PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 00/00179
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`A61K 9/14, 9/16, 9/20, 9/48, 31/20, 9/107, A1
`38/00
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`6 January 2000 (06.01.00)
`
`(21) International Application Number:
`
`PCT/KR99/00341
`
`(22) International Filing Date:
`
`28 June 1999 (28.06.99)
`
`(81) Designated States: AU, CA, CN, JP, US, European patent (AT,
`BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE).
`
`Published
`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.
`
`(30) Priority Data:
`1998/24563
`1999/24437
`
`27 June 1998 (27.06.98)
`26 June 1999 (26.06.99)
`
`KR
`KR
`
`(71) Applicant (for all designated States except US): WON JIN
`BIOPHARMA CO., LTD. [KR/KR]; 1626-2, Socho-dong,
`Socho-ku, Seoul 137-070 (KR).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): LEE, Beom, Jin [KR/KR];
`#501-213 Hyundai 5th Apt., Hupyoung 2-dong, Chun(cid:173)
`cheon-si, Kangwon--do 200-162 (KR).
`
`(74) Agent: LEE, Won-Hee; 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 THEREOF
`
`4000
`
`2000
`
`--E -Ol
`-t.i
`
`c
`
`=
`tS
`til e
`"' ~
`
`~
`
`0 L-.-----'--------'--------''-----·-'--~----'
`2
`6
`8
`0
`10
`4
`TJME(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 drugs 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 formulated 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 formulated,
`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
`LUPIN v SENJU
`IPR2015-01105
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`cz
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Be latus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gennany
`Denmark
`Estonia
`
`ES
`1!'1
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The fonner Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Sl
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`VietNam
`Yugoslavia
`Zimbabwe
`
`Page 2 of 67
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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
`
`5
`
`The present invention relates to a solid dispersed
`
`preparation for poorly water-soluble drugs or biologically
`
`active substances. More particularly,
`
`this
`
`invention
`
`10
`
`relates to a solid dispersed preparation which allows
`
`poorly water-soluble drugs to be increased in the uptake
`
`efficiency in the gastro-intestinal track and is convenient
`
`to make in a pharmaceutical formulation.
`
`15 Description of the Prior Art
`
`A good many drugs poorly dissolve in water. When being
`
`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
`
`2 0 bioavailabili ty decreased.
`
`In order to solve this problem,
`
`various preparation methods were developed with the aim of
`
`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
`
`1
`
`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,
`
`the drugs to be
`
`administered do not show a constant increase in solubility.
`
`5
`
`Thus,
`
`they are problematic in terms of preparation,
`
`commercialization, and efficiency.
`
`For 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
`
`semi solid or
`
`liquid
`
`form, giving disadvantages
`
`in
`
`pharmaceutics,
`
`especially in formulating, molding and
`
`processing.
`
`15
`
`SUMMARY OF THE INVENTION
`
`We,
`
`the inventors made the intensive and thorough
`
`research on the formulation of poorly water-soluble drugs,
`
`to
`
`improve
`
`the bioavailability of
`
`the drugs upon
`
`20
`
`administration. As a result, we found that the dispersion or
`
`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
`
`provide a solid dispersed preparation which improves the
`
`2
`
`Page 4 of 67
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`

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`wo 00/00179
`
`PCT/KR99/00341
`
`bioa va i lability of poorly water-soluble drugs by enhancing
`
`the release of the drugs in the gastro-intestinal tract.
`
`It is another object of the present invention to
`
`provide a solid dispersed preparation which can be prepared
`
`5
`
`by simple and convenient process with an economical
`
`benefit.
`
`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 fa tty acid
`
`10
`
`or a mixture thereof, mixing the solution or dispersion in
`
`a water-soluble polyol matrix and drying the mixture.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`15
`
`Fig. 1 is a graph in which the plasma concentration of
`
`cyclosporine
`
`is plotted against
`
`the
`
`times after
`
`administrating the solid dispersed preparations of the
`
`present invention (closed rectangle and closed triangle)
`
`and a commercially available preparation (Neoral, closed
`
`2 0
`
`lozenge) ;
`
`Fig. 2 is a graph in which the plasma concentration of
`
`aceclofenac is plotted against the times after orally
`
`administrating aceclofenac powder (closed circle) and the
`
`solid dispersed preparation of the present invention (open
`
`25
`
`circle, oleic acid 5%)
`
`to rats;
`
`Fig. 3 is a graph in which the plasma concentration of
`
`cyclosporine
`
`is plotted against
`
`the
`
`times after
`
`3
`
`Page 5 of 67
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`

`
`WO 00/00179
`
`PCT IKR99/00341
`
`administrating the solid dispersed preparation of the
`
`present invention (closed circle, capsule containing 100 mg
`
`of
`
`the preparation)
`
`and
`
`a
`
`commercially available
`
`preparation (open circle, Airtal capsule 100 mg) to bealgle
`
`5
`
`dogs;
`
`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
`
`present invention (closed circle, capsule containing 100 mg
`
`10
`
`of
`
`the preparation)
`
`and
`
`a
`
`commercially available
`
`preparation (open circle, Airtal capsule 100 mg) to humans;
`
`and
`
`Fig. 5 is a graph in which the plasma concentration of
`
`cisapride is plotted against
`
`the
`
`times after orally
`
`15
`
`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.
`
`20 DETAILED DESCRIPTION OF THE INVENTION
`
`Hereinafter, the present invention will be described
`
`in detail.
`
`In accordance with the present invention, there is
`
`25
`
`provided a solid dispersed preparation for poorly water(cid:173)
`
`soluble drugs, which
`
`is prepared by dispersing or
`
`dissolving the drugs in an oil, a fatty acid or a mixture
`
`4
`
`Page 6 of 67
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`

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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
`
`5
`
`solid granular preparation.
`
`The preparation method of the solid dispersed powders
`
`comprises the following steps; Dissolving or dispersing the
`
`poorly water-soluble drugs in an oil, a fatty acid or the
`
`mixture thereof; mixing with the water-soluble polymer
`
`10 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 the poorly water-soluble drugs in
`
`15
`
`an oil, a fatty acid or the mixture thereof; mixing with the
`
`water-soluble
`
`polymer matrix;
`
`spraying
`
`onto
`
`a
`
`pharmaceutically acceptable nucleus,
`
`resulting
`
`the
`
`granules.
`
`In a preferred embodiment, the pharmaceutically
`
`acceptable nucleus may be a sugar sphere.
`
`20
`
`The solid dispersed powdery preparation or the solid
`
`dispersed granular preparation of this invention can be
`
`formulated into the pharmaceutically acceptable medicines
`
`for internal use such as powders, granules, tablets and
`
`capsules.
`
`25
`
`Hereinafter, the word "solid dispersed preparation"
`
`means "solid dispersed powdery preparation", "solid
`
`dispersed granular preparation" or the both.
`
`5
`
`Page 7 of 67
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`

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`wo 00/00179
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`PCT IKR99/00341
`
`In this regard, the oil, the fatty acid or the mixture
`
`thereof may be used alone or in a form of an emulsion or
`
`microemulsion inclusive of itself. When dispersing or
`
`dissolving poorly water-soluble drugs in the oil, fatty
`
`5
`
`acid or mixture thereof, a surfactant may be added together.
`
`Further,
`
`the water-soluble polymer matrix may be used
`
`alone or in combination with another water-soluble matrix.
`
`Illustrative examples of the oil that can be used in
`
`the preparation of the present invention include lipid
`
`10
`
`additives, such as a-bisabolol, stearyl glycerrhetinate,
`
`salicylic acid, tocopheryl acetate, a mixture of water,
`
`alcohol
`
`and
`
`Perilla extract,
`
`sodium hyaluronate,
`
`panthenol, propylene glycol and apple(Pirus Malus),
`
`propylene glycol and pineapple, ivy (Hedera halix) extract
`
`15
`
`and 1, 3-B.G, peach (Prumspersica) leaf extract, hydrolyzed
`
`soy flour, wheat (Triticum Vulgare) protein, birch (Betula
`
`alba) extract and 1,3-B.G, burdock (Arctium majus)extract
`
`and 1, 3-B. G; liposomes; phosphatidylcholines; esters, such
`
`as glyceryl stearate, captyliclcapric triglyceride, cetyl
`
`20
`
`octanolate, isopropyl myristate, 2-ethylene isopelagonate,
`
`di-C12-13 alkyl malate, ceteatyl octanoate, butylene
`
`glycol dicapt yla te I dicapra te,
`
`isononyl
`
`isosteara te,
`
`isostearyl
`
`isostearate, coco-captylatelcaprate, cetyl
`
`octanoate, octyldodecyl myristate, cetyl esters, C10-30
`
`2 5
`
`cholesterol I lanosterol ester, hydrogenated castor oil,
`
`monoglycerides,
`
`diglycerides,
`
`and
`
`triglycerides;
`
`hydrocarbons,
`
`such as beeswax, canauba wax,
`
`suctose
`
`6
`
`Page 8 of 67
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`

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`wo 00/00179
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`PCT /KR99/00341
`
`distearate,
`
`PEG-8 beeswax and candelilla
`
`(euphorbia
`
`cerifera) wax; mineral oils such as ceresin and ozokerite;
`
`vegetable oils such as macadamia ternifolia nut oil,
`
`hydrogenated hi -erucic acid rape seed oi 1, olive oil,
`
`5
`
`jojoba oil, hybridsunflower (Helian thus annuus) oil, neen
`
`(melia azadirachta) seed oil, dog rose (rosa canina) lips
`
`oil with preference to mineral oils, squalene, squalane,
`
`monoglycerides, diglycerides, triglycerides, medium-chain
`
`glyceride, myglyol, cremophor, hydrogenated caster oil,
`
`10
`
`corn oil, Perilla oil, cotton seed oil and lipid-soluble
`
`vitamins.
`
`As for the fatty acid, it is preferable to use oleic
`
`acid, cetyl alcohol, stearyl alcohol, stearic acid,
`
`myristic acid,
`
`linoleic acid or
`
`lauric acid. More
`
`15 preferable is to use oleic acid,
`
`linoleic
`
`acid, or
`
`isopropyl myristate.
`
`As
`
`the water-soluble matrix, polyethylene glycol
`
`(PEG), carbowax or polyvinylpyrrolidone (PVP) is available.
`
`Aforementioned water soluble matrix may be used
`
`in
`
`20
`
`combination with other matrixces, examples of which include
`
`water-soluble matrices such as gelatin, gum, carbohydrates,
`
`cell uloses, polyvinyl alcohol, polyacrylic acid, inorganic
`
`compounds and mixtures thereof; and enteric matrices such
`
`as hydroxypropylmethylcellulose acetyl succinate (HPMCAS),
`
`25
`
`cellulose acetate phthalate, shellac, zein, polyvinyl
`
`acetate phthalate, Eudragit 1100, Eudragit SlOO, sodium
`
`arginate and poly-1-lysine.
`
`7
`
`Page 9 of 67
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`

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`wo 00/00179
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`PCT /KR99/00341
`
`In order to enhance the dispersion or dissolution of
`
`poorly water-soluble drugs in the oil, fatty acid or their
`
`mixture, a surfactant may be added, which is selected from
`
`the group comprising glyceryl stearate, polysorbate 60,
`
`5
`
`polysorbate 8 0, sorbitan tr iolea te, sorbitan sesquiolea te,
`
`sorbitan stearate, PEG-20 glyceryl isostearate, ceteth-25,
`
`PEG-60 hydrogenated castor oil, nonoxynol-15, PEG-6-
`
`decyl tetradeceth -2 0,
`
`dimethicone
`
`copolyol,
`
`glyceryl
`
`diisostearate,
`
`ceteth-24,
`
`cetearyl
`
`alcohol,
`
`10
`
`pol yoxylethylene nonyphenyl ether, PEG- 4 0 hydrogenated
`
`castor oil, cetyl dimethicone copolyol, polyglyceryl 3-
`
`methylglucose distearate, PEG-100 stearate,
`
`sorbitan
`
`isostearate,
`
`sodium
`
`lauryl
`
`glutamate,
`
`dis odium
`
`cocoamphodiacetate, lauric acid diethanolamide, coconut
`
`15
`
`fatty acid diethanolamide, N, N-bis- (2-hydroxy ethyl)(cid:173)
`
`cocomide, and cocoamidopropyl betain.
`
`The solid dispersed preparation of
`
`the present
`
`invention can be applied for all the poorly water-soluble '
`
`drugs and preferably for ketoconazole; itraconazole and its
`
`20
`
`derivatives; cyclosporine; cisapride;
`
`acetaminophen;
`
`aspirin; acetylsalicylic acid;
`
`indomethacin; naproxen;
`
`warfarin;
`
`papaverine;
`
`thiabendazole;
`
`miconazole;
`
`cinnarizine; doxorubicin; omeprazole; cholecalciferol;
`
`melphalan; nifedipine; digoxin; benzoic acid; tryptophan;
`
`2 5
`
`tyrosine;
`
`phenylalanine;
`
`a ztreonam;
`
`ibuprofen;
`
`phenoxymethylpenicillin; thalidomide; methyltestosterone;
`
`prochlorperazine;
`
`hydrocortisone;
`
`dideoxypurine
`
`8
`
`Page 10 of 67
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`nucleoside; vitamin D,;
`
`sulfonamide; sulfonylurea; p(cid:173)
`
`aminobenzoic
`
`acid;
`
`melatonin;
`
`benzylpenicillin;
`
`chlorambucil;
`
`diazepin;
`
`digitoxin;
`
`hydrocortisone
`
`butyrate;
`
`metronidazole
`
`benzoate;
`
`tolbutamide;
`
`5
`
`prostaglandin
`
`El(PGE 1 ); fludrocortisone;
`
`griseofulvin;
`
`miconazole
`
`nitrate;
`
`leukotriene
`
`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-1-carnitine; baclofen;
`
`sodium
`
`alendronate;
`
`lovocarni tine; 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;
`
`metergol
`
`2 0 mercaptopurine;
`
`vancomycin hydrochloride;
`
`cefixime;
`
`cefuroxim axetil; dirithramycin; and dadanosin and more
`
`preferably
`
`for ketoconazole,
`
`i traconazole
`
`and
`
`its
`
`derivatives, cisapride, cyclosporine and nifedipine.
`
`Over conventional methods, the present invention has
`
`25
`
`an advantage, in that, the solid dispersed preparation can
`
`be prepared with ease and show high efficiency in absorption
`
`and release.
`
`9
`
`Page 11 of 67
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`

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`wo 00/00179
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`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
`
`molten at room temperature or about 60-80 °C, after which the
`
`5
`
`resulting mixture is cooled rapidly to room temperature and
`
`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
`
`1 0
`
`the o i 1 , fatty acid or their mixture , the o i 1 , fatty acid or
`
`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
`
`the poorly water-soluble drug is added in the water-soluble
`
`15
`
`polymer rna trix mol ten at about 60-8 0 °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
`
`20 artificial gastric juice, the solubility of the solid
`
`dispersed preparation is found to be better than those of
`
`poorly water-soluble drugs themselves. Particularly, a
`
`great advance can be brought into the solubility of poorly
`
`water-soluble drugs when they are incorporated into a solid
`
`25
`
`dispersed preparation containing oleic acid or micro(cid:173)
`
`emulsified oleic acid.
`
`The data obtained from the experiments in which the
`
`10
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`solid dispersed preparations of the present invention are
`
`eluted
`
`in artificial gastric
`
`juice and artificial
`
`intestinal
`
`juice,
`
`show
`
`that
`
`the
`
`solid dispersed
`
`preparations of the present invention are superior to the
`
`5
`
`poorly water-soluble drugs themselves in releasing rate.
`
`A significant improvement in releasing rate is observed
`
`when a solid dispersed preparation containing oleic acid or
`
`microemulsified oleic acid is used.
`
`In the artificial
`
`intestinal juice, a severer condition in which for drugs to
`
`10
`
`dissolve, rather than in the artificial gastric juice, the
`
`improvement in the releasing rate by virtue of the solid
`
`dispersed preparation is more apparent.
`
`Through an experiment which is conducted for examining
`
`the uptake efficiency of poorly water-soluble drugs in the
`
`15 gastro-intestinal tract,
`
`the superiority of the solid
`
`dispersed preparation according to the present invention is
`
`also demonstrated. Even when only a water-soluble matrix
`
`is used, the uptake efficiency of the drugs is minutely
`
`increased.
`
`In particular, the uptake efficiency of drugs
`
`20
`
`in the gastro-intestinal tract is remarkably improved when
`
`they are incorporated in a solid dispersed preparation
`
`using oleic acid-containing microemulsions.
`
`In addition, comparison of the plasma concentration of
`
`target drug molecule after oral administration between the
`
`25
`
`solid dispersed preparation and conventional preparations,
`
`is helpful in understanding the present invention. As a
`
`result, similar levels are observed, suggesting that the
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`solid dispersed preparation of the present invention can
`
`substitute for conventional preparations when account is
`
`taken of pharmaceutical aspects.
`
`A better understanding of the present invention may be
`
`5
`
`obtained in light of the following examples which are set
`
`forth to illustrate, but are not to be construed to limit the
`
`present invention.
`
`Following are
`
`the compositions of emulsions and
`
`microemulsions used in Examples.
`
`10
`
`EMULSIONS
`
`PREPARATION EXAMPLE I
`
`15
`
`Waxes
`
`Composition
`
`(%)
`
`KALCHOL 6870
`
`EMERSOL 132
`
`Multi-Wax W-445
`
`20
`
`Emulsifiers
`
`ATLAS G-144
`
`ATLAS G-610
`
`ATMOS 370
`
`KM-105
`
`25
`
`Oils
`
`1. 800
`
`1. 000
`
`1.700
`
`1. 800
`
`1.900
`
`0.800
`
`2.000
`
`CRODALAN SWL
`
`1.500
`
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`LEXOL GT 865
`
`NIKKOL CIO
`
`SEPERIOR JOJOBA OIL
`
`SF 1202
`
`5
`
`KF-96(100CS)
`
`DRAKEOL 7
`
`Squalane
`
`dl-a-Tocopheryl Acetate
`
`POLYOLPERPOLYMER-2
`
`10
`
`Aqueous Phase
`
`DI-WATER
`
`glycerin
`
`P.G
`
`15
`
`NATURAL EXT.AP
`
`LUBRAGEL CG
`
`Carbopo 1940
`
`KELTROL F
`
`NaOH
`
`20
`
`4.000
`
`4.000
`
`1.000
`
`0.200
`
`0.300
`
`5.000
`
`2.000
`
`0.100
`
`0.200
`
`60.852
`
`2.000
`
`7.000
`
`0.500
`
`0.200
`
`0.100
`
`0.020
`
`0.028
`
`PREPARATION EXAMPLE II
`
`Waxes
`
`KALCHOL 6870
`
`25
`
`EMERSOL 132
`
`Multi-wax W-445
`
`1.800
`
`1.000
`
`1.700
`
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`Emulsifiers
`
`RHEODOL A0-15
`
`RHEODOL MS-162
`
`RHEODOL TW-Sl20
`
`5
`
`KM-105
`
`Oils
`
`CRODALAN SWL
`
`LEXOL GT 865
`
`10
`
`NIKKOL CIO
`
`0.800
`
`2.000
`
`1.900
`
`2.000
`
`1. 500
`
`5.000
`
`2.500
`
`Macadamia ternifolia nut oil 1.000
`
`SF 1202
`
`KF-96(100CS)
`
`DRAKEOL 7
`
`15
`
`Squalane
`
`dl-a-Tocopheryl Acetate
`
`POLYOLPERPOLYMER-2
`
`20
`
`Aqueous phase
`
`DI-WATER
`
`glycerin
`
`1.3-B.G
`
`NATURAL EXT.AP
`
`LUBRAGEL CG
`
`' 25
`
`Carbopol 940
`
`KELTROL F
`
`TEA
`
`0.300
`
`0.300
`
`7.000
`
`0.500
`
`0.100
`
`0.100
`
`61.780
`
`2.000
`
`6.000
`
`0.300
`
`0.200
`
`0.100
`
`0.020
`
`0.100
`
`14
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`PREPARATION EXAMPLE III
`
`Waxes
`
`KALCHOL 6870
`
`5
`
`EMERSOL 132
`
`Beeswax
`
`Emulsifiers
`
`ATLAS G-114
`
`10
`
`ATLAS G-610
`
`ATMOS 370
`
`KM-105
`
`Oils
`
`15
`
`CRODALAN SWL
`
`LEXOL GT 865
`
`NIKKOL CIO
`
`SUPERIOR JOJOGA
`
`OIL
`
`SR 1202
`
`20
`
`KF-96 ( 100CS)
`
`DRAKEOL 7
`
`Squalane
`
`dl-a-Tocopheryl
`
`Acetate
`
`POLYOLPERPOLYMER-2
`
`25
`
`Aqueous phase
`
`DI-WATER
`
`0.500
`
`0.500
`
`0.400
`
`2.200
`
`0.800
`
`0.800
`
`0.700
`
`0.500
`
`3.000
`
`3.000
`
`0.500
`
`0.200
`
`0.100
`
`3.000
`
`0.500
`
`0.100
`
`0.200
`
`74.146
`
`15
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`Glycerin
`
`P.G
`
`NATURAL EXT.AP
`
`LUBRAGEL CG
`
`5
`
`Carbopol 940
`
`KELTROL F
`
`NaOH
`
`2.000
`
`6.000
`
`0.500
`
`0.200
`
`0.100
`
`0.020
`
`0.0336
`
`PREPARATION EXAMPLE IV
`
`10
`
`15
`
`Waxes
`
`KALCHOL 6870
`
`EMERSOL 132
`
`Multi-Wax W-445
`
`Emulsifiers
`
`RHEODOL A0-15
`
`RHEODOL MS-165
`
`RHEODOL TW-5120
`
`20
`
`KM-105
`
`Oils
`
`CRODALAN SWL
`
`LEXOL GT 865
`
`0. 4 00
`
`0.500
`
`0. 400
`
`0.800
`
`2.200
`
`0.800
`
`0.600
`
`0.500
`
`3.000
`
`25
`
`NIKKOL CIO
`
`2.000
`
`Macadamia ternifolia nut oil 1.000
`
`SF 1202
`
`0.400
`
`16
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`DRAKEOL 7
`
`Squalane
`
`dl a tocopheryl acetate
`
`POLYOLPERPOLYMER-2
`
`5
`
`Aqueous phase
`
`DI-WATER
`
`glycerin
`
`1,3-B.G
`
`10
`
`NATURAL EXT.AP
`
`LUBRAGEL CG
`
`Cabopol
`
`KELTROL F
`
`TEA
`
`15
`
`MICROEMULSIQNS
`
`4.500
`
`0.500
`
`0.100
`
`0.100
`
`73.480
`
`2.000
`
`6.000
`
`0.300
`
`0.200
`
`0.100
`
`0.020
`
`0.100
`
`PREPARATION EXAMPLE V
`
`20 Waxes
`
`Cetyl Alcohol
`
`3.000
`
`Emulsifiers
`
`NIKKOL HC0-60
`
`25
`
`RHEODOL TW-0120
`
`Cremophor EL
`
`5.000
`
`5.000
`
`20.000
`
`17
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`Page 19 of 67
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`

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`Oils
`
`I. P .M
`
`CAPT EX
`
`5
`
`J.\queous phase
`
`DI-WATER
`
`Ethanol
`
`5.000
`
`5.000
`
`52.000
`
`5.000
`
`PREPARATION EXAMPLE VI
`
`10
`
`Emulsifiers
`
`NIKKOL HC0-60
`
`RHEODOL TW-0120
`
`Cremophor EL
`
`15
`
`Oils
`
`I. P.M
`
`Lanolin
`
`oil
`
`CAPT EX
`
`Aqueous phase
`
`DI-WATER
`
`Surfactant
`
`LABRASOL
`
`20
`
`25
`
`5.000
`
`5.000
`
`5.000
`
`5.000
`
`5.000
`
`5.000
`
`50.000
`
`PREPARATION EXAMPLE VII
`
`15.000
`
`18
`
`Page 20 of 67
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`

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`Surfactant Aid
`
`Polyglyceryl oleate
`
`PLURL OLEIQUE
`
`5.000
`
`5.000
`
`5
`
`Oil phase
`
`LABRAFIL M1994CS
`
`4.500
`
`Sub-Solvent
`
`10
`
`Transcutol
`
`5.000
`
`Aqueous phase
`
`Phosphate buffer(pH 6)
`
`64.500
`
`15
`
`PREPARATION EXAMPLE VIII
`
`Oil phase
`
`GELUCIRE 44/14
`
`GELUCIRE 48/09
`
`20 Surfactant
`
`11.429
`
`11.429
`
`LABRAFAC CM 10
`
`10.714
`
`Surfactant Aid
`
`LAUROGLYCOL
`
`25
`
`Transcutol
`
`7.143
`
`59.285
`
`PREPARATION EXAMPLE IX
`
`19
`
`Page 21 of 67
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`Aqueous Phase
`
`Water (Buffer)
`
`57,050
`
`Physiological Saline Solution 4,000
`
`5
`
`Glucose
`
`1,000
`
`Propylene Glycol PEG 300,400 5,000
`
`Glycerol
`
`5,000
`
`Oil Phase
`
`10
`
`Fatty Acid Esters
`
`Modified Vegetable Oil
`
`Silicon Oil
`
`Surfactant Aid
`
`15
`
`Long Chain Alcohol
`
`Glycol Derivative
`
`5,000
`
`0.500
`
`0.500
`
`3,750
`
`2,500
`
`Propylene Glycol Derivative
`
`1,200
`
`Polyglycerol Derivative
`
`4,500
`
`20 Surfactant
`
`Non-ionic Surfactant
`
`10,000
`
`PREPARATION EXAMPLE X
`
`25 Oil Phase
`
`Oleic Acid
`
`6,250
`
`20
`
`Page 22 of 67
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`Surfactant
`
`Tween 80
`
`Surfactant Aid
`
`5
`
`Transcutol
`
`Aqueous Phase
`
`Water
`
`12,500
`
`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
`
`After being melted at about 70 °C, 90 g of PEG 6000 was
`
`added with 10 g of ketoconazole, cooled rapidly to room
`
`21
`
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`temperature and dried in an oven for 12 hours or more.
`
`The dried solid dispersed preparation was milled in a
`
`mortar and passed through a sieve to give a powder which was
`
`uniform in particle size.
`
`5
`
`EXAMPLE I
`
`In 5 g of oleic acid were homogeneously mixed and
`
`dispersed 10 g of ketoconazole which was, then, added into
`
`10
`
`85 g of PEG 6000 which was molten at about 70 °C. After being
`
`cooled rapidly to room temperature and dried in an oven for
`
`12 hours or more, the dried solid dispersed preparation was
`
`milled in a mortar and passed through a sieve to give a powder
`
`which was uniform in particular size.
`
`15
`
`EXAMPLE II
`
`In 5 g of oleic acid and 5 g of Tween 80 were
`
`homogeneously mixed and dispersed 10 g of ketoconazole
`
`20 which was, then, added in 80 g of PEG 6000 which was molten
`
`at about 70 °C. Using this mixture, a dispersed powdery
`
`preparation was obtained in the same procedure as in Example
`
`I.
`
`25
`
`EXAMPLE III
`
`In 5 g of isopropyl myristate was homogeneously mixed
`
`22
`
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`and dispersed 10 g of ketoconazole which was, then, added in
`
`80 g of PEG 6000 which was mol ten at about 70 °C. Using this
`
`mixture, a dispersed powdery preparation was obtained in
`
`the same procedure as in Example I.
`
`5
`
`EXAMPLE IV
`
`In 5 g of liquid paraffin was homogeneously mixed and
`
`dispersed 10 g of ketoconazole which was, then, added in 80
`
`10
`
`g of PEG 6000 which was molten at about 70 °C. Using this
`
`mixture, a dispersed powdery preparation was obtained in
`
`the same procedure as in Example I.
`
`EXAMPLE V
`
`15
`
`In 5 g of cremophor was homogeneously mixed and
`
`dispersed 10 g of ketoconazole which was, then, added in 80
`
`g of PEG 6000 which was molten at about 70 °C. Using this
`
`mixture, a dispersed powdery preparation was obtained in
`
`20
`
`the same procedure as in Example I.
`
`EXAMPLE VI
`
`In 5 g of cremophor and 5 g of Tween 80 was homogeneously
`
`25 mixed and dispersed 10 g of ketoconazole which was, then,
`
`added in 80 g of PEG 6000 which was molten at about 70 °C.
`
`Using this mixture, a dispersed powdery preparation was
`
`23
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`obtained in the same procedure as in Example I.
`
`EXAMPLE VII
`
`5
`
`In 5 g of isopropyl myristate and 5 g of Tween 80 was
`
`homogeneously mixed and dispersed 10 g of ketoconazole
`
`which was, then, added in 80 g of PEG 6000 which was molten
`
`at about 70 °C. Using this mixture, a dispersed powdery
`
`preparation was obtained in the same procedure as in Example
`
`10
`
`I.
`
`EXAMPLE VIII
`
`In 5 g of liquid paraffin and 5 g of Tween 80 was
`
`15
`
`homogeneously mixed and dispersed 10 g of ketoconazole
`
`which was, then, added in 80 g of PEG 6000 which was molten
`
`at about 70 °C. Using this mixture, a dispersed powdery
`
`preparation was obtained in the same procedure as in Example
`
`I.
`
`20
`
`EXAMPLE IX
`
`In a microemulsion containing 5 g of cremophor, 5 g of
`
`oleic acid, 35 g of alcohol and 1 g of transcutol was
`
`25
`
`homogeneously dissolved and dispersed 10 g of ketoconazole,
`
`followed by evaporating the alcohol. The solid residue was,
`
`then, added in 43 g of PEG 6000 molten at about 70 °C.
`
`24
`
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`Using this mixture, a dispersed powdery preparation was
`
`obtained in the same procedure as in Example I.
`
`EXAMPLE X
`
`5
`
`In a microemulsion containing 5 g of cremophor, 5 g of
`
`oleic acid and 1 g of transcutol was dissolved 10 g of
`
`ketoconazole which was, then, dispersed in 35 g of distilled
`
`water, followed by evaporating the distilled water in an
`
`10
`
`oven. The solid residue was added in 43 g of PEG 6000 molten
`
`at about 70 °C. Using this mixture, a dispersed powdery
`
`preparation was obtained in the same procedure as in Example
`
`I.
`
`15
`
`EXAMPLE XI
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed
`
`10
`
`g
`
`of
`
`ketoconazole.
`
`40
`
`g
`
`of
`
`hydroxypropylmethylcellulose, an enteric matrix, was added
`
`20
`
`in 40 g of PEG 6000 molten at 70 °C. Using the mixture of
`
`the above two solutions, a dispersed powdery preparation
`
`was obtained in the same procedure as in Example I.
`
`25
`
`EXAMPLE XII
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed 10 g of i traconazole which was, then, added in 8 0
`
`25
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`g of PEG 6000 which was molten at 70 °C. Using this mixture,
`
`a dispersed powdery preparation was obtained in the same
`
`procedure as in Example I.
`
`5
`
`EXAMPLE XIII
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed
`
`10
`
`g
`
`of
`
`i traconazole.
`
`4 0
`
`g
`
`of
`
`hydroxypropylmethylcellulose, an enteric matrix, was added
`
`10
`
`in 40 g of PEG 6000 which was molten at 70 °C. Using the
`
`mixture of the above two solutions, a dispersed powdery
`
`preparation was obtained in the same procedure as in Example
`
`I.
`
`15
`
`EXAMPLE XIV
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed 10 g of an itraconazole derivative
`
`(Dong-A
`
`Pharmacy Co., Ltd., Korea) which was, then, added in 80 g
`
`20
`
`of PEG 6000 which was molten at 70 °C. Using this mixture,
`
`a dispersed powdery preparation was obtained in the same
`
`procedure as in Example I.
`
`25
`
`EXAMPLE XV
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed 10 g of cyclosporine which was, then, added in 80
`
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`g of PEG 6000 which was molten at 70 °C. Using this mixture,
`
`a dispersed powdery preparation was obtained in the same
`
`procedure as in Example I.
`
`5
`
`EXAMPLE XVI
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed
`
`10
`
`g
`
`of
`
`cyclosporine.
`
`40
`
`g
`
`of
`
`hydroxypropylmethylcellulose, an enteric matrix, was added
`
`10
`
`in 40 g of PEG 6000 which was molten at 70 °C. Using the
`
`mixture of the above two solutions, a dispersed powdery
`
`preparation was obtained in the same procedure as in Example
`
`I.
`
`15
`
`EXAMPLE XVII
`
`In 5 g of oleic acid was homogeneously mixed and
`
`dispersed 10 g of cisapride which was, then, added in 80 g
`
`of PEG 6000 which was molten at 70 °C. Using this mixture,
`
`20
`
`a dispersed powdery preparation was obtained in the same
`
`procedure as in Example I.
`
`EXAMPLE XVIII
`
`25
`
`In 5 g