(12) United States Patent
`Itoh et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,221,402 B1
`Apr. 24, 2001
`
`US006221402B1
`
`RAPIDLY RELEASING AND TASTE-
`MASKING PHARMACEUTICAL DOSAGE
`FORM
`
`Inventors: Akinori Itoh, Taketoyo-cho; Toshiyuki
`Niwa, Handa, both of (JP)
`
`Assignee: Pfizer Inc., New York, NY (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Appl. No.:
`PCT Filed:
`
`09/341,312
`
`Nov. 20, 1997
`
`PCT N0.:
`
`PCT/IB97/01471
`
`§ 371 Date:
`
`Sep. 20, 1999
`
`§ 102(e) Date: Sep. 20, 1999
`PCT Pub. N0.: W098/30209
`
`PCT Pub. Date:Jul. 16, 1998
`
`Int. Cl.7 ..................................................... .. A61K 9/14
`U.S. Cl.
`........................ .. 424/494; 424/490; 424/493;
`424/495; 424/497; 514/781; 514/951
`Field of Search ................................... .. 424/489, 464,
`424/465, 451, 452, 455, 458, 459, 461,
`462, 493, 494, 497, 490, 495
`
`(56)
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`0409254
`0458751
`63—258809
`6—56700
`2576927
`9601623
`
`(EP)
`
`1/1991
`.............................. .. A61K/9/14
`11/1991
`A61K,/31/195
`10/1988
`..... .. A61K/9/50
`A61K/47/38
`3/1994
`A61K/47/38
`1/1997
`6/1995 (wo) ............................ .. A61K/9/26
`OTHER PUBLICATIONS
`
`Merck Index, 11th Merck & Co. NJ, 1989, pp. 935.
`Remington farmacia Practica, Second Spanish Ed. pp. 510,
`511, 512 Editorial Utheha 1985.
`Database WPI; Section Ch, Week 9413, Derwent Publica-
`tions, Ltd., London, GB; Class A96, AN 94—106744;
`XP002059781.
`Databasc WPI; Scction Ch, Week 8849, Dcrwcnt Publica-
`tions Ltd., London, GB; Class A96, AN 88—348774,
`XP002059782.
`
`Primary Examiner—James M. Spear
`(74) Attorney, Agent, or Firm—Peter C. Richardson; Gregg
`C. Benson; Michelle A. Sherwood
`
`(57)
`
`ABSTRACT
`
`A rapidly-releasing and taste-masking pharmaceutical dos-
`age form and a process for preparing such oral dosage form
`are disclosed.
`
`9 Claims, N0 Drawings
`
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`
`US 6,221,402 B1
`
`1
`RAPIDLY RELEASING AND TASTE-
`MASKING PHARMACEUTICAL DOSAGE
`FORM
`
`This is a National Stage filing under 35 USC §371 based
`on PCT/IB97/01471 which was filed internationally on Nov.
`20, 1997.
`
`TECHNICAL FIELD
`
`This invention relates to rapidly releasing and taste-
`masking pharmaceutical dosage form, and a process for
`preparation thereof. More specifically, this invention relates
`to a pharmaceutical dosage form which can be orally admin-
`istered without bitter taste, with improved drug release
`properties in a gastrointestinal tract.
`BACKGROUND ART
`
`The bitter taste of many drugs which are orally adminis-
`tered are disadvantageous in several aspects. For example,
`the disagreeable taste of drugs causes difficulties in swal-
`lowing or causes patients to avoid taking their medication,
`whereby resulting in low compliance of patients. Thus,
`taste—masking technologies are considered very important,
`and are being developed by many researchers. The taste-
`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.
`European Patent Application No. EP 0409254 discloses
`rapid -releasing oral particle pharmaceutical preparation with
`unpleasant taste masked. The oral particle pharmaceutical
`preparation comprises a core and a film layer coating the
`core, the core at least containing a drug having an unpleasant
`taste and a water-swelling agent, and the film layer at least
`containing ethylcellulose and a water-soluble substance.
`However, this technology usually requires the heating of
`final product (e.g., at 60—75° C., 10-20 hr) to attain good
`drug release properties. The heating treatment is not pref-
`erable for heat-sensitive drugs which may be decomposed or
`melt at such high 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 those with artificial
`teeth. Also, the previous technology cannot avoid the use of
`acetone and chlorine solvent (e.g., methyene chloride),
`which is harmful to human bodies, to provide the sufficient
`masking effect.
`Japanese Patent Application Laid-Open Publication No.
`S63-258809 discloses fine granules prepared by forming 1 to
`10 wt. % of an outer layer on a core particle having a bitter
`active ingredient, and forming 3 to 10 wt. % of a saliva-
`i11soluble layer on the outer layer. However, this technology
`cannot provide fine granules having rapid release properties
`in neutral and alkalic pH media. This is because the polymer
`composed of the outer layer has solubility strongly depen-
`dent on pH in media, and cannot be dissolved and disrupted
`in the neutral and alkalic pH media.
`Accordingly,
`it would be desired if oral dosage form
`having improved drug release properties and taste—masking
`properties were provided.
`BRIEF DISCLOSURE OF THE INVENTION
`
`The present invention provides a rapidly releasing and
`taste—masking pharmaceutical dosage form (or pharmaceu-
`
`2
`tical preparation) comprising a core containing a pharma-
`ceutically active ingredient, low-substituted hydroxypropyl
`cellulose and microcrystalline cellulose, the amount of the
`microcrystalline cellulose being at least 26.0 weight percent
`based on the total weight of the core; an inner coating layer
`formed on the core and containing a water-soluble polymer;
`and an outer coating layer formed on the inner coating layer
`and containing a saliva-insoluble polymer. In the dosage
`form of this invention, the core, the inner coating layer and
`the outer coating layer are preferably contained in an amount
`of from 49.9 to 95.1, from 0.1 to 45.3 and from 4.8 to 50.0
`weight percent, respectively, based on the total weight of the
`dosage form. Thc dosage form may further comprises a
`sugar coating layer formed on the outer coating layer. The
`core is preferably in a spherical form and has an average
`particle diameter of 80 to 400 micrometers, more preferably
`100 to 300 micrometers.
`
`Suitable inner coating layer comprises 70.0 to 100 weight
`percent of a water-soluble polymer such as hydroxypropy-
`lmethyl cellulose, and up to 30.0 weight percent of a
`water-insoluble polymer such as (1) an ethyl acrylate/methyl
`methacrylate copolymer,
`(2) an ethyl acrylate/methyl
`methacrylate/trimethylammonioethyl methacrylate copoly-
`mer. Suitable outer coating layer comprises 70.0 to 100
`weight percent of a saliva-insoluble polymer such as (3) a
`buthyl methacrylate/(2—dimethylaminoethyl)
`methacrylatelmethyl methacrylate copolymer, and up to
`30.0 wcight pcrccnt of a water-soluble or watcr-insoluble
`copolymer.
`According to the present invention, oral dosage forms
`having improved drug release properties and taste—masking
`properties (for example, more than 50 seconds) can be
`provided.
`The present invention also provides a process for prepar-
`ing the dosage form as mentioned above, which comprises
`mixing core materials containing a pharmaceutically active
`ingredient,
`low-substituted hydroxypropyl cellulose and
`microcrystalline cellulose and subject the mixed core mate-
`rials to wet agitation granulation, dry treatment and sieving
`treatment in this order to obtain core particles; forming an
`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 an aqueous solution containing a
`saliva-insoluble polymer. This process can be carried out in
`the absence of a solvent harmful to a human body (e.g.,
`acetone and chlorine solvent such as methylene chloride,
`chloroform and methyl chloride). Thus,
`this process is
`advantageous in view of safety and ecology.
`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
`particle) containing a pharmaceutically active ingredient,
`low-substituted hydroxypropyl cellulose and microcrystal-
`line cellulose; an inner coating layer containing a water-
`soluble polymer; and an outer coating layer containing a
`saliva-insoluble polymer.
`Active ingredients which usually used in this invention
`have a bitter taste, although those having no bitter taste can
`also be used. Active ingredients useful in this invention
`include, for example, antifungal agents such as fluconazole,
`_ pain relievers such as acetaminophen and acetylsalicylic
`acid, antihistamines such as diphenhydramine, doxylamine
`succinate and meclizine, decongestants such as pse11doephe-
`
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`
`US 6,221,402 B1
`
`3
`drine hydrochloride, anti—impotence such as sildenafil, anti-
`biotics such as azithromycin, erythromycin and
`cepholosporin, penicillins such as sultamicillin tosylate and
`amoxicillin trihydrate, enzyme inhibitors such as sulbactam
`sodium, anthihypertensives such as nifedipine, doxazosin
`mesylate and arnlodipine besylate, antidiabetics such as
`glipizide, bronchodilators such as pirbuterol hydrochloride
`and theophyfline, anti—inflammatory agents such as piroxi—
`cam and tenidap, anti-depressants such as sertaraline
`hydrochloride, antacids such as calcium carbonate and mag-
`nesium oxide, and non-sedative antihistamines such as
`cetirizine, cardiotonics such as digitoxin and digoxin.
`As used herein, “microcrystalline cellulose” means
`purified, partially depolymerized cellulose prepared by treat-
`ing alpha cellulose. Examples of the microcrystalline cellu-
`lose are those soled under the tradename of AvicelTM
`(manufactured by Asahi Chemical Industry), Ccolusw
`(manufactured by Asahi Chemical Industry), VivacelTM
`(manufactured by J. Rettenmaier & Sohne GmbH), and
`EmcocelTM(manufactured by Edward Mendell Co. Inc.).
`Suitable microcrystalline celluloses include those sold under
`the trade name of AvicelTM PH-101, PH- 102, PH-301 and
`PH-302 (manufactured by Asahi Chemical Industry), and
`mixtures of two or more of these celluloses. Most preferred
`are Avice'“"‘ PH-101.
`
`As used herein, “low-substituted hydroxypropyl cellu-
`lose” me ans a low-substituted poly (hydroxypropyl) ether of
`cellulose, which contains not less than 5.0% and not more
`than 16.0 % of hydroxypropoxy groups on a dried basis.
`Examples of
`low-substituted hydroxypropyl cellulose
`include one sold under
`the trade name of LH-31
`
`(manufactured by Shin-Etsu Co. Ltd.)
`If desired,
`the other additives may be added to the
`above—mentioned core materials. Such additives include a
`
`binder such as hydroxypropyl methyl cellulose, or hydrox-
`ypropyl cellulose, a masking agent such as calcium
`gluconate, magnesium oxide and a lubricant such as talc and
`magnesium stearate.
`The core particles used in this invention are preferably in
`a spherical form, and has an average particle diameter of 80
`to 400 micrometers, more preferably 100 to 300 microme-
`tcrs. Preferably, the cores may have a sphcricity of 0.85 to
`1.0, more preferably 0.9 to 1.0. The spherical core particles
`used in this invention are advantageous in that coating
`efficiency can be improved in subsequent coatings of an
`inner layer and an outer layer.
`Suitable cores (also referred to as core particles) used in
`the present invention comprises 0.1 to 73.5, 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 to 34.0,
`more preferably 3.0 to 30.0 weight percent of the low-
`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-
`talline cellulose is outside of the above—mentioned 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
`formation of the inner coating layer is smoothing of core
`surface and easy separation of the outer coating layer from
`an acidic solution of an active ingredient such as sildenafil
`citrate (about pH3.85). Suitable inner coating layer com-
`prises 70.0 to 100 weight percent of a water-soluble
`polymer, and up to 30.0 weight percent of a water-insoluble
`polymer.
`
`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-
`soluble polymers include, for example, hydroxypropylm-
`ethyl cellulose, hydroxypropyl cellulose, polyvinyl pyroli—
`dore and polyvinyl alcohol. Most preferred water-soluble
`polymers used in this invention are hydroxypropylmethyl
`cellulose and hydroxypropyl cellulose. As used herein, the
`term “Water-insoluble polymer” means a conventional poly-
`mer for pharmaceutical use, having a solubility of not more
`than 10 mg/ml in water. Suitable watcr-insolublc polymers
`include, for example, ethylcellulose, methacrylate copoly-
`mcrs and aminoalkyl mcthacrylatc copolymcrs such as an
`ethyl acrylate/methyl methacrylate copolymer and an ethyl
`acrylate/methyl methacrylate/trimethylammonioethyl meth-
`acrylate copolymer. Commercially available water-insoluble
`polymers may be used. Such water-insoluble polymers are
`those sold under the trade name of Aquacoat (manufactured
`by Asahi Chemical Industry) Eudragit NE and Eudragit RS
`(manufactured by Rohm Pharma).
`If desired, the other additives may be added to the inner
`coating materials. Such additives include, for example, a
`lubricant such as magnesium stearate or talc.
`Then, an outer coating layer is formed on the above-
`mentioned inner layer. The outer coating layer mainly has a
`taste-masking effect to prevent an active ingredient from
`being released when a patient hold a coated drug in his
`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 the total weight
`of the outer coating layer. As used herein, the term “saliva-
`soluble polymer” means a conventional synthetic polymer
`for pharmaceutical use, having a solubility of less than 10
`mg/ml in neutral pH (6.0—7.5) and more than 10 mg/ml in
`acidic pH (1.2—5.0). Suitable saliva—insoluble polymers
`include, for example, aminoalkyl methacrylate copolymers
`such as a buthyl methacrylate/(2-dimethylaminoethyl)
`methacrylate/methyl methacrylate copolymer and polyviny-
`lacetal diethylaminoacetate. Commercially available poly-
`mers may be used. Such polymers are those sold under the
`trade name of Eudragit E (manufactured by Rohm Pharma)
`and the trade name of AEA (Sankyo) (manufactured by
`Sankyo). Suitable water-soluble polymers used as outer
`coating materials include, for example, hydroxypropylm-
`ethyl cellulose and hydroxypropyl cellulose. Suitable water-
`insoluble polymers used as inner coating materials include,
`for example, ethylcellulose and Eudragit RS.
`In the oral dosage forms of the present invention, the core,
`the inner coating layer and the outer coating layer may be
`contained in an amount of from 49.9 to 95.1 (more prefer-
`ably from 60.0 to 87.0), from 0.1 to 45.3 (more preferably
`from 4.0 to 31.0, most preferably from 4.0 to 10.0) and from
`4.8 to 50.0 (more preferably from 9.0 to 36.0) weight
`percent, respectively, based on the total weight of the dosage
`form. The component ratio may be determined depending on
`the kind of active ingredient used, the kind of polymers used,
`desired drug release profile and the like. In general,
`the
`resultant coated drugs with the above component ratio, may
`give good drug release profiles and taste-masking elfects.
`The process for preparing the above—mentioned oral dos-
`age forms will be described below.
`Firstly, a core or core particles may be prepared by mixing
`_ core materials containing a pharmaceutically active
`ingredient,
`low-substituted hydroxypropyl cellulose and
`microcrystalline cellulose and subject the mixed core mate-
`
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`US 6,221,402 B1
`
`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 this invention, are well
`described in Kokai H06-5 6700. For example, powders of an
`active ingredient such as sildenafil citrate is mixed with
`microcrystalline cellulose, L-IIPC and other additives such
`as a masking agent (e.g., calcium gluconate), binder (e.g.
`hydroxypropyl methyl cellulose), lubricant (e.g., tale), in a
`vessel of the granulator. Then, the mixture is granulated for
`10 to 60 minutes after addition of water at room temperature
`by a wet agitation granulation method known to those
`skilled in the art. The granulated core particles may be dried
`with a fluidized bed dryer and sieved, to obtain substantially
`spherical core particles. Preferably, the core particles may be
`fractionated to obtain fine particles having an average par-
`ticle size of 80 to 400, preferably 100 to 300 micrometers.
`Then, the core particles 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 with an
`aqueous solution composed of a water-soluble polymer,
`water-insoluble polymer, water and other additives such as
`tale in a centrifugal
`fluidizing granulator
`(e.g.,
`C14-Granulator under the trade name of CF-360 manufac-
`
`tured by Freund, Inc.). The coating conditions may be
`determined depending on the kind of granulator used, the
`kind of ingredients, component ratio and the like. Suitable
`conditions, when using the above CF-Granulator, may be a
`slit air temperature of 30 to 70° C.; a slit air rate of 200 to
`3501/min; a rotating speed of 100 to 200 rpm; a spray speed
`of 2 to 7 g/min; and a spray air pressure of 2 to 4 kg/C1112.
`After spray, the particles may be dried with, for example, a
`fluidized bed dryer or tray dryer.
`Further, the core particles maybe coated by spraying with
`an aqueous ethanolic solution (e.g., 80% EtOH) composed
`of a saliva-insoluble polymer, ethanol, water and other
`additives such as tale in a centrifugal fluidizing granulator
`(e.g., CF—Granulator under the tradename of CF—360 manu-
`factured by Freund, Inc.). The coating conditions may be
`determined depending on the kind of granulator used, the
`kind of ingredients, component ratio and the like. The
`similar conditions as mentioned above may be used. After
`spray,
`the particles may be dried with, for example, a
`fluidized bed dryer, and then oven—cured, to obtain three-
`layer core particles of this invention.
`In addition, to achieve a good taste and mouth feeling, a
`sugar coating layer may be formed on the outer coating layer
`of the three layer particles thus prepared. A known coating
`method can be used to form such sugar coating layer. For
`example,
`the 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-
`charide generated from natural source) may be added to
`provide a good mouth feeling. The amount of the sugar
`coating layer may be in a range of 15.0 to 270.0 weight
`percent based on the total weight of the coated particle
`composed of the core, the inner and outer coating layers. The
`pharmacological dosage forms of this invention can be used
`in the form of fine granules, tablets, POS (powder for oral
`suspension), capsules or the like.
`
`6
`EXAMPLES AND COMPARATIVE EXAMPLES
`
`The present 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: Sildenafil citrate
`L-HPC: Low-substituted hydroxypropyl cellulose (LH-
`31; Shin-Etsu)
`MCC: Microcrystalline cellulose (Avicel PH101, Asahi
`Chemical Industry)
`HPMC: Hydroxypropyl methyl cellulose2910 as a binder
`(TC-5E, Shin-Etsu)
`Calcium gluconate (Tomita Pharmaceuticals).
`Inner Coating Layer
`Water-Soluble polymer:
`MPMC: Hydroxypropyl methyl cellulose2910 (TC-5E,
`Shin-Etsu)
`Water-insoluble polymer: methacrylate copolymer
`(Eudragit NE30D, Rohm Pharma)
`Outer Coating Layer
`Saliva-insoluble polymer: aminoalkyl methacrylate
`copolymer under the trade name of Eudragit E100, (Rohm
`Pharma).
`When needed, other excipients such as talc and magne-
`sium stearate, hydroxypropyl methyl cellulose and
`ethylcellulose, 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 gluconate(64.8 g), and hydroxypropyl methyl
`cellulose2910(7.2 g) as a binder in a vessel of the granulator.
`The amount ratio of the components used are indicated in
`Table 1. Then, the mixture was granulated by a wet agitation
`granulation method (Vertical Granulator, VG—05, Powrex)
`for 30 min after addition of water (699.0 g) at room
`temperature (blade speed, 200 rpm; cross screw speed, 3600
`rpm). The granulated cores were dried with a fluidized bed
`dryer (FBD) (Multiplex, MP-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 with three layers (inner layer, outer layer, sugar layer)
`by using a centrifugal fluidizing 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 the coating solution composed
`of TC-5E(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 electrostatic aggregation of each particles. The
`amount ratio of the components used are indicated in Table
`1. The conditions used were as follows: slit air temperature,
`70° C.; slit air rate, 2501/min; rotating speed, 150 rpm, spray
`speed, 3.4 g/min; and spray air pressure, 3.0 kg/cmz. After
`spray,
`the particles were dried with fluidized bed dryer
`(Multiplex, MP-01, Powrex) for 25 min (inlet, 80° C. outlet,
`50° C.).
`
`_
`
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`US 6,221,402 B1
`
`7
`
`(3) Coating of Outer Layer
`Eudragit El00( 66.5 g), which was dissolved in 950.2 g of
`aqueous ethanolic solution (80% EtOII), was applied to coat
`on the inner
`layer-coated particles (190.0 g) with a
`CF-Granulator (slit air temperature, 34° C.; slit air rate, 300 5
`l/min; rotating speed, 140 rpm; spray speed, 5.0 g/min). The
`coating level of the outer layer was adjusted as indicated in
`Table 1. After spray, the particles were transferred to FBD
`and oven-cured at the same conditions described above to 10
`increase the protect effect to obtain three layer products.
`(4) Coating of Sugar Layer
`In some Examples and Comparative Examples, an addi-
`tional sugar layer coating was formed on the three-layer
`products as prepared in the above Step
`More 15
`specifically, the coated particles (137.8 g) were fed by spray
`solution composed of sucrose (170.5 g) and D—mannitol
`(55.0 g) dissolved in water (138.0 g) to the CF-Granulator to
`
`8
`form the sugar layer for adjustment of taste. The conditions
`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 fine particles. Xanthan 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 flavor(0.4 g) were supplied in a powder
`state. After drying in FBD (outlet air : 67° C.) and sieving
`(<500 mm), the sugar layer coated product was obtained.
`The amount of each ingredient used are as indicated in Table
`1(a).
`
`Examples 2 to 5 and Comparative Example
`
`The oral dosage forms were prepared in the same manner
`as indicated in Example 1 except that the amount of each
`ingredient was changed as shown in Tables 1(a) to 1(c).
`
`Cure Material
`
`Sildenafil
`talc
`L-HPC
`MCC
`HPMC
`Ca gluconate
`
`Total
`Inner Layer
`
`HPMC
`NE—30D
`Mg—St
`Tale
`
`Total
`Out Layer
`
`E100
`TC-SE
`Talc
`Mg-St
`
`Total
`Sub-total
`Sugar Layer
`
`Sucrose
`D—mannitol
`Primojel
`Xantan gum
`Asparteme
`Flavor
`TiO2
`
`Total
`
`Grand Total
`
`TABLE 1(a)
`
`Example 1
`
`Example 2
`
`Amount of
`Ingredient
`(myg)
`
`% of
`Core
`Ingredient
`
`Product % Amount of
`of
`Ingredient
`Coated
`(mg/g)
`
`% of
`Core
`Ingredient
`
`% of
`Coated
`Product
`
`210.220
`
`100.000
`
`1.200
`
`23.930
`245.739
`
`0.488
`
`9.738
`100.000
`
`444.96
`143.50
`
`1.00
`30.00
`1.00
`20.00
`
`640.46
`
`1000.00
`
`23.758
`39.912
`
`0.278
`8.344
`0.278
`5.563
`
`178.133
`
`278.134
`
`16.904
`
`116.904
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022338
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,221,402 B1
`
`TABLE 1(b)
`Example 3
`% of
`Core
`Ingredient
`
`% of
`Coated
`Product
`
`Amount of
`Ingredient
`(mg/g)
`
`Example 4
`% of
`Core
`Ingredient
`
`Amount of
`Ingredient
`(mg/g)
`
`% of
`Coated
`Product
`
`.
`
`100.000
`
`.
`
`.
`
`100.000
`
`24.065
`—
`6.877
`0.299
`31.241
`100.000
`
`112.090
`36.748
`—
`0.263
`7.875
`0.263
`5.250
`162.49
`
`262.489
`
`Core Material
`
`Sildenafil
`talc
`L—HPC
`MCC
`HPMC
`Ca gluconate
`Total
`Inner Layer
`HPMC
`NE-30D
`Mg-St
`Tale
`
`Total
`Out Layer
`E100
`TC-5E
`Talc
`Mg—St
`Total
`Sub Total
`Sugar Layer
`Sucrose
`D-mannitol
`Primojel
`Xantan gum
`Asparteme
`Flavor
`TiO2
`Total
`
`—
`—
`0.30
`36.11
`274.85
`
`533.15
`140.00
`—
`1.00
`30.00
`1.00
`20.00
`725.15
`
`—
`—
`0.110
`13.140
`100.000
`
`193.979
`50.937
`—
`0.364
`10.915
`0.364
`7.277
`263.836
`
`427.03
`140.00
`—
`1.00
`30.00
`1.00
`20.00
`619.03
`
`Grand Total
`
`1000.00
`
`363.836
`
`1000.00
`
`TABLE 1(c)
`
`EXamEle 5
`% of
`Core
`Ingredient
`
`Amount of
`Ingredient
`(mg/g)
`
`% of
`Coated
`Product
`
`ComEaratiVe EXamEle 1
`Amount of
`% of
`% of
`Ingredient
`Core
`Coated
`(mg/g)
`Ingredient
`Product
`
`.
`
`.
`
`..
`
`.
`
`100.000
`
`.
`
`.
`
`100.000
`
`Core Material
`
`Sildenafil
`talc
`L-HPC
`MCC
`HPMC
`Ca gluconate
`polysorbate 80
`Citric acid
`
`Total
`Inner Layer
`
`HPMC
`NE-30D
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022339
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`11
`
`US 6,221,402 B1
`
`TABLE 1(c)-continued
`Example 5
`%of
`Core
`Ingredient
`
`% of
`Coated
`Product
`
`Comparative Example 1
`Amount of
`‘.70 of
`% of
`Core
`Coated
`Ingredient
`Product
`Ingredient
`(mg/g)
`—
`1.37
`
`43.053
`100.000
`
`82.558
`31.631
`—
`0.226
`6.778
`0.226
`4.519
`
`125.94
`
`225.938
`
`Amount of
`Ingredient
`(mg/g)
`0.16
`i
`26.65
`
`441.26
`140.00
`—
`1.00
`30.00
`1.00
`20.00
`
`633.26
`
`Mg-St
`Tale
`
`Total
`Out Layer
`E100
`TC-5E
`Talc
`Mg-St
`Total
`Sub-total
`Sugar layer
`Sucrose
`D-mannitol
`Primojel
`Xantan gum
`Asparteme
`Flavor
`TiO2
`
`Total
`
`0.044
`1.033
`
`7.266
`
`28.574
`100.000
`
`120.320
`38.174
`—
`0.273
`8.180
`0.273
`5.453
`
`172.673
`
`24.07
`
`—
`—
`1.50
`190.55
`442.60
`
`365.40
`140.00
`—
`1 .00
`30.00
`1.00
`20.00
`
`557.40
`
`(jrand Total
`
`1000.00
`
`272.673
`
`1000.00
`
`EXPERIMENTS
`
`(1) Bitterness Test
`Five (5) panelists held 1 g of the three or four layered
`products prepared by the above procedures in their mouth
`for 1 min, and measured a time period until
`they felt
`bitterness. The average time (in seconds) was used for
`evaluation. The desirable masking time period is more than
`50 seconds. The results are indicated in Table 2.
`
`(2) Drug Release Test
`According to the guideline published by Minister of
`Health and Welfare (MHW) in Japan, the dissolution test
`were conducted in 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-
`ments from the particles were performed by the Japanese
`Pharmacopeia (JP) paddle method in 900 ml of media at 37°
`C. The three or four layered products prepared in the above
`procedures were spread over the media with constant stirring
`at 100 rpm. The media used in this study were the 1st fluid
`(disintegration test
`fluid, Japanese Pharmacopoeia 13,
`pH1.2), 0.1M acetate buffer (pH4.0), and 0.05M phosphate
`buffers (pH5.5, 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 into each
`media. The results are indicated in Table 2.
`
`TABLE 2
`
`Examples
`
`Comp. Desirable
`
`1
`
`>120
`
`2
`
`>55
`
`3
`
`>75
`
`4
`
`>120
`
`5
`
`>53
`
`Example Value
`
`>120
`
`>50 sec.
`
`Bitterness Test (sec.)
`(Drug Release Test)
`RA (%, pH 1.2 after 5 min.)
`RA (%, pH 1.2 after 10 min.)
`RA (%, pH 1.2 after 20 min.)
`RA (%, pH 4.0 after 5 min.)
`RA (%, pH 4.0 after 10 min.)
`RA (%, pH 4.0 after 20 min.
`RA (%, pH 5.5 after 5 min.)
`RA (%, pH 5.5 after 10 min.)
`RA (%, pH 5.5 after 20 min.)
`RA (%, pH 6.0 after 5 min.)
`RA (%, pII 6.0 after 10 min.)
`RA (%, pH 6.0 after 20 min.)
`RA (%, pH 6.5 after 2.5 min.)
`RA (%, pH 6.5 after 5 min.)
`RA (%, pH 6.5 after 20 min.)
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022340
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,221,402 B1
`
`13
`As shown in Table 2, it was confirmed that the oral dosage
`forms of this invention (Examples 1 to 5) have good taste
`masking properties and good drug release profiles.
`More specifically,
`the time period until panelists felt
`bitterness showed more than 50 sec. in all examples. Further,
`it was found that the oral dosage forms of this invention have
`fast onset release profiles in media within a range of pH1.2
`to pH5.5 (gastric juice). It was reported that pH values of the
`empty stomach in thirty subjects varied from less than 2 to
`5.5. It was also confirmed that the release profiles, of the
`products of this invention, in media of pH value ranging 1.2
`to 5.5 were satisfactory even in the case of lower- and
`non-acidity humans.
`Further, normal humans have a saliva with a pH value of
`about 6.5, and thus small drug release amount after 2.5
`minutes stirring from administration in the media with pH
`6.5 is preferable. The release profiles, at pII6.5, of the
`products of this invention showed the sigmoidal release
`pattern, that is, the rapid release profile after the time lag for
`a few minutes. This is a good drug release profile since some
`aged patients have a gastric juice with a pH value of about
`6.5. In this case, preferably the drug should be released in an
`amount of more than 30% after 20 minutes stirring. The
`desirable dissolution value at 20 min, was 30% (pH6.5)
`rather than 75% (pH 1.2, 4.0, 5.5, 6.0), since the solubility
`of sildenafil at pH6.5 is low. All
`the products of this
`invention showed a drug release percentage, at pH 6.5 after
`20 minutes stirring, of more than 30% although the product
`prepared in the Comparative Example showed a drug release
`percentage of only 5 .4.
`In summary, it was substantiated that the oral dosage
`forms of this invention have good drug release properties
`and good taste-masking properties.
`What is claimed is:
`
`1. A rapidly releasing and taste-masking pharmaceutical
`dosage form comprising a core containing a pharmaceuti-
`cally active ingredient, low-substituted hydroxypropyl cel-
`lulose containing not less than 5.0% and not more than
`16.0% hydroxypropoxy groups on a dried basis, and micro-
`crystalline cellulose,
`the amount of the microcrystalline
`cellulose being at least 26.0 weight percent based on the
`total weight of the core; an inner coating layer formed on the
`core and containing a water-soluble polymer; and an outer
`coating layer formed on the inner coating layer and con-
`taining a saliva-insoluble polymer, wherein the core, the
`inner coating layer and the outer coating layer are contained
`in an amount of from 60.0 to 87.0, from 4.0 to 31.0 and from
`9.0 to 36.0 weight percent, respectively, based on the total
`weight of the dosage form.
`2. A dosage form according to claim 1, which is further
`coated by a sugar coating layer formed on the outer coating
`layer in an amount of 15.0 to 270.0 weight percent based on
`
`14
`the total weight of a coated particle composed of the core,
`the inner and outer coating layers.
`3. A dosage for