PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 96/36318
`
`(51) International Patent Classification 6 :
`A61K 9/22
`
`A2 (cid:9)
`
`(11) International Publication Number: (cid:9)
`
`(43) International Publication Date:
`
`21 November 1996 (21.11.96)
`
`(21) International Application Number:
`
`PCT/SI96/00012
`
`(22) International Filing Date:
`
`17 May 1996 (17.05.96)
`
`(30) Priority Data:
`P-9500173 (cid:9)
`
`19 May 1995 (19.05.95) (cid:9)
`
`SI
`
`(71) Applicant (for all designated States except US): LEK,
`TOVARNA FARMACEVTSKIH IN KEMINIH
`IZDELKOV,D.D. [SUSI]; Verovlkova 57, 1526 Ljubljana
`(SI).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KERt, Janez [SUSI];
`Trebinjska 7, 1000 Ljubljana (SI). REBIe, Ljubomira,
`Barbara [SUSI]; Dergomaka 50, 1000 Ljubljana (SI).
`KOFLER, Bojan [SUSI]; Podlubnik 301, 4220 Skofja Loka
`(SI).
`
`(74) Agent: PATENTNA PISARNA D.0.0.; t opova 14, P.O. Box
`322, 1000 Ljubljana (SI).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BB, BG, BR, BY,
`CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IS,
`JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV, MD,
`MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
`SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN,
`ARIPO patent (KE, LS, MW, SD, SZ, UG), Eurasian patent
`(AM, AZ, BY, KG, KZ, MD, RU, Ti, TM), European patent
`(AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, ML, MR, NE, SN, TD, TG).
`
`Published
`Without international search report and to be republished
`upon receipt of that report.
`
`(54) Title: THREE-PHASE PHARMACEUTICAL FORM WITH CONSTANT AND CONTROLLED RELEASE OF AMORPHOUS
`ACTIVE INGREDIENT FOR SINGLE DAILY APPLICATION
`
`(57) Abstract
`
`Described is a novel three-phase pharmaceutical form with constant and controlled release of an amorphous active ingredient stabilized
`with polymers for a single daily peroral application, which is especially suitable for active ingredients existing in amorphous form or in
`one or more polymorphous forms, which exhibit poor solubility in crystal form depending on the polymorphous form, particle size and
`the specific surface area of the active ingredient. The active ingredient can be used in its amorphous or any polymorphous form, which
`in the process of the preparation of the three-phase pharmaceutical form according to the invention is converted into the amorphous form.
`The three-phase pharmaceutical form with constant and controlled release of an amorphous active ingredient for a single daily peroral
`application contains a core consisting of a first and a second phase and a coating representing the third phase. In the first phase the three-
`phase pharmaceutical form contains an amorphous active ingredient, the water-soluble polymer polyvinylpyrrolidone and a cellulose ether
`as carriers of the amorphous active ingredient and simultaneously as inhibitors of its crystallization, a surfactant that improves the solubility
`of the active ingredient and promotes the absorption of the amorphous active ingredient from gastrointestinal tract, in the second phase it
`contains a cellulose ether and a mixture of mono-, di- and triglycerides as sustained release agents and the third phase is represented by a
`poorly soluble or gastro-resistant film coating, which in the first few hours after the application controls the release of the active ingredient
`and can consist of an ester of hydroxypropylmethylcellulose with phthalic anhydride or of a copolymerizate based on methacrylic acid and
`ethyl acrylate. Described is also a process for the preparation of this pharmaceutical form.
`
`Exhibit 1022
`ARGENTUM
`IPR2018-00080
`
`000001
`
`(cid:9)
`(cid:9)
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`EE
`ES
`Fl
`FR
`GA
`
`Armenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LR
`LT
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`MR
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TT
`UA
`UG
`US
`UZ
`VN
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`
`000002
`
`

`

`WO 96/36318 (cid:9)
`
`1 (cid:9)
`
`PCT/S196/00012
`
`Three-phase Pharmaceutical Form with Constant and Controlled Release of
`Amorphous Active Ingredient for Single Daily Application
`
`Technical Field of the Invention
`
`IPC A 61K 9/22
`
`The invention belongs to the field of pharmaceutical industry and relates to a novel
`medicinal preparation with prolonged action for peroral application (sustained
`release tablets) based on a combination of an amorphous active ingredient, water-
`soluble polymer polyvinylpyrrolidone, cellulose ethers and a mixture of mono-, di-
`and triglycerides, an ester of hydroxypropylmethylcellulose with phthalic anhydride
`or a copolymer based on methacrylic acid and ethyl acrylate.
`
`Particularly, the invention relates to a novel three-phase pharmaceutical form with a
`constant and controlled release of an amorphous active ingredient stabilized with
`polymers for a single daily peroral application such as tablets and capsules. A three-
`phase pharmaceutical form with constant and controlled release of an amorphous
`active ingredient for a single daily peroral application is especially suitable for active
`ingredients existing in amorphous form or in one or more polymorphous forms,
`which exhibit poor solubility in crystal form depending on the polymorphous form,
`particle size and specific surface area of the active ingredient. The active ingredient
`can be used in amorphous or any polymorphous form which is converted into the
`amorphous form during the manufacturing process of the three-phase pharmaceuti-
`cal form of the invention. The three-phase pharmaceutical form with constant and
`controlled release of the amorphous active ingredient for a single daily peroral ap-
`plication contains a core consisting of a first and a second phase and a coating repre-
`senting the third phase. The three-phase pharmaceutical form contains as the first
`phase an amorphous active ingredient, the water-soluble polymer polyvinylpyr-
`rolidone and a cellulose ether as carriers of the amorphous active ingredient and
`simultaneously as inhibitors of crystallization of the amorphous active ingredient as
`well as a surfactant improving the solubility of the active ingredient and promoting
`the absorption of the amorphous active ingredient from the gastrointestinal tract; as
`the second phase it contains sustained-release agents such as cellulose ether and a
`mixture of mono-, di- and triglycerides, and the third phase is represented by a poorly
`soluble or gastro-resistant film coating, which in the first few hours after the applica-
`tion controls the release of the active ingredient and can consist of an ester of
`
`000003
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`

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`WO 96/36318 (cid:9)
`
`2 (cid:9)
`
`PCT/S196/00012
`
`hydroxypropylmethylcellulose with phthalic anhydride or of a copolymerizate based
`on methacrylic acid and ethyl acrylate.
`
`Technical Problem
`
`There exists a constant need to develop pharmaceutical forms in which solubility and
`dissolution rate of the active ingredient will be independent of its polymorphous
`form, crystallinity, particle size and specific surface area. Hitherto known pharma-
`ceutical forms with prolonged release of the active ingredient containing a crystalline
`active ingredient in the pharmaceutical form have the essential disadvantage that,
`due to the presence of the crystalline active ingredient in several polymorphous
`modifications, the release rate of the active ingredient depends on the polymorphous
`modification, the crystal size and thus on the specific surface area of the active in-
`gredient. The dissolution rate of a crystalline substance is not constant and it
`changes depending on various shapes and size distribution of the crystals of the ac-
`tive ingredient.
`
`Prior Art
`
`The use of cellulose ethers of various viscosities and molecular weights in the func-
`tion of controlling the release rate has been known for a long time. In US patent
`4,259,314 there is described a method for the preparation of a dry pharmaceutical
`preparation with controlled and sustained release, which is provided by a mixture of
`hydroxypropylmethylcellulose and hydroxypropylcellulose together with a hygro-
`scopic active ingredient.
`
`N.A. Shaikh, S.E. Abidi and L.H. Block (Drug Development and Industrial Phar-
`macy, 13 (8), 1345-1369 (1987)) studied the influence of the concentration of ethyl-
`cellulose in a pharmaceutical preparation on the release rate of the active ingredient
`(e.g. acetaminophen, theophyline). It was found that the higher is the viscosity of
`ethylcellulose the lower is the release rate of the active ingredient from a solid dis-
`persion.
`
`In US patent 4,389,393 there is described a carrier basis for active ingredients consist-
`ing of one or more hydroxypropylmethylcelluloses with various contents of methoxy
`or hydroxypropoxy groups and various average molecular weights, which combina-
`tion gives a pharmaceutical preparation with sustained release.
`
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`

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`WO 96/36318 (cid:9)
`
`3 (cid:9)
`
`PCT/S196/00012
`
`In US patent 4,792,452 there is described a pharmaceutical form with a controlled
`release of the active ingredient (selected from the group of calcium antagonists) in-
`dependently of the pH-value of the environment, which contains up to 45 wt.% of a
`polymer dependent of the pH value, which is an alginic acid salt e.g. sodium alginate,
`and a gelatinizing agent independent of the pH-value such as hydroxypropylmethyl-
`cellulose.
`
`In WO 87/00044 there is described the use of bimodal hydroxypropylmethylcellulose
`in a carrier basis which together with the active ingredient gives a bimodal profile of
`the release of the active ingredient.
`
`In WO 91/17743 a pharmaceutical preparation for a slow release of granules contain-
`ing low and high viscous ethylcellulose is described.
`
`In US patent 5,009,895 there is described a carrier basis in combination with an ac-
`tive ingredient (e.g. ibuprofen or its salt) that is formed and compressed in a solid
`pharmaceutical form with a sustained release, of the active ingredient. The carrier
`basis contains two hydroxypropylmethylcelluloses of different viscosities in such a
`ratio that the release rate of the active ingredient is of zero order. In the pharma-
`ceutical form there is also present polyvinylpyrrolidone (Povidon USP) acting as a
`binding agent.
`
`In EP-A-596 203 there is described a pharmaceutical form containing solid particles,
`which is prepared by mixing an active ingredient (e.g. nifedipine) with a water-
`soluble melt consisting of two sorts of polymers with different viscosities (polymer A
`with a viscosity from 1000 to 120000 mPa.s, polymer B with a viscosity from .1 to 500
`mPa.$) as a carrier.
`
`A dosage form containing cellulose ethers with various molecular weights is
`described also in US patent 4,871,548. .
`
`In US patent 5,015,479, there is described a pharmaceutical preparation for a single
`daily application in the form of an adsorbate containing amorphous dihydropyridine
`(such as felodipine, nicardipine, nifedipine) and polyvinylpyrrolidone with average
`molecular weight above 55000 g/mol, whose role is to change the dissolution rate of
`dihydropyridine from cross-linked polyvinylpyrrolidone and to prevent the crystal-
`lization of dihydropyridine. Dihydropyridine and polyvinylpyrrolidone are adsorbed
`on cross-linked polyvinylpyrrolidone and mixed with a polymer which gelatinates in
`
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`

`WO 96/36318 (cid:9)
`
`4 (cid:9)
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`PCT/S196/00012
`
`the presence of water (e.g. polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl-
`cellulose, sodium carboxymethylcellulose etc.). The quantity and the ratio between
`water-soluble and water-insoluble polymers with regard to the viscosity of polyvinyl-
`pyrrolidone provides the desired sustained release.
`
`Description of the Solution to the Technical Problem with Examples
`
`The aim of the invention is to prepare a novel pharmaceutical preparation for a
`single daily peroral application, wherefrom the amorphous active ingredient is
`released with a constant and controlled rate of zero order and wherein the solubility
`and dissolution rate of the active ingredient are independent of its polymorphous
`form, crystallinity, particle size and specific surface area. This aim was achieved by
`the preparation of a three-phase pharmaceutical form according to the invention,
`wherein the active ingredient in amorphous form is stabilized by a mixture of
`polymers comprising water-soluble polymer polyvinylpyrrolidone and cellulose
`ethers of various viscosities. The release of the amorphous active ingredient from
`the three-phase pharmaceutical form is determined by the mixture of water-soluble
`polymer polyvinylpyrrolidone, a surfactant, cellulose ethers of various viscosities, a
`mixture of mono-, di- and triglycerides and, additionally, the release is also influenced
`by a film coating consisting of an ester of hydroxypropylmethylcellulose with phthalic
`anhydride or of a copolymerizate based on methacrylic acid and ethyl acrylate. The
`amorphous active ingredient stabilized with polymers is dispersed in a mixture of
`these polymers at the molecular level and has therefore always the same particle size,
`the same specific surface area and, consequently, a constant release rate in a 24-hour
`interval. For various active ingredients the pharmaceutical preparation of the inven-
`tion has such bioavailability as determined by clinical tests that is comparable with •
`known commercial preparations based on completely different principles of releas-
`ing the active ingredient (e.g. the principle of osmosis in OROS-system described in
`US patents 4,327,725, 4,612,008, 4,765,989 and 4,783,337, suitable for various active
`ingredients such as nifedipine).
`
`The main aim of the invention refers to a novel three-phase pharmaceutical form
`with constant and controlled release of an amorphous active ingredient for a single
`daily peroral application, containing a core consisting of a first and a second phase
`containing an amorphous active ingredient, the water-soluble polymer polyvinyl-
`pyrrolidone, a surfactant, cellulose ethers and a mixture of mono-, di- and
`triglycerides, and a coating representing the third phase and consisting of an ester of
`
`000006
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`

`

`WO 96/36318 (cid:9)
`
`5 (cid:9)
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`PCT/S196/00012
`
`hydroxypropylmethylcellulose with phthalic anhydride or a copolymerizate based on
`methacrylic acid and ethyl acrylate.
`
`A schematic presentation of the three-phase pharmaceutical form is given in Fig. 1.
`Therein the first phase of the three-phase pharmaceutical form contains an amor-
`phous active ingredient (0), a surfactant (1), the water-soluble polymer polyvinyl-
`pyrrolidone (2) and a cellulose ether (3). The second phase of the three-phase
`pharmaceutical form contains a cellulose ether (4) of the second phase and a mixture
`(5) of mono-, di- and triglycerides. The third phase is represented by a film coating
`consisting of an ester of hydroxypropylmethylcellulose with phthalic anhydride or a
`copolymerizate based on methacrylic acid and ethyl acrylate.
`
`The first phase of the three-phase pharmaceutical form with constant and controlled
`release of an amorphous active ingredient for a single daily peroral application con-
`tains an amorphous active ingredient, the water-soluble polymer polyvinylpyr-
`rolidone, a surfactant and a cellulose ether.
`
`In the novel three-phase pharmaceutical form with constant and controlled release
`of an amorphous active ingredient for a single daily peroral application according to
`the invention, various active ingredients in amounts ranging from 0,05 mg to 300 mg
`can be used, which exist in amorphous form or in one or more polymorphous
`modifications, which have poor solubility in crystal form depending on its polymor-
`phous form, particle size and specific surface area. As active ingredients in the
`three-phase pharmaceutical form with constant and controlled release of an amor-
`phous active ingredient for a single daily peroral application there can be used
`various active ingredients acting as analgesics, anticonvulsants, antiparkinsonian
`drugs, anesthetics, antibiotics, antimalarials, antihypertensives, antihistaminics, anti-
`pyretics, alpha-blockers, alpha-adrenergic agonists, bactericides, bronchodilators,
`beta-adrenergic stimulants, beta-adrenergic blockers, contraceptives, cardiovascular
`active ingredients, calcium channel inhibitors, diuretics, hypnotics, hormones, hyper-
`glycemics, hypoglycemics, muscle relaxants and contractors, parasympathomimetics,
`sedatives, sympathomimetics, tranquilizers, antimigraine drugs, vitamins- and many
`others.
`
`The three-phase pharmaceutical form with constant and controlled release of an
`amorphous active ingredient for a single daily peroral application is especially useful
`for dihydropyridines selected from a group comprising nicardipine hydrochloride,
`
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`WO 96/36318 (cid:9)
`
`6 (cid:9)
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`PCT/S196/00012
`
`amlodipine benzenesulfonate, nifedipine, felodipine and fenofibrate and other active
`ingredients poorly soluble in water.
`
`The water-soluble polymer polyvinylpyrrolidone in the first phase of the three-phase
`pharmaceutical form with constant and controlled release of an amorphous active
`ingredient for a single daily peroral application prevents the crystallization of the
`amorphous active ingredient, simultaneously it is a carrier of the amorphous active
`ingredient and it improves the wettability and dissolving rate of the amorphous active
`ingredient. As the water-soluble polymer polyvinylpyrrolidone there can be used a
`polyvinylpyrrolidone with a K-value (relative viscosity of the compound in water
`solution with regard to water) ranging from 10 to 95, preferably in the range from 24
`to 32, with an average molecular weight ranging from 2000 g/mol to 1100000 g/mol,
`preferably in the range from 25000 g/mol to .50000 g/mol. The water-soluble polymer
`polyvinylpyrrolidone is present in the three-phase pharmaceutical form in the range
`from 1 to 40 wt.%, preferably from 4 to 20 wt.%, with respect to the total weight of
`the three-phase pharmaceutical form.
`
`In the first phase of the three-phase pharmaceutical form with constant and control-
`led release of an amorphous active ingredient for a single daily peroral application
`the added surfactant improves the wettability, solubility and dissolution rate, and
`provides a perfect absorption of the dissolved amorphous active ingredient from the
`gastrointestinal tract. As the surfactant there can be used ionic surfactants such as
`sodium lauryl sulfate or non-ionic surfactants such as various types of poloxamers
`(copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecithins
`and esters of sorbitan and fatty acids (such as Span® (Atlas Chemie)), esters of
`polyoxyethylene sorbitan and fatty acids (such as Tween® (Atlas Chemie)),
`polyoxyethylated hydrogenated castor oil (such as Cremophor® (BASF)), poly-
`oxyethylene stearates (such as Myrj® (Atlas Chemie)) or any other combinations of
`the cited surfactants. In the three-phase pharmaceutical form the surfactant is
`present in the range from 0.1 to 20 wt.%, preferably from 0.2 to 10 wt.% with respect
`to the total weight of the three-phase pharmaceutical form. For providing the wet-
`tability of the active ingredient and its absorption from the gastrointestinal tract the
`required weight ratio between the surfactant and the active ingredient is in the range
`from 0.1:100 to 10:1, preferably in the range from 0.5:100 to 3:1.
`
`The cellulose ether in the first phase of the three-phase pharmaceutical form with
`constant and controlled release of an amorphous active ingredient for a single daily
`peroral application acts as a carrier of the amorphous active ingredient which simul-
`
`000008
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`

`

`WO 96/36318 (cid:9)
`
`7 (cid:9)
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`PCT/S196/00012
`
`taneously inhibits its crystallization. As the cellulose ether there can be used methyl-
`cellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropyl-
`cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, preferably
`hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose with
`viscosity in the range from 3 to 1500 mPa.s, preferably in the range from 5 to 400
`mPa.s and with an average molecular weight in the range from 5000 g/mol to 50000
`g/mol, preferably in the range from 10000 g/mol to 30000 g/mol. As the cellulose
`ether hydroxypropylmethylcellulose with a content of methoxy groups ranging from
`19 to 30% and with a content of hydroxypropoxy groups ranging from 4 to 12% can
`be used. In the first phase of the three-phase pharmaceutical form the cellulose ether
`is present in a quantity from 10 to 70 wt.%, preferably from 20 to 60 wt.%, with
`respect to the total weight of the three-phase pharmaceutical form.
`
`For providing a stable amorphous form of the active ingredient in the novel three-
`phase pharmaceutical form with constant dissolution rate the required weight ratio
`between the water-soluble polymer polyvinylpyrrolidone and the cellulose ether in
`the first phase of the three-phase pharmaceutical form with constant and controlled
`release of the amorphous active ingredient for a single daily peroral application is in
`the range from 1:10 to 10:1, preferably in the range from 1:3 to 3:1.
`
`The combination of the carriers i.e. the water-soluble polymer polyvinylpyrrolidone
`and the cellulose ether has a double effect and the advantage that it stabilizes the
`amorphous form of the active ingredient and simultaneously modifies the release of
`the amorphous active ingredient in such a way that it is sustained, repeatable and in-
`dependent of the amorphous or polymorphous form of the active ingredient, its par-
`ticle size and specific surface area.
`
`For providing a stable amorphous form of the active ingredient with a constant dis-
`solution rate, the required weight ratio between the amorphous active ingredient,
`water soluble polymer polyvinylpyrrolidone and cellulose ether in the first phase of
`the three-phase pharmaceutical form is in the range from 1:20:30 to 10:2:1,
`preferably in the range from 1:2:3 to 3:2:1.
`
`The second phase of the three-phase pharmaceutical form with constant and control-
`led release of an amorphous active ingredient for a single daily peroral application
`contains a cellulose ether, a mixture of mono-, di- and triglycerides and other usual
`adjuvants useful in the preparation of solid pharmaceutical forms such as fillers,
`binders, swelling auxiliaries, glidants, lubricants etc. The cellulose ethers and the
`
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`WO 96/36318 (cid:9)
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`8 (cid:9)
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`PCT/S196/00012
`
`mixture of mono-, di- and triglycerides modify the release rate of the amorphous ac-
`tive ingredient in such a manner that a constant release (a release of zero order) of
`the amorphous active ingredient in a 24-hour interval is achieved.
`
`In the second phase of the three-phase pharmaceutical form with constant and con-
`trolled release of an amorphous active ingredient for a single daily peroral applica-
`tion as cellulose ethers gelatinizing in the rn presence of water there can be used
`methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxy-
`propylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, preferably
`hydroxypropylcellulose and hydroxypropylmethylcellulose with viscosity in the range
`from 1500 to 150000 mPa.s, preferably in the range from 4000 to 100000 mPa.s and
`with an average molecular weight ranging from 50000 g/mol to 300000 g/mol,
`preferably in the range from 80000 g/mol to 250000 g/mol. As the cellulose ether
`hydroxypropylmethylcellulose with a content of methoxy groups ranging from 19 to
`30% and with a content of hydroxypropoxy groups ranging from 4 to 12% can be
`used. In the second phase of the tree-phase pharmaceutical form the cellulose ether
`is present in the amount from 5 to 40 wt.%, preferably from 10 to 30 wt.%, with
`respect to the total weight of the three-phase pharmaceutical form. The cellulose
`ethers in the second phase act as an agent for sustained and controlled release of the
`amorphous active ingredient. Thus the cellulose ethers in the first and in the second
`phases of the three-phase pharmaceutical form have a different function.
`
`The mixture of mono-, di- and triglycerides acts as a glidant with a sustained release
`action. As the mixture of mono-, di- and triglycerides there can be used a mixture of
`glycerol mono-, di- and tristearate, a mixture of glycerol mono-, di- and tripalmitate,
`a mixture of glycerol mono-, di- and trioleate, a mixture of glycerol mono-, di- and
`tripalmitostearate, preferably a mixture of glycerol mono-, di- and tripalmitostearate
`with a weight content from 20 to 60 wt.% of triglyceride, from 25 to 65 wt.% of
`diglyceride, from 10 to 20 wt.% of monoglyceride and from 0 to 5 wt.% of glycerol,
`preferably from 35 to 45 wt.% of triglyceride, from 40 to 50 wt.% of diglyceride,
`from 12 to 16 wt.% of monoglyceride and from 1 to 2 wt.% of glycerol. The mixture
`of mono-, di- and triglycerides is present in the second phase of the three-phase
`pharmaceutical form in an amount from 0 to 10 wt.%, preferably from 0 to 5 wt.%
`with respect to the total weight of the three-phase pharmaceutical form.
`
`For providing a constant and controlled release of zero order of the amorphous ac-
`tive ingredient from the three-phase pharmaceutical form with constant and control-
`led release of an amorphous active ingredient for a single daily peroral application
`
`000010
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`WO 96/36318 (cid:9)
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`9 (cid:9)
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`PCT/S196/00012
`
`the required weight ratio between the cellulose ether in the first phase and the cel-
`lulose ether in the second phase is in the range from 5:1 to 1:5, preferably in the
`range from 3:1 to 1:3.
`
`In the second phase the three-phase pharmaceutical form with constant and control-
`led release of an amorphous active ingredient for a single daily peroral application
`can, beside cited ingredients, contain also other nontoxic excipients useful in pharma-
`ceutical forms. The three-phase form can also contain one or more fillers such as lac-
`tose, starch, saccharose, glucose, microcrystalline cellulose, mannitol, sorbitol, cal-
`cium hydrogen phosphate, aluminum silicate, sodium chloride etc., one or more
`binders such as starch, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, cross-
`linked polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose etc., one or
`more disintegrants such as starch, cross-linked sodium carboxymethylcellulose,
`cross-linked polyvinylpyrrolidone, sodium starch glycolate etc., one or more glidants
`such as magnesium stearate, calcium stearate, aluminum stearate, stearic acid, pal-
`mitic acid, cetanol, stearol, polyethylene glycols of various molecular weights, talc
`etc., one or more lubricants such as stearic acid, calcium, magnesium or aluminum
`stearate, siliconized talc etc.
`
`The third phase of the three-phase pharmaceutical form with constant and control-
`led release of an amorphous active ingredient for a single daily peroral application is
`represented by a poorly soluble or gastro-resistant film coating for additional delay in
`release and for adaptation to in vivo release rates of known commercial prepara-
`tions.
`
`The film coating consists of
`an ester of hydroxypropylmethylcellulose with phthalic anhydride with an average
`molecular weight ranging from 2000 g/mol to 100000 g/mol, with a content of
`methoxy groups from 18 to 25%, a content of hydroxypropoxy groups from 4 to
`10%, a content of carboxybenzoyl groups from 20 to 35%, a viscosity in the range
`from 120 to 180 mPa.s; the weight ratio of the coating with respect to the core is
`from 2 to 10 wt.%, preferably from 3 to 7 wt.%;
`or of
`- a copolymerizate of methacrylic acid and ethyl acrylate with an average molecular
`weight ranging from 100000 g/mol to 300000 g/mol, a content of methacrylic
`groups from 40 to 50% and a viscosity in the range from 100 to 200 mPa.s; the
`weight ratio of the coating with respect to the core is from 2 to 15 wt.%, preferably
`from 3 to 10 wt.%.
`
`000011
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`

`WO 96/36318 (cid:9)
`
`10 (cid:9)
`
`PCT/S196/00012
`
`In addition to the cited polymers, the third phase can also contain one or more
`plasticizers such as polyethylene glycols of various molecular weights, triacetine,
`dibutyl sebacate, triethyl citrate, cellulose ethers such as hydroxypropylcellulose,
`hydroxypropylmethylcellulose etc., additives such as talc, pigments such as synthetic
`ferric (III) oxide, synthetic ferric (III) oxide hydrate, titanium dioxide etc.
`
`The object of the invention also relates to a process for the preparation of the three-
`phase pharmaceutical form with constant and controlled release of an amorphous
`active ingredient for a single daily peroral application, wherein as the active in-
`gredient an amorphous or a polymorphous form of the active ingredient can be used.
`
`In the first step of the preparation of the three-phase pharmaceutical form with con-
`stant and controlled release of an amorphous active ingredient for a single daily
`peroral application an active ingredient, a surfactant and the water-soluble polymer
`polyvinylpyrrolidone are dissolved in an organic solvent at a temperature from 30°C
`to 70°C, and in a fluid bed granulator the obtained solution is sprayed onto cellulose
`ether in the fluid bed. As the active ingredient there can be used an amorphous form
`or a polymorphous form of the active ingredient which in the process of coprecipita-
`tion according to the invention is converted into an amorphous form stabilized with
`the water-soluble polymer polyvinylpyrrolidone and a cellulose ether. Organic sol-
`vents useful for this purpose can be selected from a group of alcohols, ketones,
`esters, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, cycloaliphatic,
`aromatic, heterocyclic solvents or mixtures thereof. Typical solvents can be ethanol,
`methanol, isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate,
`isopropyl acetate, methyl acetate, dichloromethane, chloroform, mixtures of these
`solvents such as ethanol and acetone, methanol and acetone, dichloromethane and
`methanol and mixtures thereof. If a polymorphous form of the active ingredient is
`chosen, it is in the process of the invention converted into an amorphous form which
`is stabilized with the water-soluble polymer polyvinylpyrrolidone and a cellulose
`ether. The obtained granulate is regranulated through a sieve of mesh size 0.5 mm at
`room temperature.
`
`The second step of the preparation of the three-phase pharmaceutical form is con-
`ducted in such a manner that at room temperature the granulate obtained in the first
`step is homogeneously mixed with a cellulose ether and other usual adjuvants useful
`in the preparation of solid pharmaceutical forms such as lactose, polyvinyl-
`pyrrolidone, cross-linked polyvinylpyrrolidone, starch, calcium hydrogen phosphate,
`
`000012
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`

`

`WO 96/36318
`
`PCT/S196/00012
`
`11
`
`aluminum silicate, magnesium stearate, talc, or generally with fillers, binders, disin-
`tegrants, glidants, lubricants etc.
`
`The components are compressed into tablets by means of known tableting machines.
`Thus it is possible to prepare tablets with constant and controlled release of an amor-
`phous active ingredient in a relatively simple and economical way.
`
`In the third step of the preparation of the three-phase pharmaceutical form by
`means of a film coating an additional delay of the release of the amorphous active in-
`gredient from t