12 United States Patent
`Matsuura et al.
`
`111111119I9III191191Ii
`
`IIII
`
`IIIII
`
`IIIII IIIII VIIIIIIII111111IIIIIIIIII11
`
`US006649180B1
`
`10 Patent No.
`45 Date of Patent
`
`US 6649180 B1
`Nov. 18 2003
`
`54 HARD CAPSULE FORMED OF CELLULOSE
`ETHER FILM WITH A SPECIFIC CONTENT
`OF METHOXYL AND HYDROXYPROPOXYL
`GROUPS
`
`5431917 A
`5431919 A
`6228416
`131
`6326026 Bl
`
`1212001
`
`7/1995
`
`Yamamoto et al..........
`
`424/451
`
`424/473
`
`........
`
`7/1995 Maruyama et al.
`512001
`
`Reibert
`
`et al
`
`4261573
`Parekh et at ............... 4241451
`
`.............
`
`75 Inventors
`
`Seinosuke Matsuura Kyoto JP
`Masaru Tanjoh Sakurai JP
`
`73 Assignee
`
`Shionogi Qualicaps Co. Ltd.
`Yamalokoriyama JP
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`
`JP
`WO
`
`0592130
`
`A2
`0714656 Al
`
`B2-2552937
`9827151 Al
`
`41994
`
`6/1996
`
`8/1996
`
`6/1998
`
`Notice
`
`Subject
`
`to any disclaimer
`is extended
`or adjusted under
`patent
`U.S.C. 154b by 0 days.
`
`the term of this
`
`35
`
`cited by examiner
`
`21 Appl. No. 09/549205
`22 Filed
`
`Apr. 13 2000
`
`30
`
`Foreign Application
`
`Priority Data
`
`PrimaryExaminer-Paul Thibodeau
`
`Assistant Examiner--Kevin M. Bematz
`74 Attorney Agent or Firm-Birch Stewart Kolasch
`Birch LLP
`
`Apr. 14 1999
`
`JP ..........................................
`
`11-106689
`
`57
`
`ABSTRACT
`
`Acellulose
`
`ether film is formed of a composition
`in which some of
`a cellulose ether as a base
`atoms of cellulosic
`
`comprising
`
`the
`
`hydrogen
`
`51 Int. Cl.
`52 U.S. Cl.
`
`...............................................
`
`......................
`
`424/402
`
`................................
`
`B29D 22/00
`424/403
`424/451
`428/34.3 428/532
`58 Field of Search
`424/435 436
`424/451 452 455 456 463 DIG. 15
`402 403 428/34.3 532
`
`56
`
`Reference- Cited
`
`PATENT DOCUMENTS
`
`appear-U.S.
`
`hydroxyl
`replaced by alkyl
`groups are
`groups and/or hydroxyalkyl
`groups a gelling agent and a
`gelling aid. The total content of alkoxyl and hydroxyalkoxyl
`cellulose ether
`is limited to 23-37.6% by
`groups
`weight which is effective
`the gelling aid from
`for preventing
`precipitating out and maintaining
`a favorable
`ance during long-term storage.
`
`in the
`
`outer
`
`4365.060 A
`
`12/1982
`
`Onda et al
`
`..................
`
`536/65
`
`5 Claims No Drawings
`
`DEPOSITION
`EXHIBIT
`
`3..ZZ e 7 P3ii9
`
`WCDELZ_00029723
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2065 - 1/4
`
`

`

`Espe-OF
`cap-This
`
`1
`HARD CAPSULEFORMED OF CELLULOSE
`ETHER FILM WITH A SPECIFIC CONTENT
`METHOXYL
`AND HYDROXYPROPOXYL
`GROUPS
`
`invention
`
`relates
`
`use in forming
`
`pharmaceutical
`
`to a cellulose ether film suited for
`and food hard capsules.
`
`BACKGROUND OF THE INVENTION
`
`Hard capsules are commonly
`used
`in the pharmaceutical
`and health food fields. Of the hard capsules gelatin capsules
`are most widely
`used. They are formed from a film of a
`gelatin as a base a plasticizer
`comprising
`e.g.
`glycerin or sorbitol
`and
`other addenda.
`
`composition
`
`opacifying
`
`agent dye pigment
`
`Typically gelatin capsules are manufactured
`by dipping
`pins in an aqueous
`gelatin solution having the
`above
`components blended drawing out
`the pins with the
`aqueous gelatin solution adhering to the pins and drying the
`
`gelatin
`
`coats.
`
`2
`
`The precipitates
`to the practical
`
`cially
`
`in the
`
`develop
`
`of the gelling aid give rise to no problem
`usage but are unpleasant
`to look at.
`case of colorless clear
`film the
`as cloud and sometimes cloud spots rather than
`uniform cloud exacerbating
`the outer
`of
`appearance
`sules noticeably.
`
`precipitates
`
`SUMMARY OFTHE INVENTION
`
`5
`
`10
`
`the
`
`invention
`
`a novel
`
`and
`
`An object of
`is to provide
`film of a composition
`improved cellulose ether
`comprising
`a cellulose ether as a base a gelling agent and a gelling aid
`which prevents
`the gelling aid from precipitating out and
`maintains
`favorable
`outer appearance
`
`a
`
`storage.
`
`15
`
`during long-term
`
`It has been found
`that when a film typically a capsule film
`is formed of a composition
`a base
`in which some of
`
`comprising
`
`the
`
`hydrogen
`
`a cellulose ether as
`atoms of cellulosic
`
`hydroxyl
`
`Z0
`
`hydroxyalkyl
`
`are replaced
`by alkyl
`and/or
`groups
`groups
`groups a gelling agent and
`a gelling aid the
`use of the
`cellulose ether having an alkoxyl and
`alkoxyl content of up to 37.6% by weight
`preventing
`precipitation of
`the gelling aid thereby
`taining a favorable
`outer appearance
`even
`
`is effective
`
`for
`
`after
`
`long-term
`
`hydroxy-largely
`main-withstand
`
`US 6649180 B1
`
`and
`
`a
`
`film
`
`to
`
`of gelatin-based
`other properties
`Flexibility
`film. A film with
`depend on the water content of the
`low water
`is too low in impact
`content
`resistance
`encountered
`
`the shocks
`
`upon filling of medica-
`ment. Also as the water content decreases
`by drying during
`film contracts to undesirably
`loosen the cap-to-
`To prevent
`such
`body engagement.
`inconvenience
`gelatin
`capsules must be kept at an optimum water content of about
`13 to 15% by weight. Because of the necessity to have such
`high water content
`to apply the
`capsules to those medicaments which give rise to a
`problem upon contact with water. When the gelatin capsules
`contain a hygroscopic
`capsules gradually
`the strength
`
`storage
`
`the
`
`a
`
`relatively
`
`gelatin
`
`it
`
`is restricted
`
`water content
`
`and hence
`
`inviting the
`
`risk of
`
`fill
`
`the
`
`lose
`
`the
`
`failure.
`
`the
`
`studies have
`
`been made on the
`
`avoid the
`
`Under
`circumstances
`capsules which can
`problems associated with
`water contents and which are applicable
`One exemplary substitute
`whose
`film is formed of
`
`for
`
`to any type of fill.
`the gelatin capsules is capsules
`a cellulose ether
`
`are
`
`hydroxypropyl
`
`25
`
`storage.
`
`invention
`Accordingly the
`formed of a composition
`in which some of
`base
`
`comprising
`the hydrogen
`
`hydroxyl
`
`wherein
`
`and/or
`
`provides a cellulose ether film
`a cellulose ether as a
`atoms of cellulosic
`are replaced
`by alkyl groups
`groups
`groups a gelling agent and
`30 hydroxyalkyl
`a gelling aid
`the total content of alkoxyl and hydroxyalkoxyl
`groups in the cellulose ether
`is up to 37.6% by weight.
`reason why precipitation of the gelling aid
`Although the
`can be restrained by limiting the
`total content of alkoxyl and
`35 hydroxyalkoxyl
`groups in the cellulose ether
`to 37.6% by
`lower
`is not well understood the
`weight
`or
`following
`mechanism is inferred.
`In the cellulose ether used as the
`
`film
`
`base some of
`
`the
`
`hydrogen
`
`atoms of cellulosic
`
`groups
`
`are
`
`45
`
`the
`
`into
`
`the
`
`composition
`a water-soluble
`cellulose ether as a base in which
`comprising
`some of the hydrogen atoms of cellulosic hydroxyl
`groups
`and hydroxyalkyl
`replaced by alkyl
`groups or hydroxy-
`alkyl groups a gelling agent and a gelling aid as disclosed
`Patent No. 2552937. Some
`in Japanese
`capsules based on
`methyl cellulose l-IPMC have
`been
`used in
`capsules of cellulose ether film maintain
`at a low water
`
`practice.
`
`sufficient
`
`These
`
`strength even
`such
`as dissolution are
`
`behaviors
`
`conventional
`
`manufactured
`
`hydroxyl
`replaced by alkyl groups and/or hydroxyalkyl
`40 groups whereby the
`groups are converted-onverted
`hydroxyl
`alkoxyl or hydroxyalkoxyl
`groups. By limiting the
`total
`content of alkoxyl and hydroxyalkoxyl
`groups to 37.6% by
`weight or lower the
`of remaining hydroxyl
`proportion
`groups having high affinity to water becomes relatively
`high
`that
`the water-holding
`so
`force of
`film is effectively
`This ensures that potassium or calcium as
`gelling aid is retained in ion form within the water held in
`the
`
`film effectively
`
`restraining precipitation of
`
`the gelling
`
`improved.
`
`content
`
`and
`
`their
`
`a
`
`equivalent
`
`to
`
`those of
`
`aid.
`
`they can
`capsules. Additionally
`gelatin
`by the so-called
`dipping method as are
`capsules.
`
`be
`
`con-
`
`50
`
`DESCRIPTION OF TI-IE PREFERRED
`EMBODIMENT
`
`ventional
`
`gelatin
`
`However
`
`the
`
`the
`
`assisting
`
`capsules of cellulose ether film suffer
`the problem that
`gelling aid which is blended
`in film formation will precipitate out on the
`surface during long-term storage.
`More particularly in one appropriate
`cellulose ether
`film for
`
`from
`
`for
`
`film
`
`5S
`
`Briefly stated the cellulose ether
`manufactured
`by using a cellulose
`and
`
`a gelling agent
`
`ether as a base blending
`a gelling aid therein and
`the
`
`forming
`
`film of the
`
`invention
`
`is
`
`is
`
`The cellulose ether used as the base is one
`
`in which some
`
`formulation
`
`of the
`
`composition
`
`into
`
`a film.
`
`forming
`
`capsules
`
`carrageenan
`
`for HPMC and
`a potassium or
`form of a
`as a gelling aid in the
`such
`
`used
`
`as
`
`a gelling agent
`calcium ion is incorporated
`water-soluble
`
`compound
`
`as potassium chloride
`
`or
`
`of
`
`the
`
`60
`
`replaced
`
`hydrogen
`by alkyl groups and/or
`whereby alkoxyl and/or hydroxyalkoxyl
`
`atoms
`
`of cellulosic
`
`hydroxyl
`
`groups are
`
`hydroxyalkyl
`
`groups
`
`groups are
`
`created.
`
`calcium chloride.
`
`During
`
`lose ether
`
`film capsules
`
`long-term storage of these cellu-
`the water content of the
`
`film can he
`
`Though not critical
`in which some of the
`
`hydrogen
`
`the cellulose ether
`
`is preferably
`
`one
`
`lowered
`
`the
`
`arc
`
`storage environment
`owing to
`or the water
`replaced by alkyl
`groups
`absorption of the
`fill. Then the potassium or calcium ion as 65 groups or by only
`hydroxyalkoxyl
`the gelling aid will
`re-form potassium chloride or calcium
`is preferred. Of the
`groups methyl
`chloride which precipitates
`out on the
`
`film surface.
`
`hydroxypropyl
`
`or hydroxycthyl
`
`is preferred.
`
`Illustrative
`
`WCDELZ 00029724
`
`atoms of cellulosic
`
`hydroxyl
`and hydroxyalkyl
`groups
`groups. Of
`the alkyl
`
`hydroxyalkyl
`
`groups
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2065 - 2/4
`
`

`

`US 6649180 B1
`
`3
`
`4
`
`and lambda-carrageenan
`
`kappa-carrageenan
`
`and/or
`
`the invention
`recommends
`to use
`iota-carrageenan which have
`
`a
`
`ability.
`
`used
`
`is not critical
`
`and
`
`with the
`
`the
`
`examples of the cellulose ether substituted with these groups
`cellulose HPMC hydrox-
`include hydroxypropyl
`methyl
`cellulose HPC hydroxyethyl
`HEMC and methyl cellulose MC. Of these HPMC is
`
`methyl
`
`cellulose
`
`ypropyl
`
`best suited for capsule film application
`film formation
`and mechanical
`
`strength
`
`because
`
`of effective
`
`at
`
`low water con-
`
`tents.
`
`sponds
`
`to the
`
`the
`
`0.25 to 15
`
`groups abbreviated
`
`fail
`
`are
`
`of the
`
`good gelation
`The amount of
`the gelling agent
`5 may be suitably determined
`in accordance
`type of
`cellulose ether and gelling agent
`intended application of
`film forming method. When
`film and
`capsule shells
`the total content of alkoxyl
`formed by the well-known dipping method
`invention
`According
`for example it
`and hydroxyalkoxyl
`groups created in the cellulose ether by
`is recommended
`to use about 0.05 to 25 parts
`and especially
`above
`is limited to 37.6% by 10 about
`introducing
`substituents
`parts by weight of the gelling agent per 100
`weight or lower. More particularly
`the
`total content corre-
`parts by weight of the cellulose ether.
`Less
`than 0.05 part of
`to the total content of methoxyl groups abbreviated
`the gelling agent may achieve
`a lower degree of gelation and
`as MO groups and hydroxypropoxyl
`a film of a sufficient
`to produce
`thickness to enable shell
`as HPO groups in the case of HPMC the content of HPO
`formation by the dipping method. More than 25 parts
`case of HPC the total content of MO groups
`groups in the
`1s gelling agent may achieve
`a too high degree of gelation and
`groups in the case of HEMC and the
`and hydroxyethoxyl
`solution with
`a dipping
`provide
`content of MO groups in the case of MC. A cellulose ether
`having a total content of such substituents of up to 37.6% by
`is used.
`weight
`
`ammo-tation
`pro-alkoxyl
`potas-limited
`
`a viscosity higher
`to form a uniform coat or film.
`
`than
`
`that
`
`necessity making it difficult
`As the gelling aid used
`substance
`herein
`can
`any
`gelation by the gelling agent may be employed.
`promote
`on the
`type of
`the gelling agent the gelling aid
`Depending
`may be selected from a potassium ion calcium ion
`nium ion and various organic
`compounds which can
`mote gelation by the gelling agent.
`Especially when capsule
`formed using carrageenan
`shells
`as the gelling agent
`potassium ion or calcium ion or both are preferably
`used.
`The potassium ion may be
`blended
`form of
`water-soluble
`compound such
`as potassium chloride
`sium phosphate
`or potassium citrate. The calcium ion may
`in the form of its water-soluble
`be blended
`such
`compound
`as calcium chloride.
`
`The lower
`
`the
`
`20
`
`precipi-
`
`if the
`
`erably
`
`thereto.
`
`shells the total
`
`though
`
`not
`
`30
`
`for
`
`are
`
`in the
`
`a
`
`its
`
`the
`
`the
`
`above-described
`
`it
`
`with
`
`In the
`
`the
`
`35
`
`the
`
`total content of alkoxyl and hydroxyalkoxyl
`becomes the effect of preventing
`groups the better
`of
`the gelling aid. However
`total content of
`and hydroxyalkoxyl
`groups is too low the resulting
`strength or other performance
`film may lose flexibility
`which is inconvenient
`in some applications. Therefore
`the
`total content of alkoxyl and hydroxyalkoxyl
`groups is pref-
`range of 23 to 37.6% by weight
`in the
`Especially when the film is used
`as capsule
`content of alkoxyl
`and hydroxyalkoxyl
`range of 29 to 37% by weight
`in the
`groups is preferably
`finding a good compromise between the film strength and
`effect of preventing
`precipitation of
`the gelling aid.
`cellulose ethers HPMC HPC
`Of
`and MC are
`specified in the Pharmacopoeia of Japan.
`is recommended
`capsule shell
`to
`application
`use
`
`hydroxypropyl
`
`methyl
`
`28
`
`It
`
`methyl
`
`40
`
`45
`
`50
`
`the
`
`pharmacopoeia-specified
`products.
`IIPMC the Pharmacopoeia specifies
`For
`three types
`hydroxypropyl methyl cellulose 2208 hydroxypropyl
`methyl cellulose 2906 and hydroxypropyl
`methyl cellulose
`on the contents of MO and HPO groups.
`2910 depending
`is specified that hydroxypropyl methylcellulose 2208 con-
`19 to 24 wt % of MO groups and 4 to 12 wt % of HPO
`tains
`groups in a total of 23 to 36 wt % hydroxypropyl
`cellulose 2906 contains 27 to 30 wt % of MO groups and 4
`to 7.5 wt % of HPO groups in a total of 31 to 37.5 wt % and
`cellulose 2910 contains
`to 30
`wt % of MO groups and 7 to 12 wt % of HPO groups in a
`total of 35 to 42 wt %. Any of these celluloses may he used
`in the practice of the
`invention
`total content
`as long as the
`of MO and HPO groups is up to 37.6 wt %. Also acceptable
`in which any two or more of these celluloses
`are mixtures
`total content of MO and HPO groups
`are mixed to adjust
`
`Like the gelling agent the amount of the gelling aid used
`is not critical
`in accordance
`and may be suitably determined
`the type of cellulose ether and gelling agent
`intended
`of
`method.
`film and
`film forming
`application
`When capsule shells
`formed by the well-known dipping
`method
`is recommended
`for example it
`to use about
`0.05
`to 25 parts and especially
`about 0.25 to 15 parts by weight
`calculated as ion of the gelling aid per 100 parts by weight
`of the cellulose ether.
`than 0 05 part of the gelling aid
`Less
`
`are
`
`may promote gelation of
`
`to a less extent
`
`and fail
`
`shell
`
`of
`
`the gelling agent
`a film of a sufficient
`thickness to enable
`to produce
`formation
`by the dipping method. More than 25 parts
`the gelling aid may form a gel
`in a dipping
`solution for
`form a film and in addition
`rendering
`
`it
`
`difficult
`
`to
`
`affect
`
`adversely
`
`the disintegration i.e. dissolution after
`film which is inconvenient
`administration of the resulting
`as the capsule shells.
`
`While the cellulose ether
`
`film of
`
`the
`
`invention
`
`contains
`
`the
`
`and the
`
`appropriate
`
`cellulose ether as the base the gelling agent
`gelling aid there may be added
`amounts of
`various additives
`
`agents such as dyes and
`including coloring
`agents and perfumes.
`pigments opacifying
`
`r The cellulose ether
`
`film can
`
`he manufactured
`
`by any
`55 well-known method
`When
`on its
`depending
`application.
`hard capsules are
`formed from the cellulose ether film of the
`film can he prepared in the
`form
`for example the
`invention
`of capsule shells by a well-known dipping method as in the
`manufacture
`of conventional
`In one
`gelatin capsules.
`the cellulose ether gelling agent gelling aid
`60 plary process
`and optional
`additives
`are dissolved
`in water
`in appropriate
`amounts as mentioned
`to form a dipping
`in the dipping
`dipped
`solution
`The solution adhering to the
`the pins is dried to form capsule shells
`caps or bodies on the
`outside surface of
`removed from the
`shells
`upon the
`
`above
`
`solution
`
`pins are
`capsule-forming
`then drawn out of the
`
`solution.
`
`65 outside surface of
`
`the pins
`In this way the
`
`pins.
`
`WCDELZ 00029725
`
`exem-The
`where-known
`
`to that
`
`range.
`
`It
`
`the
`
`is noted that
`the contents of alkoxyl and hydroxyalkoxyl
`groups in cellulose ether can be determined
`by the measure-
`ment method
`described
`in the Pharmacopoeia for
`HPMC HPC and MC specified
`known method for
`
`the
`
`therein and by a well-
`cellulose ethers.
`remaining
`gelling agent used may be selected from among for
`example earragccnan
`tamarind seed polysaccharide
`pectin
`furcellaran gellan gum and mixtures
`thereof. Of
`is especially
`these carrageenan
`preferred because
`high gel strength and exhibits good gelling properties
`of a specific
`ion so that
`it may achieve
`effective
`co-presence
`gelation even when added
`in small amounts. While there
`
`curdlan
`
`it has a
`
`in the
`
`are
`
`three
`
`types
`
`kappa -carragecnan or iota-carragecnan
`
`are
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2065 - 3/4
`
`

`

`US 6649180 B1
`
`5
`
`ether
`film of
`cellulose
`the
`of capsule shells. The shells
`then cut
`are
`to a predetermined
`size and mated to construct hard capsules of the cellulose
`
`is obtained in the
`
`form
`
`invention
`
`ether
`
`film according
`
`to the invention.
`
`6
`
`TABLE 1
`
`Cellulose
`
`mixture of
`
`Total content
`
`of
`
`29102208
`
`OCII3
`
`weight
`
`ratio
`
`OC1II5OII
`
`wt o
`
`Precipitation of KCl
`surface
`on capsule
`40 C. 1 month
`in glass bottle
`
`Comparison
`
`Example 1
`
`Example 2
`Example 3
`Example 4
`
`1000
`
`955
`
`8020
`
`7030
`
`0100
`
`38.1%
`
`37.6%
`
`36.4%
`
`35.5%
`29.4%
`
`o
`precipitates
`look
`whiteite
`lookk
`
`locally
`
`a few orecipitates
`
`but acceptable
`
`outer appearance
`
`no precipitates
`
`no precipitates
`
`no precipitates
`
`5
`
`10
`
`11
`
`As seen
`
`from Table 1 controlling the
`alkoxyl and hydroxyalkoxyl
`groups in the cellulose ether
`37.6% by weight or lower
`is effective
`the
`for preventing
`in these examples from
`gelling aid potassium chloride
`20 precipitating on the film surface.
`
`total content of
`
`to
`
`There
`
`has been described
`
`a cellulose ether
`
`film in which
`
`blended
`
`pared
`
`to
`
`a
`
`re-
`pre-
`
`and
`
`Less
`
`As mentioned
`solution is an aqueous
`above the dipping
`solution having
`amounts of
`cellulose
`the
`predetermined
`gelling agent gelling aid and optional
`additives
`ether
`This aqueous solution is preferably
`therein.
`to 30% by weight
`a concentration
`of 15
`18 to 25% by weight of the cellulose ether.
`especially
`than 15% by weight of the cellulose ether may fail
`to form
`film of a sufficient
`thickness
`to serve as capsule shells
`whereasmore than 30% by weight of the cellulose ether may
`solution with too high a viscosity to
`the dipping
`provide
`form a uniform film. The remaining
`same as
`used
`those customarily
`cellulose ether-based capsules.
`
`conditions may be the
`manufacture
`of
`
`in the
`
`The cellulose ether
`
`film of the invention
`
`is suitable
`
`as the
`
`shell of hard capsules
`
`for use
`
`in the
`
`pharmaceutical
`
`and
`
`the
`
`application
`
`is not
`
`limited
`
`thereto.
`
`health food fields although
`The film may find
`capsules.
`
`use in applications
`
`EXAMPLE
`
`illustration
`
`the
`
`are given below by way of
`of
`invention
`and not by way of limitation.
`
`other
`
`than hard
`
`the cellulose ether used
`as the base has an optimum content
`of alkoxyl and hydroxyalkoxyl
`groups which is effective
`the gelling aid from precipitating out and
`preventing
`
`for
`
`main-25
`stor-Examples
`incorpo-Chemical
`
`taining a favorable outer appearance
`during long-term
`age. The cellulose ether film is thus suitable
`
`hard capsules for use in the pharmaceutical
`
`fields.
`
`as the
`shell of
`and health food
`
`Japanese
`
`Patent Application
`rated herein by reference.
`
`No.
`
`11-106689
`
`is
`
`Hydroxypropyl methyl
`
`in the
`
`Note that
`
`the
`
`35
`
`that
`
`It
`
`departing
`
`compris-2910
`
`cellulose 2910 specified
`60SH by Shin-Etsu
`Pharmacopoeia of Japan Metolose
`Co. Ltd. and hydroxypropyl
`cellulose 30
`methyl
`90SH by Shin-Etsu Chemical Co. Ltd.
`2208 Metolose
`were mixed in the proportion
`shown in Table
`1. Using this
`solution of the
`hydroxypropyl
`methyl cellulose a dipping
`shown below was prepared. By a conventional
`composition
`dipping method size No.
`2 hard capsules of colorless clear
`methyl cellulose film of about
`100 microns
`hydroxypropyl
`thick were prepared therefrom.
`contents of methoxyl and hydroxypropoxyl
`methyl cellulose
`Metolose
`groups in hydroxypropyl
`methyl cellulose 2208 Metolose
`60SH and hydroxypropyl
`90SfI were determined
`by the measurement method pre-
`scribed
`in the Pharmacopoeia of Japan with
`shown below.
`
`some
`been
`embodiments have
`Although
`preferred
`and variations may be made
`described many modifications
`above
`thereto in light of the
`is therefore to be
`teachings.
`understood
`the invention may he practiced otherwise
`from the
`described without
`than as specifically
`scope of the appended claims.
`What
`is claimed is
`1. A hard capsule formed of a film composition
`cellulose as a base a gelling
`ing a hydroxypropyl
`methyl
`40 agent and a gelling aid wherein said hydroxypropyl
`cellulose has a content of hydroxypropoxyl
`groups of at
`4% by weight of the hydroxypropyl
`methyl cellulose and
`and hydroxypropoxyl
`content of methoxyl groups
`combined
`of 23 to 37.6% by weight of
`
`methyl
`
`least
`
`a
`
`groups
`
`the hydroxypropyl
`
`the
`
`results
`
`-UCtotal
`3H OH 9.3%
`
`2910 60SH
`38.1%
`
`-OCH
`
`3 Zt1.8%
`
`2208 90SH
`-OCH3 23.5% -IC3H6OH 5.9% total 29.4%
`
`Dipping Solution Composition
`
`Hydroxypropyl
`
`methyl
`
`cellulose
`
`Ic-carrageenan
`
`gelling
`
`agent
`
`Potassium
`
`chloride gelling aid
`
`20 wt %
`
`0.1 wt %O
`0.1 wt %
`0.052 wt % of K
`
`balance
`
`cellulose.
`
`of
`
`4S
`
`50
`
`55
`
`methyl
`2. The hard capsule formed of a film of claim 1 wherein
`100 parts by weight of
`said
`contains
`composition
`the
`methyl cellulose 0.05 to 25 parts by weight
`hydroxypropyl
`the gelling agent and 0.05 to 25 parts by weight of the
`gelling aid.
`3. The hard capsule formed of a film of claim 1 wherein
`is selected from the
`the gelling agent
`consisting of
`group
`tamarind seed polysaccharide
`carragecnan
`furcellaran gellan gum and mixtures
`4. The hard capsule formed of a film of claim 1 wherein
`the content of methoxyl and hydroxypropoxyl
`groups
`bined is 29 to 37% by weight of the hydroxypropyl
`
`pectin
`
`curdlan
`
`thereof.
`
`methyl
`
`com-water
`mix-surface
`
`bottle
`
`The capsules thus obtained were contained
`in a glass
`and stored at 40 C.
`for one month. The capsule
`was visually observed
`to
`inspect
`thereon. The results
`potassium chloride
`
`of
`precipitates
`shown in Table
`
`are
`
`cellulose.
`
`5. The hard capsule formed of a
`film of claim I or 4
`60 wherein the gelling aid is selected from the group
`consisting
`of a potassium ion calcium ion ammonium ion and
`tures
`thereof.
`
`1.
`
`WCDELZ_00029726
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2065 - 4/4
`
`