[I
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`(12) INTERNATIONAL APPLICATI(
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`Doc Ref. FP17
`Appl. No. 11/273,575
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`1|
`.
`,ATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`Illllllllllllllllllllllllllll|llIllllllllllllllllllllllfllflllll|||llll||lllllllll
`
`(10) International Publication Number
`(43) International Publication Date
`WO 03/063834 A1
`7 August 2003 (07.08.2003)
`PCT
`
`(51) International Patent Classification’:
`
`A61K 9/16
`
`(21) InternationalApplication Number:
`
`PCT/KR03/00200
`
`(22) International Filing Date: 29 January 2003 (29.01.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`10-2002-0005858
`
`1 February 2002 (01.02.2002)
`
`KR
`
`(7]) Applicant: PACIFIC CORPORATION [KR/KR]; 181,
`Hankang-ro 2-ka, Yongsan-ku, 140-777 Seoul (KR).
`
`(72) Inventors: PARK, Jin Woo; 410410, Gayang Apt.,
`GayangZ-dong, Gangseo—gu, 157-744 Seoul (KR). BAE,
`Joon Ho; 106—1801, Daerim ApL, Daebang-dong, Dong-
`jak-gu, 156-761 Seoul (KR). KIM, Jung Ju; 102-601,
`Dongbo Apt., 703, Pungdukchon-l-dong, Yongin—si,
`449-759 Gyeonggi—do (KR).
`
`(74) Agent: SUH, Jong Wan; 7TH. FL, New-Seoul Bldg.,
`828-8, Yeoksam-dong, Kangnam-ku, 135-080 Seoul (KR).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG. KP, KZ, LC, LK,
`LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
`MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL, TJ, TM, TN, TR, TI, TZ, UA, UG, UZ, VC, VN,
`YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GI-I, GM,
`KE, LS, MW, MZ SD, SL, SZ, ’12, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PI‘, SE, SI,
`SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`O03/063834A1
`
`(54) Title: MULTI-STAGE ORAL DRUG CONTROLLED-RELEASE SYSTEM
`
`(57) Abstract: The present invention relates to, as a novel oral drug delivery system for control of drug release, a preparation for
`maintaining drug concentration in blood at a certain level for a prolonged time by allowing the drug to be released by a constant rate
`through stepwise control of drug release upon the administration of the preparation.
`
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`PCT/KR03100200
`
`MULTI—STAGE ORAL DRUG CONTROLLED-RELEASE SYSTEM
`
`Technical Field
`
`The present invention relates to, as a novel oral drug delivery system for
`
`controlling drug release, a preparation for maintaining drug concentration in blood at a
`
`certain level for prolonged time by allowing the drug to be released by a constant rate
`
`through stepwise control of drug release upon the administration ofthe preparation.
`
`Background Art
`
`10
`
`Administration forms capable of controlling drug release become an important
`
`part of medication in terms of improved treatment effect, reduction of side efiects and
`
`patient’s convenience.
`
`Such controlled-release of drug is accomplished through.
`
`designing of a system comprising the drug. Controlled-release of drug brings many
`
`therapeutic advantages, and the most important point is that blood level of drug can be
`
`15
`
`maintained for long time while minimizing fluctuation of the blood level. Accordingly,
`
`allowing drug to be released at a constant rate from a preparation is the most important
`
`aspect in controlled—release preparation, and in particular, an amount of drug equivalent
`
`to that eliminated from the body should be released from the preparation and
`
`continuously absorbed while passing through the gastrointestinal tract.
`
`20
`
`Controlled-release preparations developed so far can be divided into three
`
`types, i.e. a type in which drug-containing particles (granules) are coated, matrix type
`
`mainly based on polymers, and a type based on osmotic pressure, and among them, the
`
`matrix form tablet has been interested greatly as a drug delivery system for the
`
`advantage of easy manufacture. When comparedwith tablets, because of the size and
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`25
`
`resultant increase of surface area, granules lead to relatively fast disintegration, resulting
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`1
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`in the disadvantage of a short drug-release time in a body.
`
`Most matrix preparations release a drug via diffusion, and regarding with the
`
`matrix preparations, various techniques such as introducing water-insoluble coating
`
`layer on matrix particles in which drug is dispersed have been developed.
`
`In case
`
`components of coating layer and the matrix are insoluble in body fluid, difi‘usion of
`
`drug is controlled by the components of coating layer or matrix. Drug release from
`
`such preparation occurs by concentration gradient of drug introduced by water
`
`penetrated to the preparation.
`
`Such type of release shows a tendency of decline in the
`
`release rate at the last stage due to the gradual reduction of concentration gradient and
`
`10
`
`the gradual increase of diffusion distance. Accordingly, release rate of drug cannot be
`
`maintained at a constant level but gradually reduces as a function of time, finally failing
`
`to maintain constant blood level of drug.
`
`Such simple matrix tablets just extend the period of drug release, and exhibit
`
`inherent limit of releasing drug by first order kinetics or at a rate of (time) 0'5. To
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`15
`
`maintain constant release rate, attempts to modify the previous matrix formulations
`
`have been made.
`
`Representative methods are to reduce initial drug release rate by
`
`introduction of a coating layer, to induce zero-order release rate by morphological
`
`approach to preparation, and to combine said two methods. Another approach is
`
`method of maintaining constant release rate by allowing diffusion distance to be
`
`20
`
`reduced as a function of time through using erodible and swelling polymer as a main
`
`component of matrix.
`
`Majority of the complements to the mauix preparation via coating were
`
`attempted for special object besides the control of release rate, e.g. enteric coated tablet
`
`or delayed release of drug in colon. As the best example of morphological approach to
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`25
`
`preparation, a method of regulating release area by introducing hydrophilic or
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`2
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`hydrophobic layer on both sides of drug-containing layer and a method of exposing
`
`constant area of the coated tablet can be enumerated.
`
`Matrix formulation mainly consists of a drug and a biocompatible polymer,
`
`and in particular, in controlled-release preparation, polymer acts a very important role.
`
`Polymer matrix with the characteristic of swelling and erosion consists of swelling layer,
`
`diffusion layer and erosion layer, and has the advantage that drug release rate can be
`
`regulated at a fixed level based on the moving rates of swelling layer and erosion layer.
`
`However, also in case of using erosive polymer, release area deceases with time and this
`
`leads to typical matrix release mechanism pattern where release rate decreases with
`
`10
`
`reduction of release area. To correct such drug release pattern, coating layer and a
`
`factor capable of controlling swelling were introduced. USP 6,156,343 retarded
`
`swelling and initial release by use of polyvinyl alcohol as material for matrix core, and
`
`by addition of a salt and introduction of a coating layer.
`
`However, besides the simple erodible polymeric matrix system, non-erodible
`
`15
`
`preparation with coating layer comprising water-insoluble polymer such as lacquer is
`
`still defective for time-dependent reduction of drug release, and osmotic preparation is
`
`disadvantageous for complicacy of the system and cost problem.
`
`To overcome the declination of drug release with time, DE 1,767,765
`
`20
`
`developed multi—layer tablets, layers with different concentration of drug, and DE
`
`2,651,176 designed a tablet in which drug concentration can increase from the outer
`
`layer towards the center. However, like osmotic preparation, the multi—layer tablet also
`
`has some disadvantages, necessity for special facility and complicate manufacture.
`
`USP 4,252,786 designed a preparation in which the core of water—insoluble
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`25
`
`swelling polymer swells with penetration of water to lead to burst of coating layer.
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`3
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`Such pulsitile drug release is desirable for improving bioavailability of a drug whose
`
`first pass effect can be saturated, and it was revealed that drug release from the
`
`preparation is less sensitive to pH value of GI tract. Such preparation can freely
`
`control the delay of initial drug release, yet, drug release after the burst of the coating
`
`layer, still, depends on concentration gradient of drug.
`
`USP 4,610,870 (Jain et al.) disclosed a coated tablet showing zero-order
`
`release rate. The core of this tablet includes hydroxypropyhnethylcellulose and/or
`
`methylcellulose, one or more non—swellable binders and/or wax binders, one or more
`
`10
`
`inert fillers or excipients, and one or more lubricant.
`
`USP 4,252,786. by Weiss et al. resolved the rapid initial—release problem of
`
`swelling and credible formulation by coating the swelling matrix core with a
`
`hydrophobic film coating layer capable of burst. Drug release in this preparation
`
`occurs via difi'usion through initial non-damaged coating layer, and core expands by
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`15
`
`continuous penetration of external
`
`fluid,
`
`leading to burst of the coating layer.
`
`Thereafter, the swelling matrix core controls the drug release. Overall drug release is
`
`continuous based on such control of initial release, and zero-order release can be
`
`achieved.
`
`Though said two patents resolved the problem of non-linear drug release that
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`20
`
`can occur in swelling and erodible matrix tablet by introducing a coating layer, it is still
`
`only simple coated tablet, therefore has failed in overcoming the feature and basic
`
`limitations of swelling and erodible matrix. Further, in case of a drug with high water-
`
`solubility, it is not effective for prolonged release over 24 hr.
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`25
`
`USP Nos.
`
`4,309,404
`
`and
`
`4,248,857
`
`(DeNeale
`
`et
`
`al.)
`
`used
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`4
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`PCT/KR03/00200
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`carboxypolymethylene as substance for core and introduced seal coating and sugar
`
`coating thereon, and USP No. 4,309,405 (Guley et al.) disclosed the similar formulation
`
`with the above one, using a combination of hydroxypropylmethylcellulose or
`
`hydroxypropylcellulose and hydrophobic polymer as core substance.
`
`These two
`
`formulations demonstrated zero-order release pattern over 12 hr, yet only after rapid
`
`initial drug release for 1 hr.
`
`USP No. 4,610,870 discloses a coated tablet showing zero-order release
`
`pattern over 8 to 12 hr, and the coating layer of this tablet inhibits the rapid initial
`
`release while being gradually disappeared by swelling of the core layer, and then, drug
`
`10
`
`is released with erosion of the core.
`
`USP No. 5,464,633 introduced compressed layer instead of coating layer to
`
`swelling and erodible core matrix tablet in order to modify drug release rate, thereby
`
`preventing rapid initial drug release, and at the same time, endowed sustained release
`
`effect over prolonged time.
`
`In case of such multi-layer
`
`tablet,
`
`to remove
`
`15
`
`inconvenience of coating for coated tablet, compressed layer was introduced, yet, for
`
`formation of compressed layered tablet, special facility and complicate calculation of
`
`release area were necessary.
`
`USP No. 6,083,532 compensated for pH dependent behavior of drug
`
`solubility by using a combination of pH dependent substance and pH-independent
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`20
`
`polymer as a constituent of core matrix. Such release-modifying attempts were to
`
`make the release uninfluenced by individual patient’s physiological condition, and
`
`applied as means for maximizing drug action.
`
`Such preparations can be applied to
`
`only specific group of drugs with specific pH—dependency, and as external fluid
`
`penetrates continuously into inside of the matrix, it sensitively reacts to pH within the
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`25
`
`gastrointestinal tract, thus it is difficult to expect continuously steady drug release.
`
`5
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`USP No. 4,610,870 used a mixture of hydroxypropylmethylcellulose and
`
`methylcellulose as a gel-forming substance, and introduced a coating layer consisting of
`
`hydrophilic and hydrophobic materials on the core tablet. Based on this attempt, a
`
`preparation was designed to release procaine hydrochloride by zero-order over 8 to 12
`
`hr.
`
`USP No. 6,068,859 discloses controlled-release preparation of azithromycin
`
`where, in order to control time-dependent release of drug, the drug was dispersed and
`
`embedded in core matrix comprising four
`
`lcinds of hydro~colloida1 gel-forming
`
`substance and drug release was induced by erosion of the matrix, and when needed, a
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`10
`
`coating layer was introduced. As another method, a mixture of coated particles and
`
`particles without coating layer was introduced into a single capsule or tablet to allow
`
`drug to be released via release channel formed through the uncoated particles. Such
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`preparations were attempted to achieve a comprehensive continuousness by combining
`
`each portions with different characteristics such as multi-particulate system, yet control
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`15
`
`on each part and mixing ratio thereof is necessary, so large amount of time and effort is
`
`required.
`
`WO 99/47128 relates to tablet or capsule as biphasic sustained release
`
`delivery system, where particles comprising hydrophilic drug and hydrophobic polymer
`
`are dispersed in hydrophilic polymer. This system is applied to drugs with high water-
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`20
`
`solubility, such as metformin hydrochloride,
`
`to lead to increased release time and
`
`increased transit time in upper gastrointestinal tract by swelling of the preparation.
`
`Though the sustained release is effectively accomplished by controlling. drug diffusion
`
`via adequate application of discontinuous phase of hydrophilic and hydrophobic
`
`substance, still, depends on concentration gradient. Therefore, it shows disadvantage of
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`25
`
`dumping efl‘ect due to rapid initial release and time-dependent reduction of release rate.
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`Therefore, it exhibits sustained release effect for about 10 hr in case of drug with high
`
`water-solubility, yet represents typical release profile for a matrix tablet, and thus not
`
`efi‘ective in terms of long term drug release for more than 24 hr and release rate control.
`
`The conventional techniques as described above experienced difficulty in
`
`releasing drug at constant rate for prolonged time due to substantial problems such as
`
`time-dependent reduction of drug release area and increase of diffusion distance.
`
`In
`
`case of preparation based on osmotic pressure, zero-order release can be induced, but it
`
`has problem of complicated manufacturing process and high manufacturing cost.
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`10
`
`The present invention makes it the object to provide an oral drug controlled-
`
`release preparation with minimized solubility-limit for drug to apply and improved
`
`stability, which can' release drug at a constant rate for a long time without
`
`the
`
`disadvantages such as complicate manufacturing process and high manufacturing cost
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`15
`
`as in osmotic preparation or substantial problems such as time-dependent reduction of
`
`drug release area and increase of diffusion distance
`
`Disclosure of the Invention
`
`The present invention relates to, as a novel oral drug delivery system for
`
`20
`
`control of drug release, a preparation for maintaining drug concentration in blood at a
`
`certain level for a prolonged time by allowing the drug to be' released by a constant rate
`
`through stepwise control of drug release upon the administration of the preparation.
`
`More specifically, the present invention relates to controlled-release oral preparation
`
`characterized by stepwise release of granules from matrix and of drug fiom the granules,
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`25
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`comprising
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`.
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`PCT/KR03/00200
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`(l) granules comprising a drug and a carrier material in size of 0.1 ~ 1 mm, said
`
`carrier material is hydrophobic material in case of a drug with water—solubility
`
`of 1 mg/ml or more, while hydrophilic material in case of a drug with water-
`
`solubility of less than 1 mg/ml;
`
`(2) a matrix in which said granules are embedded, comprising swelling and erodible
`
`polymer(s) and swelling-regulating material(s); and
`
`(3) a release—modifying layer comprising hydrophobic release—modifying polymer,
`
`hydrophilic
`
`release-modifying polymer,
`
`pH-dependent
`
`release-modifying
`
`polymer or a mixture thereof.
`
`In general, the term “very soluble” is applied to what has water-solubility of 1
`
`mg/ml or more and there is no upper limit of the solubility. The preparation in the
`
`present invention can be applied to any drug whose water-solubility 'is 1 mg/ml or more,
`
`accordingly, can also be applied to a drug with water-solubility of about 1 g/ml.
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`10
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`15
`
`The preparation of the present invention is also applied to a drug with water-
`
`solubility of less than 1 mg/ml besides “very soluble” drug and there is no lower limit of
`
`the solubility. The preparation of the present invention can be applied to any drug with
`
`water-solubility of less than 1 mg/ml, accordingly, can be applied to a drug whose
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`20
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`water-solubility is about 0.1 ng/ml.
`
`It is preferred for the preparation of the present invention that 50 to 100% of
`
`the drug is present in granules, and the remaining exists within the erodible and swelling
`
`matrix or the release-modifying layer, or within the matrix and release—modifying layer
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`25
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`in directly dispersed form.
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`The coated swelling-matrix oral preparation for control of drug release,
`
`according to the present invention, consists of three components:
`
`(1) Granules
`
`containing a drug; (2) swelling and erodible matrix where the drug-containing granules
`
`are embedded; and (3) a coating layer surrounding the matrix. Considering the drug
`
`release mechanism, coating layer provides initial lag-time for a certain amount of time.
`
`This is for enteric preparation or for release at specific site in the body. Further,
`
`coating layer functions in inhibiting dumping effect of drug release and in raising drug
`
`stability under storage. When said controlled-release preparation is exposed in the
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`10
`
`body fluid, coating layer disappears with swelling of inner matrix after the certain
`
`amount of time, leading to active swelling and erosion of the matrix. Swelling and
`
`erosion of the matrix leads to controlled-release of granules embedded in matrix and
`
`then drug is released in controlled way from the granules.
`
`In case of conventional
`
`swelling matrix system, direct release of drug from inner matrix leads to tendency of
`
`15
`
`time-dependent decrease of drug release rate, while in case of the system according to
`
`the present invention, drug within the granules is directly released into matrix, and at
`
`the same time, drug-containing granules are continuously released and drug is released
`
`from the granules,
`
`i.e. multi-stage controlled-release, accordingly, drug release area
`
`increases with time due to cumulated granules to compensate the reduction of release
`
`20
`
`rate according to reduction of surface area of erodible matrix itself, ultimately leading to
`
`drug release at constant rate.
`
`The first constitution of the preparation according to the present invention is
`
`granules comprising a drug and a carrier material, wherein the size of said granules is
`
`0.1 ~ 1 mm, said carrier material is hydrophobic material in case of drug with water- ‘
`
`25
`
`solubility of 1 mg/ml or more, and hydrophilic material in case of drug with water-
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`9
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`solubility of less than 1 mg/ml.
`
`In the preparation of the present invention, it is preferred that in case drug has a
`
`water-solubility within range from 1 mgjml to 100 mg/ml, the drug—containing granules
`
`are prepared by wet granulation, and in case the drug has water—solubility of 100 nag/ml
`
`or more, the drug-containing granules are prepared into granules by dispersing the drug
`
`in hydrophobic fusible materials forming the granules.
`
`Additionally, when water-solubility of the drug is less than 1 mg/ml, it is
`
`10
`
`preferred to prepare the drug-containing granules according to solid dispersion method.
`
`In case of drug with water-solubility of 1 mg/ml or more, it is preferred for said
`
`hydrophobic material forming the granules to be at least one selected from the group
`
`consisting of fatty acids, fatty acid esters, fatty acid alcohols, fatty acid mono—, di—, tri-
`
`15
`
`glycerides, waxes, hydrogenated castor oil, hydrogenated vegetable oil and as like.
`
`Examples of the fatty acid alcohols include cetostearyl alcohol, stearyl alcohol, lauryl
`
`alcohol, myristyl alcohol and as like. Examples of the fatty acid esters include
`
`glyceryl monostearate, glycerol monooleate, acetylated monoglycen'de,
`
`tristearin,
`
`tripalmitin, cetyl ester wax, glyceryl palmitostearate, glyceryl behanate (Compritol 888
`
`20
`
`ATOTM) and as like. Examples of the waxes include beeswax, carnauba wax, glyco
`
`wax, castor wax and as like.
`
`In case of drug with water—solubility of less than 1 mg/ml, for the preparation
`
`of the present invention, it is preferable that said hydrophilic carrier material forming
`
`granules is at least one selected from the group consisting of polyalkylene glycol and
`
`25
`
`carboxyvinyl hydrophilic polymer. As specific example, polyethyleneglycol with
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`10
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`PCT/KRO3/00200
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`molecular
`
`weight
`
`of
`
`LOGO-6,000,
`
`carbomer
`
`(CarbopolTM ),
`
`calcium
`
`carboxymethylcellulose and sodium carboxymethylcellulose can be enumerated.
`
`The granules of the preparation according to the present invention can further
`
`comprise other additives. and excipients. As example,
`
`lactose, starch, mannitol,
`
`saccharose, glucose, sorbitol, dibasic calcium phosphate dihydrate, anhydrous dibasic
`
`calcium phosphate, microcrystalline cellulose (AvicelTM), gelatin, polyvinylpyrrolidone
`
`and salt can be enumerated. The granules can contain at least one of the above
`
`additives. The granules can further contain,
`
`if necessary,
`
`cross—linked sodium
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`10
`
`carboxymethylcellulose or
`
`cross-linked polyvinylpyrrolidone, which accelerates
`
`disintegration of granules, and to correct pH dependence of drug, can contain inorganic
`
`acid and its conjugate base, or organic acid (such as citric acid and tartaric acid) and its
`
`conjugate base. The granules prepared as described above are the part that finally
`
`controls release and absorption of drug.
`
`In case of hydrophilic drugs, the control is
`
`15
`
`achieved by diffusion through hydrophobic substance forming the granules, while in
`
`hydrophobic drugs, hydrophilic substance formingthe granules, hydration environment
`
`established around the granules and increased surface area improve wettability of drug
`
`to increase the water-solubility thereof.
`
`The second constitution of the preparation according to the present invention is
`
`matrix having said granule embedded therein, which comprising swelling and erodible
`
`polymer(s) and swelling—regulating material(s).
`
`As the swelling and credible polymer forming the matrix, for the formation of
`
`25
`
`hydrogel matrix,
`
`at
`
`least
`
`one
`
`selected
`
`from the
`
`group
`
`consisting
`
`of
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`PCT/KR03/00200
`
`hydroxyalkylcellulose,
`
`hydroxypropylalkylcellulose, polyalkylene
`
`oxide,
`
`sodium
`
`alginate, povidone, polyvinyl alcohol and sodium carboxymethylcellulose can be used.
`
`In particular, it is preferred to use at least one selected from the group consisting of
`
`hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, sodium
`
`alginate, povidone polyvinyl alcohol and sodium carboxymethyl cellulose.
`
`In addition,
`
`the matrix can flirther include adjuvant for formation of the
`
`swelling and erodible matrix, and at least one selected fiom the group consisting of
`
`cross-linked sodium carboxymethylcellulose or cross-linked polyvinylpyrrolidone,
`
`10
`
`lactose, starch, mannitol, saccharose, glucose, sorbitol, dibasic calcium phosphate
`
`dihydrate, anhydrous dibasic calcium phosphate, microcrystalline cellulose (AvicelTM),
`
`gelatin, polyvinylpyrrolidone, magnesium stearate, stearic acid, sodium stearate, talc,
`
`sodium benzoate, boric acid and colloidal silica, can be used. Also, the matrix can
`
`contain a portion of drug to be contained in granules.
`
`15
`
`Swelling-regulating material among said matrix components is used to control
`
`the degree and velocity of swelling of the polymer, and as the swelling-regulating
`
`material,
`
`cross-linked
`
`sodium
`
`carboxymethylcellulose
`
`or
`
`cross-linked
`
`polyvinylpyrrolidone, or a mixture thereof can be used.
`
`The swelling—regulating
`
`material is preferred to be used in a content of 1 to 10% by weight to the total weight of
`
`20
`
`matrix. The swelling and erodible polymer forming the core matrix provides, via
`
`swelling, hydration environment around the granules dispersed within the matrix.
`
`In
`
`particular, it acts a role of raising drug solubility in case of granules comprising
`
`hydrophobic drug. Further, it carries out fimction, secondary drug release control, by
`
`controlling the release of granules fiom the surface by erosion.
`
`25
`
`12
`
`

`

`W0 03/063834
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`PCT/KR03/00200
`
`The third constitution of the preparation according to the present invention is
`
`release-modifying layer, and comprises at least one selected from the group consisting
`
`of hydrophobic release-modifying polymer, hydrophilic release-modifying polymer and
`
`pH-dependent release—modifying polymer.
`
`In said release-modifying layer, the term “modifying” means that drug release
`
`from the preparation is again controlled by this layer, that is, release—modifying layer.
`
`Hydrophobic release-modifying polymer as adequate material for forming the
`
`10
`
`coating layer includes ethylcellulose, shellac and ammonio methacrylate copolymer
`
`(Eudragit RSTM or Eudragit RLTM) and at least one of them can be used.
`
`As adequate material for forming the coating layer, hydrophilic release-
`
`modifying polymer can be selected from the group consisting of hydroxyalkylcellulose
`
`15
`
`and hydoxypropylalkylcellulose and at least one of them can be used, and preferably,
`
`selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose,
`
`hydroxypropylcellulose,
`
`hydroxybutylcellulose,
`
`hydroxypentylcellulose,
`
`hydroxypropylmethylcellulose,
`
`hydroxypropylbutylcellulose
`
`and
`
`hydroxypropylpentylcellulose.
`
`20
`
`As material suitable for the formation of the coating layer, pH-dependent
`
`release-modifying polymer includes generally used enteric polymer.
`
`Specifically, it is
`
`possible
`
`to
`
`enumerate
`
`as
`
`follows:
`
`hydroxyalkylcellulose
`
`phthalate,
`
`hydroxyalkylmethylcellulose phthalate, cellulose acetyl phthalate, sodium cellulose
`
`25
`
`acetate phthalate, cellulose ester phthalate, cellulose ether phthalate and anionic
`
`13
`
`

`

`W0 03/063834
`
`PCT/KR03/00200
`
`copolymer of methacrylic acid and methyl or ethyl methacrylate. At least one selected
`
`from the group consisting of them can be used. As example for the anionic copolymer
`
`of methacrylic acid and methyl or ethyl methacrylate, Eudragit L and S can be
`
`enumerated.
`
`Said release modifying layer can further includes plasticizer and, for example,
`
`it can be selected from the group consisting of castor oil, hydrogenated castor oil, fatty
`
`acid, substituted triglycerides and glyceride, polyethylene glycol of molecular weight
`
`within range of 300 to 50,000 and its derivatives.
`
`Such release modifying layer, i.e.
`
`10
`
`coating layer, acts a role of primary drug release control and fimctions in modifying
`
`zero-order release rate of the matrix core. Using of pH dependent or hydrophobic
`
`polymer coating enables target-oriented system. For the coating layer, hydrophobic,
`
`hydrophilic and pH dependent polymers are used individually or in a combination of
`
`them. Coating solution includes plasticizer in a ratio of 5 to 50% by weight of the
`
`15
`
`coating substance.
`
`It is preferred for said release modifying layer to be 1 to 20% by weight to total
`
`weight of matrix. For the preparation of coating solution, water or organic solvent is
`
`used and as
`
`suitable organic solvent, methanol, ethanol,
`
`isopropanol, acetone,
`
`20
`
`chloroform, dichloromethane and a mixture thereof can be used.
`
`The oral drug controlled-release system of the present invention comprises
`
`granules containing effective amount of drug, swelling and erodible polymer matrix in
`
`which the granules are embedded, and a coating layer surrounding the core matrix
`
`25
`
`consisting of the granules and matrix.
`
`It is preferred that granules containing the drug
`
`14
`
`

`

`W0 03/063834
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`PCT/KR03/00200
`
`reach 50 to 80% by weight to total weight of the preparation.
`
`In the preparation according to the present
`
`invention, examples of the
`
`applicable drug is as follows:
`
`therapeutic agents for aconuresis of oxybutynin,
`
`tolterodine and therapeutically
`
`equivalent salts thereof;
`
`calcium channel blockers of nifedipine, verapamil, isradipin, nilvadipin, flunarizine,
`
`nimodipine, diltiazem, nicardipine, nisoldipin,
`
`felodipin, arnlodipin, cinarizin and
`
`pendilin and pharmaceutically acceptable derivatives thereof;
`
`10
`
`beta—adrenergic antagonists of propranolol, metoprolol and pharmaceutically acceptable
`
`derivatives thereof;
`
`angiotensin—converting enzyme inhibitors of captopril, enalapril, ramipril, fosinopril,
`
`altiopril, benazepril, libenzapril, alacepril, cilazapril, cilazaprilat, perindopril, zofedopril,
`
`lisinopril, imidapril, spirapril, rentiapril, delapril, alindapril, indalapril, quinalapril and
`
`15
`
`therapeutically equivalent salts thereof;
`
`non—steroidal
`
`anti-inflammatory agents of ketorolac, ketoprofen, benoxaprofen,
`
`caprofen, flubiprofen, fenoprofen, suprofen, fenbufen, ibuprofen, indoprofen, naproxen,
`
`mjroprofen,
`
`oxaprozine,
`
`pranoprofen,
`
`pirprofen,
`
`thiaprofenic
`
`acid,
`
`fluprofen,
`
`alminoprofen, bucloxic acid, alclofenac acematacin, aspirin, indomethacin, ibufenac,
`
`20
`
`isoxepac, profenac,
`
`fentiazac, clidanac, oxpinac,
`
`sulindac,
`
`tolmetin, zomepirac,
`
`zidometacin,
`
`tenclofenac,
`
`tiopinac, mefenamic acid, flufenamic acid, niflumic acid,
`
`meclofenamic
`
`acid,
`
`tolfenamic
`
`acid,
`
`diflufenisal,
`
`isoxicam,
`
`sudoxicam and
`
`therapeutically equivalent salts thereof;
`
`therapeutic agents for respiratory disorders of theophylline, salbutamol, aminophylline,
`
`25
`
`dextromethorphan, pseudoephedrine and therapeutically equivalent salts thereof;
`
`15
`
`

`

`W0 03/063834
`
`PCT/KR03/00200
`
`analgesics of tramadol,
`
`acetaminophen, morphine, hydromorphone, oxycodone,
`
`propoxyphene and therapeutically equivalent salts thereof;
`
`psychoneural drugs of fluoxetine, paroxetine, buspirone, bupropion, carmabazepine,
`
`carvidopa,
`
`levodopa, methylphenidate,
`
`trazodone, valproic
`
`acid,
`
`amihiptyline,
`
`carbamazepine, ergoloid, haloperidol, lorazepam and therapeutically equivalent salts
`
`thereof;
`
`antibiotics of azithromycin dihydrate, cepha antibiotics, clarithromycin, doxycycline,
`
`nitrofurantonin and therapeutically equivalent salts thereof;
`
`antihyperlipidemic agent of bezafibrate,
`
`fenofibrate, ethofibrate,
`
`lovastatin and
`
`10
`
`therapeutically equivalent salts thereof;
`
`antidiabetic agent of glyburide, glipizide, metformin and therapeutically equivalent salts
`
`thereof; and
`
`cyclobenzaprin,
`
`favotidin,
`
`nizatidine,
`
`propafenone,
`
`clonazepam,
`
`hyoscyamine,
`
`diphenhydramine, olistat, doxazosin and therapeutically equivalent salts thereof.
`
`15
`
`It is preferable for the granules to be prepared by wet granulation, in case of
`
`water-soluble drug. For example, a drug, substance forming the granules as described
`
`above and at least one kind of additives are mixed and combined by adding binder
`
`solution comprising hydrophilic polymer and water or organic solvent such as denatured
`
`20
`
`anhydrous ethanol as granulating fluid. Granulating fluid is added until wet mixture is
`
`formed and then the wet mixture is passed through 6~18 mesh sieve. This is dried in
`
`an oven at 24 to 60°C for 12 to 24 hr. The dried granules are screened with 10~24
`
`mesh sieve.
`
`25
`
`In case a drug has water—solubility of 50 mg/ml or more, for effective release-
`
`16
`
`

`

`W0 03/063834
`
`PCT/KRO3/00200
`
`delay, drug particles can be covered with hydrophobic substance by melt-granulation.
`
`At a temperature of at least melting point of delivery system component, drug and other
`
`additives are mixed, dispersed and slowly cooled to obtain solid body of the delivery
`
`system, and granules are obtained by pulverization and screening.
`
`In case of hydrophobic drug, it is preferable that drug, granule component
`
`described above and at least one additiv