`
`Exhibit 1007
`
`European Patent Application No. 0 671 168
`A1 (“EP ‘168”)
`
`

`
`J
`
`
`
`Europaisches Patentamt
`European Patent Office
`Office europeen des brevets
`
`© Publication number:
`
`0 6 7 1 1 6 8 A 1
`
`EUROPEAN PATENT A P P L I C A T I O N
`
`© Application number: 95103493.3
`
`int. ci e: A61K 9/24
`
`@ Date of filing: 10.03.95
`
`® Priority: 11.03.94 JP 40911/94
`
`@ Date of publication of application:
`13.09.95 Bulletin 95/37
`
`© Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IE IT LI LU MC
`NL PT SE
`
`© Applicant: TANABE SEIYAKU CO., LTD.
`2-10, Dosho-machi 3-chome
`Chuo-ku
`Osaka (JP)
`
`@ Inventor: Hirakawa, Yoshiyuki
`No. 1-4-130-102, Koyochonaka,
`Higashinada-ku
`Kobe-shi,
`Hyogo-ken (JP)
`Inventor: Yoshino, Hiroyuki
`No. 2-8-A9-101, Yamadanishi
`Suita-shi,
`Osaka-fu (JP)
`Inventor: Fukui, Eiji
`No. 433-15, Furuouchi,
`Noguchicho
`Kakogawa-shi,
`Hyogo-ken (JP)
`Inventor: Hanamori, Tami, nee Komoda, Tami
`No. 3-14-32, Mikatadai,
`Nishi-ku
`Kobe-shi,
`Hyogo-ken (JP)
`
`© Representative: Hansen, Bernd, Dr.
`Dipl.-Chem. et al
`Hoffmann, Eitle & Partner,
`Patentanwalte,
`Arabellastrasse 4
`D-81925 Munchen (DE)
`
`00
`CO
`
`CO
`
`Pharmaceutical preparation controlled to release medicinal active ingredient at targeted site in
`intestinal tract.
`
`© A pharmaceutical preparation for oral administra-
`tion which is controlled to release a medicinal active
`ingredient at a targeted site in the intestinal tract
`comprising
`(a) a core containing a medicinal active ingredient
`and
`(b) a press-coated layer comprising an enteric
`polymer, said layer being provided around the
`
`core. In the pharmaceutical preparation of the
`present invention, the medicinal active ingredient
`is not released during residence in the stomach
`and, after discharged from the stomach, until
`reaching a targeted site in the intestine, and
`thereafter is quickly released, so that the medici-
`nal active ingredient is efficiently delivered to the
`targeted site in the intestinal tract.
`
`Rank Xerox (UK) Business Services
`(3. 10/3.09/3.3.4)
`
`

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`1
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`EP 0 671 168 A1
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`2
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`The present invention relates to a pharmaceuti-
`cal preparation controlled to release a medicinal
`active ingredient at a targeted site in the gastroin-
`testinal tract, and more particularly to a pharma-
`ceutical preparation for oral administration from
`which a medicinal active ingredient can be selec-
`tively delivered to any specific site in the intestinal
`tract.
`Selective delivery of a medicinal active ingre-
`dient to a specific site in the intestinal tract has
`been desired in drug therapies, for instance, a local
`therapy for inflammatory disease in the intestinal
`tract such as ulcerative colitis or Crohn's disease,
`or an oral administrative therapy with a medicinal
`compound of a peptide which is apt to be de-
`composed chemically or enzymatically in the intes-
`tinal tract, with a medicinal compound of which the
`absorption site is limited, or with other medicinal
`compound.
`In order to efficiently realize the selective deliv-
`ery of a medicinal active ingredient to a specific
`site in the intestinal tract, it is necessary to design
`a pharmaceutical preparation taking into account
`the physical and physiological environment in the
`human gastrointestinal tract and the traveling time
`of the pharmaceutical preparation through the in-
`testinal tract. With respect to the physical and
`physiological environment in the gastrointestinal
`tract, it is recognized that the value of pH in the
`stomach is usually 1.8 to 4.5 in a healthy human
`and that the value of pH in the intestines is 6.5 to
`7.5 and the pH does not essentially differ between
`the small intestine and the large intestine. Accord-
`ing to the results of the widespread research of
`Davis et al., the residence time of a pharmaceutical
`preparation in the human stomach is 0.5 to 10
`hours and further not only the inter-individual vari-
`ation thereof is large, but also the residence time is
`considerably influenced, for example, by feeding, a
`size of the pharmaceutical preparation to be admin-
`istered and the like. However, the traveling time of
`a pharmaceutical preparation through the small in-
`testine is generally recognized to be 3±1 hours and
`the inter- and intra-individual variation is relatively
`small (Journal of Controlled Release, 2, 27-38
`(1985)).
`With respect to a method by which a medicinal
`active ingredient can be selectively delivered to a
`specific site in the intestinal tract, hitherto various
`researches have been done. There have been pro-
`posed a pharmaceutical preparation wherein a sus-
`tained release pharmaceutical preparation is coated
`with an enteric coating (Annals of the New York
`Academy of Science, 618, 428-440 (1991)), a phar-
`maceutical preparation obtained by utilizing a tech-
`nique for controlling the starting time of the release
`(Chemical & Pharmaceutical Bulletin, 40, 3036-
`3041 (1992)) and the like, as well as pharmaceuti-
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`cal preparations obtained by using known tech-
`niques such as an enteric pharmaceutical prepara-
`tion and a sustained release pharmaceutical prep-
`aration.
`However, every conventional method has a
`problem such as insufficient site-selectivity or poor
`practicality due to peculiarity of the material to be
`used. For example, in case of using the enteric
`pharmaceutical preparation, the release of a me-
`dicinal active ingredient starts abruptly at the upper
`small intestine resulting in consumption of almost
`of the medicinal active ingredient by absorption or
`decomposition before the medicinal active ingre-
`dient reaches the targeted site in the intestine,
`although the release of the medicinal active ingre-
`dient can be effectively suppressed in the stomach.
`In case of using the sustained release pharmaceuti-
`cal preparation, a considerable amount of a medici-
`nal active ingredient is released when the phar-
`20 maceutical preparation stays in the stomach and
`passes through the small intestine because the
`medicinal active
`is continuously re-
`ingredient
`leased.
`Further, in order to release a medicinal active
`ingredient at the large intestine, there has been
`the ec-
`recently developed a system utilizing
`osystem of specific microorganisms in the large
`intestine. For example, in a pharmaceutical prep-
`aration wherein a composition containing a medici-
`nal active ingredient is coated with a novel polymer
`having an azo group, or the composition containing
`a medicinal active ingredient is dispersed in the
`new polymer having an azo group to form a matrix
`type of pharmaceutical preparation (Science, 233,
`1081-1084 (1986)), the polymer is decomposed in
`the large intestine by enterobacteria having azo-
`reductase activity and the medicinal active ingre-
`dient is thereby released at the large intestine.
`However, for practical use, there are still many
`problems to be solved, for example, regarding the
`safety of the polymer itself, the controllability of the
`decomposition rate thereof, and the like.
`An object of the present invention is to solve
`the above-mentioned problems in the conventional
`pharmaceutical preparations, and to provide a phar-
`maceutical preparation for oral administration of
`high practical use by which a medicinal active
`ingredient can be effectively released at a targeted
`site in the intestinal tract.
`This and the other objects of the present inven-
`tion will become apparent from the description
`hereinafter.
`In accordance with the present invention, there
`is provided a pharmaceutical preparation for oral
`administration which is controlled to release a me-
`dicinal active ingredient at a targeted site in the
`intestinal tract comprising (a) a core containing a
`medicinal active ingredient and (b) a press-coated
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`EP 0 671 168 A1
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`layer comprising an enteric polymer, said layer
`being provided around the core.
`the
`In
`the pharmaceutical preparation of
`present invention, a lipophilic or hydrophobic sub-
`stance may be included in the press-coated layer
`in order to control a dissolution rate of the layer in
`the intestine.
`The pharmaceutical preparation of the present
`invention has the following characteristics: when
`the pharmaceutical preparation is orally adminis-
`tered, the release of a medicinal active ingredient
`does not occur at all during residence of the phar-
`maceutical preparation in the stomach and, after
`discharge from the stomach, until the preparation
`reaches a desirable targeted site in the intestine
`and thereafter, the release of the ingredient starts
`rapidly. In case of using a medicinal active ingre-
`dient as a drug required to be selectively delivered
`to a specific site in the intestinal tract, an excellent
`pharmaceutical preparation having high availability
`can be provided.
`Fig. 1
`is a graph showing the result of the
`dissolution test with the first fluid and the second
`fluid of the dissolution test in Japanese Pharmaco-
`poeia XII (hereinafter referred to as JPXII) using a
`pharmaceutical preparation in Example 1 .
`Fig. 2 is a graph showing the result of the
`dissolution test with the second fluid of the dissolu-
`tion test in JPXII using a pharmaceutical prepara-
`tion after immersing in the first fluid of the dissolu-
`tion test in JPXII for a certain time in Experimental
`Example 1 .
`The present invention has been accomplished
`based on viewpoints that a press-coated
`layer
`comprising an enteric polymer starts to dissolve
`more slowly in the intestine than a film-coated layer
`comprising the enteric polymer and that the start-
`ing time of dissolution of a medicinal active ingre-
`dient can be controlled by varying an amount of
`the press-coated layer.
`the
`In
`the pharmaceutical preparation of
`present invention, the press-coated layer (b) com-
`prising an enteric polymer is capable of suppress-
`ing the release of a medicinal active ingredient in
`the intestine until the pharmaceutical preparation
`reaches near the desirable targeted site. Namely,
`during residence of the pharmaceutical preparation
`in the stomach, the press-coated layer (b) does not
`dissolve and protects the core (a) so that the
`release of a medicinal active ingredient can be
`perfectly supressed, and after discharge of the
`pharmaceutical preparation from the stomach, the
`layer (b) gradually dissolves, and
`press-coated
`therefore the release of a medicinal active ingre-
`dient is substantially suppressed in the intestine
`until the pharmaceutical preparation reaches near
`the desirable targeted site.
`
`In order to sufficiently exhibit the above-men-
`tioned capacity in the pharmaceutical preparation
`of the present invention, it is desirable to determine
`the time required for dissolution of the press-coat-
`ed layer (b) in the intestine so that the press-
`coated layer (b) has sufficient acid resistance and
`does not dissolve during residence in the stomach,
`and after discharge from the stomach, the press-
`coated layer (b) can substantially suppress the
`release of a medicinal active ingredient until the
`pharmaceutical preparation reaches near the desir-
`able targeted site in the intestine.
`From the above-mentioned viewpoints, it is de-
`sirable that the coating amount of the press-coated
`layer (b) is usually determined so that a medicinal
`active ingredient is not released in the stomach for
`a period of about 10 hours which is recognized as
`the maximum residence time of a pharmaceutical
`preparation in the stomach, and in case of targeting
`the upper large intestine, can suppress the release
`of a medicinal active ingredient in the intestines for
`about 3±1 hours which is recognized as a general
`time of a pharmaceutical preparation
`traveling
`through the small intestine.
`The pharmaceutical preparation of the present
`invention can be suitably designed so that when a
`dissolution test is carried out according to the
`dissolution test (puddle method; 37 °C; 100 rpm;
`900 mi of dissolution fluid) of JPXII (refer to Exam-
`pie 1), release of a medicinal active ingredient is
`substantially suppressed for at least 10 hours in the
`first fluid (pH 1 .2), and the release of the medicinal
`active ingredient is substantially suppressed for at
`least about 2 hours in the second fluid (pH 6.8) and
`thereafter the release of the medicinal active ingre-
`dient starts quickly. The time required to start the
`release
`of
`the medicinal
`active
`ingredient
`(hereinafter referred to as "lag-time") in the second
`fluid is set to meet the desired target-site in the
`intestinal tract. For example, in case that the phar-
`maceutical preparation of the present invention is
`designed to have the lag-time of about 2 hours,
`about 4 hours or about 7 hours, there can be
`obtained a pharmaceutical preparation wherein re-
`lease of a medicinal active ingredient is intended to
`occur at the lower ileum, the ascending colon or
`the transverse colon. If the pharmaceutical prepara-
`tion of the present invention is designed to have
`the lag-time being longer than about 7 hours, there
`can be obtained a pharmaceutical preparation
`wherein release of a medicinal active ingredient is
`intended to occur at the lower large intestine such
`as the descending colon or the sigmoid colon.
`the
`In
`the pharmaceutical preparation of
`present invention, the core (a) is not particularly
`limited if only a medicinal active ingredient is in-
`cluded in the core (a). The core (a) may comprise
`a medicinal active ingredient only. Or if required,
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`EP 0 671 168 A1
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`various pharmaceutical additives such as an ex-
`cipient and a disintegrant which are generally used
`in the art of pharmaceutical preparation, may be
`included in the core (a) as described below. The
`form of the core (a) may be a tablet, a granule, a
`pellet or the like.
`The medicinal active ingredient to be included
`in the above-mentioned core (a) in the present
`invention is not particularly limited as long as it is
`orally administerable. Concrete examples of such
`medicinal
`active
`intredient
`include
`chemotherapeutic agents, antibiotics, respiratory
`stimulants, antitussives, expectorants, antimalignan-
`ttumor agents, autonomic agents, psychotropic
`agents, local anesthetics, muscle relaxants, agents
`tox-
`affecting digestive organs, antihistamines,
`icopetic agents, hypnotics, sedatives, antiepileptics,
`antipyretics, analgesics, antiinflammatory agents,
`diuretics,
`cardiotonics,
`antiarrhythmic
`agents,
`vasodilators, antilipemic agents, nutrients, tonics,
`alteratives, anticoagulants, agents for liver disease,
`hypoglycemics, antihypertensives and the like.
`The amount of a medicinal active ingredient to
`be included in the core (a) is not particularly limited
`and may be determined according to an effective
`dose of the medicinal active ingredient to be used,
`and the like. The amount is preferably about 0.2 to
`about 100 w/w %, more preferably 0.5 to 50 w/w
`%, based on a weight of the core (a).
`As an enteric polymer used for the press-
`coated layer (b), any film-formable polymer soluble
`in an aqueous medium of a pH of not less than 5
`and insoluble in an aqueous medium of a pH of
`less than 5 can be used in the pharmaceutical
`preparation of the present invention. Examples of
`the enteric polymer include a cellulose derivative, a
`polyvinyl derivative, a maleic acid-vinyl compound
`copolymer, an acrylic copolymer and the like.
`Concrete examples of the cellulose derivative
`include carboxymethylethylcellulose, cellulose ace-
`tate phthalate, cellulose acetate succinate, methyl-
`cellulose phthalate, hydroxymethylethylcellulose
`phthalate, hydroxypropylmethylcellulose phthalate,
`succinate
`acetate
`hydroxypropylmethylcellulose
`and the like. Concrete examples of the polyvinyl
`derivative include polyvinyl alcohol phthalate, poly-
`vinyl butylate phthalate, polyvinyl acetoacetal
`phthalate and the like. Concrete examples of the
`include
`maleic acid-vinyl compound copolymer
`polyvinyl acetate, maleic acid anhydride), poly-
`vinyl butyl ether, maleic acid anhydride), poly-
`styrene, maleic acid monoester), and the like.
`Concrete examples of the acrylic copolymer in-
`clude poly(ethyl acrylate, methacrylic acid), poly-
`styrene,
`acrylic
`acid),
`poly(methyl
`acrylate,
`methacrylic acid, octyl acrylate), poly(methacrylic
`acid, methyl methacrylate) (e.g. Eudragit L and
`Eudragit S, each being trade name, available from
`
`Rohm Pharma, Germany), and the like.
`Among these examples, carboxymethylethyl-
`acetate
`cellulose,
`hydroxypropylmethylcellulose
`succinate, hydroxypropylmethylcellulose phthalate
`and poly(methacrylic acid, methyl methacrylate)
`(Eudragit L and Endragit S) are preferably used as
`the enteric polymer, and particularly hydrox-
`ypropylmethylcellulose acetate succinate and poly-
`(methacrylic acid, methyl methacrylate) (Eudragit L
`and Endragit S) are preferable, and more particu-
`larly hydroxypropylmethylcellulose acetate suc-
`cinate is preferable.
`The above-mentioned enteric polymers are dif-
`ferent in various physical properties such as a
`dissolution pH (enteric polymers may be somewhat
`different in a dissolution pH), a molecular weight
`and a polymerization degree. However, any enteric
`polymer can be suitably used for preparing a
`press-coated layer in the pharmaceutical prepara-
`tion of the present invention by selecting a kind
`and an amount of the enteric polymer, a compress-
`ing pressure of a press-coated layer and the like so
`that the press-coated layer (b) is capable of sup-
`pressing release of a medicinal active ingredient
`until the pharmaceutical preparation reaches near a
`desirable targeted site in the intestine, namely can
`substantially suppress the release of a medicinal
`active ingredient for any desired period of time (for
`example, at least 2 hours) in the second fluid of the
`dissolution test in JPXII.
`Thus, with respect to the above-mentioned
`preparation of the press-coated layer, there is no
`particular difficulty for a person skilled in the art to
`select a type or a grade of the enteric polymer and
`an amount thereof, a compressing pressure and
`the like so that a medicinal active ingredient can be
`released at a desired site in the intestinal tract,
`particularly a targeted site in between the upper
`small intestine and the lower large intestine.
`For instance, a usually used enteric polymer in
`a commercially available form can be used for
`tabletting by means of a tabletting machine to
`obtain a pharmaceutical preparation of the present
`invention in a form of a tablet.
`If an enteric polymer cannot be used as it is for
`tabletting because of having a very small particle
`size (e.g. in a form of a fine powder), the enteric
`polymer is once transformed to a form of granules
`having a suitable particle size for tabletting and
`thereafter the granules are tabletted together with a
`core tablet. Then, the pharmaceutical preparation
`of the present invention in a form of a tablet can be
`obtained. For example, an acrylic enteric polymer
`which is commercially available under the trade
`name of Eudragit S or Eudragit L generally has a
`small particle size, and the acrylic enteric polymer
`can be used as it is, however, the acrylic enteric
`polymer can be more suitably used in a form of
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`EP 0 671 168 A1
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`granules prepared as described above rather than
`as it is.
`The press-coated layer (b) comprising an en-
`teric polymer in the pharmaceutical preparation of
`the present invention may be a press-coated layer
`having a multiple layer, which is formed by press-
`coating a core containing a medicinal active ingre-
`dient with one kind of an enteric polymer and
`providing a further press-coated layer comprising
`the same or different kind of an enteric polymer
`around the layer. Additionally, the press-coated lay-
`er (b) may be formed by using two or more kinds
`of enteric polymers in admixture. Each of the
`above-mentioned press-coated layer having a mul-
`tiple layer or that comprising two or more kinds of
`enteric polymers can be suitably used as the
`press-coated layer (b) in the pharmaceutical prep-
`aration of the present invention so long as the
`press-coated layer (b) is capable of suppressing
`the release of a medicinal active ingredient until the
`pharmaceutical preparation reaches near a desir-
`able targeted site in the intestine, namely can sub-
`stantially suppress the release of a medicinal active
`ingredient for any desired period of time (for exam-
`ple, at least 2 hours) in the second fluid of the
`dissolution test in JPXII.
`In the press-coated layer (b) in the pharmaceu-
`tical preparation of
`the present
`invention, a
`lipophilic or hydrophobic substance (i.e. a sub-
`stance having lipophilic property or hydrophobic
`hereinafter
`reffered
`to
`as
`property,
`"lipophilic/hydrophobic substance") can be suitably
`included in addition to an enteric polymer in order
`to control a dissolution rate of the press-coated
`layer (b), if required. As such lipophilic/hydrophobic
`substance, a substance which exerts an effect to
`decrease a dissolution rate of the press-coated
`layer (b) in aqueous medium at a pH of not less
`than 5, may be used alone or in admixture of at
`least two kinds of substances. It is considered that
`the effect that a dissolution rate of the press-coated
`layer in aqueous medium of a pH of not less than 5
`is decreased, is exerted owing to either a function
`that the lipophilic/hydrophobic substance prevents
`the enteric polymer from wetting with water or a
`mechanism
`that the
`lipophilic/hydrophobic sub-
`stance physically interacts with the enteric polymer
`to form more tight press-coated layer.
`The above-mentioned effect is varied depend-
`ing on a physical property and an amount of a
`lipophilic/hydrophobic substance to be used and a
`kind of the enteric polymer to be used. For in-
`stance, generally, the more effect is exerted by
`using the substance having a lower melting point,
`and in case of using a metallic salt of a fatty acid
`as a lipophilic/hydrophobic substance, a multivalent
`metallic salt thereof exerts more intensive effect
`than a monovalent metallic salt thereof. Accord-
`
`ingly, the dissolution rate of a press-coated layer
`can be also controlled by using two or more kinds
`of the lipophilic/ hydrophobic substances.
`of
`the
`above-mentioned
`Examples
`lipophilic/hydrophobic substance suitably used are,
`for example, a fat and oil, a wax, a hydrocarbon, a
`higher alcohol, an ester, a higher fatty acid, a
`metallic salt of a higher fatty acid, other plasticizer
`and the like.
`Concrete examples of the fat and oil include,
`for example, a vegetable fat and oil such as cacao
`butter, palm oil, Japan wax or coconut oil; an
`animal fat and oil such as beef tallow, lard, horse
`fat or mutton tallow; a hydrogenated oil obtained
`from animals such as hydrogenated fish oil, hy-
`drogenated whale oil or hydrogenated beef tallow;
`a hydrogenated oil obtained from plants such as
`hydrogenated rape seed oil, hydrogenated castor
`oil, hydrogenated coconut oil or hydrogenated
`soybean oil; and the like.
`Concrete examples of the wax include, for ex-
`ample, a vegetable wax such as carnauba wax,
`candelilla wax, bayberry wax, ouricury wax or es-
`parto wax, an animal wax such as beeswax, white
`beeswax, spermaceti, shellac wax or wool wax, and
`the like.
`Concrete examples of the hydrocarbon include,
`for example, paraffin, vaseline, microcrystalline wax
`and the like.
`As the higher alcohol, a saturated linear alcohol
`is exemplified, and concrete examples thereof in-
`clude, for example, a saturated linear monohydric
`alcohol having 12 to 30 carbon atoms such as
`lauryl alcohol, tridecyl alcohol, myristyl alcohol,
`pentadecyl alcohol, cetyl alcohol, heptadecyl al-
`cohol, stearyl alcohol, nonadecyl alcohol, arachic
`alcohol, behenyl alcohol, carnaubyl alcohol, ceryl
`alcohol, corianyl alcohol or melissyl alcohol.
`Concrete examples of the ester include, for
`example, an ester of a fatty acid such as myristyl
`palmitate, stearyl stearate, myristyl myristate or
`behenyl behenate; a glycerine ester of a fatty acid
`including a monoglyceride such as glyceryl mon-
`olaurate, glyceryl monomyristate, glyceryl mon-
`ostearate or glyceryl monooleate, a diglyceride
`such as glyceryl distearate or glyceryl dilaurate, a
`triglyceride such as glyceryl trilaurate, glyceryl
`tristearate or glyceryl triacetyl stearate; and the
`like.
`As the higher fatty acid, a saturated linear fatty
`acid is exemplified, and concrete examples thereof
`include, for example, a saturated monobasic linear
`fatty acid having 10 to 32 carbon atoms such as
`undecanoic
`lauric
`acid,
`acid,
`acid,
`capric
`tridecanoic acid, myristic acid, palmitic acid, mar-
`garic acid, stearic acid, nonadecanoic acid, arachic
`acid, heneicosanoic acid, behenic acid, tricosanoic
`acid, lignoceric acid, pentacosanoic acid, cerotic
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`acid, heptacosanoic acid, montanic acid, non-
`acosanoic acid, melissic acid, hentriacontanoic acid
`or dotriacontanoic acid. Among these higher fatty
`acids, capric acid and lauric acid are preferable.
`As the metallic salt of a higher fatty acid, an
`alkali metal salt and an alkaline earth metal salt of
`a higher fatty acid are exemplified, and concrete
`examples of the metallic salt of a higher fatty acid
`include a calcium salt, a sodium salt, a potassium
`salt, a magnesium salt, a barium salt and the like,
`of the above-mentioned higher fatty acids. Among
`these metallic salts of a higher fatty acid, calcium
`stearate and magnesium stearate are preferable.
`Concrete examples of the plasticizer include,
`for example, triacetin, triethyl citrate, acetyl tributyl
`citrate, acetyl
`triethyl citrate, diethyl phthalate,
`polyethyleneglycol, polysorbate and
`the
`like.
`Among these plasticizers, triacetin, triethyl citrate
`and acetyl triethyl citrate are preferable.
`Among such lipophilic/hydrophobic substances,
`magnesium stearate, calcium stearate, triacetin,
`lauric acid, capric acid, triethyl citrate, acetyl tri-
`ethyl citrate and the like are preferable. Particularly,
`magnesium stearate, calcium stearate, triacetin,
`lauric acid, capric acid and triethyl citrate are pref-
`erable, and more particularly, magnesium stearate,
`calcium stearate, triacetin and lauric acid are pref-
`erable.
`The lipophilic/hydrophobic substance may be
`used alone or in admisture of two or more kinds of
`the above-mentioned substances.
`A preferable combination of the enteric poly-
`mer and the lipophilic/hydrophobic substance in
`the press-coated layer of the pharmaceutical prep-
`aration of the present invention is, for example, a
`combination of a cellulose derivative and a higher
`fatty acid or a metallic salt thereof, a combination
`of a cellulose derivative and a plasticizer, and the
`like. In the more preferable combination, the enteric
`polymer is hydroxypropylmethylcellulose acetate
`succinate and the lipophilic/hydrophobic substance
`is magnesium stearate, calcium stearate, triacetin,
`lauric acid, or a mixture of magnesium stearate and
`calcium stearate.
`An amount of the lipophilic/hydrophobic sub-
`stance in the press-coated layer (b) is about 5 to
`about 100 % by weight, preferably 20 to 60 % by
`weight based on a weight of the enteric polymer.
`In the core (a) and the press-coated layer (b) of
`the pharmaceutical preparation of the present in-
`vention, various additives such as an excipient, a
`binder, a disintegrant, a lubricant and an aggrega-
`tion-preventing agent which are generally used in
`the field of pharmaceutical preparation may be
`included, if desired.
`Concrete examples of the excipient include a
`saccharide such as sucrose, lactose, mannitol or
`glucose, starch, partially pregelatinized starch, cry-
`
`5
`
`io
`
`stalline cellulose, calcium phosphate, calcium sul-
`fate, precipitated calcium carbonate, hydrated sili-
`con dioxide and the like. Concrete examples of the
`binder include an oligosaccharide or a sugar a\-
`cohol such as sucrose, glucose, lactose, maltose,
`sorbitol or mannitol; a polysaccharide such as dex-
`trin, starch, sodium alginate, carrageenan, guar
`gum, arabic gum or agar; a natural polymer such
`as tragacanth, gelatin or gluten; a cellulose deriva-
`tive such as methylcellulose, ethylcellulose, sodium
`carboxymethylcellulose or hydroxypropylmethylcel-
`lulose; a synthetic polymer such as polyvinylpyr-
`rolidone,
`polyvinylalcohol,
`polyvinylacetate,
`a
`acid or poly-
`polyethyleneglycol, polyacrylic
`15 methacrylic acid; and the like. Concrete examples
`of the disintegrant include calcium carboxymethyl-
`sodium
`cellulose,
`carboxymethylstarch,
`corn
`starch, hydroxypropylstarch, partially pr