United States Patent c191
`Stupak et al.
`
`[54] CONTROLLED RELEASE FLUTAMIDE
`COMPOSITION
`
`[75]
`
`Inventors: Elliot Stupak, West Caldwell; W.
`Philip Cho, Princeton, both of N.J.
`
`[73] Assignee: Scbering Corporation, Kenilworth,
`N.J.
`
`[21] Appl. No.: 796,195
`
`[22] Filed:
`
`Nov. 22, 1991
`
`Int. Cl.s .......................... A61K 9/30; A61K 9/24
`[51]
`[52] U.S. Cl ..................................... 424/475; 424/472;
`424/474;424/476;424/479;424/480;424/481;
`424/482; 424/465; 424/497
`[58] Field of Search ............... 424/464, 465, 497, 472,
`424/474,475,476,479,480,481,482
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US005162117A
`5,162,117
`[11] Patent Number:
`[45] Date of Patent: Nov. 10, 1992
`
`[56]
`
`l{eferences Cited
`U.S. PATENT DOCUMENTS
`4,329,364 5/1982 Neri et al. ........................... 424/324
`4,474,813 10/1984 Neri et al. ........................... 424/324
`
`FOREIGN PATENT DOCUMENTS
`2222947 3/1990 United Kingdom .
`Primary Examiner-Thurman K. Page
`Assistant Examiner-James M. Spear
`Attorney, Agent, or Firm-John J. Maitner; Eric S.
`Dicker
`ABSTRACT
`[57]
`A controlled release solid dosage tablet of flutamide is
`disclosed that is designed to provide an immediate re(cid:173)
`lease dose and a second delayed dose in· pulsatile man(cid:173)
`ner in the gastrointestinal tract for twice a day use.
`
`9 Claims, No Drawings
`
`1
`
`Complex Innovations EX 1004
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`1
`
`CONTROLLED RELEASE FLUTAMIDE
`COMPOSITION
`
`5, 162,117
`
`10
`
`15
`
`BACKGROUND OF THE INVENTION
`The present invention relates to pharmaceutical com(cid:173)
`positions of flutamide. Specifically, the invention relates
`to a controlled release form which is designed to pro(cid:173)
`vide an immediate release dose and a second delayed
`dose.
`U.S. Pat. No. 4,329,364 discloses that flutamide is
`useful in treating, alleviating and palliation of androgen(cid:173)
`caused and/or androgen-dependant conditions such as
`prostatic hyperplasia, for example benign prostatic hy-
`pertrophy and prostatic carcinoma.
`· U.S. Pat. No. 4,474,813 discloses conventional phar(cid:173)
`maceutical preparations of flutamide adapted for sys(cid:173)
`temic administration providing a therapeutic effect
`against prostatic carcinoma.
`Flutamide which has the chemical name 2-methyl-N- 20
`[4-nitro-3-(trifluoromethyl)phenyl]propanamide, or N(cid:173)
`isobutyryl-4-nitro-3-trifluoromethylanilide, is a nonste(cid:173)
`roidal compound devoid of androgenic, adrenocortical,
`anti-estrogenic, estrogenic, progestational, and antifer(cid:173)
`tility actions. This compound has proved to be a potent 25
`antiandrogen and is approved for the palliative treat(cid:173)
`ment of advanced prostate cancer in man. The ap(cid:173)
`proved therapeutic dose is 750 mg/day of flutamide in
`three divided doses of 250 mg/dose. The approved
`product, Eulixin @, is available in capsules containing 30
`125 mg of flutamide, therefore, the patient takes two
`·
`capsules three times a day. Patient compliance with the
`recommended dosage schedule is sometimes poor, since
`a large number of patients undergoing this treatment are
`elderly and are forgetful.
`One of the objects of the present invention was to
`develop a controlled release oral dosage form of fluta(cid:173)
`mide which would allow for twice a day use. In addi(cid:173)
`tion, the novel controlled release dosage form would
`provide comparable bioavailability when compared to 40
`the standard capsule dosage form.
`
`2
`360,000), citric acid, succinic acid and bile acid. The
`preferred carriers are polyethylene glycols which are
`linear polymers formed by the addition reaction of eth(cid:173)
`ylene oxide. The polyethylene glycols utilized in this
`5 invention are solids at room temperature with molecu(cid:173)
`lar weights of 1,000 to 20,000. Examples of polyethyl(cid:173)
`ene glycols useful in the formulation of this invention
`are commercially available from Union Carbide Corpo-
`ration in various grades under the trademark Car(cid:173)
`bowax @. A particularly useful polyethylene glycol is
`Carbowax ® 3350 which has a molecular weight range
`of 3000 to 3700 and a melting range of 54 • to 58° C. This
`material is also known as PEG-75 according to the
`Cosmetic, Toilertries and Frangrances Association
`(CTFA) nomenclature.
`The tablet core may also include other auxiliary ex(cid:173)
`cipients, such as, diluents, lubricants, glidants and dis(cid:173)
`integrants.
`Examples of diluents that may be utilized in the pres(cid:173)
`ent invention include: dicalcium phosphate, calcium
`phosphate, lactose, cellulose, mannitol, sodium chlo(cid:173)
`ride, starch, and microcrystalline cellulose. The pre-
`ferred diluent in the core is microcrystalline cellulose.
`The diluent comprises from about 15 to 35 percent by
`weight of the core and preferably 23 percent by weight
`of the core.
`Examples of lubricants that may be utilized in the
`present invention include talc, magnesium stearate, cal(cid:173)
`cium stearate, stearic acid, hydrogenated vegetable oils.
`and the like. The preferred lubricant in the core is mag(cid:173)
`nesium stearate. The lubricant comprises from about 0.1
`to 1.0 percent by weight of the core and preferably 0.26
`percent by weight of the core.
`Examples of glidants that may be utilized in the pres(cid:173)
`ent invention include silicon dioxide and talc. The pre(cid:173)
`ferred glidant in the core is silicon dioxide. The glidant
`comprises from about 0.5 to 2.0 percent by weight of
`the core and preferably 1.33 percent by weight of the
`core.
`Examples of disintegrants that may be utilized in this
`invention include starches, celluloses, algins, gums,
`cross-linked polymers, such as croscarmellose sodium
`(a crosslinked polymer of carboxymethylcellulose so(cid:173)
`dium), crospovidone and the like. The preferred disinte(cid:173)
`grant in the core is the croscarmellose sodium. The
`disintegrant comprises from about 4 to 12 percent by
`weight of the core, preferably 8 percent by weight of
`the core.
`The core component of the tablet of this invention is
`coated with an enteric coating material. The enteric
`coating resists solution in gastric fluid but disintegrates
`and dissolves in the intestine. The enteric coating com(cid:173)
`prises 4 to 15 percent by weight of the core, and prefera-
`bly 6 to 12 percent by weight of the core. Examples of
`enteric coatings that may be utilized in the present in-
`vention include polyvinyl acetate phthalate, meth(cid:173)
`acrylic acid copolymer, hydroxypropyl methylcellulose
`phthalate, hydroxypropyl methylcellulose acetate suc(cid:173)
`cinate, cellulose acetate phthalate, cellulose acetate
`succinate and cellulose acetate trimellitate.
`The preferred enteric coating material is polyvinyl
`acetate phthalate (PV AP). This enteric coating is pro(cid:173)
`duced by the esterification of a partially hydrolyzed
`polyvinyl acetate with phthalic anhydride. The acetate
`polymer is low molecular weight and 87 to 89 mole
`percent hydrolyzed. An example of a PV AP prepara(cid:173)
`tion useful in the formulation of this invention is com-
`
`35
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention provides a controlled release 45
`solid dosage form of flutamide. The controlled release
`dosage form is designed to provide an immediate release
`dose and a second delayed dose in pulsatile manner in
`the gastrointestinal tract for twice a day use. The de(cid:173)
`sired release is obtained by forming a core containing a 50
`rapidly dissolving solid dispersion of flutamide in a
`carrier which is capable of forming a solid dispersion
`with flutamide. The release of flutamide from the core is
`delayed by coating the .core tablet with a barrier or
`enteric coating. A layer of flutamide is then applied to 55
`the coated core tablet to provide the immediate release
`initial dose.
`The core of the novel table formulation provides the
`second dose of this invention comprising 20 to 80 per(cid:173)
`cent by weight of the total amount of flutamide in the 60
`tablet and a carrier capable of forming a solid dispersion
`with flutamide, said carrier being present in the range of
`1:1 to 1:5 parts by weight of the flutamide in the core,
`and preferably 1:3 parts by weight of flutamide in the
`core.
`Carriers utilized in the core of the tablet are selected
`from the group consisting of polyethylene glycols,
`polyvinylpyrrolidones, (molecular weight 10,000 to
`
`65
`
`2
`
`

`
`5,162,117
`
`4
`-continued
`
`INGREDIENTS
`
`MG/TABLET
`
`Sodium Laury! Sulfate
`Calcium Sulfate
`Acacia
`Butylparaben
`Sugar
`Dye Color Dispersion (Solids)
`White Wax
`Carnauba Wax
`Approximate Coating Weight
`Approximate Coated Tablet Weight
`
`3.2
`220
`27
`0.03
`200
`14
`0.3
`0.3
`674
`1124
`
`3
`mercially available from Colorcon, Inc., West Point,
`Pa.
`The immediate release initial dose component of the
`tablet of the present invention contains flutamide. The
`amount of flutamide present in the immediate release 5
`outer coating is 80 to 20 percent of the total amount of
`flutamide in the tablet. The amount of immediate dose
`flutamide is applied to the enteric coated core as a dust(cid:173)
`ing powder. The flutamide may be combined with aux(cid:173)
`iliary excipients, such as the excipients utilized in pre- IO
`paring the core of this invention. Examples of such
`excipients include lactose, croscarmellose sodium, so(cid:173)
`dium lauryl sulfate, calcium sulfate, microcrystalline
`cellulose and acacia which is utilizied as a binder.
`In preparing the tablet of the invention, conventional 15
`tabletting techniques are employed to prepare the core
`component. For example, dry granulation, wet granula(cid:173)
`tion or direct compression can be used to prepare the
`core. One method for manufacturing the core for the
`tablet of this invention involves forming a solid disper- 20
`sion by melting the carrier material and dissolving the
`flutamide in the melted carrier material. After the solid
`dispersion solidifies, the dispersion is milled using con(cid:173)
`ventional milling equipment. Any other ingredients
`such as diluents (e.g. microcrystalline cellulose), disinte- 25
`grants (e.g. sodium croscarmellose), glidants (e.g. sili(cid:173)
`con dioxide), lubricants (e.g. magnesium stearate) and
`the like are added to the milled solid dispersion material,
`mixed and compressed into a suitable size and shape
`using conventional tabletting machines.
`The core material is then coated with an enteric coat(cid:173)
`ing known to those skilled in the art (e.g. polyvinyl
`acetate phthalate) using conventional coating tech-
`niques.
`·
`The immediate release dose of flutamide is then ap- 35
`plied as a dusting powder to the enteric coated core.
`The flutamide dusting powder is prepared by blending
`flutamide with excipients such as lactose, croscarmel(cid:173)
`lose sodium and sodium lauryl sulfate in a suitable
`mixer. The enteric coated cores are coated with the 40
`flutamide dusting powder using a binder (e.g. acacia)
`with suitable coating equipment. The tablets may then
`be used as is or they can be film, sugar and color coated
`by techniques well known in the art.
`The following examples described typical tablet for- 45
`mulations, dissolution profiles and a bioavailability
`study of the controlled release dosage forms of the
`present invention, but are not to be interpreted as limit(cid:173)
`ing the scope of the appended claims in any way.
`
`Preparation of the tablet is as follows:
`Core:
`A solid dispersion was prepared by melting the poly(cid:173)
`ethylene glycol in a suitable size container. The fluta(cid:173)
`mide was dissolved in the melted polyethylene glycol
`and the solid dispersion was allowed to solidify. The
`solid dispersion was milled using a suitable size screen.
`The flutamide solid dispersion was blended with the
`microcrystalline cellulose, sodium croscarmellose, sili(cid:173)
`con dioxide and magnesium stearate in a suitable mixer.
`The blended material was compressed into a suitable
`size and shape core tablet.
`B. Enteric and Active Coatings:
`The cores were coated with an enteric material (e.g.
`polyvinyl acetate phthalate) in a suitable coating pan. A
`precoat and/or overcoat of HPMC/PEG may be ap-
`30 plied if desired. A flutamide dusting powder was pre(cid:173)
`pared by blending flutamide, lactose, croscarmellose
`sodium and sodium lauryl sulfate in a suitable mixer.
`The enteric coated cores were coated with the fluta-
`mide dusting powder using acacia as binder in a suitable
`coating pan. The tablets may then coated with a film
`coat, sugar coat or color coat using standard proce-
`dures. The coated tablets can be polished using the wax
`solutions.
`Release rates of the tablet of this example were deter(cid:173)
`mined using U.S.P. paddle method (as described in
`U.S.P. XXII) at 75 revolutions per minute in 1000 ml of
`0.05 sodium phosphate monobasic in 3% SLS, pH 3.0.
`After the second hour 5.0 ml of 15% sodium hydroxide
`was added to provide a pH 6. A typical profile is shown
`below:
`
`so
`
`In-Vitro Tablet Dissolution
`Time (hour)
`Percent Dissolved
`
`2
`3
`4
`
`60
`102
`IOI
`
`EXAMPLE2
`A controlled release tablet was prepared from the
`following ingredients:
`
`60
`
`INGREDIENTS
`
`MG/TABLET
`
`Core Tablet
`Autamide
`Polyethylene Glycol 3350
`Microcrystalline Cellulose
`Sodium Croscarmellose
`Silicon Dioxide
`Magnesium Stearate
`Approximate Core Tablet Weight
`Coating
`
`65
`
`75
`225
`106.8
`36
`6
`__ 1._2_
`450
`
`EXAMPLE 1
`A controlled release tablet was prepared from the
`following ingredients:
`
`INGREDIENTS
`
`MG/TABLET
`
`Core Tablet
`Autamide
`Polyethylene Glycol 3350
`Microcrystalline Cellulose
`Sodium Croscarmellose
`Silicon Dioxide
`Magnesium Stearate
`Approximate Core Tablet Weight
`Coating
`Flutamide
`Polyvinyl Acetate Phthalate
`HPMC/PEG Clear Solution (Solids)
`Hydrous Lactose
`Sodium Croscarmellose
`
`75
`225
`106.8
`36
`6
`__ 1._2_
`450
`
`112.5
`45
`6.75
`28.9
`16.1
`
`3
`
`

`
`5
`-continued
`
`I.NGREDIENTS
`Flutamide
`Polyvinyl Acetate Phthalate
`HPMC/PEG Clear Solution (Solids)
`Hydrous Lactose
`Sodium Croscarmellose
`Sodium Laury! Sulfate
`Calcium Sulfate
`Acacia
`Butylparaben
`Sugar
`Approximate Coating Weight
`Approximate Coated Tablet Weight
`
`5,162,117
`
`5
`
`MG/TABLET
`112.5
`27
`4-0
`28.9
`16.1
`3.2
`77.4
`25.9
`0.03
`10
`~
`435
`885
`
`6
`lose acetate phthalate, cellulose acetate succinate and
`cellulose acetate trimellitate.
`6. The controlled release tablet of claim S wherein the
`enteric coating is polyvinyl acetate phthalate.
`7. A controlled release flutamide tablet which com(cid:173)
`prises:
`(a) a core comprising:
`20 to 80 percent by weight of the total weight of
`flutamide in the tablet and a carrier capable of
`forming a solid solution with flutamide, said
`carrier being present in the range of 1:1 to 1:5
`parts by weight of the flutamide in the core;
`15 to 35 percent by weight of the core of a diluent;
`0.1 to 1 percent by weight of the core of a lubri(cid:173)
`cant;
`0.5 to 2 percent by weight of the core of a glidant;
`4 to 12 percent by weight of the core of a disinte(cid:173)
`grant;
`{b) 4 to 15 percent by weight of the core of an enteric
`coating; and
`(c) 80 to 20 percent by weight of total amount of
`flutamide in the tablet is present in the immediate
`release outer coating.
`8. A controlled release tablet comprising:
`
`The tablet was prepared according to the procedure 15
`of Example 1.
`Release rates of the tablet of this example were deter(cid:173)
`mined using U.S.P. paddle method (as described in
`U.S.P. XXII) at 75 revolutions per minute in 1000 ml of
`0.05 sodium phosphate monobasic in 3% SLS, pH 3.0. 20
`After the second hour 5.0 ml of 15% sodium hydroxide
`was added to provide a pH 6. A typical profile is shown
`below:
`
`· Jn-Vitro Tablet Dissolution
`Percent Dissolved
`Time (hour)
`58
`2
`98
`3
`101
`4
`
`25
`
`30
`
`The tablets of the above example were tested in a
`randomized, open-label four-way crossover design
`wherein the volunteers received each of the following
`treatments:
`Treatment A: Two 125 mg flutamide conventional cap- 35
`sules (Eulixin @-Schering Labs) at 8 a.m., 4 p.m. and
`12 midnight.
`Treatment B: Two 187.5 mg tablets of the above exam(cid:173)
`ple at 8 a.m. and 8 p.m.
`Results of the study demonstrated comparable bi- 40
`oavailability (area under the curve-ADC) between the
`Eulixin ® capsule and the tablets of this invention.
`We claim:
`1. A controlled release flutamide tablet comprising:
`(a) a core which comprises 20 to 80 percent by weight 45
`of the total weight of flutamide in the tablet and a
`carrier capable of forming a solid dispersion with
`flutamide, said carrier being present in the range of
`1:1 to 1:5 parts by weight of the flutamide in the
`core;
`{b) 4 to 15 percent by weight of the core of an enteric
`coating material; and
`(c) 80 to 20 percent by weight bf the total amount of
`flutamide in the tablet is present in the immediate
`release outer coating.
`2. The controlled release tablet of claim 1 wherein the 55
`carrier material in the core is selected from the group
`consisting of polyethylene glycol, polyvinylpyrroli(cid:173)
`done, citric acid, succinic acid and bile acid.
`3. The controlled release tablet of claim 1 wherein the
`carrier material in the core is polyethylene glycol.
`4. The controlled release tablet of claim 1 wherein the
`range of carrier present in the core is 1:3 by weight of
`the flutamide in said core.
`S. The controlled release tablet of claim 1 wherein the
`enteric coating is selected from the group consisting of 65
`polyvinyl acetate phthalate, methacrylic acid copoly(cid:173)
`mer, hydroxypropyl methylcellulose phtl.talate and hy(cid:173)
`droxypropyl, methylcellulose acetate succinate, cellu-
`
`50
`
`60
`
`INGREDIENTS
`Core Tablet
`Flutamide
`Polyethylene Glycol 3350
`Microcrystalline Cellulose
`Sodium Croscarmellose
`Silicon Dioxide
`Magnesium Stearate
`Approximate Core Tablet Weight
`Coating
`Flutamide
`Polyvinyl Acetate Phthalate
`HPMC/PEG Clear Solution (Solids)
`Hydrous Lactose
`Sodium Croscarmellose
`Sodium Laury! Sulfate
`Calcium Sulfate
`Acacia
`Butylparaben
`Sugar
`Dye Opulux White (Solids)
`White Wax
`Camauba Wax
`Approximate Coating Weight
`Approximate Coated Tablet Weight
`
`MG/TABLET
`
`75
`225
`106.8
`36
`6
`__ 1._2_
`450
`
`112.5
`45
`6.75
`28.9
`16.1
`3.2
`220
`27
`O.o3
`200
`14
`0.3
`0.3
`674
`1124
`
`9. A controlled release tablet comprising:
`
`INGREDIENTS
`Core Tablet
`Flutamide
`Polyethylene Glycol 3350
`Microcrystalline Cellulose
`Sodium Croscarmellose
`Silicon Dioxide
`Magnesium Stearate
`Approximate Core Tablet Weight
`Coating
`Flutamide
`Polyvinyl Acetate Phthalate
`HPMC/PEG Clear Solution (Solids)
`Hydrous Lactose
`Sodium Croscarmellose
`Sodium Laury! Sulfate
`Calcium Sulfate
`Acacia
`Butylparaben
`Sugar
`Approximate Coating Weight
`Approximate Coated Tablet Weight
`
`MG/TABLET
`
`1S
`22S
`106.8
`36
`6
`__ 1._2_
`•so
`112.5
`27
`<40
`28.9
`16.1
`3.2
`77.<4
`2S.9
`O.o3
`~
`43S
`88S
`
`• • • • •
`
`4