173)
`tion according to the above (7), which is in the form
`of a tablet.
`
`[0020]
`(9) An oral preparation with good disintegra(cid:173)
`tion, which comprises an active ingredient-contain(cid:173)
`ing layered composite, said layered composite being
`made by setting a slightly water-soluble active ingre(cid:173)
`dient-containing layer onto the internal layer con(cid:173)
`sisting of a sugar alcohol and a first disintegrant via
`a layer of a water-soluble polymer binder.
`
`[0021]
`(10) An oral preparation with good disinte(cid:173)
`gration, 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 alco(cid:173)
`hol and a first disintegrant.
`
`[0022]
`(11) The oral preparation with good disinte(cid:173)
`gration according to the above (10), which is in the
`form of a tablet.
`
`[0023]
`(12) An oral preparation with good disinte(cid:173)
`gration, which comprises an active ingredient-con(cid:173)
`taining granule, said granule being obtained by com(cid:173)
`bining a slightly water-soluble medicament, a sugar
`alcohol and a first disintegrant each other by a
`water-soluble polymer binder.
`
`[0024]
`(13) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0025]
`(14) The oral preparation with good disinte(cid:173)
`gration 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 ,urn.
`
`[0026]
`(15) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0027]
`(16) The oral preparation with good disinte(cid:173)
`gration according to any one of the above (1), (2),
`(3), ( 4), (5) and ( 6), wherein the water-soluble
`excipient is a sugar alcohol.
`
`[0028]
`(17) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0029]
`(18) The oral preparation with good disinte(cid:173)
`gration 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, maltotet(cid:173)
`raose, fructose, isomerized lactose, lactitol, honey
`sugar, D-sorbitol, D-mannitol, maltitol, erythritol,
`and xylitol.
`
`[0030]
`(19) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0031]
`(20) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0032]
`(21) The oral preparation with good disinte(cid:173)
`gration 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 com(cid:173)
`prises one or more water-soluble excipients selected
`from lactose, sucrose, fructo-oligosaccharide, para(cid:173)
`tinose, glucose, maltose, hydrogenated maltose, mal(cid:173)
`totetraose, fructose, lactulose, lactitol and honey
`sugar.
`
`[0033]
`(22) The oral preparation with good disinte(cid:173)
`gration 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, glu(cid:173)
`case, maltose, hydrogenated maltose, maltotetraose,
`fructose, lactulose, lactitol and honey sugar.
`
`[0034]
`(23) The oral preparation with good disinte(cid:173)
`gration 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 ,urn to 150 ,urn.
`
`[0035]
`(24) The oral preparation with good disinte(cid:173)
`gration 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
`,urn to 150 ,urn.
`
`[0036]
`(25) The oral preparation with good disinte(cid:173)
`gration according to any one of the above (1) to (12),
`wherein the first disintegrant is selected from corn
`starch, micro-crystalline cellulose, low substituted
`
`Par Pharm., Inc.
`Exhibit 1039
`Page 003
`
`

`

`US 2004/00287 41 A1
`
`Feb. 12,2004
`
`3
`
`hydroxypropyl-cellulose, carmellose, carmellose
`calcium, carmellose sodium, croscarmellose sodium,
`carboxymethyl starch sodium and crosspovidone.
`
`[0037]
`(26) The oral preparation with good disinte(cid:173)
`gration according to any one of the above (1) to (12),
`wherein the water-soluble polymer binder is selected
`from hydroxy-propylcellulose, hydroxypropylmeth(cid:173)
`ylcellulose, polyvinyl-pyrrolidone, polyvinyl alco(cid:173)
`hol, agar, starch, dextrin and gelatin.
`
`[0038]
`(27) The oral preparation with good disinte(cid:173)
`gration 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 phosphate, dibasic cal(cid:173)
`cium phosphate, microcrystalline cellulose, low sub(cid:173)
`stituted hydroxypropylcellulose, carmellose, carmel(cid:173)
`lose calcium, carmellose sodium, croscarmellose
`sodium, carboxymethyl starch sodium and cross(cid:173)
`povidone.
`
`[0039]
`(28) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0040]
`(29) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0041]
`(30) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0042]
`(31) The oral preparation with good disinte(cid:173)
`gration 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 ingre(cid:173)
`dient.
`
`[0043]
`(32) The oral preparation with good disinte(cid:173)
`gration 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 about 250 to 2000%
`by weight (w/w %, hereinafer the same) to the
`weight of the slightly water-soluble active ingredi(cid:173)
`ent.
`
`[0044]
`(33) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0045]
`(34) The oral preparation with good disinte(cid:173)
`gration 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 ingre(cid:173)
`dient.
`
`[0046]
`(35) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0047]
`(36) The oral preparation with good disinte(cid:173)
`gration 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.
`
`[0048]
`(37) A granule, which is obtained by granu(cid:173)
`lating with spraying an aqueous suspension contain(cid:173)
`ing a slightly water-soluble active ingredient and a
`water-soluble polymer binder to a mixture of a
`water-soluble excipient and a first disintegrant.
`
`[0049]
`(38) A slightly water-soluble active ingredi(cid:173)
`ent-containing granule, which is obtained by adding
`a water-soluble polymer binder to a powdery mixture
`consisting of a water-soluble excipient, a first excipi(cid:173)
`ent and a slightly water-soluble active ingredient and
`combining them each other.
`
`[0050]
`(39) A granule, which is obtained by granu(cid:173)
`lating with spraying an aqueous suspension contain(cid:173)
`ing a slightly water-soluble active ingredient and a
`water-soluble polymer binder to a mixture of a sugar
`alcohol and a first disintegrant.
`
`[0051]
`(40) A slightly water-soluble active ingredi(cid:173)
`ent-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 com(cid:173)
`bining them each other.
`
`[0052]
`(41) The oral preparation with good disinte(cid:173)
`gration 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-y 1)-1-piperaziny 1 ](cid:173)
`(2R, 3R)-2,3-tetra-methylenebutyl]-(1'R, 2'S, 3'R,
`4'S)-2,3-bicyclo[2.2.1 ]-heptanedicarboximide
`hydrochloride.
`
`[0053] 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-pip(cid:173)
`erazinyl]-(2R, 3R)-2,3-tetramethylenebutyl]-(1'R, 2'S, 3'R,
`4'S)-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride
`of the following formula:
`
`Par Pharm., Inc.
`Exhibit 1039
`Page 004
`
`

`

`US 2004/00287 41 A1
`
`Feb. 12,2004
`
`4
`
`:
`
`r \ N
`
`~H 0 K
`N",,,,,.··
`~ N N-s'-.S
`
`H
`
`-
`H
`
`\__ /
`
`- -
`
`HCl
`
`H H
`
`o
`
`~ j
`
`[0054]
`(hereinafter, referred to as Compound 1) (cf. Japa(cid:173)
`nese 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.
`
`[0055]
`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 ,urn.
`
`[0056] The "water-soluble polymer binder" includes, for
`example, hydroxypropylcellulose, hydroxypropylmethyl(cid:173)
`cellulose, polyvinylpyrrolidone, polyvinyl alcohol (partially
`saponificated one), pull ulan, starch, dextrin, gelatin, etc.,
`and preferable ones are hydroxypropyl-cellulose, hydrox(cid:173)
`ypropylmethylcellulose, polyvinyl-pyrrolidone, and polyvi(cid:173)
`nyl alcohol (partially saponificated one). These water(cid:173)
`soluble polymer binders may be used alone, or two or more
`thereof may be used together.
`
`[0057] The "first disintegrant" includes, for example, corn
`starch, microcrystalline cellulose, low substituted hydrox(cid:173)
`ypropylcellulose, carmellose, carmellose calcium, carmel(cid:173)
`lose 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 ,urn, and
`preferable first disintegrant is ones having an average par(cid:173)
`ticle diameter in the range of about 5 to about 75 ,urn,
`wherein the ratio of particles having a particle diameter of
`more than 75 ,urn is not more than 5% to the total.
`
`[0058] The "second disintegrant" includes, for example,
`lactose, anhydrous dibasic calcium phosphate, dibasic cal(cid:173)
`cium phosphate, microcrystalline cellulose, magnesium alu(cid:173)
`minometasilicate, synthesized hydrotalcite, synthesized alu(cid:173)
`minum silicate, low substituted hydroxypropyl cellulose,
`carmellose, carmellose calcium, carmellose sodium, cros(cid:173)
`carmellose sodium, carboxymethyl starch sodium, cross(cid:173)
`povidone, 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, car(cid:173)
`boxymethyl starch sodium, and crosspovidone. These sec(cid:173)
`ond disintegrants may be used alone, or two or more thereof
`may be used together.
`
`[0059] The average particle diameter of the second disin(cid:173)
`tegrant is, for example, in the range of about 5 to about 500
`,urn, preferably in the range of about 30 to 350 ,urn.
`
`[0060] The
`for
`includes,
`"water-soluble excipient"
`example, a sugar alcohol and a saccharide. Specific
`
`examples are saccharides such as lactose, sucrose, fructo(cid:173)
`oligo-saccharide, paratinose, glucose, maltose, hydroge(cid:173)
`nated maltose, maltotetraose, fructose, lactulose, lactitol,
`honey sugar, and sugar alcohols such as D-sorbitol, D-man(cid:173)
`nitol, maltitol, erythritol, and xylitol. These water-soluble
`excipients may be used alone, or one or more thereof may
`be used together.
`
`[0061] 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-sor(cid:173)
`bitol, D-mannitol, erythritol, xylitol, etc. In these cases, a
`saccharide such as lactose, sucrose, fructo-oligosaccharide,
`paratinose, glucose, maltose, hydrogenated maltose, mal(cid:173)
`totetraose, fructose, lactulose, lactitol, honey sugar, etc. may
`simultaneously be contained in said oral preparation.
`
`[0062] When orally administered, the oral preparation of
`the present invention can release a slightly water-soluble
`active ingredient rapidly and can show equivalent dissolu(cid:173)
`tion 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.
`
`[0063] 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.
`
`[0064] Preparation Method 1
`
`[0065]
`(1) Preparation of an Aqueous Solution of a Water(cid:173)
`Soluble Polymer Binder:
`
`[0066] 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.
`
`[0067]
`(2) Preparation of an Aqueous Suspension Con(cid:173)
`taining a Water-Soluble Polymer Binder and a Slightly
`Water-Soluble Active Ingredient:
`
`[0068] A slightly water-soluble active ingredient is dis(cid:173)
`persed and suspended in the aqueous water-soluble polymer
`binder solution obtained in the above (1), for example, at a
`
`Par Pharm., Inc.
`Exhibit 1039
`Page 005
`
`

`

`US 2004/00287 41 A1
`
`Feb. 12,2004
`
`5
`
`temperature of about 20° C. to about 90° C., preferably at a
`temperature of about 20° C. to 40° C.
`
`active ingredient and a water-soluble polymer binder to a
`mixture of a first disintegrant and a water-soluble excipient.
`
`[0069] 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.
`
`[0070] The slightly water-soluble active ingredient is pref(cid:173)
`erably finely milled, and the average particle diameter
`thereof is, for example, in the range of about 0.5 to 5 ,urn.
`
`[0071]
`(3) Mixing and Granulation of the Active Ingredi(cid:173)
`ent-Containing Aqueous Suspension with a First Disinte(cid:173)
`grant:
`
`[0072] 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
`obtained in the above (2), and the mixture is granulated.
`
`[0073] 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.
`
`[0074] The apparatus for granulation is, for example, ones
`classified into fluid bed granulation and rota granulation,
`and preferable one is a fluid bed granulator, a rota fluid bed
`granulator, etc.
`
`[0075] 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.
`
`[0076] 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.
`
`[0077]
`
`( 4) Drying of the Granule:
`
`[0078] The above granule containing a slightly water(cid:173)
`soluble active ingredient and a first disintegrant is dried
`either under reduced pressure or under atmospheric pres(cid:173)
`sure. 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.
`
`[0079]
`(5) Mixing of the Dried Granule and a Second
`Disintegrant:
`
`[0080] 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 tum(cid:173)
`bler, etc. The impact mills are, for example, a hammer
`conventional mill, etc.
`
`[0081] 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
`
`[0082]
`
`( 6) Blending of a Lubricant:
`
`[0083] 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 lubri(cid:173)
`cant.
`
`[0084] The lubricant may be blended by adding it into the
`mixture of the above (5). The mixing apparatus is, for
`example, ones classified into diffusion mixers (tumble mix(cid:173)
`ers), such as tumble blender, V blender, double cone, bin
`tumbler, etc.
`
`[0085] The lubricant is, for example, magnesium stearate,
`talc, hydrogenated oil, stearic acid, calcium stearate, glyc(cid:173)
`eryl behenate, sodium stearylfumarate, etc.
`
`[0086] 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.
`
`[0087]
`
`(7) Compression:
`
`[0088] The above mixture is compressed in a conventional
`manner to give tablets.
`
`[0089] The compression apparatus is preferably ones clas(cid:173)
`sified into tablet press.
`
`[0090] The compression hardness is, for example, in the
`range of about 50 to 200 N.
`
`[0091]
`
`(8) Film Coating:
`
`[0092] 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.
`
`[0093] The coating agent is, for example, a mixture of a
`base material (e.g., hydroxypropylmethylcellulose, hydro(cid:173)
`propyl-cellulose, polyvinylpyrrolidone, etc.) and a plasti(cid:173)
`cizer (e.g., polyethylene glycol, propylene glycol, triacetine,
`triethyl citrate, glycerin, glycerin fatty acid ester, polyeth(cid:173)
`ylene glycol, etc.). If necessary, an additive such as titanium
`oxide or mannitol may be added therein.
`
`[0094]
`
`(9) Drying:
`
`[0095] The tablets obtained above are dried. The drying is
`carried out either under reduced pressure or under atmo(cid:173)
`spheric 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.
`
`[0096] Preparation Method 2
`
`[0097]
`(1) Preparation of an Aqueous Solution of a Water(cid:173)
`soluble Polymer Binder:
`
`[0098] 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.
`
`Par Pharm., Inc.
`Exhibit 1039
`Page 006
`
`

`

`US 2004/00287 41 A1
`
`Feb. 12,2004
`
`6
`
`[0099]
`(2) Preparation of an Active Ingredient-Containing
`Granule:
`
`[0100] A slightly water-soluble active ingredient, a water(cid:173)
`soluble excipient and a first disintegrant are charged into a
`fluid bed granulator, and thereto is sprayed the aq