111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007141249B2
`
`c12) United States Patent
`Ohashi et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,141,249 B2
`*Nov. 28, 2006
`
`(54) RAPIDLY SOLUBLE DRUG COMPOSITION
`
`(75)
`
`Inventors: Mamoru Ohashi, Amagasaki (JP);
`Kazuyoshi Ogasawara,
`Kitakatsuragi-gun (JP); Yoshimi Shirai,
`Suita (JP); Hiroshi Fujioka, Ibaraki
`(JP)
`
`(73) Assignee: Dainippon Sumitomo Pharma Co.,
`Ltd., Osaka-fu (JP)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(58) Field of Classification Search ................ 514/249,
`514/951, 960; 424/94.4, 400, 464, 465, 489,
`424/451, 452, 470
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,910,022 A *
`3/1990 Bavitz eta!. ............... 424/465
`1111993 Negoro eta!. .............. 514/249
`5,258,382 A
`5,356,636 A * 10/1994 Schneider et a!.
`.......... 424/489
`5,858,410 A *
`111999 Muller et al ................ 424/489
`5,952,356 A *
`9/1999 Ikeda et a!. . . . . . . . . . . . . . . . . . 514/340
`6,297,244 B1 * 10/2001 Ohashi eta!. .............. 514/249
`6,458,811 B1* 10/2002 Arbuthnot et a!. .......... 514/324
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`FOREIGN PATENT DOCUMENTS
`
`(21)
`
`Appl. No.:
`
`09/529,715
`
`JP
`
`5-186472
`
`4/1996
`
`(22)
`
`PCT Filed:
`
`Oct. 15, 1998
`
`(86)
`
`PCTNo.:
`
`PCT I JP98/04658
`
`§ 371 (c)(l),
`(2), ( 4) Date: Apr. 19, 2000
`
`(87)
`
`PCT Pub. No.: W099/20277
`
`PCT Pub. Date: Apr. 29, 1999
`
`(65)
`
`Prior Publication Data
`
`US 2002/0197308 Al
`
`Dec. 26, 2002
`
`(30)
`
`Foreign Application Priority Data
`
`Oct. 20, 1997
`
`(JP)
`
`................................... 9-306635
`
`(51)
`
`Int. Cl.
`A61K 9120
`(2006.01)
`A61K 9114
`(2006.01)
`A61K 311495
`(2006.01)
`(52) U.S. Cl. ...................... 424/465; 424/464; 424/489;
`514/951; 514/960; 514/249
`
`OTHER PUBLICATIONS
`
`English Language Translation of the Document: "Design and Evalu(cid:173)
`ation of Peroral Pharmaceutical Preparations (In Japanese)", edited
`by Mitsuru Hashida, Yakugyo Jihosya, Feb. 10, 1995, pp. 81-84,
`168-171 (cited in the International Search Report of the original
`PCT/JP98/04658) thereof.
`
`(Continued)
`
`Primary Examiner-Sharmilla S. Gollamudi
`(7 4) Attorney, Agent, or Firm-Wenderoth, Lind & Ponack,
`L.L.P.
`
`(57)
`
`ABSTRACT
`
`A fast-dissolving pharmaceutical composition comprising
`micronized
`(R)-2-( 4-bromo-2-fluorobenzyl)-1 ,2,3,4-tet(cid:173)
`rahydropyrrolo[ 1 ,2-a ]pyrazine-4-spiro-3'-pyrrolidine-1 ,2' ,3,
`5'-tetrone (hereinafter, referred to as AS-3201). The present
`pharmaceutical composition has improved dissolution char(cid:173)
`acteristics as well as a good bioavailability.
`
`5 Claims, 1 Drawing Sheet
`
`110
`w 100
`C)
`~ 90
`z
`80
`w
`(..)
`70
`0:: w 60
`n.
`z
`50
`0
`40
`i=
`::J
`30
`__J
`0
`en en
`20
`10
`0
`
`--TabletA
`_._Tablet B
`__.._ Tablet C
`
`15
`
`30
`TIME (MIN.)
`
`45
`
`60
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 001
`
`

`

`US 7,141,249 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`English Language translation of the Document "Practical Drug
`Additives (In Japanese)", cited by Research Team Concerning Drug
`Additives, Mar. 5, 1974, pp. 215-217, 258-259 (cited in the Inter(cid:173)
`national Search Report of the original PCT /JP98/04658) thereof.
`Chemical Abstracts, 122, 9860 (1995) (English Abstract of JP-A-
`6-192222).
`Chemical Abstracts, 125, 221569 (1996) (English Abstract of JP-A-
`8-176105).
`
`J. Lutomski et al., "Postep W Technice Farrnaceutyusznej", p. 102,
`1981 (English translation also enclosed).
`"Design and Evaluation of Peroral Pharmaceutical Preparations (in
`Japanese)", edited by Mitsuru Hashida, Yakygyo Jihosha, Feb. 10,
`1995, pp. 81-84, 168-171, Trans. Sep. 20,2000.
`"Practical Drug Additives (in Japanese)", Research Team Concern(cid:173)
`ing Drug Additives, Mar. 5, 1974, pp. 258-259, Trans Sep. 26, 2000.
`* cited by examiner
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 002
`
`

`

`U.S. Patent
`
`Nov.28,2006
`
`US 7,141,249 B2
`
`FIG. 1
`
`110
`w 100
`(!)
`~ 90
`z
`80
`w
`(.)
`70
`0:: w 60
`a..
`z
`50
`0
`40
`1-
`::::»
`30
`_J
`0
`en en
`20
`10
`0
`
`0
`
`--e- Tablet A
`-Tablets
`__,..._ Tablet C
`
`0
`
`15
`
`30
`TIME (MIN.)
`
`45
`
`60
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 003
`
`

`

`US 7,141,249 B2
`
`1
`RAPIDLY SOLUBLE DRUG COMPOSITION
`
`TECHNICAL FIELD
`
`The present invention relates to a fast-dissolving pharma-
`ceutical composition of (R)-2-( 4-bromo-2-fluorobenzyl)-1,
`2,3 ,4-tetrahydropyrrolo[ 1 ,2-a ]pyrazine-4-spiro-3 '-pyrroli(cid:173)
`dine-1,2',3,5'-tetrone (hereinafter, referred to as "AS-3201")
`having a potent aldose reductase inhibitory activity.
`
`BACKGROUND ART
`
`AS-3201 is the compound of the following formula. Said
`compound is described in Example 22 of Japanese Patent
`No. 2516147 (U.S. Pat. No. 5,258,382), Reference Example
`12 of JP-A-6-192222 (Chern. Abstr., 122, 9860 (1995)), and
`Experiment of JP-A-8-176105 (Chern. Abstr., 125, 221569
`(1996)), and its potent aldose reductase inhibitory activities
`are disclosed therein.
`
`Example 28 of Japanese Patent No. 2516147 (USP
`5258382) describes a method for preparing specific tablets
`of AS-3201. That is, it is described therein that AS-3201 (1
`g), com starch (25 g), lactose (58 g), crystalline cellulose (11
`g), hydroxypropylcellulose (3 g), light anhydrous silicic acid
`(1 g) and magnesium stearate (1 g) are blended, granulated
`and made into 1,000 tablets each weighing 100 mg by a
`conventional method.
`During the studies on methods for preparing AS-3201-
`containing pharmaceutical compositions having an excellent
`bioavailability, the present inventors have found that the
`water-solubility of said substance is extremely low in the
`range oflow pH to the extent of several f.tg/ml, and therefore,
`the plasma concentration of AS-3201 varies widely among
`the individuals to be administered.
`Under such circumstances, the present inventors have
`further intensively studied, and have found that by using
`micronizedAS-3201 in a composition, the dissolution char(cid:173)
`acteristics of said substance from the composition are
`remarkably improved, and as a result, an AS-3201-contain(cid:173)
`ing fast-dissolving pharmaceutical composition having a
`good bioavailability can be obtained, and finally have
`accomplished the present invention.
`
`DISCLOSURE OF INVENTION
`
`The present invention provides a fast-dissolving pharma(cid:173)
`ceutical composition comprising micronized AS-3201.
`The terms used in the present specification are explained
`below.
`The "micronized AS-3201" means powders of AS-3201
`having a mean particle size of less than about 20 flill. The
`"mean particle size" means a particle size of being at 50%
`in cumulative particle distribution on weight or volume basis
`(ref., HA Lieberman et a!., "Pharmaceutical Dosage Forms:
`
`5
`
`20
`
`25
`
`2
`Tablets", Marcel Dekker, Inc., New York, 1990, vol. 2,
`174-186; Kouichi IINOYA (edit.) "Handbook of Powder
`and Particle Measurement (in Japanese)", The NIKKAN
`KOGYO SHINBUN LTD., 1981, 29-36). The "dissolution
`test" means a test in which the dissolution of AS-3201 from
`test pharmaceutical compositions in an amount correspond(cid:173)
`ing to 20 mg of AS-3201 is evaluated according to Paddle
`method (50 rpm) specified in the Twelfth Edition of the
`10 Pharmacopoeia of Japan, using a 0.2 M phosphate buffer
`(pH 6.5, 900 ml) as a test solution, and assaying AS-3201 by
`spectrophotometry at 300 nm. The "pKa 1 " means an acid
`dissociation exponent of an acidic substance at 25° C. in an
`infinitely diluted solution thereof. When an acidic substance
`15 is a polybasic acid, it means an acid dissociation exponent
`at the first step of dissociation. The "water-solubility" means
`a maximum amount of a solute being dissolved in 100 ml of
`water. The term "about" is used with the intention of
`including values following said term.
`The mean particle size of the micronized AS-3201 is
`preferably less than about 10 urn, more preferably less than
`about 5 flill, and most preferably in the range of about 0.5 urn
`to about 3 flill.
`According to the method disclosed in Japanese Patent No.
`2516147 (U.S. Pat. No. 5,258,382), crystals of AS-3201
`having a mean particle size of about 60 flill to about 120 flill
`can usually be obtained. The micronization of AS-3201
`crystals is carried out using a mill that is conventionally used
`30 in the pharmaceutical field. Mills are, for example, a fluid
`energy mill such as Jet Mill (manufactured by SEISHIN
`ENTERPRISE Co., LTD., Japan), a high speed rotative
`impact mill such as Sample Mill (manufactured by
`Hosokawa Micron Corporation, Japan), Pin Mill (manufac-
`35 tured by ALPINE, Germany), or Angmill (manufactured by
`Hosokawa Micron Corporation, Japan), a wet form high
`speed tumbling trituration mill such as MICROS (manufac(cid:173)
`tured by Nara Machinery Co., Ltd., Japan), and a tumbling
`mill such as a ball mill. In order to obtain micronized
`powders having a mean particle size of less than about 5 flill,
`a fluid energy mill is preferably used. The micronization can
`be carried out onAS-3201 crystals alone, or on a mixture of
`AS-3201 crystals and a part or whole of pharmaceutical
`excipients or carriers, which are used in the preparation of
`pharmaceutical compositions.
`The AS-3201-containing fast-dissolving pharmaceutical
`composition of the present invention may be solid dosage
`forms, and includes, for example, tablets, capsules, granules,
`50 powders, etc. These pharmaceutical compositions can be
`prepared by mixing micronized AS-3201 with pharmaceu(cid:173)
`tical excipients or carriers such as diluents, disintegrators,
`binders and lubricants by a conventional method. For
`example, the mixture is granulated by wet-granulation such
`55 as high-shear granulation, fluid bed granulation, agitation
`fluid bed granulation, centrifugal fluid bed granulation, or
`extrusion granulation, or by dry-granulation such as roller
`compaction or slugging, and then the resulting granules are
`60 put into capsules for capsule preparations, or compressed for
`tablet preparations. Alternatively, a mixture of micronized
`AS-3201 and pharmaceutical excipients or carriers can
`directly be put into capsules for capsule preparations, or
`compressed for tablet preparations. These pharmaceutical
`65 compositions may optionally be coated, or may additionally
`contain stabilizers, surfactants, coloring agents, flavoring
`agents, etc.
`
`40
`
`45
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 004
`
`

`

`US 7,141,249 B2
`
`4
`present composition usually comprises a diluent in a ratio of
`about 16% by weight-about 84.3% by weight, a disinte(cid:173)
`grator in a ratio of about 10% by weight-about 50% by
`weight, a binder in a ratio of about 0.5% by weight-about
`5% by weight, and a lubricant in a ratio of about 0.2% by
`weight-about 4% by weight, and more preferably, a diluent
`in a ratio of about 29% by weight-about 73.5% by weight,
`a disintegrator in a ratio of about 20% by weight-about
`40% by weight, a binder in a ratio of about 1% by weight-
`10 about 3% by weight, and a lubricant in a ratio of about 0.5%
`by weight-about 3% by weight.
`Since AS-3201 has an extremely low water-solubility to
`the extent of several flg/ml in the range of low pH, there is
`a correlation between the initial dissolution rate and the
`15 bioavailability of AS-3201-containing pharmaceutical com(cid:173)
`positions, and compositions having a better initial dissolu(cid:173)
`tion rate can show a better bioavailability. From the view(cid:173)
`point of the above, preferable compositions are ones having
`a dissolution percentage of the active substance of 50% or
`20 more for 15 minutes after the start of the dissolution test, and
`more preferable pharmaceutical compositions are ones hav(cid:173)
`ing a dissolution percentage of the active substance of 80%
`or more for 15 minutes after the start of the dissolution test.
`The AS-3201-containing fast-dissolving pharmaceutical
`25 composition of the present invention may be packed in a
`bottle using materials of low moisture-permeability or in
`damp-proof packages such as heat-sealed packages, if nee-
`essary.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`FIG. 1 is a graph showing a dissolution pattern of the
`tablets of Examples 1 and 2, and Comparative Example 1.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`3
`The pharmaceutical excipients or carriers may be any
`ones except for ones showing a bad compatibility with
`AS-3201. The diluents include, for example, lactose, starch,
`crystalline cellulose, D-mannitol, sucrose, glucose, erythri(cid:173)
`tol, xylitol, D-sorbitol, anhydrous dibasic calcium phos(cid:173)
`phate, and calcium sulfate. The disintegrators are, for
`example, starch, crystalline cellulose,
`low substituted
`hydroxypropylcellulose, carmellose, carmellose calcium,
`sodium carboxymethyl starch, croscarmellose sodium,
`partly pregelatinized starch, and hydroxypropyl starch. The
`binders are, for example, acacia, starch, hydroxypropylcel(cid:173)
`lulose, hydroxypropylmethylcellulose, polyvinyl alcohol,
`pullulan, gelatin, ethylcellulose, methylcellulose, carmel(cid:173)
`lose sodium, and dextrin. The lubricants are, for example,
`magnesium stearate, calcium stearate, stearic acid, sucrose
`esters of fatty acids, light anhydrous silicic acid, talc,
`hydrogenated oil, and macrogol.
`The stabilizer may be any pharmaceutically acceptable
`acidic substances having an acidity more potent than that of
`AS-3201, i.e., pKa=5.6-5.8, and preferable acidic sub(cid:173)
`stances are ones having a pKa 1 of less than about 4.5 and a
`water-solubility of larger than about 10 g/100 ml at 15°
`C.-25° C. More preferable acidic substances are ones having
`a pKa 1 ofless than about 3.3 and a water-solubility oflarger
`than about 50 g/100 ml at 15° C.-25° C. Especially prefer(cid:173)
`able acidic substances are, for example, citric acid, tartaric
`acid, maleic acid, and phosphoric acid. Among these acidic
`substances, tartaric acid is most preferable. The content of
`the acidic substance is preferably in the range of about 0.5%
`by weight to about 2.5% by weight. It is preferable to add a 30
`stabilizer in the case of preparing a pharmaceutical compo(cid:173)
`sition containing AS-3201 in a ratio ofless than about 5% by
`weight.
`The surfactants to be used in the present pharmaceutical
`composition are, for example, sorbitan fatty acid esters and 35
`polysorbates. The coloring agents are, for example, tar color,
`caramel, and red iron oxide. The flavoring agents are, for
`example, sweeteners and perfumes.
`The dissolution characteristics of the active substance
`from the composition can be remarkably improved by using
`micronizedAS-3201, and by further controlling the combi(cid:173)
`nation ratio of pharmaceutical excipients or carriers,
`AS-3201-containing fast-dissolving pharmaceutical compo(cid:173)
`sitions having more improved dissolution characteristics as
`well as good bioavailability can be obtained. The combina- 45
`tion ratio of the pharmaceutical excipients or carriers may
`vary depending on the content of AS-3201. The content of
`AS-3201 in the present fast-dissolving pharmaceutical com(cid:173)
`position is usually in the range of about 0.5% by weight to
`about 25% by weight, to the total weight of the pharmaceu- 50
`tical composition. When the content of AS-3201 is in the
`range of about 0.5% by weight to 5% by weight to the total
`weight of the pharmaceutical composition, then the phar(cid:173)
`maceutical composition usually comprises a diluent in a
`ratio of about 51% by weight-about 93.8% by weight, a 55
`disintegrator in a ratio of about 5% by weight-about 35%
`by weight, a binder in a ratio of about 0.5% by weight(cid:173)
`about 5% by weight, and a lubricant in a ratio of about 0.2%
`by weight-about 4% by weight. More preferably, the
`pharmaceutical composition comprises a diluent in a ratio of 60
`about 59% by weight-about 88% by weight, a disintegrator
`in a ratio of about 10% by weight-about 30% by weight,
`a binder in a ratio of about 1% by weight-about 3% by
`weight, and a lubricant in a ratio of about 0.5% by weight(cid:173)
`about 3% by weight. When the content of AS-3201 is more 65
`than 5% by weight and less than about 25% by weight to the
`total weight of the pharmaceutical composition, then the
`
`The present invention is illustrated in more detail by
`Examples and Comparative Example, but the present inven-
`40 tion should not be construed to be limited thereto. The mean
`particle size was measured using a laser diffraction particle
`size distribution analyzer (HELOS & RODOS (trademark),
`manufactured by SYMPATEC GmbH, Germany), and cal(cid:173)
`culated from cumulative particle distribution on volume
`basis by dry air dispersion method (dispersion air pressure:
`0.5 atm).
`
`EXAMPLE 1
`
`Preparation of tablets:
`
`AS-3201
`Tartaric acid
`Lactose
`Low substitnted hydroxypropylcellulose
`Hydroxypropylcellulose
`Magnesium stearate
`
`Total
`
`160 g
`8 g
`492 g
`300 g
`20 g
`~
`
`1000 g
`
`AS-3201 crystals were micronized using Single Truck Jet
`Mill (manufactured by SEISHIN ENTERPRISE CO., LTD.,
`hereinafter abbreviated as "Jet Mill") with compression air
`pressure of 6 kgf/cm2 to give powders having a mean
`particle size of about 1.5 flill· The micronized AS-3201
`powders thus obtained, lactose, and low substituted hydrox-
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 005
`
`

`

`US 7,141,249 B2
`
`5
`ypropylcellulose were charged into a fluid bed granulator
`and drier, and then the mixture was granulated by spraying
`thereto a solution of tartaric acid in a 5% aqueous hydrox(cid:173)
`ypropylcellulose solution. The granules were dried, and
`thereto was added magnesium stearate, and the mixture was
`blended in a V-blender. The resultant was compressed on a
`rotary tableting machine to give tablets weighing 125 mg
`and containing 20 mg of AS-3201 each.
`
`EXAMPLE 2
`
`10
`
`Preparation of Tablets:
`AS-3201 crystals were micronized by Sample Mill
`(manufactured by Hosokawa Micron Corporation) to give 15
`powders having a mean particle size of about 10 f.tm. The
`micronized AS-3201 powders thus obtained were granu(cid:173)
`lated, dried and compressed in the same manner as in
`Example 1, to give tablets weighing 125 mg and containing
`20 mg of AS-3201 each.
`
`20
`
`6
`dissolution percentage of the active substance from the
`tablets thus obtained for 15 minutes after the start of the
`dissolution test was 72.6%.
`
`EXAMPLE 4
`
`Preparation of tablets:
`
`AS-3201
`Tartaric acid
`Lactose
`Low substitnted hydroxypropylcellulose
`Hydroxypropylcellulose
`Magnesium stearate
`
`Total
`
`20 g
`8 g
`732 g
`200 g
`20 g
`20 g
`
`1000 g
`
`COMPARATIVE EXAMPLE 1
`
`Preparation of Tablets:
`Non-micronized AS-3201 crystals having a mean particle
`size of about 87 f.tm were granulated, dried and compressed
`in the same manner as in Example 1, to give tablets weighing
`125 mg and containing 20 mg of AS-3201 each.
`
`EXPERIMENT 1
`
`Dissolution Test:
`The dissolution of the active substance from the tablets
`obtained in Examples 1 and 2 and Comparative Example 1
`was evaluated according to Paddle method (50 rpm) speci(cid:173)
`fied in the Twelfth Edition of the Pharmacopoeia of Japan,
`using a 0.2 M phosphate buffer (pH 6.5, 900 ml) as a test
`solution. The quantitative assay of AS-3201 was carried out
`by spectrophotometry at 300 nm.
`The results are shown in FIG. 1. Each point of FIG. 1
`shows the mean value of the results in three repeats of the
`experiments on each tablet of Example 1, Example 2 and
`Comparative Example 1.
`As is shown in FIG. 1, the tablets of Example 1 and
`Example 2 show remarkably improved dissolution charac(cid:173)
`teristics, as compared with the tablets of Comparative
`Example 1.
`
`25
`
`AS-3201 crystals were micronized using Jet Mill with
`compression air pressure of 6 kgf/cm2
`, and the resultant was
`charged into a fluid bed granulator and drier together with
`lactose and low substituted hydroxypropylcellulose, and
`then, the resultant was granulated by spraying thereto a
`solution of tartaric acid in a 5% aqueous hydroxypropylcel(cid:173)
`lulose solution. The granules were dried, and thereto was
`added magnesium stearate, and the mixture was blended in
`30 a V-blender. The resultant was compressed on a rotary
`tableting machine to give tablets weighing 125 mg and
`containing 2.5 mg of AS-3201 each.
`The dissolution percentage of the active substance from
`35 the tablets thus obtained for 15 minutes after the start of the
`dissolution test was 93.0%.
`
`EXAMPLE 5
`
`40
`
`45
`
`Preparation of tablets:
`
`AS-3201
`Tartaric acid
`Lactose
`Low substitnted hydroxypropylcellulose
`Hydroxypropylcellulose
`Magnesium stearate
`
`80 g
`4 g
`246 g
`150 g
`10 g
`~
`
`500 g
`
`EXAMPLE 3
`
`50
`
`Total
`
`Preparation of tablets:
`
`AS-3201
`Tartaric acid
`Lactose
`Low substitnted hydroxypropylcellulose
`Hydroxypropylcellulose
`Magnesiwn stearate
`
`Total
`
`160 g
`10 g
`600 g
`200 g
`20 g
`~
`
`1000 g
`
`The above components were treated in the same manner 65
`as in Example 1, and compressed to give tablets weighing
`125 mg and containing 20 mg of AS-3201 each. The
`
`AS-3201 crystals were micronized using Jet Mill with
`compression air pressure of 6 kgf/cm2
`, and thereto were
`55 added lactose and low substituted hydroxypropylcellulose,
`and then, the resulting mixture was blended in a Versatile
`Mixer for 5 minutes. To the mixture was added a solution of
`tartaric acid in a 4% aqueous hydroxypropylcellulose solu(cid:173)
`tion, and the mixture was further kneaded for 10 minutes.
`60 The mixture was dried, and thereto was added magnesium
`stearate, and the resulting mixture was compressed on a
`single-pnnch tableting machine to give tablets weighing 125
`mg and containing 20 mg of AS-3201 each.
`The dissolution percentage of the active substance from
`the tablets thus obtained for 15 minutes after the start of the
`dissolution test was 93.2%.
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 006
`
`

`

`US 7,141,249 B2
`
`7
`EXAMPLE 6
`
`8
`
`-continued
`
`Pre12aration of tablets:
`
`Preparation of tablets:
`
`AS-3201
`Lactose
`Low substitnted hydroxypropylcellulose
`Hydroxypropylcellulose
`Magnesiwn stearate
`
`Total
`
`144 g
`549 g
`180 g
`18 g
`~
`
`900 g
`
`Low substitnted hydroxy-
`propylcellulose
`Hydroxypropylcellulose
`Magnesium stearate
`
`10
`
`Total
`
`Ex. 10
`
`Ex. 11
`
`Ex. 12
`
`200 g
`
`240 g
`
`280 g
`
`20 g
`20 g
`
`20 g
`20 g
`
`20 g
`20 g
`
`1000 g
`
`1000 g
`
`1000 g
`
`AS-3201 crystals were micronized using Jet Mill with
`compression air pressure of 6 kgf/cm2
`, and the resultant was
`put into a fluid bed granulator and drier together with lactose
`and low substituted hydroxypropylcellulose, and then, the
`mixture was granulated by spraying thereto a 5% aqueous
`hydroxypropylcellulose solution. After drying, to the gran(cid:173)
`ules was added magnesium stearate, and the mixture was
`blended in a V-blender. The resultant was compressed on a
`rotary tableting machine to give tablets weighing 125 mg
`and containing 20 mg of AS-3201 each.
`The dissolution percentage of the active substance from
`the tablets thus obtained for 15 minutes after the start of the 25
`dissolution test was 92.0%.
`
`AS-3201 micronized using Jet Mill was granulated, dried
`and compressed in the same manner as in Example 1 to give
`15 tablets weighing 125 mg and containing 10 mg of AS-3201
`each.
`The dissolution percentages of the active substance from
`the tablets of Examples 10, 11 and 12 for 15 minutes after
`the start of the dissolution test were 89.4%, 91.6% and
`20 92.2%, respectively.
`
`INDUSTRIAL APPLICABILITY
`
`As explained above, theAS-3201-containing fast-dissolv(cid:173)
`ing pharmaceutical composition of the present invention has
`improved dissolution characteristics as well as a good bio(cid:173)
`availability.
`
`EXAMPLES 7-9
`
`Pre12aration of tablets:
`
`AS-3201
`Tartaric acid
`Lactose
`Low substitnted hydroxy-
`propylcellulose
`Hydroxypropylcellulose
`Magnesium stearate
`
`Ex. 7
`
`Ex. 8
`
`Ex. 9
`
`40 g
`8 g
`712 g
`200 g
`
`20 g
`20 g
`
`40 g
`8 g
`672 g
`240 g
`
`20 g
`20 g
`
`40 g
`8 g
`632 g
`280 g
`
`20 g
`20 g
`
`Total
`
`1000 g
`
`1000 g
`
`1000 g
`
`30
`
`40
`
`AS-3201 micronized using Jet Mill was granulated, dried 45
`and compressed in the same manner as in Example 1 to give
`tablets weighing 125 mg and containing 5 mg of AS-3201
`each.
`The dissolution percentages of the active substance from
`the tablets of Examples 7, 8 and 9 for 15 minutes after the 50
`start of the dissolution test were 91.0%, 94.5% and 92.7%,
`respectively.
`
`EXAMPLES 10-12
`
`Pre12aration of tablets:
`
`Ex. 10
`
`Ex. 11
`
`Ex. 12
`
`80 g
`8 g
`672 g
`
`80 g
`8 g
`632 g
`
`80 g
`8 g
`592 g
`
`AS-3201
`Tartaric acid
`Lactose
`
`60
`
`The invention claimed is:
`1. A fast-dissolving pharmaceutical composition in a solid
`dosage form, comprising micronized (R)-2-( 4-bromo-2-
`fluorobenzyl)-1 ,2,3,4-tetrahydropyrrolo[ 1 ,2-a ]pyrazine-4-
`spiro-3'-pyrrolidine-1 ,2',3,5'-tetrone (hereinafter referred to
`35 as "AS-3201") having a mean particle size of in a range of
`about 1.5 f.Ull to less than about 10 f.Ull in a ratio of about
`0.5% by weight to about 25% by weight of the total weight
`of the pharmaceutical composition, and as a stabilizer at
`least one acidic substance having a pKa less than about 5.6,
`wherein the acidic substance is a member selected from
`the group consisting of citric acid, tartaric acid, maleic
`acid, and phosphoric acid, and
`wherein when in a dissolution percentage of AS-3201
`from the composition is measured according to the
`Paddle method, 50% or more of the AS-3201 in the
`composition is dissolved with 15 minutes from the start
`of the method.
`2. The
`fast-dissolving pharmaceutical compos1t10n
`according to claim 1, wherein the mean particle size of the
`micronizedAS-3201 is in the range of about 1.5 f.tm to about
`5 pin.
`fast-dissolving pharmaceutical compos1t10n
`3. The
`according to claim 1, wherein the mean particle size of the
`55 micronizedAS-3201 is in the range of about 1.5 f.tm to about
`3 f.tm.
`fast-dissolving pharmaceutical compos1t10n
`4. The
`according to claim 1, wherein the solid dosage form is
`tablets, capsules, granules or powder.
`5. The
`fast-dissolving pharmaceutical compos1t10n
`according to claim 1, wherein the acidic substance is tartaric
`acid.
`
`* * * * *
`
`Par Pharm., Inc.
`Exhibit 1038
`Page 007
`
`