PCT
`
`lntemauonal Bureau
`WORLD [N'l'ELLECl'UAL_ PROPERTY ORGANIZATION
`
`INTERNA’I‘IONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) lniemamml Pill’-'1‘ Chsslfimfim 6 3
`9/14' 9,16’ 9,20’ 9/48’ 31/20’ 9,107’
`
`Al
`
`(11) International Publication Number:
`(43) International Publication Date:
`
`W0 00/00179
`6 January 2000 (0601.00)
`
`(21) International Application Number:
`
`PCT/KR99l0034l
`
`(22) International Filing Date:
`
`28 June 1999 (2806.99)
`
`(81) Designated States: AU. CA, CN. JP, US, European patent (AT,
`BE, CH, CY, DE, DK, ES. Fl. FR, GB, GR, IE, IT, LU,
`MC. NL, PT, SE).
`
`(30) Priority Data:
`I998/24563
`1999/24437
`
`27 June I998 (2706.98)
`26 June 1999 (2606.99)
`
`KR
`KR
`
`Publislwd
`With International search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(71) Applicant (for all designated States except US): WON JIN
`BIOPIIARMA CO.. LTD. [KR/KR]; I626-2, Socho-dong,
`Socho—lcu. Seoul 137-070 (KR).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for (IS only): LEE, Boom, Iin [KR/KR];
`#50l—2l3 Hyundai Sth Apt.,
`I-Iupyoung 2—dong, Chun«
`cheon—si, Kangwon-do 200-I62 (KR).
`
`(74) Agent: LEE, Won-Hce; Suite 805, Sung-ji Heights II, 642-16
`Yoksam—dong. Kangnam—ku, Seoul 135-080 (KR).
`
`(54) Title: SOLID DISPERSED PREPARATION OF POORLY WATER—SOLUBLE DRUG CONTAINING OIL, FATTY ACID OR
`MIXTURES TEIEREOF
`
`
`
`Plasmaconc.(ng/ml)
`
`'I'IME(hour)
`
`(57) Abstract
`
`Disclosed is a solid dispersed preparation for poorly water—-soluble drugs. which is prepared by dissolving or dispersing the poorly
`water-soluble dmgs in an oil. a fatty acid or a mixture thereof. mixing the solution or dispersion in a water-soluble polyol matrix and
`drying the mixture. The solid dispersed preparation can be fonnulated into a power formulation or a granule formulation. The solid
`dispersed preparation is improved in the solubility of poorly water-soluble drugs in the gastro-intestinal tract. resulting in a great increase
`in the bioavailability of the drugs. In addition. the solid dispersed preparation gives the pharmaceutical solutions to the problems that the
`conventional semi—solid or liquid preparations possess, enabling medicinally effective, poorly water—soluble compounds to be fonnulated,
`molded and processed, quickly and in an economically favorable manner without use of any organic solvent.
`
`Page 1 of 67
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`SENJU EXHIBIT 2121
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`LUPIN v SENJU
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`IPR2015—01100
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`FOR THE PURPOSES OF INFORMATION ONLY
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`Finland
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`France
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`Gabon
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`United Kingdom
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`Georgia
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`Ghana
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`Guinea
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`Greece
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`Niger
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`Netherlands
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`Norway
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`New Zealand
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`Poland
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`Portugal
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`Romania
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`Russian Federation
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`Sudan
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`Singapore
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`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
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`Page 2 of 67
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`Page 2 of 67
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`

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`WO 00/00179
`
`PCT/KR99/00341
`
`SOLID DISPERSED PREPARATION OF POORLY WATER-SOLUBLE DRUG
`
`CONTAINING OIL, FATTY ACID OR MIXTURES THEREOF
`
`BACKGROUND OF THE INVENTION
`
`,
`
`3
`
`I
`
`.
`
`The present
`
`invention relates to a solid dispersed
`
`preparation for poorly water-soluble drugs or biologically
`
`active substances. More particularly,
`
`this invention
`
`l0
`
`relates to a solid dispersed preparation which allows
`
`poorly water—soluble drugs to be increased in the uptake
`
`efficiencyjmxthegastro—intestinaltrackandixsconvenient
`
`to make in a pharmaceutical formulation.
`
`l5
`
`Agoodmanydrugspoorlydissolweinwater. Whenbeing
`
`administered to a body,
`
`these poorly water-soluble drugs
`
`have so low solubility and releasing rate in digestive
`
`juices as
`
`to retard their absorption,
`
`resulting the
`
`20
`
`bioavailabilitydecreased.
`
`Inordertosolvethisproblem,
`
`various preparationxnethods were developed with the ainaof
`
`solubilizing
`
`these
`
`poorly water-soluble
`
`drugs
`
`and
`
`increasing their releasing rates.
`
`For
`
`instance,
`
`there
`
`have
`
`been
`
`reported many methods
`
`for
`
`improving the
`
`25
`
`bioavailability of
`
`drugs,
`
`including micronization,
`
`formation of micelles by use of surfactant,
`
`solvent
`
`deposition, utilization of dry elixirs, co—precipitation
`
`Page 3 of 67
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`

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`WO 00/00179
`
`
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`PCT/KR99/00341
`
`
`
`
`
`
`
`
`
`
`by use of inert water-soluble carriers, solid—dispersion
`
`
`
`
`
`
`
`
`
`and formation of inclusion complexes using cyclodextrins.
`
`
`
`
`
`
`
`In conducting these methods, however,
`
`
`
`
`
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`the drugs to be
`
`
`
`
`
`
`
`
`
`
`
`administeredckbnot showeaconstant increaseimisolubility.
`
`
`
`
`
`5
`
`Thus,
`
`
`
`
`
`
`
`
`
`they are problematic in terms of preparation,
`
`
`
`
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`commercialization, and efficiency.
`
`
`
`For
`
`
`
`
`
`
`
`
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`the poorly water-soluble drugs, which are also
`
`
`
`
`
`
`poor in internal uptake,
`
`
`
`
`
`
`
`
`there have been made attempts to
`
`
`
`enhance
`
`
`
`their
`
`
`
`
`bioavailability upon
`
`
`
`administration.
`
`
`
`10
`
`
`
`However,
`
`
`
`
`
`
`
`the dosage forms developed thus
`
`
`
`
`
`far, are of
`
`
`
`
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`semi-solid or
`
`
`liquid form,
`
`
`
`
`giving disadvantages
`
`
`
`in
`
`
`
`
`
`
`
`
`
`
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`pharmaceutics, especially in formulating, molding and
`
`processing.
`
`
`
`15
`
`
`
`
`
`
`
`SUMMARY OF THE INVENTION
`
`
`We,
`
`
`
`
`
`
`
`the inventors made the intensive and thorough
`
`
`
`
`
`
`
`
`
`
`research<M1the formulationudfpoorlyrwater-soluble drugs,
`
`
`
`
`to improve
`
`
`
`
`
`the bioavailability of
`
`
`
`the
`
`
`
`drugs
`
`
`
`upon
`
`
`
`20
`
`
`
`administration.Asearesult,wefoundthatthedispersionor
`
`
`
`
`
`
`
`
`
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`
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`solution of the poorly water—soluble drugs in oils, fatty
`
`
`
`
`
`
`acids or mixtures thereof,
`
`
`
`
`
`
`
`
`followed by mixing with a
`
`water—soluble
`
`
`
`
`polymer matrix
`
`
`
`allowed
`
`
`
`the
`
`
`
`drugs
`
`
`
`to
`
`
`
`
`
`
`
`
`
`
`efficiently release in the gastro—intestinal tract and the
`
`
`
`
`
`
`
`
`
`
`
`25 mixture can be formed into a solid form.
`
`
`
`
`
`
`
`
`
`
`
`
`Therefore, it is an object of the present invention to
`
`
`
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`
`
`
`
`
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`provide a solid dispersed preparation which improves the
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`
`
`
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`Page 4 of 67
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`Page 4 of 67
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`

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`W0 00/00179
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`
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`PCT/KR99/00341
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`
`
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`
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`bioavailability<3fpoorlywater-solubledrugskn/enhancing
`
`
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`
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`the release of the drugs in the gastro-intestinal tract.
`
`
`
`It
`
`
`
`
`
`
`is another object of
`
`
`
`
`the present
`
`
`
`
`invention to
`
`
`
`
`
`
`
`
`
`
`provideeasoliddispersedpreparationwhichcankxaprepared
`
`
`
`
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`5
`
`by
`
`
`
`
`
`
`
`
`simple and convenient process with an
`
`
`
`economical
`
`
`
`benefit.
`
`
`
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`
`
`
`
`
`
`According to the present invention, a solid dispersed
`
`
`
`
`
`
`
`
`
`
`preparation for poorly water-soluble drugs is prepared by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dissolving or dispersing the drugs in an oil, a fatty acid
`
`
`
`10
`
`
`
`
`
`
`
`
`
`
`
`or axnixture thereof, mixing the solution or dispersion in
`
`
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`
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`
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`a water~soluble polyol matrix and drying the mixture.
`
`
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`
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`15
`
`
`
`
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`
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`
`
`
`
`
`Fig. 1 iseagraph in which the plasma concentration of
`
`
`
`cyclosporine
`
`is
`
`plotted
`
`against
`
`the
`
`times
`
`after
`
`
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`
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`
`
`
`
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`
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`
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`administrating the solid dispersed preparations of
`
`
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`the
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`
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`
`
`
`
`
`
`present invention (closed rectangle and closed triangle)
`
`
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`
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`
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`and a commercially available preparation (Neoral, closed
`
`
`
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`20
`
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`lozenge);
`
`
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`
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`
`
`
`
`
`Fig. 2 is a«graph in which the plasma concentration of
`
`
`
`
`
`
`aceclofenac is plotted against
`
`
`
`
`
`
`the times after orally
`
`
`
`
`
`
`
`administratingaceclofenacpowder(closedcircle)
`
`
`
`
`andthe
`
`
`
`
`
`
`
`
`
`
`solid dispersed preparation of the present invention (open
`
`
`
`25
`
`
`
`
`
`
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`circle, oleic acid 5%)
`
`
`to rats;
`
`
`
`
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`
`
`
`
`
`
`Fig. 3 is acqraph in which the plasma concentration of
`
`
`
`cyclosporine
`
`
`
`is
`
`
`
`plotted
`
`
`
`against
`
`
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`the
`
`
`
`times
`
`
`
`after
`
`
`
`
`
`Page 5 of 67
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`Page 5 of 67
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`

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`W0 00/00179
`
`
`
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`PCT/KR99/00341
`
`
`
`
`
`
`
`
`
`administrating the solid dispersed preparation of
`
`
`
`the
`
`
`
`
`
`
`
`
`
`
`
`presentinvention(closedcircle,capsulecontaining100ng
`
`of
`
`
`
`the
`
`
`
`preparation)
`
`
`
`and
`
`
`
`
`a
`
`commercially
`
`
`
`available
`
`
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`preparation(opencircle,AirtalcapsulelOOImfi tobealgle
`
`
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`
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`dogs;
`
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`
`
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`
`
`Fig; 4 is a graph in which the plasma concentration of
`
`
`
`
`
`
`aceclofenac is plotted against
`
`
`
`
`
`
`the times after orally
`
`
`
`
`
`
`
`
`administrating the solid dispersed preparation of
`
`
`
`the
`
`
`
`
`
`
`
`
`
`
`
`presentinvention(closedcircle,capsulecontainingloomg
`
`
`
`of
`
`
`
`the
`
`
`
`preparation)
`
`
`
`and
`
`
`
`
`a
`
`commercially
`
`
`
`available
`
`
`
`
`
`
`
`
`
`
`
`preparation (open circle, Airtal capsule lOO1ng)tx)humans;
`
`
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`and
`
`
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`
`
`
`
`
`
`
`
`Figx 5 is a graph in which the plasma concentration of
`
`
`
`
`
`
`the times after orally
`
`
`
`
`
`
`cisapride is plotted against
`
`
`
`
`
`
`
`
`
`
`administrating the solid granular preparations of
`
`
`
`the
`
`
`
`present
`
`
`
`invention
`
`
`
`
`(open circle,
`
`
`
`
`
`bead 10 mg)
`
`
`
`and
`
`
`
`
`a
`
`commercially
`
`
`
`available
`
`
`
`preparation
`
`
`
`(closed
`
`
`
`circle,
`
`
`
`
`
`
`prepulsid 10 mg)
`
`
`to humans.
`
`
`
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`
`
`
`
`DETAILED DESCRIPTION OF THE INVEN'1‘ION
`
`Hereinafter,
`
`
`
`
`the present
`
`
`
`
`
`
`invention will be described
`
`
`
`
`in detail.
`
`
`
`
`
`
`
`In accordance with the present
`
`
`
`invention,
`
`
`
`
`there is
`
`
`
`
`
`
`
`
`
`
`
`
`provided a solid dispersed preparation for poorly water-
`
`
`
`soluble drugs, which
`
`
`
`
`
`
`
`is prepared by dispersing or
`
`
`
`
`
`
`
`
`dissolving the drugs in an oil,
`
`
`
`
`
`
`
`
`a fatty acid or a mixture
`
`
`
`
`
`Page 6 of 67
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`Page 6 of 67
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`

`
`
`WO 00/00179
`
`
`
`PCT/KR99/00341
`
`
`
`
`thereof,
`
`
`
`
`
`
`
`
`
`incorporating the dispersion or solution into a
`
`
`
`
`
`
`
`
`
`
`water-soluble polymer matrix and drying this mixture.
`
`
`
`
`In particular,
`
`
`
`
`
`
`
`
`this invention provides two types of
`
`
`
`fomulation,
`
`
`
`i.e.,
`
`
`
`
`
`
`
`
`the solid powdery preparation and the
`
`
`
`
`
`
`
`solid granular preparation.
`
`
`
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`
`
`The preparation method of the solid dispersed powders
`
`
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`
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`
`
`comprisesthe followingsteps;Dissolving<n:dispersingthe
`
`
`
`
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`
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`
`
`
`
`
`
`poorly water—soluble drugs in an oil, a fatty acid or the
`
`
`
`
`
`
`
`
`
`mixture thereof; mixing with the water—soluble polymer
`
`
`
`
`
`
`
`
`
`
`
`
`
`matrix; drying the mixture; and grinding the pellet into
`
`
`
`powders.
`
`
`
`
`In addition,
`
`
`
`
`
`
`the preparation method of
`
`
`
`
`the solid
`
`
`
`
`
`
`
`
`dispersed granules comprises the following steps;
`
`
`
`
`
`
`
`
`
`
`Dissolving or dispersing theepoorly water—soluble drugs in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`an oil, a fatty acid.or thernixture thereof; mixing with the
`
`
`
`water—soluble
`
`
`
`
`polymer matrix;
`
`
`
`spraying
`
`
`
`onto
`
`
`
`
`a
`
`pharmaceutically
`
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`acceptable
`
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`nucleus,
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`resulting the
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`granules. Zhiapreferredembodiment,thepharmaceutically
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`acceptable nucleus may be a sugar sphere.
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`The solid dispersed powdery preparation or the solid
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`dispersed granular preparation of this invention can be
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`formulated into the pharmaceutically acceptable medicines
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`for internal use such as powders, granules,
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`tablets and
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`capsules.
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`Hereinafter,
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`
`the word “solid dispersed preparation”
`
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`
`means
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`“solid dispersed powdery preparation",
`
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`“solid
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`dispersed granular preparation” or the both.
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`Page 7 of 67
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`Page 7 of 67
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`

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`WO 00/00179
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`PCT/KR99/0034]
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`In this regard, the oil, the fatty acid or the mixture
`
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`
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`
`thereof may be used alone or in a
`
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`form of an emulsion or
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`microemulsion inclusive of itself. When dispersing or
`
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`dissolving poorly water—soluble drugs in the oil, fatty
`
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`acid<n:mixture thereof, asurfactantneykxaaddedtogether.
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`Further,
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`the water—soluble polymer matrix may be used
`
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`alone or in combination with another water—soluble1natrix.
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`Illustrative examples of the oil that can be used in
`
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`the preparation of the present
`
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`invention include lipid
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`additives, such as d—bisabolol, stearyl glycerrhetinate,
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`salicylic acid,
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`tocopheryl acetate,
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`a mixture of water,
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`alcohol
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`and
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`Perilla
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`extract,
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`sodium hyaluronate,
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`panthenol,
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`propylene glycol
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`and apple(Pirus Malus),
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`propylene glycol and pineapple, ivy (Hedera halix) extract
`
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`andl,3—B.G,peach(Prumspersica)leafextract,hydrolyzed
`
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`soy flour, wheat (Triticum Vulgare) protein, birch (Betula
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`alba) extract and 1,3-B.G, burdock (Arctium majus)extract
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`andl,3—B.G;liposomes;phosphatidylcholines;esters,such
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`as glyceryl stearate, captylic/capric triglyceride, cetyl
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`octanolate,isopropylmyristate,2—ethyleneisopelagonate,
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`di—Cl2-13 alkyl malate, ceteatyl octanoate, butylene
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`glycol
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`dicaptylate/dicaprate,
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`isononyl
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`isostearate,
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`isostearyl
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`isostearate,
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`coco—captylate/caprate,
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`cetyl
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`octanoate, octyldodecyl myristate, cetyl esters, C10—3O
`
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`cholesterol/lanosterol ester, hydrogenated Castor oil,
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`monoglycerides,
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`diglycerides,
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`and
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`
`
`triglycerides;
`
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`hydrocarbons,
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`such as beeswax,
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`canauba wax,
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`suctose
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`Page 8 of 67
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`Page 8 of 67
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`

`
`
`WO 00/001759
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`
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`PCT/KR99/00341
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`distearate,
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`PEG-8
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`beeswax
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`and candelilla
`
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`(euphorbia
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`cerifera) wax; mineral oils such as ceresin and ozokerite;
`
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`vegetable oils such as nmcadamia
`
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`ternifolia nut oil,
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`hydrogenated hi—erucic acid rape seed oil, olive oil,
`
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`jojoba oil, hybridsunflower (Helian thus annuus) oil, neen
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`(melia azadirachta) seed oil, dog rose (rosa canina)
`
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`lips
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`oil with preference to mineral oils, squalene, squalane,
`
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`monoglycerides, diglycerides,
`
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`triglycerides, medium~chain
`
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`glyceride, myglyol, cremophor, hydrogenated caster oil,
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`corn oil, Perilla oil, cotton seed oil and lipid—soluble
`
`
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`vitamins.
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`
`
`As for the fatty acid, it is preferable to use oleic
`
`
`
`acid,
`
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`cetyl alcohol,
`
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`
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`stearyl alcohol,
`
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`stearic acid,
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`myristic acid,
`
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`linoleic acid or
`
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`lauric acid. More
`
`
`
`15
`
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`
`
`preferable is to use oleic acid,
`
`
`
`linoleic
`
`
`
`
`acid, or
`
`
`
`
`isopropyl myristate.
`
`
`
`As
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`
`
`the water-soluble matrix, polyethylene glycol
`
`
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`
`(PEG),carbowaxorpolyvinylpyrrolidone(PVP)isavailable.
`
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`
`
`Aforementioned water~soluble matrix may be used in
`
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`
`combinationwithothernmtrixces,examplesofvmichinclude
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`water—solublenmtricessuchasgelatin,gum,carbohydrates,
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`celluloses,polyvinylalcohol,polyacrylicacid,inorganic
`
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`compounds and mixtures thereof; and enteric matrices such
`
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`
`ashydroxypropylmethylcelluloseacetylsuccinate(HPMCAS),
`
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`cellulose acetate phthalate,
`
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`
`shellac, zein, polyvinyl
`
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`
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`acetate phthalate, Eudragit L100, Eudragit S100,
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`sodium
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`arginate and poly—L—lysine.
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`Page 9 of 67
`
`Page 9 of 67
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`

`
`
`WO 00/00179
`
`
`
`PCT/KR99/00341
`
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`
`
`In order to enhance the dispersion or dissolution of
`
`
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`
`
`
`
`
`
`
`poorly water—soluble drugs in the oil, fatty acid or their
`
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`
`
`
`mixture, a surfactant may be added, which is selected from
`
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`
`
`the group comprising glyceryl stearate, polysorbate 60,
`
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`
`
`polysorbate80,sorbitantrioleate,sorbitansesquioleate,
`
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`
`
`sorbitanstearate,PEG-20glycerylisostearate,ceteth—25,
`
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`
`
`PEG—6O hydrogenated castor oil,
`
`
`
`nonoxynol—l5,
`
`
`
`PEG~6—
`
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`
`
`decyltetradeceth~20,
`
`
`
`dimethicone
`
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`
`copolyol,
`
`
`
`glyceryl
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`diisostearate,
`
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`ceteth—24,
`
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`
`cetearyl
`
`
`
`alcohol,
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`polyoxylethylene nonyphenyl ether,
`
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`
`
`PEG—4O hydrogenated
`
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`
`Castor oil, cetyl dimethicone copolyol, polyglyceryl~3~
`
`
`methylglucose distearate,
`
`
`
`PEG—lO0
`
`
`
`stearate,
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`
`
`sorbitan
`
`
`
`isostearate,
`
`
`
`sodium
`
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`lauryl
`
`
`
`glutamate,
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`
`
`disodium
`
`
`
`cocoamphodiacetate,
`
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`
`
`lauric acid diethanolamide, coconut
`
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`
`
`fatty acid diethanolamide, N,N—bis—(2~hydroxy ethyl)-
`
`
`
`
`cocomide, and cocoamidopropyl betain.
`
`
`
`The
`
`
`
`
`
`
`solid dispersed preparation of
`
`
`
`
`the present
`
`
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`
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`
`
`
`
`
`
`invention can be applied for all the poorly water~soluble
`
`
`
`
`
`
`
`
`
`
`drugsandpreferablyforketoconazole;itraconazoleandits
`
`
`
`
`
`derivatives;
`
`
`
`cyclosporine;
`
`
`
`cisapride;
`
`
`
`acetaminophen;
`
`
`
`
`
`aspirin; acetylsalicylic acid;
`
`
`
`
`indomethacin; naproxen;
`
`
`
`warfarin;
`
`
`
`papaverine;
`
`
`
`thiabendazole;
`
`
`
`miconazole;
`
`
`
`
`
`
`cinnarizine; doxorubicin; omeprazole; cholecalciferol;
`
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`
`
`
`melphalan; nifedipine; digoxin; benzoic acid;
`
`
`
`tryptophan;
`
`
`
`
`
`tyrosine;
`
`
`
`phenylalanine;
`
`
`
`
`aztreonam;
`
`
`
`ibuprofen;
`
`
`
`phenoxymethylpenicillin;
`
`
`
`
`thalidomide; methyltestosterone;
`
`
`
`prochlorperazine;
`
`
`
`hydrocortisone;
`
`
`
`dideoxypurine
`
`
`
`
`
`Page 10 of 67
`
`Page 10 of 67
`
`

`
`
`WO 00/00179
`
`
`
`‘
`
`PCT/KR99/00341
`
`
`
`
`
`
`nucleoside; vitamin D3;
`
`
`
`
`
`sulfonamide; Sulfonylurea; p-
`
`aminobenzoic
`
`
`
`acid;
`
`
`
`melatonin;
`
`
`
`benzylpenicillin;
`
`
`
`chlorambucil;
`
`
`
`diazepin;
`
`
`
`digitoxin;
`
`
`
`hydrocortisone
`
`
`
`butyrate;
`
`
`
`metronidazole
`
`
`
`benzoate;
`
`
`
`tolbutamide;
`
`5
`
`
`
`
`prostaglandin El(PGEQ;
`
`
`
`
`fludrocortisone; griseofulvin;
`
`miconazole
`
`
`
`nitrate;
`
`
`
`leukotriene
`
`
`
`B4
`
`antagonist;
`
`propranolol;
`
`
`
`thephylline;
`
`
`
`flubiprofen;
`
`
`
`
`sodium benzoate;
`
`
`
`
`
`
`
`benzoic acid; riboflavin; benzodiazepine; phenobardital;
`
`
`
`
`
`glyburide; sulfadiazine; sulfaethylthiadiazole;
`
`
`
`sodium
`
`
`
`
`
`10
`
`
`
`diclofenac;
`
`
`
`aceclofenac;
`
`
`
`phyniroin;
`
`hioridazinehydrochloride;
`
`
`
`bropirimine;
`
`hydrochlorothiazide;
`
`
`
`
`
`fluconazole; acyclovir; bucillamine;
`
`
`
`ciprofluoxacin;
`
`
`
`acetyl~L—carnitine;
`
`
`
`baclofen;
`
`
`
`sodium
`
`
`
`alendronate;
`
`
`
`
`
`
`
`lovocarnitine; nimodipine or nimodifine;
`
`
`
`15
`
`
`
`
`
`atenolol; provastatin sodium;
`
`
`
`lovastatin;
`
`
`
`isotretinoin;
`
`
`
`
`
`etidronate disodium; doxifluridine;
`
`
`
`
`fosfomycin calcium;
`
`
`
`sotepine;
`
`
`
`epinastine
`
`
`
`hydrochloride;
`
`
`
`carvedilol;
`
`epinastine
`
`
`
`hydrochloride;
`
`
`
`carvedilol;
`
`
`
`fosinopril;
`
`trandolapril;
`
`
`
`etretinate
`
`
`
`cap;
`
`
`
`
`metergoline;
`
`
`20
`
`nmrcaptopurine;
`
`
`
`Vancomycin
`
`
`
`hydrochloride;
`
`
`
`cefixime;
`
`
`
`
`
`
`
`
`
`
`
`
`
`cefuroxim axetil; dirithramycin; and dadanosin and more
`
`
`
`preferably
`
`
`
`for
`
`
`
`ketoconazole,
`
`
`
`
`itraconazole
`
`
`
`and
`
`
`
`its
`
`
`
`
`
`
`
`derivatives, cisapride, cyclosporine and nifedipine.
`
`
`
`
`
`Over conventional methods,
`
`
`
`
`
`
`the present invention has
`
`
`
`25
`
`
`
`
`
`
`
`
`
`
`
`an advantage, in that, the solid dispersed preparation can
`
`
`
`
`
`
`
`
`
`
`
`
`bepreparedwitheaseandshowhighefficiencyinabsorption
`
`
`
`and release.
`
`
`
`
`
`
`Page 11 of 67
`
`Page 11 of 67
`
`

`
`
`W0 00/00179
`
`
`
`PCT/KR99/00341
`
`
`
`
`First,
`
`
`
`
`a
`
`
`
`poorly water-soluble medicine
`
`
`
`is
`
`
`
`
`
`
`
`
`
`
`
`
`homogeneously mixed and dispersed in an oil, fatty acid or
`
`
`
`
`
`
`
`
`
`
`their mixture and added in water~soluble polymer matrices
`
`
`
`
`
`
`
`
`
`
`
`
`
`moltenatroomtemperatureorabout60~80°C,afterwhichthe
`
`
`
`
`
`
`
`
`
`
`
`
`
`resultingnuxture iscooledrapidlytxbromntemperatureand
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dried in an oven for 12 hours or more. The dried pellet is
`
`
`
`
`
`
`
`
`
`
`
`
`
`powdered in a mortar and passed through a sieve to give
`
`
`
`
`powder which
`
`
`
`is
`
`
`
`
`
`uniform in particle
`
`
`
`size.
`
`
`
`As
`
`
`
`
`
`
`
`
`
`
`
`aforementioned, when the drug is dispersed or dissolved in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the oil, fatty acid or theirrnixture, the oil, fatty acid<3r
`
`
`
`
`
`
`
`
`
`their mixture may be emulsified or micro-emulsified.
`
`
`
`In
`
`
`
`
`this case,
`
`
`
`
`
`
`
`
`
`
`a surfactant may be added to the solution.
`
`
`
`
`
`
`
`
`Alternatively, after the homogeneous dispersion of
`
`
`
`
`
`
`
`
`
`
`
`thepoorlywater~solubledrugitsaddedjxxthewater-soluble
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`polymer matrix molten at about 60-80 °C, it may be sprayed
`
`
`
`
`
`
`
`
`
`
`to pharmaceutically acceptable nucleus to give a granule.
`
`
`
`
`
`
`
`
`
`
`
`
`As a consequence of an examination which was made on
`
`
`
`
`
`the solubility of
`
`
`
`
`
`
`
`the solid dispersed preparation in
`
`
`
`
`distilled water,
`
`
`
`artificial
`
`
`
`intestinal
`
`
`
`juice
`
`
`
`and
`
`
`
`
`
`
`
`artificial gastric juice,
`
`
`
`
`
`the solubility of
`
`
`
`
`the solid
`
`
`
`
`
`
`
`
`
`
`
`
`dispersed preparation is found to be better than those of
`
`
`
`
`
`
`
`poorly wateresoluble drugs themselves. Particularly,
`
`
`
`
`a
`
`
`
`
`
`
`
`
`
`
`great advance can be brought into the solubility of poorly
`
`
`
`
`
`
`
`
`
`
`water—solublezdrugs when they*are incorporated.intc>a solid
`
`
`
`
`
`
`
`
`
`
`
`dispersed preparation containing oleic acid or uncro-
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`emulsified oleic acid.
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`The data obtained from the experiments in which the
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`solid dispersed preparations of the present
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`invention are
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`eluted in artificial gastric
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`juice
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`and artificial
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`intestinal
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`juice,
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`show
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`that
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`solid
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`dispersed
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`preparations of the present
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`invention are superior to the
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`poorly water—soluble drugs themselves in releasing rate.
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`A significant improvement
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`in releasing rate is observed
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`wheneasoliddispersedpreparationcontainingoleicacidor
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`microemulsified oleic acid is used.
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`In the artificial
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`intestinal juice, a severer condition in which for drugs to
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`dissolve, rather than in the artificial gastric juice, the
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`improvement
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`in the releasing rate by virtue of the solid
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`dispersed preparation is more apparent.
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`Through an experiment which is conducted for examining
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`the uptake efficiency of poorly water-soluble drugs in the
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`15
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`gastro—intestinal
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`tract,
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`the superiority of
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`the solid
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`dispersedpreparationaccordingtx>thepresentinventionis
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`also demonstrated. Even when only a water—soluble matrix
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`is used,
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`the uptake efficiency of the drugs is minutely
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`increased.
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`In particular,
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`the uptake efficiency of drugs
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`20
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`in the gastro—intestinal tract is remarkably improveclwhen
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`they are incorporated in a solid dispersed preparation
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`using oleic acid—containing microemulsions.
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`Inaddition,comparisoncflftheplasmaconcentrationof
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`target drugxnolecule after oral administration between the
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`25
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`soliddispersedpreparationandconventionalpreparations,
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`is helpful
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`in understanding the present invention. As a
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`result, similar levels are observed, suggesting that the
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`solid dispersed preparation of the present
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`invention can
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`substitute for conventional preparations when account is
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`taken of pharmaceutical aspects.
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`Abetterunderstandingcfifthepresentinventionmaybe
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`obtained in light of the following examples which are set
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`forth to illustrate, but are not to be construed to limit the
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`present
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`invention.
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`Following are the Compositions of emulsions
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`and
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`microemulsions used in Examples.
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`E
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`SI NS
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`PREPARATION EXAMPLE I
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`Composition (%)
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`1.800
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`1.000
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`.700
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`KALCHOL 6870
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`EMERSOL 132
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`Multi~Wax W-445
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`Emulsifiers
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`ATLAS G—l44
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`ATLAS G~61O
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`ATMOS 370
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`KM-105
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`Oils
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`CRODALAN SWL
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`Page 14 of 67
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`Page 14 of 67
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`LEXOL GT 865
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`NIKKOL CIO
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`SEPERIOR JOJOBA OIL
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`SF 1202
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`KF~96(1OOCS)
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`DRAKEOL 7
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`Squalane
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`dl-a—Tocopheryl Acetate
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`POLYOLPERPOLYMER-2
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`Aqueous Phase
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`DI-WATER
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`glycerin
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`P.G
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`NATURAL EXT.AP
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`LUBRAGEL CG
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`Carbopo 1940
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`KELTROL F
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`NaOH
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`PREPARATION EXAMPLE II
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`Waxes
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`KALCHOL 6870
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`EMERSOL 132
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`Multi—wax W—445
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`Page 15 of 67
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`Page 15 of 67
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`PCT/KR99/00341
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`Emulsifiers
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`RHEODOL A0-15
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`RHEODOL MS—162
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`RHEODOL TW—Sl2O
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`KM*105
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`CRODALAN SWL
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`LEXOL GT 865
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`NIKKOL CIO
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`Macadamia ternifolia nut oil
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`SF 1202
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`KF~96(lOOCS)
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`DRAKEOL 7
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`Squalane
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`dl—a~Tocopheryl Acetate
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`POLYOLPERPOLYMER-Z
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`
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`Aqueous phase
`
`DI—WATER
`
`glycerin
`
`l.3—B.G
`
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`NATURAL EXT.AP
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`LUBRAGEL CG
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`Carbopol 940
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`KELTROL F
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`TEA
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`Page 16 of 67
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`Page 16 of 67
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`PREPARATION EXAMPLE III
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`Waxes
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`KALCHOL 6870
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`EMERSOL 132
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`Beeswax
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`Emulsifiers
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`ATLAS G-114
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`ATLAS G—61O
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`ATMOS 370
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`KM-105
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`CRODALAN SWL
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`LEXOL GT 865
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`NIKKOL CIO
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`SUPERIOR JOJOGA OIL
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`SR 1202
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`KF—96(1OOCS)
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`DRAKEOL 7
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`Squalane
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`dl—a—Tocopheryl Acetate
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`POLYOLPERPOLYMER~2
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`Aqueous phase
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`DI~WATER
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`Page 17 of 67
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`Page 17 of 67
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`PCT/KR99/00341
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`Glycerin
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`P.G
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`NATURAL EXT.AP
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`LUBRAGEL CG
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`Carbopol 940
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`KELTROL F
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`NaOH
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`PREPARATION EXAMPLE IV
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`Waxes
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`KALCHOL 6870
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`EMERSOL 132
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`Multi~Wax W-445
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`Emulsifiers
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`RHEODOL AO—l5
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`RHEODOL MS-165
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`RHEODOL TW-S120
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`KM-105
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`CRODALAN SWL
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`LEXOL GT 865
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`NIKKOL CIO
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`2.000
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`Macadamia ternifolia nut oil
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`SF 1202
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`1.
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`0.
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`Page 18 of 67
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`Page 18 of 67
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`DRAKEOL 7
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`Squalane
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`dl—a-tocopheryl acetate
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`POLYOLPERPOLYMER-2
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`Aqueous phase
`
`DI-WATER
`
`glycerin
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`1,3-B.G
`
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`NATURAL EXT.AP
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`LUBRAGEL CG
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`Cabopol
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`KELTROL F
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`TEA
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`MICROEMUL§lQNS
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`PREPARATION EXAMPLE V
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`Waxes
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`Cetyl Alcohol
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`Emulsifiers
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`NIKKOL HCO-60
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`RHEODOL TW-0120
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`Cremophor EL
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`Page 19 of 67
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`Page 19 of 67
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`PREPARATION EXAMPLE VI
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`I.P.M
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`CAPTEX
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`Aqueous phase
`
`DI—WATER
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`Ethanol
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`Aqueous phase
`
`DI-WATER
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`Surfactant
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`LABRASOL
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`Page 20 of 67
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`Emulsifiers
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`NIKKOL HCO-60
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`RHEODOL TW-0120
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`Cremophor EL
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`I.P.M
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`Lanolin oil
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`CAPTEX
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`PREPARATION EXAMPLE VII
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`Page 20 of 67
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`Surfactant Aid
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`Polyglyceryl oleate
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`PLURL OLEIQUE
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`Oil phase
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`LABRAFIL Ml994CS
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`Sub-Solvent
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`Transcutol
`
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`Aqueous phase
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`Phosphate buffer(pH 6)
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`PREPARATION EXAMPLE VIII
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`Oil phase
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`GELUCIRE 44/14
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`
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`GELUCIRE 48/O9
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`Surfactant
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`LABRAFAC CM 10
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`Surfactant Aid
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`LAUROGLYCOL
`
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`Transcutol
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`PREPARATION EXAMPLE IX
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`19
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`Page 21 of 67
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`Page 21 of 67
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`Aqueous Phase
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`Water
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`(Buffer)
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`Physiological Saline Solution
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`Glucose
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`Propylene Glycol PEG 300,400
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`
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`Glycerol
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`Oil Phase
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`Fatty Acid Esters
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`Modified Vegetable Oil
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`Silicon Oil
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`Surfactant Aid
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`Long Chain Alcohol
`
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`Glycol Derivative
`
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`Propylene Glycol Derivative
`
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`Polyqlycerol Derivative
`
`
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`
`
`Surfactant
`
`
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`Non—ionic Surfactant
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`
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`
`PREPARATION EXAMPLE X
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`
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`Oil Phase
`
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`Oleic Acid
`
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`Page 22 of 67
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`Page 22 of 67
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`12,500
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`WO 00/00179
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`Surfactant
`
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`Tween 80
`
`
`Surfactant Aid
`
`
`
`5
`
`
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`Transcutol
`
`
`
`
`Aqueous Phase
`
`
`
`Water
`
`
`
`8,750
`
`
`
`72,500
`
`
`
`10
`
`
`
`
`
`PREPARATION EXAMPLE XI
`
`
`
`Oil Phase
`
`
`
`
`Captex
`
`
`
`15
`
`
`
`Surfactant
`
`
`
`5,000
`
`
`
`Cremophor
`
`
`
`12,500
`
`
`
`
`Surfactant Aid
`
`
`
`Transcutol
`
`
`
`
`Aqueous Phase
`
`
`
`Water
`
`
`
`20
`
`
`
`
`25
`
`6,250
`
`
`
`76,250
`
`
`
`COMPARATIVE EXAMPLE I
`
`
`
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`
`
`
`
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`
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`
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`
`
`
`After being melted at about 70°C, 90 g of PEG 6000 was
`
`
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`added with 10 g of ketoconazole, cooled rapidly to room
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`21
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`Page 23 of 67
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`Page 23 of 67
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`temperature and dried in an oven for 12 hours or more.
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`The dried solid dispersed preparation was milled in a
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`mortar and passed through a sieve to give a powder which was
`
`
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`
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`uniform in particle size.
`
`
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`
`
`EXAMPLE I
`
`
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`
`
`In 5 g of oleic acid were homogeneously mixed and
`
`
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`
`
`dispersed 10 g of ketoconazole which was, then, added into
`
`
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`10
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`85 g of PEG 6000 which was molten at about 70 °C. After being
`
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`cooled rapidly to room temperature and dried in an oven for
`
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`12 hours or more, the dried solid dispersed preparation was
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`milled in a mortar and passed through a sieve to give a powder
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`which was uniform in particular size.
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`15
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`EXAMPLE I I
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`In 5
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`g of oleic acid and 5
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`g of Tween 80 were
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`homogeneously mixed and dispersed 10 g of ketoconazole
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`20 which was, then, added in 80 g of PEG 6000 which was molten
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`at about 70 °C. Using this mixture,
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`a dispersed powdery
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`preparation was obtained in the same procedure as in Example
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`I .
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`25
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`EXAMPLE III
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`In 5 g of isopropyl myristate was homogeneously mixed
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`22
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`Page 24 of 67
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`Page 24 of 67
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`W0 00/00179
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`PCT/KR99/00341
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`anddispersedl0<gofketoconazolewhichwas,then,addedin
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`80q3of PEG 6000 which was molten at about 70°C. Using this
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`mixture,
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`a dispersed powdery preparation was obtained in
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`the same procedure as in Example I.
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`EXAMPLE IV
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`In 5 g of liquid paraffin was homogeneously mixed and
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`dispersecilO g of ketoconazole which was, then, added in 80
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`10
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`g of PEG 6000 which was molten at about 70 °C. Using this
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`mixture,
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`a dispersed powdery preparation was obt