(12) United States Patent
`Itoh et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006221402Bl
`US 6,221,402 Bl
`Apr. 24, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) RAPIDLY RELEASING AND TASTE(cid:173)
`MASKING PHARMACEUTICAL DOSAGE
`FORM
`
`(56)
`
`References C ited
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventors: Akinori Itoh, Taketoyo-cho; Toshiyuki
`Niwa, Handa, both of (JP)
`
`(73) Assignee: Pfizer Inc., New York, NY (US)
`
`(*) Notice:
`
`Subject lo any disclaimer, tbe term of Ibis
`paleni is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`09/341,312
`
`(22) PCT F iled:
`
`Nov. 20, 1997
`
`(86) PCT No.:
`
`PCT/ IB97/01471
`
`§ 371 Date:
`
`Sep. 20, 1999
`
`§ 102(e) Date: Sep. 20, 1999
`
`(87) PCT Pub. No.: W098/30209
`
`PCT Pub. Date: Jul. 16, 1998
`lnt. Cl.7
`................... .................................... A61K 9/14
`(51)
`(52) U.S. C l ........................... 424/494; 424/490; 424/493;
`424/495; 424/497; 514/781; 514/951
`(58) Field of Search ..................................... 424/489, 464,
`424/465, 451, 452, 455, 458, 459, 461,
`462,493, 494,497,490,495
`
`0409254
`0458751
`63-258809
`6-56700
`2576927
`9601623
`
`1/ 199 t (EP) ................................ A6 IK/9/ 14
`11/1991
`(EP) ............................ A61K/31/195
`10/ l988 (JP) ................................. A61 K/9/50
`3/J994 (JP) ............................... A6 l K/47/38
`1/1997 (JP) ............................... A61K/47/38
`6/1995 (WO) .............................. A61K/9(26
`OTHER PUBUCAI'JONS
`Merck Index, 11th Merck & Co. NJ, 1989, pp. 935.
`Remington farmacia Practica, Second Spanish Ed. pp. 510,
`511, 512 Editorial Utheba 1985.
`Database WPI; Section Cb, week 9413, Derwent Publica(cid:173)
`tions, Lid., London, GB; Class A96, AN 94-106744;
`XP002059781.
`Database WPI; Section Cb, Weck 8849, Derwent Publica(cid:173)
`tions Ltd., London, GB; Class A96, AN 88-348774,
`XP002059782.
`Primary Examiner-James M. Spear
`(74) Auorney, Agenr, or Firm-Peter C. Richardson; Gregg
`C. Beason; Michelle A. Sherwood
`(57)
`ABSTRACT
`
`/\ rapidly-releasing and taste-masking pharmaceutical dos(cid:173)
`age fo rm aad a process for preparing such oral dosage form
`are disclosed.
`
`9 C la ims, No Drawings
`
`DRL - EXHIBIT 1011
`DRL001
`
`

`
`2
`tical preparation) comprising a core containing a pharma(cid:173)
`ceutically active ingredient, low-substituted hydroxypropyl
`cellulose and microcrystalline cellulose, the amount of the
`microcrystalline cellulose being at least 26.0 weight percent
`based oo the total weight of the core; an inner coaling layer
`fo rmed on tbe core and containing a water-soluble polymer;
`and an outer coating layer formed on 1be inner coating layer
`and containing a saliva-insoluble polymer. Ia the dosage
`form of Ibis invention, the core, tbe inner coating layer and
`10 the outer coating layer are preferably contained in an amount
`of from 49.9 to 95.l, from 0.J. to 45.3 and from 4.8 to 50.0
`weigbt percent, respectively, based on the total weight of tbe
`dosage form. The dosage form may further comprises a
`sugar coating layer formed on the outer coating layer. Tbe
`15 core is preferably in a spherical form and has an average
`parlicle diameter of 80 to 400 micrometers, more preferably
`JOO to 300 micrometcrs.
`Suitable inner coating layer comprises 70.0 to 100 weight
`perceni of a water-soluble polymer such as hydroxypropy-
`20 lmetbyl cellulose, and up to 30.0 weight percent of a
`water-insoluble polymer such as (1) ao etbyl acrylate/methyl
`metbacrylate copolymer, (2) an eth yl acrylate/ methyl
`metbacrylate/trimetbylammonioethyl methacrylate copoly(cid:173)
`mer. Suitable outer coating layer comprises 70.0 to 100
`25 weigbt percenl of a saliva-insoluble polymer sucb as (3) a
`but by I met b a cry la t e / (2-d i methy l a mi ooet by 1)
`melhacrylatelmethyl methacrylate copolymer, and up to
`30.0 weigbL percent of a water-soluble or water-insoluble
`copolymer.
`According to the presem invention, oral dosage forms
`having improved drug release properties and taste-masking
`properties (for example, more than 50 seconds) can be
`provided.
`Tbe present ioventioo aJso provides a process for prepar(cid:173)
`ing the dosage form as mentioned above, which comprises
`mixing core materials containing a pharmaceutically active
`ingredient, low-substituted bydroxypropyl cellulose and
`microcrystallioe cellulose aod subject the mixed core mate(cid:173)
`rials to wet agitation granulation, dry treatment and sieving
`treatment in this order to obtain core particles; forming ao
`inner coating layer on the core particles by spraying with an
`aqueous solution containing a water-soluble polymer; and
`then forming an outer coating layer on the inner coating
`layer by spraying with ao aqueous solution cootaioiog a
`saliva-insoluble polymer. This process can be carried out in
`the absence of a solveat harrafol to a human body (e.g.,
`acetone and chlorine solvent such as methylene chloride,
`chloroform and metbyl cbloride). Thus, this process is
`advantageous in view of safety and ecology.
`
`30
`
`45
`
`50
`
`US 6,221,402 Bl
`
`1
`RAPIDLY RELEASING AND TASTE(cid:173)
`MASKING PHARMACEUTICAL DOSAGE
`FORM
`
`11tis is a National Stage filing under 35 USC §371 based s
`on PCT/ IB97/01471 wbicb was filed internationally on Nov.
`20, 1997.
`
`TECHNICAL FIELD
`
`This invention relates to rapidly releasing and taste(cid:173)
`maskiag pbarmaceutical dosage form, and a process for
`preparation there-0f. More specifically, this invention relates
`to a pharmaceutical dosage form which can be orally admin(cid:173)
`istered without bitter taste, with improved drug release
`properties in a gastroimestinal tract.
`
`BACKGROUND ART
`The biller taste of many drugs which are orally adminis(cid:173)
`tered arc disadvantageous in several aspects. For example,
`the disagreeable taste of drugs causes difficulties in swal(cid:173)
`lowing or causes patients to avoid taking their medication,
`wbereby resulting in low compliance of patients. Tbus,
`taste-masking technologies are considered very important,
`and are being developed by many researchers. Tbe taste(cid:173)
`masking is usually achieved by forming a taste-masking
`layer on a particle having an active ingredient. However, the
`taste-masking layer may cause poor drug release profiles.
`Thus, the formulation design is difficult to provide oral
`dosage forms having good taste-masking properties and
`good drug release properties.
`Eu.ropean Patent Application No. EP 0409254 discloses
`rapid-releasing oral particle pharmaceutical preparation with
`unpleasant taste masked. The oral particle pharmaceutical
`preparation comprises a core aod a fi lm layer coating tbe 35
`core, the core at least containing a drug having an unpleasant
`taste and a water-swelling agent, and tbe film layer at least
`contai ning ethylcellulose and a water-soluble substance.
`However, this tecboology usually requires the beating of
`.final product (e.g., at 60-75° C., 10-20 hr) to attain good 40
`drug release properties. Tbe beati.ng treatment is oot pref(cid:173)
`erable for heat-sensitive drugs which may be decomposed or
`melt at such bigb temperature. Further, in this technology,
`the effective masking time is described as more than 20
`seconds. Such time period is not enough to provide complete
`masking effect for some patinets such as tbose with artificial
`teeth. Also, the previous technology cannoi avoid the use of
`acetone and cblorine solvent (e.g., metbyene chloride),
`which is harmful lo buman bodies, to provide the sufficient
`masking effect.
`Japanese Patent Application Laid-Open Publication No.
`S63-258809 discloses fine granules prepared by forming l to
`10 wt. % of an outer layer on a core particle having a bitter
`active ingredient, and forming 3 to lO wt. % o f a saliva(cid:173)
`iasoluble layer on the outer layer. However, this technology 55
`cannot provide (foe granules baving rapid release properties
`in neutral and alkalic pH media. This is because the polymer
`composed of the outer layer bas solubiJjty strongly depen(cid:173)
`dent on pH in media, and cannot be dissolved and disrupted
`in the oeutral aod alkalic pH media.
`Accordingly, it would be desired if oral dosage form
`having improved drug release properties and taste-masking
`properties were provided.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`In the present invention, the oral dosage form comprises
`at least three layers, i.e., a core (also referred to as core
`1>article) containing a pharmaceutically active ingredient,
`low-substituted hydroxypropyl cellulose aod microcrystal(cid:173)
`line cellulose; an inner coating layer containing a water(cid:173)
`soluble polymer; and ao outer coating layer contaioing a
`60 saliva-insoluble polymer.
`Active ingredients which usually used in tbis invention
`bave a biller taste, altbougb those having no bitter taste can
`also be used. Active ingredients useful in this invco1ioo
`include, for example, antifungal agents such as lluconazole,
`65 pain rel.ievers such as acetaminopben and acetylsalicylic
`acid, antihistamines such as diphenhydramiot:, doxylamint:
`succinate and raecliziae, decongestants such as pseudoephe-
`
`BRlEF DISCLOSURE OF T1-lE INVENTION
`The present invention provides a rapidly releasing and
`taste-masking pharmaceutical dosage form (or pbarmaceu-
`
`DRL - EXHIBIT 1011
`DRL002
`
`

`
`US 6,221,402 BI
`
`3
`drine hydrochloride, anti-impotence such as sildenafil, anti(cid:173)
`biotics such as azithromycin, crythromycin and
`cepholosporin, penicillins such as sultamicillin 1osyla1e and
`amoxicillin trihydratc, enzyme inhibitors such as sulbactam
`sodium, antbibypertcnsives such as nifedipine, doxazosin 5
`mcsylate and amlodipine bcsylatc, antidiabetics such as
`glipi£ide, broncbodilators such as pirbuterol hydrochloride
`and theophyflinc, anti-inflammatory agents such as piroxi(cid:173)
`cam and tenidap, anti-depressants such as sertaralinc
`hydrochloride, antacids such as calcium carbonate aad mag(cid:173)
`nesium oxide, aad non-sedative antihistamines such as IO
`cctirizinc, cardiotoaics such as digitoxia aad digoxia.
`As used herein, "microcrystalliae cellulose" means
`purilicd, partially depolymerized cellulose prepared by treat(cid:173)
`ing alpha cellulose. Examples of the microcrystalline cellu(cid:173)
`lose are those soled under the tradeaame of Avicelni ts
`(manufactured by Asahi Chemical Industry), CcolusT"
`(manufactured by Asahi Chemical Industry), Vivace(TM
`(manufactured by J. Reltenmaier & Sohne GmbH), and
`Emcocc(T"(manufactured by Edward Mendell Co. Joe.).
`Suitable microcrystallioe celluloses include those sold uoder 20
`the trade name of Avicetrn PH-101, PH- 102, Pl-1-301 and
`Pl.1-302 (manufactured by Asahi Chemical lodustry), aod
`mixtures of two or more of these celluloses. Most preferred
`arc /\vice™ Pll-101.
`As used hereio, "low-substituted hydroxypropyl cellu- '.!5
`lose" meaos a low-substituted poly (bydroxypropyl) ether of
`cellulose, which contains not less than 5.0% and not more
`than 16.0 % of bydroxypropoxy groups on a dried basis.
`Examples of low-substituted hydroxypropyl cellulose
`include ooe sold uoder the trade name of LI 1-31 30
`(manufactured by Shin-Etsu Co. Ltd.)
`If desired, the other additives may be added 10 the
`above-mentioned core materials. Such additives include a
`binder such as hydroxypropyl methyl cellulose, or hydrox(cid:173)
`ypropyl cellulose, a masking ageat such as calcium 35
`gluconate, magnesium oxide and a lubricant such as talc and
`magnesium s1earate.
`The core particles used in 1bjs inveotioo are preferably in
`a spherical form, and has an average particle diameter of 80
`to 400 micrometers, more preferably 100 to 300 microme- 40
`tcrs. Prcl'crably, the cores may have a sphericity of 0.85 10
`1.0, more preferably 0.9 to 1.0. The spherical core particles
`used in lhis inveotioo are advantageous in that coating
`efficiency can be improved in subsequent coatings of an
`inner layer aod an outer layer.
`Suitable cores (a lso referred lo as core particles) used in
`the present invention comprises 0.1 to 73.S, more preferably
`20.0 to 40.0 of the active ingredient; 26.0 to 99.4, more
`preferably 28.0 to 80.0, most preferably 30.0 to 60.0 weight
`percent of the microcrystalline cellulose; and 0.5 10 34.0, so
`more preferably 3.0 to 30.0 weight percent of the low(cid:173)
`substituted hydroxypropyl cellulose, the weight percent
`being based on the total weight of the core material. Use of
`core particles with these component ratios may give good
`drug release profiles. When the amount of the microcrys- ss
`tallinc cellulose is outside of the above-memioned level, the
`sphericity of the resultant core particles may be decreased,
`resulting in decrease in coating efficiency.
`In the present invention, an inner coating layer is formed
`on the above-mentioned core particles. The purpose of 60
`formation of the inner coa1iog layer is smoothing of core
`surface and easy separation of the outer coating layer from
`an acidic solution of an active iogrcdieot such as sildcoafil
`citrate (about pll3.85). Suitable inner coating layer com(cid:173)
`prises 70.0 to LOO weight percent of a water-soluble 65
`polymer, aocl up lo 30.0 weight percent of a water-insoluble
`polymer.
`
`45
`
`4
`As used herein, the term "water-soluble polymer" means
`a conventional polymer for pharmaceutical use, having a
`solubility of more than 10 mg/ml in water. Suitable water(cid:173)
`soluble polymers include, for example, hydroxypropylm(cid:173)
`ethyl cellulose, hydroxypropyl cellulose, polyvinyl pyroli(cid:173)
`dore and polyvinyl alcohol. Most preferred water-soluble
`polymers used in this invention are hydroxypropylrnethyl
`cellulose and hydroxypropyl cellulose. As used herein, the
`term "water-insoluble polymer'' means a conventional poly(cid:173)
`mer for pharmaceutical use, having a solubility of not more
`than LO mg/ml in water. Suitable water-insoluble polymers
`incluclc, for example, ethylcellulose, methacrylate copoly(cid:173)
`mers and aminoalkyl methacrylate copolymers such as an
`ethyl acryla te/ methyl metbacrylate copolymer aad an ethyl
`acryla te/methyl mcthacryla1e/trimethylammonioe1hyl meth(cid:173)
`acryla tc copolymer. Commercially available water-insoluble
`polymers may be used. S uch water-insoluble polymers arc
`those sold under the trade oamc of Aquacoat (manufac111rcd
`by Asahi Chemical Industry) Eudrag it NE aod Euclragit RS
`(manufactured by Rohm Pharma).
`If clesirccl, the other additives may be added to the inner
`coaling materials. Such addi tives include, for example, a
`lubricant such as magnesium stearate or talc.
`Then, an outer coating layer is formed on the above(cid:173)
`mentioned inner layer. The outer coating layer mainly bas a
`taste-masking effect to prevent an active ingredieat from
`being released when a paticot hold a coated druo in bis
`mouth. Suitable outer coating layer comprises 70.0 to 100
`weight percent of a saliva-insoluble polymer and up to 30.0
`weight percent of a water-soluble or water-insoluble
`polymer, the weight percent being based on tbe total weight
`of the outer coating layer. As used herein, the term "saliva(cid:173)
`solublc polymer" meaos a coovcntional symbetic polymer
`for pharmaceutical use, having a solubility of less than 10
`mg/ml in neutral pll (6.0-7.5) and more than 10 mg/ml in
`acidic pll ( L.2- 5.0). Suitable saliva-insoluble polymers
`include, for example, aminoalkyl methacrylatc copolymers
`such as a buthyl metbacrylate/(2-dimethylaminoethyl)
`mc1hacryla1c/mc1hyl met bacrylate copolymer and polyviny(cid:173)
`lacctal clicthylaminoacetate. Commercially available poly-
`mers may be used. S uch polymers are those sold under the
`trade name o r Eudragit E (manufactured by Rohm Pharma)
`and tbc trade name of /\£/\ (Sankyo) (manufactured by
`Sankyo). Su itable water-soluble polymers used as outer
`coating materials include, for example, hydroxypropylm(cid:173)
`cth yl cellulose and hydroxypropyl cellulose. Suitable water(cid:173)
`insolublc polymers used as inner coating materials include,
`for example, ethylcellulose and Eudragit RS.
`lo the oral dosage forms of the present invention, the core,
`the inner coating layer and tbc outer coating layer may be
`contained in an amount of from 49.9 to 95.1 (more prefer(cid:173)
`ably from 60.0 to 87.0), from 0.1 10 45.3 (more preferably
`from 4.0 to 31.0, most preferably from 4.0 10 10.0) aod from
`4.8 to 50.0 (more preferably from 9.0 to 36.0) weight
`percent, respectively, bai.ed on the total weight of the dosage
`form. The component ratio may be determined depending on
`the kind of active iogredieot used, the kind of polymers used,
`desired drug release profile and tbc Like. Ln general, the
`resultant coated drugs with the above component ratio, may
`give good drug release profiles aod taste-masking effects.
`The process for preparing the above-mentioned oral dos(cid:173)
`age forms will be described below.
`Firstly, a core or core particles may be prepared by mixing
`core materia ls con taining a pharmaceutically active
`ingredient, low-substituted hyd roxypropyl cellulose and
`microcrysta lline cellulose and subject the mixed core mate-
`
`DRL - EXHIBIT 1011
`DRL003
`
`

`
`US 6,221,402 Bl
`
`10
`
`20
`
`5
`rials to wet agitation granulation, dry treatment and sieving
`treatment in this order. Methods for preparing the core
`particles, which can be used in Ibis invention, are wcU
`described in Kokai H06-S6700. For example, powders of an
`active ingredient sucb as sildenafil citrate is mixed with 5
`microcrystalline cellulose, L-HPC and other additives sucb
`as a masking agent (e.g., calcium glucona1e), binder (e.g.
`hydroxypropyl methyl cellulose), lubricant (e.g., talc), in a
`vessel of the granulator. Then, tbe mixture is granulated for
`10 to 60 minutes after addition of water a1 room temperature
`by a wet agitation granulation method known Lo those
`skilled in tbe art. Tbe granulated core particles may be dried
`with a fluidized bed dryer and sieved, Lo obtain substantially
`spherical core particles. Preferably, the core particles may be
`fractiona ted to obtain fine particles having an average par(cid:173)
`ticle size of 80 10 400, preferably LOO to 300 micrometers. 15
`Then, 1be core part icles thus prepared may be coated with
`an inner coating layer on the core particles by spraying with
`an aqueous solution containing a water-soluble polymer; and
`then coated with an outer coating layer on the inner coating
`layer by spraying with an aqueous solution containing a
`saliva-insoluble polymer.
`The core particles may be coated by spraying wi1b an
`aqueous solution composed of a water-soluble polymer,
`water-insoluble polymer, water and other additives such as 25
`talc in a centrifugal fluidizing g ranulator (e.g.,
`CF-Granulator under 1be trade mtme of CF-360 m11nufac(cid:173)
`tured by Freund, Inc.). Tbe coating conditions may be
`determined depending on the kind of granulalor used, the
`kind of ingredients, component ratio and the like. Suitable
`conditions, when using the above CF-Granula1or, may be a
`slit air temperature of 30 lo 70° C.; a slit air rate of 200 10
`3SO I/min; a ro1a1ing speed of 100 to 200 rpm; a spray speed
`of 2 to 7 g/min; and a spray air pressure of 2 10 4 kg/Cm2
`. 35
`After spray, the particles may be dried with, for example, a
`fluidized bed dryer or tray dryer.
`Further, the core particles may be coaled by spraying wiLh
`ao aqueous ethaoolic solution (e.g., 80% E10H) composed
`of a saliva-insoluble polymer, ethanol, water and other
`additives such as talc in a centrifugal Jluidizing granulator
`(e.g., CF-Granulalor under the lradcname of CF-360 manu(cid:173)
`factured by Freund, Inc.). The coating cooditions may be
`determined depending on tbe kind of granulator used, tbe 45
`kind of ingredients, component ratio and tbe like. The
`similar conditions as mentioned above may be used. After
`spray, tbe particles may be dried wi1b, for example, a
`fluidized bed dryer, and then oven-cured, to obtain three-
`layer core particles of this invention.
`La addition, to achieve a good taste and mouth feeling, a
`sugar coating layer may be formed on the outer coaling layer
`of the three layer particles thus prepared. A known coating
`method can be used to form such sugar coating layer. For ss
`example, tbe three layer particles may be fed by spray
`solution composed of sucrose and D-mannitol dissolved in
`water under reasonable conditions. Xanthan gum (a polysac(cid:173)
`cbaride generated from natural source) may be added to
`provide a good mourh feeling. The amount of the sugar 60
`coating layer may be in a range of lS.0 to 270.0 weight
`percent based on tbe total weight of tbe coated particle
`composed of tbe core, the inner and outer coating layers. Tbe
`pharmacological dosage forms of Ibis invention can be used 65
`in the fo rm of fine granules, tableLS, POS (powder for oral
`suspension), capsules or tbe Like.
`
`6
`EXAMPLES AND COMPARATIVE EXAMPLES
`The preseot invention will be described in more details
`with reference to the following Working and Comparative
`Examples.
`(Materials Used)
`The following materials were used in the Working and
`Comparative Examples.
`Core Material
`Active Ingredient: Si!denafil citrate
`L-HPC: Low-substituted hydroxypropyl cellulose (Ll-1-
`31; Shin-Etsu)
`MCC: Microcrystalline cellulose (Avicel PH lOl, Asahi
`Chemical Industry)
`HPMC: Hydroxypropyl metbyl cellulose2910 as a binder
`(TC-SE, Sbia-ELSu)
`Calcium gluconale (Tomita Pharmaceuticals).
`loner Coating Layer
`Waler-Soluble polymer:
`MPMC: l!ydroxypropyl metbyl cellulose2910 (TC-SE,
`Sbio-Etsu)
`Water-insoluble polymer: methacrylate copolymer
`(Eudragit NE30D, Rohm Pharma)
`Outer Coating Layer
`Saliva-insoluble polymer: aminoalkyl methacrylate
`copolymer uoder the trade name of Eudragit ElOO, (Rohm
`Pharma).
`Wbea needed, other excipients sucb as talc and magne(cid:173)
`sium siearate, hydroxypropyl methyl ce llulose and
`30 etbylcellu.Jose, are added.
`Example 1
`(1) Manufacturing of' Core Particles
`An active ingredient (sildenafil citrate, 210.66 g) was
`mixed with microcrystalline cellulose(300 g), L-HPC(97.2
`g), calcium glucoaate(64.8 g), and bydroxypropyl methyl
`cellulose2910(7.2 g) as a binder in a ves.scl of the granulalor.
`The amount ratio of the component<> used are indicated in
`Table l. Then, tbe mixture was granulated by a wet agitation
`granulation method (Vertica l Granulalor, VG-OS, Powrex)
`fo r 30 min after addition of water (699.0 g) at room
`temperalllre {blade speed, 200 rpm; cross screw speed, 3600
`rpm). Tbe granulated cores were dried with a fluidized bed
`dryer (FBD) (Multiplex, Ml)-01, Powrex, Japan) and sieved
`to obtain core particles having an average diameter of
`177-297 micrometers.
`The fractionated core fine particles (177-297 mm) were
`coated v.rith three layers (inner layer, outer layer, sugar layer)
`by using a centrifugal Iluidizing granulator (CF-Granulator,
`CF-360, Freund).
`(2) Coating of Inner Layer
`The core particles (360.0 g) prepared in the above Step (1)
`were coated by spraying with 1be coating solution composed
`of TC-SE(30.2 g), Eudragit NE30D(20.1 g) and 378.2 g of
`water in a centrifugal fluidizing granulator (CF-Granulator,
`CF-360, Freund). Talc and magnesium stearate were added
`to protect the elec1ros1atic aggregation of each particles. The
`amouot ratio of the components used are indicated in Table
`l. Tbe conditions used were as follows: slit air temperature,
`70° C.; slit air rate, 250 I/min; rotating speed, lSO rpm, spray
`speed, 3.4 g/min; and spray air pressure, 3.0 kg/cm2
`• After
`spray, the particles were dried wilb fluidized bed dryer
`(Multiplex, MP-01, Powrex) for 25 min (inlet, 80° C. oulJel,
`so° C.).
`
`40
`
`50
`
`DRL - EXHIBIT 1011
`DRL004
`
`

`
`US 6,221,402 Bl
`
`7
`
`(3) Coating of Outer Layer
`Eudragit El00(66.5 g), which was dissolved in 950.2 g of
`aqueous etbaoolic solution (80% Et OH), was applied 10 coat
`on the inner layer-coated particles (190.0 g) with a
`CF-Graoulator (slit air temperature, 34° C.; slit air rate, 300 5
`l/mio; rotating speed, 140 rpm; spray speed, 5.0 g/mio). The
`coating level of tbe outer layer was adjusted as indicated io
`Table 1. After spray, the particles were transferred 10 FBD
`aod oven-cured at the same conditions described above 10 10
`increase the protect effect to obtain tbree layer products.
`(4) Coating of Sugar Layer
`lo some Examples and Comparative Examples, an addi(cid:173)
`tional sugar layer coating was formed on the three-layer
`products as prepared
`in
`the above S tep (3). More
`specifically, the coated particles (137.8 g) were fed by spray
`solution composed of sucrose (170.5 g) and 0-mannitol
`(55.0 g) dissolved in water (138.0 g) to the CF-Granulator 10
`
`15
`
`8
`form Lhe sugar layer for adjustment of taste. Tbe cooditioos
`used were same as those at protect coating except slit air
`temperature, 50° C. Aspartame (11.5 g) was added to
`provide the sweet taste for Jine particles. Xaothan gum (0.4
`g) which is a polysaccharide generated from natural source
`is useful for good mouth feeling. During spraying titanium
`dioxide (7.7 g) and Jlavor(0.4 g) were supplied in a powder
`state. After drying in FBD (outlet air: 67° C.) and sieving
`(<500 mm), Lbe sugar layer coated product was obtained.
`The amount of each ingredient used are as indicated in Table
`l(a).
`
`Examples 2 to S and Comparative Example
`
`The oral dosage forms were prepared io the same manner
`as indicated in Example 1 except that lhe amount of each
`ingredient was changed as shown in Tables l(a) to l(c).
`
`TABLE l(a)
`
`Examete l
`
`Examele 2
`
`Amouot of
`Ingredient
`(mg/g)
`
`%of
`Core
`Ingredient
`
`Product%
`of
`Coated
`
`Amount of
`Ingredient
`(mg/g)
`
`%of
`Core
`Ingredient
`
`%of
`Coated
`Product
`
`70.22
`
`30.99
`
`19.531
`
`32.40
`100.00
`2.40
`21.60
`
`]4.30
`44.13
`1.06
`9.53
`
`9.012
`27.813
`0.668
`6.008
`
`70.220
`5.500
`6.500
`88.000
`
`33.403
`2.616
`3.092
`41.861
`
`28.575
`2.2.38
`2.645
`35.811
`
`40.000
`
`19.028
`
`16.277
`
`226.62
`
`100.00
`
`63.032
`
`210.220
`
`!00.000
`
`85.546
`
`Core Material
`
`Sildcnafit
`talc
`L-HPC
`MCC
`l!PMC
`Ca gluconate
`
`Total
`Inner Layer
`
`HPMC
`NE-300
`Mg-St
`Tale
`
`Total
`Out Layer
`
`EJOO
`TC-SE
`Talc
`Mg-St
`
`Total
`Sul>-total
`Sugar layer
`
`Sucrose
`D-mannitol
`Primojel
`xantan gum
`Asparterne
`Flavor
`Ti0 2
`
`Total
`
`19.00
`3.80
`
`3.80
`
`26.60
`
`88.62
`
`17.70
`
`106.32
`359.54
`
`444.96
`143.50
`
`l.00
`30.00
`1.00
`20.00
`
`640.46
`
`3.770
`7.819
`
`5.284
`1.057
`
`l .057
`
`7.398
`
`JJ.589
`
`24.648
`
`22.730
`
`4.923
`
`l.200
`
`29.571
`100.00
`
`23.930
`245.739
`
`123.758
`39.912
`
`0.278
`8.344
`0.278
`5.563
`
`27.000
`3.800
`0.040
`10.700
`
`J78.J33
`
`41.540
`
`1.534
`3.182
`
`4.716
`
`9.25
`
`0.488
`
`9.738
`100.000
`
`10.987
`1.546
`0.016
`4.355
`
`16.904
`
`116.904
`
`Grand Total
`
`1000.00
`
`278.134
`
`287.279
`
`DRL - EXHIBIT 1011
`DRL005
`
`

`
`US 6,221,402 Bl
`
`10
`
`9
`
`TABLE l(b)
`
`Exan1ele 3
`
`Examele 4
`
`Amount of
`lllgreclient
`(mg/g)
`
`%of
`Core
`lllgreclient
`
`%of
`Coated
`Product
`
`Amount of %of
`logredient
`Core
`(mg/g)
`Ingredient
`
`%of
`Coated
`Product
`
`70.22
`4.40
`9.40
`110.40
`J.00
`21.60
`
`32.356
`2.028
`4.331
`50.871
`0.461
`9.953
`
`25.548
`J.601
`3.420
`40.167
`0.364
`7.859
`
`4
`
`71.84
`
`57.97
`76.57
`6.82
`22.10
`
`30.531
`
`18.857
`
`24.637
`32.541
`2.898
`9.393
`
`JS.216
`20.099
`1.790
`5.801
`
`217.02
`
`100.000
`
`78.959
`
`235.30
`
`100.000
`
`61.763
`
`18.10
`3.62
`
`21.72
`
`35.81
`
`0.30
`
`36.Jl
`274.85
`
`6.584
`l.317
`
`7.901
`
`J3.030
`
`O.lJO
`
`J3.l40
`J00.000
`
`18.9]
`3.79
`0.16
`3.79
`
`26.65
`
`91.68
`
`26.20
`l.J4
`
`119.02
`380.97
`
`4.964
`0.995
`0.042
`0.995
`
`6.996
`
`24.065
`
`6.877
`0.299
`
`3l.24J
`J00.000
`
`Core Material
`
`Sildenafil
`talc
`L-HPC
`MCC
`llPMC
`Ca gluconale
`
`Total
`lllner Layer
`
`HPMC
`NE-300
`Mg-St
`Tale
`
`Tola I
`Out La~cr
`
`EJOO
`TC-SE
`T.•lc
`Mg-St
`
`Total
`Sul> Total
`Sugar T~•~er
`
`Sucrose
`D-niannitol
`Primojel
`Xantan gum
`A.spaneme
`Flavor
`Ti02
`
`Total
`
`Grand Tola!
`
`533.JS
`140.00
`
`J.00
`30.00
`J.00
`20.00
`
`725.JS
`
`1000.00
`
`193.979
`50.937
`
`427.03
`J40.00
`
`0.364
`10.915
`0.364
`7.277
`
`l.00
`30.00
`1.00
`20.00
`
`263.836
`
`619.03
`
`363.836
`
`1000.00
`
`JJ2.090
`36.748
`
`0.263
`7.875
`0.263
`5.250
`
`162.49
`
`262.489
`
`TABLE l(c)
`
`Example 5
`
`Coni2arative Exa012Je 1
`
`Amount of
`lllgredient
`(mg.lg)
`
`%of
`Core
`lngrediem
`
`% of
`Coated
`Product
`
`Amount of %of
`Ingredient
`Core
`(mg/g)
`Ingredient
`
`%of
`Coated
`Product
`
`4
`
`71.84
`
`30.531
`
`19.589
`
`70.22
`
`30.801
`
`15.865
`
`57.97
`76.57
`6.82
`22.10
`
`24.637
`32.541
`2.898
`9.393
`
`15.807
`20.879
`J 860
`6.025
`
`2J.(>()
`110.40
`1.30
`21.60
`0.76
`2.10
`
`9.475
`48.425
`0.570
`9.475
`0.333
`0.921
`
`4.880
`24.944
`0.294
`4.880
`0.172
`0.474
`
`235.30
`
`100.000
`
`64.160
`
`227.98
`
`100.000
`
`51.509
`
`18.91
`3.79
`
`5.156
`1.033
`
`18.91
`3.79
`
`4.272
`0.856
`
`Core Material
`
`Sildenafil
`talc
`L-HPC
`MCC
`J-IPMC
`Ca gluconate
`polysorl>ate 80
`Citric acid
`
`Total
`inner Layer
`
`HPMC
`NE-300
`
`DRL - EXHIBIT 1011
`DRL006
`
`

`
`US 6,221,402 Bl
`
`11
`
`12
`
`TABLE l(c)-continued
`
`Exan1ple 5
`
`Comparative Example l
`
`Amount of
`lllgreclient
`(mg/g)
`
`%of
`Core
`lllgreclient
`
`%of
`Coated
`Product
`
`Amount of
`logredient
`(mg/g)
`
`%of
`Core
`Ingredient
`
`%of
`Coated
`Product
`
`Mg-St
`Tale
`
`Total
`Out Layer
`
`ElOO
`TC-SE
`Talc
`Mg-St
`
`Total
`Sul>-total
`Sugar Layer
`
`Sucrose
`D·mannitol
`Primojel
`X.."'lntan gum
`Aspartcme
`Flavor
`Ti02
`
`Tot11I
`
`O.J6
`3.79
`
`26.65
`
`73.35
`18.34
`13.10
`
`104.19
`366.74
`
`441.26
`140.00
`
`1.00
`30.00
`J.00
`20.00
`
`633.26
`
`0.044
`l.033
`
`7.266
`
`20.001
`5.001
`3.572
`
`28.574
`100.000
`
`J.37
`
`24.07
`
`189.05
`
`l.50
`
`190.55
`442.60
`
`120.320
`38.174
`
`365.40
`140.00
`
`0.273
`8.180
`0.273
`S.453
`
`1.00
`30.00
`1.00
`20.00
`
`172.673
`
`557.40
`
`Grand To~1l
`
`1000.00
`
`272.673
`
`1000.00
`
`0.310
`
`5.438
`
`42.714
`
`0.339
`
`43.053
`100.000
`
`82.558
`31 .631
`
`0.226
`6.778
`0.226
`4.519
`
`125.94
`
`225.938
`
`EXPERIMENTS
`
`(1) Billemess Test
`Five (5) panelists held 1 g of Lbe three or four layered
`products prepared by the above procedures in their moutb
`for 1 min, and measured a lime period until they fell
`bitterness. The average time ( in seconds) was used for
`evaluation. The desirable masking time period is more than
`50 seconds. The resu lts are indicated in Table 2.
`(2) Drug Release Test
`Accordiog to the guidelioe published by Minister of
`Health and Welfare (MHW) in Japan, the dis.50lution test
`were conducted io each three media (pH 1.2, 4.0, and 6.5).
`Further, the dissolution tests in media of pH5.0, 5.5, 6.0
`
`were also investigated to predict the in vivo dissolution of
`lower- and non-gastric acidity humans. The release experi(cid:173)
`ments from the particles were performed by the Japanese
`35 Pharmacopeia (JP) paddle method in 900 ml of media at 37°
`C. The three or four layered products prepared in tbe above
`procedures were spread over the media with constant stirring
`at 100 rpm. The media used in this study were the 1st fluid
`(disintegration lest fluid, Japanese Pharmacopoeia 13,
`40 pHl.2), O.lM acetate buffer (pH4.0), and 0.05M phosphate
`buffers (pl-15.5, 6.0, 6.5). The drug release properties were
`evaluated as the amount of the drug released after 5, 10 and
`15 minutes from the introduction of the drugs ioto each
`media. Tbe results are indicated in Table 2.
`
`TABLE 2
`
`ExamJlles
`
`Comp. Ocsirable
`
`2
`
`3
`
`4
`
`Example Value
`
`>120
`
`>55
`
`>75
`
`>120
`
`>53
`
`>120
`
`>50 sec.
`
`103.1
`101.6
`102.2
`87.7
`98.8
`100.0
`
`95 .8
`95 .6
`
`87.0
`87.7
`2.0
`20.3
`44.9
`
`71.3
`86.7
`95.7
`
`83.5
`95.5
`
`90.4
`98.7
`99.3
`
`>75%
`
`90.4
`99.7 >15%
`
`90.5
`
`86.6
`
`90.5
`
`93.9
`
`74.3 >75%
`
`31.1
`33.1
`
`43.5
`45.6
`
`2.1
`8.9
`37.5
`
`18.2
`49.0
`60.3
`
`>75%
`
`5.4 >30%
`
`Bitterness Test (sec.)
`(Drug Release Test)
`RA (%, pll 1.2 after 5 min.)
`RA(%, pH 1.2 after JO min.)
`RA (%, pH 1.2 after 20 min.)
`RA (%, pl-I 4.0 after 5 m.in.)
`RA(%, pH 4.0 after 10 n1in.)
`RA (%, pll 4.0 after 20 min.
`RA (%, pH 5.5 after 5 min.)
`RA (%, pH 5.5 after 10 min.)
`RA (%, pl-I 5.5 after 20 min.)
`RA (%, pl-I 6.0 after 5 min.)
`RA (%, pH 6.0 after 10 min.)
`RA (%, pH 6.0 after 20 min.)
`RA (%, pH 6.5 after 2.5 min.)
`RA (%, pl·I 6.5 after 5 min.)
`RA (%, pit 6.5 after 20 min.)
`
`DRL - EXHIBIT 1011
`DRL007
`
`

`
`US 6,221,402 BI
`
`13
`As shown in Table 2, it was confumcd that the oral dosage
`forms of this invention (Examples l to 5) have good taste
`masking properties and good drug release profiles.
`More specifically, the time period until panelists felt
`bittemcsi, showed more than 50 sec. in all examples. Fun her, 5
`it was found that the oral dosage forms of this invention have
`fast onset release profiles in media within a range of pHl.2
`to pl 15.5 (gastric juice).