Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 1 of 10
`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 1 of 10
`
`EXHIBIT 2
`EXHIBIT 2
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 2 of 10
`
`1111111111111101111111111111M141115111111,3111 11111111111111111111111
`
`(12) United States Patent
`Muramatsu et al.
`
`US 6,465,477 B1
`(lo) Patent No.:
`(45) Date of Patent:
`Oct. 15, 2002
`
`(54) STABLE PHARMACEUTICAL
`COMPOSITION
`
`(75) Inventors: Toyojiro Muramatsu, Shizuoka (JP);
`Katsumi Mashita, Fuji (JP); Yasuo
`Shinoda, Shizuoka (JP); Hironori
`Sassa, Numazu (JP); Hiroyuki
`Kawashima, Fuji (JP); Yoshio
`Tanizawa, Okayama (JP); Hideatsu
`Takeuchi, Fuji (JP)
`
`(73) Assignees: Kowa Company, Ltd., Aichi-Ken (JP);
`Nissan Chemical Industries, Ltd.,
`Tokyo (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.
`
`(21) Appl. No.: 09/436,789
`
`(22) Filed:
`
`Nov. 8, 1999
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 08/894,279, filed on
`Aug. 18, 1997, now abandoned.
`
`(51) Int. CI.' A61K 31/435; A61K 31/44;
`A61K 31/19
`
`(52) U.S. Cl. 514/277; 514/306; 514/569;
`514/970
`(58) Field of Search 514/256, 277,
`514/306, 415, 569, 970
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,302,604 A * 4/1994 Byrne et al. 514/338
`5,356,896 A 10/1994 Kabidi et al. 514/256
`
`* cited by examiner
`
`Primary Examiner—Frederick Krass
`Assistant Examiner—Donna Jagoe
`(74) Attorney, Agent, or Finn—Peter F. Corless; Christine
`C. O'Day; Edwards & Angell, LL.P
`
`(57)
`
`ABSTRACT
`
`Disclosed is a pharmaceutical composition comprising (E)-
`3,5-dihydroxy-744'-4"-fluoropheny1-2'-cyclopropyl-
`quinolin-3'-y11-6-heptenoic acid, or its salt or ester, of which
`the aqueous solution or dispersion has pH of from 6.8 to 8.
`The composition has good time-dependent stability and has
`no change in its outward appearance even after having been
`stored long.
`
`15 Claims, 2 Drawing Sheets
`
`[NK-104]
`
`After 2 days at 40°C(pH3)
`
`Data: NK98601.D07 Method: NKSPD.MET Ch=1
`mAbs Chrom: NK98601.007 Atten5
`
`IS
`
`NK-104
`
`30-
`
`20-
`
`10-
`
`Lacton
`
`e_
`
`LACTONE
`
`5
`
`10
`
`15
`
`20
`min
`
`IS: Internal Standard
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 3 of 10
`
`U.S. Patent
`
`Oct. 15, 2002
`
`Sheet 1 of 2
`
`US 6,465,477 B1
`
`[N K-104]
`
`After 2 days at 40°C(pH3)
`
`Data: NK98601.D07 Method: NKSPD.MET Ch=1
`mAbs Chrom: NK98601.007 Atten5
`Ii
`S
`
`NK-104
`
`30-
`
`20-
`
`10-
`
`0
`
`0
`
`Lactone
`
`LACTON E
`
`5
`
`10
`
`15
`
`IS: Internal Standard
`
`20
`min
`
`FIG. 1
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 4 of 10
`
`U.S. Patent
`
`Oct. 15, 2002
`
`Sheet 2 of 2
`
`US 6,465,477 B1
`
`Data: R980605.D03 Method: Ch=1
`mAChrom: R980605.0O3 Atten4
`12.879
`'5.552
`
`15
`
`[Fluvastatin]
`
`10
`
`5
`
`3.849
`
`14.505
`
`0 '
`1_ 4.893
`0 5 10 15 20
`min
`After 2 days at 40°C(pH3)
`
`Data: R980601.D16 Method: FLUVADEG.MET Ch=1
`mAbs Chrom: NK980601.C16 Atten4
`
`15-
`
`IS
`
`Fluvastatin
`
`10-
`
`OH OH
`
`COOH
`
`Fluvastatin
`
`20
`
`40
`
`IS: Internal Standard1
`
`60
`min
`
`FIG. 2
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 5 of 10
`
`US 6,465,477 B1
`
`1
`STABLE PHARMACEUTICAL
`COMPOSITION
`
`2
`higher, desirably pH 9 or higher, but unexpectedly, it has
`been found that NK-104 and its salts and esters are still
`unstable even within a high pH range.
`Therefore, preparations comprising NK-104 or its salt or
`s ester, if formulated in conventional manners, have low
`time-dependent stability, and are problematic in that their
`outward appearance changes with the lapse of time. Given
`the situation, the development of stable preparations com-
`prising it is desired.
`
`The present application is a continuation-in-part of U.S.
`application Ser. No. 08/894,279 filed Aug. 18, 1997, now
`abandoned.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a pharmaceutical com-
`position with high stability and, more precisely, to a phar-
`maceutical composition comprising an HMG-CoA reductase
`inhibitor of which the stability varies depending on pH,
`especially (E)-3,5-dihydroxy-744'-4"-fluoropheny1-2'-
`cyclopropyl-quinolin-3'-y1]-6-heptenoic acid, or its salt or
`ester.
`
`BACKGROUND OF THE INVENTION
`
`It is known that 7-substituted-3,5-dihydroxy-6-heptenoic
`acids of a general formula:
`
`OH
`
`OH
`
`R
`
`COOII
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein R represents an organic group, have HMG-CoA
`reductase-inhibiting activity, and are useful as medicines for
`hyperlipemia and also as medicines for atherosclerosis (see
`U.S. Pat. Nos. 4,739,073, 5,001,255, 4,751,235, 4,804,679,
`EP-B-304,063).
`However, these 7-substituted-3,5-dihydroxy-6-heptenoic
`acids are unstable at low pH, and require some particular
`means for formulating them into preparations. A means of
`formulating them along with an alkaline medium, such as
`calcium carbonate or sodium carbonate, into preparations 35
`with pH of 8 or higher (see U.S. Pat. No. 5,356,896), and a
`means of formulating them along with a basic agent, such as
`magnesium oxide or sodium hydroxide, into preparations
`with pI-I of 9 or higher (see EP-B-336,298) have been
`proposed.
`(E)-3,5-dihydroxy-7-[4'-4 "-iluorophehy1-2
`'-cyclopropyl-quinolin-3'-y1]-6-heptenoic acid (hereinafter
`this may be referred to as NK-104) to be represented by a
`structural formula:
`
`40
`
`45
`
`50
`
`OH
`
`SUMMARY OF THE INVENTION
`
`We the present inventors have variously studied in order
`to obtain stable pharmaceutical compositions comprising
`NK-104 and, as a result, have found unexpectedly that
`NK-104 is stable within a relatively low pH range. On the
`basis of this finding, we have completed the present inven-
`tion.
`Furthermore, we investigated decomposition products of
`NK-104 and fluvastatin in an aqueous solution of pH3. The
`decomposition product of NK-104 was found in small
`quantity and consisted only of the lactonized form of
`NK-104 (see FIG. 1). On the other hand, decomposition
`products of fluvastatin were found in relatively large quan-
`tities consisting of tnore than one type of products which are
`believed to include an optical isomer and a lactonized form
`of fluvastatin (see FIG. 2). These results showed that the
`decomposition pattern and stability of NK-104 and fluvas-
`tatin were different in the same pH.
`In addition, we have further found that, if a basic sub-
`stance is added to a pharmaceutical composition comprising
`NK-104 in such a manner that the aqueous solution or
`dispersion of the composition may have pH of from 6.8 to
`8, the composition is stable.
`An object of the present invention is to provide a phar-
`maceutical composition comprising NK-104, or its salt or
`ester, of which the aqueous solution or dispersion has pI-I of
`from 6.8 to less than 8, preferably has pH of from 6.8 to 7.8.
`The active ingredient of the composition of the present
`invention is NK-104 to be represented by the above-
`mentioned structural formula. The configuration in this
`substance, NK-104 is not specifically defined herein. In
`addition, NK-104 may be in any form of its salts and esters.
`The salts include, for example, sodium salt, potassium salt
`and calcium salt. Preferred is calcium salt of NK-104.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`FIG. 1 is a histogram of NK-104 decomposition products
`analyzed by I-IPLC.
`FIG. 2 shows histograms of fluvastatin decomposition
`products analyzed by HPLC.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`or its salt or ester is one of HMG-CoA reductase inhibitors
`that are represented by the above-mentioned general
`formula, and is known to be useful as a medicine for
`hyperlipemia and also as a medicine for atherosclerosis (see
`EP-B-304,063). NK-104 is also unstable at low pH, and
`many difficulties have been encountered in formulating it
`into preparations.
`It has been reported that these HMG-CoA reductase
`inhibitors are formulated into preparations with pH 8 or
`
`55
`
`The pH as referred to herein indicates the pH value to be
`determined in such a manner that a unit close of a solid
`preparation comprising NK-104 or its salt or ester is
`sampled and dissolved or dispersed in from 1 to 10 ml of
`so pure water, and the pII of the resulting aqueous solution or
`dispersion is measured.
`A basic substance may be added to the pharmaceutical
`composition comprising NK-104 to control the pH of the
`composition, which may be any of antacids and pH regula-
`65 tors including, for example, antacids such as magnesium
`aluminometasilicate, magnesium aluminosilicate, magne-
`sium aluminum silicate, magnesium aluminate, dry alumi-
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 6 of 10
`
`US 6,465,477 B1
`
`3
`num hydroxide, synthetic hydrotalcite, synthetic aluminum
`silicate, magnesium carbonate, precipitated calcium
`carbonate, magnesium oxide, aluminum hydroxide, and
`sodium hydrogencarbonate; and pH regulators such as
`L-arginine, sodium phosphate, disodium
`hydrogenphosphate, sodium dihydrogenphosphate, potas-
`sium phosphate, dipotassium hydrogenphosphate, potas-
`sium dihydrogenphosphate, disodium citrate, sodium
`succinate, ammonium chloride, and sodium benzoate. Of
`these, preferred are magnesium aluminometasilicate, mag-
`nesium aluminosilicate, and L-arginine.
`Even more preferred are basic substances that may be
`added to the pharmaceutical composition comprising
`NK-104 to control the pH of the composition and that
`maintain the outward appearance and stability of said com-
`position. These may be any of alkaline earth metal silicates
`including aluminum, and organic base compounds. For
`example, alkaline earth metal means magnesium, calcium,
`barium, etc. Preferred is magnesium. Particularly preferred
`alkaline earth metal silicates including aluminum are mag-
`nesium aluminometasilicate (NEUSILIN FH2), magnesium
`aluminosilicate (NEUSILIN A), and magnesium aluminum
`silicate (VEEGUM F). The preferred organic base is argin-
`ine. An even more preferred base is L-arginine.
`The pharmaceutical composition of the present invention
`can be formulated into various forms of preparations, but
`preferred are peroral solid preparations. For example, the
`composition may be formulated into tablets, granules,
`powders, troches, capsules, chewables, film-coated prepara-
`tions of these, and even sugar-coated preparations thereof.
`Where the pharmaceutical composition of the present
`invention is formulated into such peroral solid preparations,
`any of vehicles (excipients), binders, disintegrators and
`lubricants can be added thereto, if desired. The preparations
`may be formulated from the composition along with any of
`these, in any ordinary manner.
`The vehicles (excipients) include, for example, lactose,
`corn starch, denatured corn starch, mannitol, sorbitol, wood
`cellulose, fine crystalline cellulose and calcium carbonate,
`which can be used either singly or as combined.
`The binders include, for example, hydroxypropyl
`cellulose, hydroxypropylmethyl cellulose, polyvinyl
`pyrrolidone, polyvinyl alcohol, and partial saponificates of
`these, which can be used either singly or as combined.
`Especially preferred is hydroxypropylmethyl cellulose.
`The disintegrators include, for example, low substituted
`hydroxypropyl cellulose, carmellose, sodium carboxystarch,
`calcium carmellose, corn starch, partially-alphatized starch,
`sodium closcarmellose and clospovidone, which can be used
`either singly or as combined. Especially preferred is low
`substituted hydroxypropyl cellulose.
`The lubricants includes, for example, magnesium stearate,
`stearic acid, palmitic acid, calcium stearate and talc, which
`can be used either singly or as combined.
`The amounts of the ingredients constituting the compo-
`sition of the present invention are not specifically defined.
`For example, the amount of NK-104 or its salt or ester may
`be from 0.01 to 40% by weight, preferably from 0.05 to 10%
`by weight, more preferably from 0.5 to 5% by weight; ancl
`the basic substance may be added to the composition in such
`an amount that is necessary for making the aqueous solution
`or dispersion of the composition have pH of from 6.8 to less
`than 8. Where the composition is formulated into peroral
`solid preparations, it is desirable that the vehicle is added
`thereto in an amount of from 30 to 95% by weight, the
`binder in an amount of from 1 to 20% by weight, the
`
`20
`
`4
`disintegrator in an amount of from 1 to 30% by weight, and
`the lubricant in an amount of from 0.5 to 10% by weight.
`If further desired, any additional components, such as
`sweeteners, flavorings and colorants may also be added to
`s the composition of the present invention.
`The necessary amount of the basic substance to be added
`to the composition of the invention in order to make the
`aqueous solution or dispersion of the composition have pH
`of from 6.8 to less than 8 may be from about 1 to 6.5% by
`in weight or so, if magnesium aluminometasilicate
`(NEUSILIN FH2) is used, from about 0.5 to 2% by weight
`or so, if magnesium aluminosilicate (NEUSILIN A) is used,
`from about 2 to 8% by weight or so, if magnesium alu-
`minium silicate (VEEGAM I?) is used, or from about 0.01 to
`15 0.1% by weight or so, if L-arginine is used singly. As
`mentioned above, it is preferable that the basic substance is
`used singly. However, two or more such basic substances
`can be used in combination.
`The composition of the present invention can be coated to
`give film-coated tablets or sugar-coated tablets. As the
`coating base, for example, usable are celluloses such as
`hydroxypropyl cellulose, hydroxypropylmethyl cellulose;
`and also aminoalkyl methacrylate copolymer E, white sugar,
`and pullulan. As the plasticizer for the base, for example,
`usable are macrogol 6000, triethyl citrate, and triacetylpro-
`pylene glycol.
`The pharmaceutical composition of the present invention
`can be produced according to any ordinary methods employ-
`30 able in producing peroral solid preparations. If stirring
`granulation is employed, this may be conducted as follows.
`First, NK-104, a basic substance, a vehicle, a binder and a
`disintegrator are mixed. Next, water is added to the resulting
`mixture, then granulated with stirring, dried and dressed to
`35 give dry granules. Further, the granules are mixed with a
`lubricant, and pelletized with a pelletizer into pellets. Also
`employable is fluidized bed granulation, which may be
`conducted as follows. First, NK-104, at basic substance, a
`vehicle and a disintegrator arc mixed. Then, an aqueous
`40 solution of a binder is sprayed over the resulting mixture,
`using a fluidized bed granulator, to prepare granules. These
`granules are mixed with a lubricant, and then pelletized with
`a pelletizer into pellets.
`Using ordinary coating devices, the pellets as produced
`45 according to the above-mentioned methods can be coated
`with a solution or suspension comprising a coating base and
`optionally a plasticizer and a colorant to give film-coated
`tablets or sugar-coated tablets.
`
`25
`
`BEST MODES OF CARRYING OUT TIIE
`INVENTION
`
`Examples of the pharmaceutical composition of the
`present invention are mentioned below, which, however, are
`not intended to restrict the scope of the invention.
`
`50
`
`55
`
`Example 1.
`
`Decomposition Products of NK-104 and
`Fluvastatine
`
`60
`
`Decomposition products of NK-104 were analyzed by
`HPLC after incubation for two days at 40° C. in aqueous
`solution of pH 3. NK-104 produced a single product, a
`lactonized form of NK-104 (see FIG. 1).-The decomposition
`products of fluvastatin were also analyzed for comparison.
`65 Fluvastatin produced many types of products, which are
`believed to include an optical isomer of fluvastatin and a
`lactonized form of fluvastatin (see FIG. 2).
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 7 of 10
`
`US 6,465,477 131
`
`5
`The conditions under which NK-104 and Fluvastatine
`decomposition products were analyzed are as follows:
`HPLC system: Type LC-10 (Shinn( Japan)
`Column: DEVELOSIL ODS-HG-5 (NOMURA CHEM.,
`Japan)
`Mobil Phase: Me0H/0.02 mol/L phosphate buffer (pH
`3)=.7/3
`Sample: NK-104 or fluvastatin/pH 3/40° C., 2 days
`Detector: SPD-MLOAVP, UV 245 mm
`NK-104 and fluvastatin have common a-&-dihydroxy-e-
`ene carboxylic acid chemical structure. However, NK-104
`and fluvastatin differ in the types and amount of decompo-
`sition products. Namely, NK-104 provides a small quantity
`of one type of decomposition product while fluvastatin
`provides comparatively large quantities of different types of
`decomposition products (see FIGS. 1 and 2). Such differ-
`ences show that stability of each depends not only on the
`chemical structure of a-b-dihydroxy-e-ene carboxylic acid
`but also on the chemical structures that arc unique to each.
`In the following examples, the low substituted hydrox-
`ypropyl cellulose was commercially available as sold for a
`medicine additive and contains from 5-16% of -0C,1160I1
`group. Hydroxypropylmethyl cellulose 2910 contains
`28-30% -00-13 and 7-12% -0C,116-OH. Both low
`substituted hydroxypropyl cellulose and hydroxypropylm-
`ethyl cellulose 2910 as used in the examples are described
`in 'The Pharmacopoeia of Japan, 12th edition.
`
`Example 2
`Herein produced were tablets each having the composi-
`tion mentioned below.
`
`Calcium Salt of NK-104
`Lactose
`Low Substituted Hydroxypropyl Cellulose
`Hydroxypropylmethyl Cellulose 2910
`Magnesium Aluminometasilicate
`Magnesium Stearate
`
`'Fotal (one tablet)
`
`1.0 mg
`101.4
`12.0
`2.0
`2.4
`12
`
`120.0
`
`The components of the above-mentioned composition,
`except magnesium stearate, were mixed to prepare a homo-
`geneous powdery mixture, to which was added a suitable
`amount of pure water. The resulting mixture was granulated
`with stirring, and pelletized to give pellets. Magnesium
`stearate was added to and mixed with these pellets, which
`were then tabletted into NK-104-containing tablets.
`
`Example 3
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`
`Calcium Salt of NK-104
`Lactose
`Low Substituted Hydroxypropyl Cellulose
`Hydmxypropylmethyl Cellulose 2910
`Dipotassium Hydrogenphosphate
`Magnesium Stearate
`
`Total (one tablet)
`
`1.0 mg
`102.8
`12.0
`2.0
`1.0
`1.2
`
`120.0
`
`6
`
`Calcium Salt of NK-104
`Lactose
`Low Substituted Hydroxypropyl Cellulose
`Hydroxypropylmethyl Cellulose 2910
`L-argininc
`Magnesium Stearate
`
`Total (one tablet)
`
`1.0 mg
`103.7
`12.0
`2.0
`0.1
`1.2
`
`120.0
`
`5
`
`10
`
`Example 5
`
`In the same manner as in Example 2, herein produced
`15 were tablets each having the composition mentioned below.
`
`Calcium Salt of NK-104
`Lactose
`Low Substituted Hydroxypropyl Cellulose
`Hydroxypropylmethyl Cellulose 2910
`Magnesium Aluminometasilicate
`Magnesium Stearate
`
`Total (one tablet)
`
`1.0 mg
`103.2
`12.0
`2.0
`0.6
`1.2
`
`120.0
`
`20
`
`25
`
`TEST 1
`
`The pH of a 5% suspension of tablets produced in any of
`30 Examples 2 to 5 (the suspension was prepared by suspend-
`ing one tablet in 2.4 ml of pure water) was measured.
`After having been stored at 60° C. for 2 weeks, the
`percentage retention of calcium salt of NK-104 in the tablets
`was measured according to HPLC. After having been stored
`35 at 60° C. for 3 days, the change in the outward appearance
`of the tablets was observed. The test results are shown in
`Table 1.
`
`40
`
`TABLE 1
`
`pIl of 5% Suspension
`Percentage Retention of
`Ca NK-104
`45 Change in Outward
`Appearance
`
`Example 2 Example 3 Example 4 Example 5
`
`7.8
`97%
`
`7.7
`97%
`
`7.5
`93%
`
`7.'1
`92%.
`
`No change No change No change No change
`
`Control Examples 1 to 3
`
`50
`
`In the same manner as in Example 2, herein produced
`were control tablets each having the composition mentioned
`below. These tablets were tested in the same manner as in
`Test 1, to determine the pH of the 5% suspension of each
`55 tablet, the percentage retention of Ca NK-104, and the
`change in the outward appearance of the tablets. The test
`results are shown in Table 2.
`
`'IA13111 2
`
`60
`
`Example 4
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`
`Ca NK-104
`Lactose
`65 Low Substituted Hydro
`Cellulose
`
`YProPYI
`
`Control
`Exa m plc
`1
`
`Control
`Control
`Example Example
`2
`3
`
`1.0 mg
`103.8
`12.0
`
`1.0 mg
`98.8
`12.0
`
`1.0 mg
`98.8
`12.0
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 8 of 10
`
`US 6,465,477 B1
`
`7
`
`8
`
`TABLE 2-continued
`
`TABLE 4-continued
`
`Hydroxypropyl Cellulose
`2910
`Sodium Ascorbate
`Ascorbic Acid
`Magnesium Stearate
`Total (one tablet)
`pH of 5% Suspension
`Percentage Retention of Ca NK-104,
`after stored at 60° C. for 2 weeks
`Change in Outward Appearance, after
`stored at 60° C. for 3 days
`
`Control
`Control
`Example Example
`1
`2
`
`Control
`Example
`3
`
`2.0
`
`1.2
`120.0
`6.6
`88%
`
`2.0
`
`5.0
`
`120.0
`6.3
`77%
`
`2.0
`
`5.1)
`
`120.0
`3.3
`38%
`
`No change No change No change
`
`Example
`7
`
`Control
`Control
`Example 5 Example 6
`
`1.2
`120.0
`7.5
`93.4
`
`Magnesium Stearate
`Total (one tablet)
`ptI of 5% Suspension
`NK-104 remaining (%) after 2 weeks
`at 60° C.
`Changed -
`No
`10 Change in Outward Appearance, after
`to brown
`change
`2 weeks at 60° C.
`Change in Outward Appearance, after - - Changed
`stored at 60° C. for 3 days
`to pale
`yellowish
`green
`
`1.2
`1.2
`120.0
`120.0
`9.3
`9.8
`66.0 -
`
`15
`
`As in Tables 1 and 2 showing the test results, it is obvious
`that the percentage retention of Ca NK-104 in the 5%
`suspension of the composition having pH of 7 or higher is
`high, after having been stored at 60° C. for 2 weeks, while
`the same in the 5% suspension thereof having pH of lower
`than 6.6 becomes lower with the decrease in the pH value
`thereof.
`
`Example 8 and Control Example 7
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`20 These tablets were tested in the same manner as in Test 1, to
`determine the pH of the 5% suspension of each tablet, and
`the change in the outward appearance of the tablets. The test
`results are shown in Table 5.
`
`Example 6 and Control Example 4
`
`25
`
`TABLE 5
`
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`These tablets were tested in the same manner as in Test 1, to
`determine the pH of the 5% suspension of each tablet, and
`the change in the outward appearance of the tablets. The test
`results are shown in Table 3.
`
`TABLE 3
`
`Example 6 Control Example 4
`
`Ca NK-104
`Lactose
`Low Substituted Hydroxypropyl
`Cellulose
`Hydroxypropylmethyl Cellulose 2910
`Magnesium Aluminometasilicate
`Magnesium Stearate
`Total (one tablet)
`pI-I of .5% Suspension
`Change in Outward Appearance, after
`stored at 60° C. for 3 days
`
`1.0 mg
`101.4
`12.0
`
`1.0 mg
`93.9
`12.0
`
`2.0
`2.0
`9.9
`2.4
`1.2
`1.2
`120.0
`120.0
`8.3
`7.8
`No change Changed to pale
`yellowish brown
`
`Ca NK-104
`
`30 el°scLow Substituted Hydroxypropyl Cellulose
`
`Hydroxypropylmethyl Cellulose 2910
`Sodium Hydrogencarbonatc
`Magnesium Stearate
`Total (one tablet)
`3s pH of 5% Suspension
`Change in Outward Appearance, after
`stored at 60° C. for 3 days
`
`Example 8 Control
`Example 7
`
`1.0 mg
`101.8
`12.0
`2.0
`2.0
`1.2
`120.0
`7.8.
`No change
`
`1.0 mg
`9.3.9
`12.0
`2.0
`9.9
`1.2
`120.0
`9.8
`Changed to
`dark navy
`blue
`
`40
`
`Example 9 and Control Example 8
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`These tablets were tested in the same manner as in Test 1, to
`determine the pH of the 5% suspension of each tablet, and
`45 the change in the outward appearance of the tablets. The test
`results are shown in Table 6.
`
`Example 7 and Control Examples 5 and 6
`
`TABLE 6
`
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below,
`These tablets were tested in the same manner as in 'lest 1, to
`determine the pH of the 5% suspension of each tablet, and
`the change in the outward appearance of the tablets. 'The test
`results are shown in Table 4.
`
`TABLE 4
`
`Ca NK-104
`Lactose
`Low Substituted Hydroxypropyl
`Cellulose
`Hydroxypropylmethyl Cellulose 2910
`TC-5R
`L-arginine
`
`Example
`7
`
`Control
`Example 5
`
`Control
`Example 6
`
`1.0 mg
`103.7
`12.0
`
`1.0 mg
`95.8
`12.0
`
`1.0 mg
`93.9
`12.0
`
`2.0
`
`0.1
`
`2.0
`8.0
`
`2.0
`
`9.9
`
`50
`
`Ca NK-104
`Lactose
`Low substituted Hydroxypropyl Cellulose
`55 Hydroxypropylmethyl Cellulose 2910
`Dipotassium Hydrogenphosphate
`Magnesium Stearate
`Total (one tablet)
`pH of 5% Suspension
`Change in Outward Appearance, after stored at
`60° C. for 3 days
`
`60
`
`Example 9 Control
`Example 8
`
`1.0 mg
`102.8
`12.0
`2.0
`1.0
`1.2
`120.0
`7.7
`No change
`
`1.0 mg
`93.9
`12.0
`2.0
`9.9
`1.2
`120.0
`8.4
`Changed
`to orange
`
`As is obvious from the test results in Tables 3 to 6, no
`change in the outward appearance of the tablets was found
`when the 5% suspensions of the tablets had pH of 8 or lower,
`65 even after having been stored at 60° C. for 3 days, but the
`outward appearance of the tablets changed when the 5%
`suspensions of the tablets had pH of higher than 8.
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 9 of 10
`
`US 6,465,477 B1
`
`9
`Example 10
`
`Magnesium Aluminometasilicate
`In the same manner as in Example 2, herein produced
`were tablets each having the composition 'petitioned below.
`The tablets were tested in the same manner as in Test 1 to
`determine the pH of the 5% suspension of each tablet, but
`the percentage retention of Ca NK-104 and the change in
`outward appearance of the tablets were observed one, month
`after storing at 60° C. The test results are shown in Table 7.
`
`10
`The tablets were tested in the same manner as in Test 1 to
`determine the pH of the 5% suspension of each tablet, but
`the percentage retention of Ca NK-104 and the change in
`outward appearance of the tablets were observed one month
`5 after storing at 60° C. The test results are shown in Table 9.
`
`'FABLE 7
`
`10
`
`t
`
`2
`
`3
`
`4
`
`5
`
`1.0 mg 1.0 mg 1.0 mg 1.0 mg 1 0 mg
`53.8
`101.4
`100.8
`91.8
`0
`12.0
`12.0
`12.0
`12.0
`12.0
`
`15
`
`2.0
`
`2.4
`
`1.2
`120.0
`7.8
`97.4
`
`2.0
`
`3.0
`
`2.0
`
`2.0
`
`2.0
`
`12.0
`
`50.0
`
`103.8
`
`20
`
`1.2
`120.0
`8.4
`92.2
`
`1.2
`120.0
`9.0
`84.5
`
`1.2
`120.0
`9.3
`69.1
`
`TABLE 9
`
`2
`
`4
`
`1.0 mg
`100.2
`12.0
`
`1.0 mg 1.0 mg 1.0 mg 1.0 mg
`99.4
`97.8
`91.8
`43.8
`12.0
`12.0
`12.0
`12.0
`
`2.0
`
`2.0
`
`12.0
`
`60.0
`
`2.0
`
`3.6
`
`1.2
`120.0
`7.5
`97.7
`
`2.0
`
`4.4
`
`1.2
`120.0
`8.2
`98.8
`
`2.0
`
`6.0
`
`1.2
`120.0
`8.7
`98.2
`
`1.2
`120.0
`9.1
`92.5
`
`1.2
`120.0
`9.7
`84.3
`
`Gray
`
`No
`change
`
`No
`change
`
`Pale
`yellow
`
`Pale
`gray
`
`Ca NK-104
`Lactose
`Low substituted
`Hydroxypropyl Cellulose
`Hydioxyptopylmethyl
`Cellulose 2910
`Magnesium Aluminum
`Silicate
`Magnesium Stearate
`Total (one tablet)
`pH of 5% Suspension
`NK-104 remaining rate
`(%) after 1 month at
`60° C.
`Change in Outward
`Appearance, after stored
`at 60° C. for 1 month
`
`1.2
`120.0
`8.1
`96.5
`
`No
`change
`
`Pale
`yellow
`
`Pale
`yellow
`
`Pale
`yellow
`
`No
`change
`
`25
`
`INDUSTRIAL APPLICABILITY OF THE
`INVENTION
`
`Ca NK-104
`Lactose
`Low substituted
`Hydroxypropyl Cellulose
`Hydroxypropylmethyl
`Cellulose 2910
`Magnesium
`Aluminotnetasilicate
`Magnesium Stearate
`Total (one tablet)
`pH of 5% Suspension
`NK-104 remaining rate
`(%) after 1 month at
`60° C.
`Change in Outward
`Appearance, after
`stored at 60° C.
`for 1 month
`
`30
`
`Example 11
`
`Magnesium Aluminosilicate
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`The tablets were tested in the same manner as in Test 1 to
`determine the pH of the 5% suspension of each tablet, but
`the percentage retention cif Ca NK-104 was observed at both
`2 weeks and one month after storing at 60° C. and the change
`in outward appearance of the tablets was observed one
`month after storing at 60° C. The test results are shown in
`Table 8.
`
`TABLE 8
`
`1
`
`2
`
`3
`
`4
`
`5
`
`1.0 mg 1.0 nig
`103.2
`102.6
`12.0
`12.0
`
`1.0 mg 1.0 mg 1.0 mg
`101.8
`98.8
`96.8
`12.0
`12.0
`12.0
`
`2.0
`
`0.6
`
`1.2
`120.0
`6.8
`97.3
`
`2.0
`
`1.2
`
`1.2
`120.0
`7.8
`98.5
`
`2.0
`
`2.0
`
`1.2
`120.0
`8.1
`91.7
`
`2.0
`
`5.0
`
`1.2
`120.0
`8.4
`87.4
`
`2.0
`
`7.0
`
`1.2
`120.0
`8.7
`86.8
`
`97.5
`
`93.5
`
`87.2
`
`80.7
`
`79.1
`
`No
`change
`
`No
`change
`
`No
`change
`
`No
`change
`
`No
`change
`
`Ca NK-104
`Lactose
`Low substituted
`Hydroxypropyl Cellulose
`Hydrox ypropylmethyl
`Cellulose 2910
`Magnesium
`Aluminosilicate
`Magnesium Stearate
`Total (one tablet)
`pH of 5% Suspension
`NK-104 remaining rate
`(%) after two weeks at
`60° C.
`NK-104 remaining rate
`(%) after 1 month at
`60° C.
`Change in Outward
`Appearance, after stored
`al 60° C. for 1 month
`
`Example 12
`
`Magnesium Aluminum XSilicate
`In the same manner as in Example 2, herein produced
`were tablets each having the composition mentioned below.
`
`The pharmaceutical composition of the present invention
`has good time-dependent stability, with having no change in
`the outward appearance thereof even after having been
`stored long. Therefore, the composition is good in medical
`use, especially in the form of peroral solid preparations.
`The pharmaceutical compositions of the present invention
`35 that contains NK-104 or salt or ester thereof are especially
`useful for treating a patient, particularly a human, that is
`suffering from or susceptible to hyperlipemia or atheroscle-
`rosis by administering the pharmaceutical composition to
`such patient.
`Particularly preferred unit dosages have been described in
`the examples above. It will be appreciated the specifically
`preferred dosage amounts of a pharmaceutical composition
`of the invention used in a given therapy will vary according
`to various known factors such as the particular compositions
`formulated, the specific compound utilized, the mode of
`application, the particular site of administration, etc. Opti-
`mal administration rates for a given protocol of administra-
`tion can be readily ascertained by those skilled in the art
`using conventional dosage determination tests conducted
`50 with regard to the foregoing guidelines.
`The invention has been described in detail with reference
`to preferred embodiments thereof. However, it will be
`appreciated that those skilled in the art, upon consideration
`of this disclosure, may make modifications and improve-
`55 mcnts within the spirit and scope of the invention as set forth
`in the following claims.
`What is claimed is:
`1. A pharmaceutical composition comprising (E)-3,5-
`dihydroxy-744'-4"-fluroplienyl-2'-cyclopropyl-quinolin-3'-
`y11-6-heptenoic acid, or its salt. or ester, and a pharmaceu-
`tically acceptable carrier, of which an aqueous solution or
`dispersion of the pharmaceutical composition has pH of
`from 6.8 to 7.8.
`2. The pharmaceutical composition as claimed in claim 1,
`65 wherein the salt of (E)-3,5-dihydroxy-744'-4"-
`fluorophenyl-2'-cyclopropyl-quinolin-3'-y1]-6-heptenoic
`acid is a calcium salt of the acid.
`
`40
`
`45
`
`60
`
`

`

`Case 1:14-cv-02758-PAC Document 63-2 Filed 05/08/15 Page 10 of 10
`
`US 6,465,477 B1
`
`11
`3. The pharmaceutical composition of claim 1 wherein the
`composition further comprises a basic substance.
`4. The pharmaceutical composition of claim 3 wherein the
`basic substance is an organic base compound.
`5. The pharmaceutical composition of claim 3 wherein the
`basic substance is an alkaline earth metal silicate.
`6. The pharmaceutical composition of claim 5 wherein the
`basic substance is an aluminum compound.
`7. The pharmaceutical composition of claim 5 wherein the
`alkaline earth metal silicate is a magnesium salt.
`8. The pharmaceutical composition of claim 3 wherein the
`basic substance is one or more selected from magnesium
`aluminometasilicate, magnesium aluminosilicate and mag-
`nesium aluminum silicate.
`9. The pharmaceutical composition of claim 3 wherein the
`basic substance is L-arginie.
`10. The pharmaceutical composition of claim 3 wherein
`the composition further comprises at least one material
`
`12
`selected from the group consisting of vehicles,
`disintegrators, binders and lubricants.
`11. The pharmaceutical composition of claim 3 wherein
`the composition further comprises a peroral solid prepara-
`5 tion.
`12. The pharmaceutical composition of claim 3 wherein
`the composition further comprises a lactose vehicle.
`13. The pharmaceutical composition of claim 3 wherein
`the composition further comprises hydroxypropyl cellulose
`with a low degree of substitution.
`14. The pharmaceutical composition of claim 3 wherein
`the composition further comprises a binder of hydroxy
`propylmethyl cellulose.
`15. The pharmaceutical composition of claim 1 wherein
`the composition further comprises at least one material
`selected from the group consisting of vehicles,
`disintegrators, binders and lubricants.
`
`5
`
`in
`
`