US005431917A
`’
`_
`5,431,917
`an Patent Number:
`[19]
`Umted States Patent
`Yamamoto et al. Jul. 11, 1995 [45] Date of Patent:
`
`
`
`
`
`[54] HARD CAPSULE FOR PHARMACEUTICAL
`DRUGS AND METHOD FOR PRODUCING
`THE SAME
`:
`I“"°“‘°’5
`
`.
`
`,_
`-
`feslgluglfi;
`all of, Japan
`
`’
`
`75
`
`T
`
`T
`
`_
`.
`[73] Asslgnee‘
`
`Japan Elanco Company’ Ltd" Osaka’
`5393“
`[21] Appl. No.: 114,351
`[22] Ffled:
`Se?‘ 1’ 1993
`
`[62]
`
`_
`_
`Related U'S' Apphcatmn Data
`Division of Ser. No. 957,892, Oct. 8, 1992, Pat. No.
`5,264,223.
`Int. Cl.6 .............................................. .. A61K 9/48
`[51]
`[52] U.S. Cl. .................................... 424/451; 424/452;
`424/453; 424/455; 514/952
`[53] Field of Search ............. .. 424/451, 452, 453, 454,
`424/455, 456; 514/774, 781, 779
`References Cited
`
`[56]
`
`U-S- PATENT DOCUMENTS
`4,138,013 2/1979 Okajima
`.. 206/528
`
`4,917,885 4/1990 Chiba et al. ..
`424/78
`
`FOREIGN PATENT DOCUMENTS
`474310 2/1972 Japan .
`61-100519 5/1986 Japan .
`62~26606O ll/1987 Japan .
`Primary Examiner—Thurman K. Page
`Assistant Examz'rzer—James M. Spear
`Attorney, Agent, or Firm—Birch, Stewart, Kolasch &
`Birch
`ABSTRACT
`[57]
`A hard capsule for pharmaceutical drugs comprises a
`water-soluble cellulose derivative as a capsule base, a
`gelatinizing agent and an auxiliary for gelation. The
`hard capsule is prepared by preparing an aqueous solu-
`tion of a capsule base containing a water-soluble cellu-
`1°56 derivative’ 3 gelatinizlng agent and an auxiliary for
`ge1ation._immersing a capsule molding pin in the aque-
`ous solution of the capsule base, subsequently drawmg
`out the molding pin from the aqueous solution of the
`capsule base, subjecting the aqueous solution of the
`capsule base attached to the outer surface of the mold-
`ing pin to gelate at room temperature, and forming a
`capsule film on the outer surface of the molding pin.
`
`11 Claims, No Drawings
`
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`

`1
`
`5,431,917
`
`HARD CAPSULE FOR PHARMACEUTICAL
`DRUGS AND METHOD FOR PRODUCING THE
`SAME
`
`This application is a divisional of application Ser. No.
`07/957,892, filed on Oct. 8, 1992, the entire contents of
`which are hereby incorporated by reference, now U.S.
`Pat. No. 5,264,223.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention relates to a hard capsule for
`pharmaceutical drugs, specifically a hard capsule of a
`lower water content and with no use-of known gelatin
`as the base material. More specifically, it relates to a
`hard capsule for pharmaceutical drugs using a water-
`soluble cellulose derivative as the base, and a method
`for producing the same.
`2. Prior Art
`
`As has been known, hard capsules for pharmaceutical
`drugs are molded from film compositions, wherein gela-
`tin is generally used as the base material to which are
`added a plasticizer such as glycerin and sorbitol, and
`optionally, an opaquer, a dye or pigment. Such capsules
`generally contain about 10 to 15% by weight of water in
`the capsule film thereof.
`If the water content in the capsule film decreases to
`be less than 10% by weight, the plasticity of the film is
`lost, resulting in the distinctive deterioration of the
`impact resistance during the filling process of drugs into
`the capsules with the outcome of no endurability of the
`use thereof. Irrespective of emptiness or fillingness of
`drugs, the film shrinks when the water content in the
`film is decreased during the storage of the capsules,
`inevitably involving the loosening of the engagement of
`the caps with the capsule bodies over time. Therefore, it
`is essential
`that such known gelatin hard capsules
`should contain a given amount of water as has been
`described above.
`
`However, such gelatin hard capsules may induce
`disadvantages including the reduction of the titers, dete-
`rioration and color change of drugs filled therein and
`the insolubility of the capsule film, because the drugs
`are decomposed by the water contained in the capsule
`film if the drugs filled therein are readily hydrolyzed or
`two or more drugs with interactive activity to each
`other are contained therein.
`In order to overcome these drawbacks, there have
`been made a variety of improvement and propositions
`over hard capsules for pharmaceutical drugs. For exam-
`ple, Japanese Patent Publication No. 47-4310 discloses a
`method for producing a hard capsule comprising using
`as a base material a water-soluble cellulose ether which
`is produced by substituting a part or all of the hydroxyl
`groups of cellulose with an alkyl group or a hydroxyal-
`kyl group, immersing a molding pin in the water-soluble
`cellulose ether solution, thereby forming a capsule film.
`Japanese Patent Laid-Open Nos.
`61-100519
`and
`62-266060 disclose a method for producing a hard cap-
`sule, comprising compounding the above-said water-
`soluble cellulose ether with polyvinyl alcohol (PVA),
`and yielding a hard capsule from such water-soluble
`immersing solution.
`However, these capsules for pharmaceutical drugs
`are produced by immersing a molding pin in an immers-
`ing solution of the water-soluble cellulose derivative as
`the base material, heating just the molding pin or the
`
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`2
`film attached to the pin thereby effecting gelation prior
`to molding, so that the immersing solution of the base
`material is never gelatinized but the solution is then
`fallen down from the molding pin if heating is not done
`sufficiently. Thus, capsule films practically cannot be
`obtained. If the heating temperature is too high, disad-
`vantages such as wrinkle induction into the films may be
`caused during gelation.
`In the latter case, a slight
`amount of the gel is solubilized into water when the
`water-soluble cellulose derivative attached to the mold-
`
`ing is immersed in water pin at a higher temperature for
`gelation. Therefore, it is difficult to obtain a uniform
`film, and such film may frequently develop cracking
`during the detachment of the molded article,
`i.e. the
`capsule film after drying, from the molding pin, due to
`the lower jelly strength thereof. In any case, it is diffi-
`cult to obtain a hard capsule for pharmaceutical drugs
`with a lower water content in practical sense. Further,
`specified apparatus and procedures are required for
`practicing these capsule production methods, so that
`the most commonly known capsule manufacturing ap-
`paratus for immersion and molding of the conventional
`gelatin capsules cannot be used as it is.
`SUMMARY OF THE INVENTION
`
`Under such circumstances, the present invention has
`been proposed, and intends to overcome the drawbacks
`and disadvantages of the hard capsules comprising the
`water-soluble cellulose derivative described above.
`An object of the present invention is to provide a
`hard capsule for pharmaceutical drugs having no fragil-
`ity under the condition of a lower humidity due to the
`lower water content in equilibrium in the capsule film
`thereby preventing the cracking of the capsule film.
`The drugs filled therein can be prevented from deterio-
`rating because of the lower water content. Another
`object of the present invention is to provide a method
`for producing such a hard capsule.
`According to the present invention, by using a water-
`soluble cellulose as a base material, and adding a gelati-
`nizing agent and an auxiliary for gelation thereto, the
`gelation can be achieved at room temperature.
`Thus, the present invention provides a hard capsule
`for pharmaceutical drugs comprising a water-soluble
`cellulose derivatives as a base material, a gelatinizing
`agent and an auxiliary for gelation.
`The present invention also provides a method for
`producing a hard capsule for pharmaceutical drugs,
`comprising preparing an aqueous solution of a capsule
`base containing a water-soluble cellulose derivative, a
`gelatinizing agent and an auxiliary for gelation, immers-
`ing a capsule molding pin in the aqueous solution of the
`capsule base, subsequently drawing out the molding pin
`from the aqueous solution of the capsule base, subject-
`ing the aqueous solution of the capsule base attached to
`the outer surface of the molding pin to gelate at room
`temperature, and forming a capsule film on the outer
`surface of the molding pin.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`For water-soluble cellulose derivatives to be used in
`the present invention, it is preferred a cellulose ether in
`which some or all of hydroxyl groups thereof are substi-
`tuted with a lower alkyl group and/or a hydroxyl-
`lower alkyl group. Examples of the cellulose deriva-
`tives include hydroxypropylmethyl cellulose, hydroxy-
`ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-
`
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`5,431,917
`
`3
`methyl cellulose and the like. Among them, hydroxy-
`propylmethyl cellulose is the most preferable in terms
`of film molding and mechanical strength at a condition
`of a lower water content.
`Examples of the gelatinizing agent to be used in the
`present invention include carrageenan, polysaccharide
`of tamarind seed, pectin, curdlan, gelatin, furcellaran,
`agar, and the like. Among them, carrageenan is specifi-
`cally preferred because it has a higher gel strength and
`shows excellent gelatinization property under the coex-
`istence of a specific ion described later, and thus, it can
`be added at a small amount for use. The carrageenan
`includes three types, i.e. kappa-carrageenan, iota-car-
`rageenan, and ramda-carrageenan. In accordance with
`the present invention, kappa- and iota-carrageenan hav-
`ing gelation ability can be preferably used.
`For the auxiliary for the gelation of a gelatinizing
`agent, a water-soluble compound having potassium ion,
`ammonium ion or calcium ion including potassium chlo-
`ride, potassium phosphate, calcium chloride, ammo-
`nium chloride and the like may be illustrated for kappa-
`carrageenan, while water-soluble compounds having
`calcium ion including calcium chloride and the like may
`be illustrated for iota-carrageenan.
`As to the concentration of the immersing solution, i.e.
`the aqueous solution of the capsule base, during the
`molding or producing of the hard capsule for pharma-
`ceutical drugs according to the present invention, a
`water-soluble cellulose derivative, a gelatinizing agent,
`and an auxiliary for gelation may be contained in ranges
`of 5 to 25% by weight, 0.1 to 0.5% by weight and 0.01
`to 0.5% by weight, respectively.
`If the concentration of the water-soluble cellulose
`derivative in the aqueous solution of the capsule base is
`less than 5% by weight, it is difficult to form a capsule
`film of a sufficient thickness. If the concentration of the
`water-soluble cellulose derivative exceeds 25% by
`weight, the jelly viscosity of the aqueous solution in-
`creases, resulting in the difficult molding of a uniform
`capsule film by the immersion methods. Therefore, it is
`particularly preferred that
`the concentration of the
`water-soluble cellulose derivative is 13 to 17% by
`weight.
`If the concentration of the gelatinizing agent is less
`than 0.1% by weight, the aqueous solution of the cap-
`sule base attached to a molding pin‘ is not formed into
`gel, thus leading to the detachment thereof from the pin.
`If the concentration of the gelatinizing agent exceeds
`0.5% by weight, the jelly viscosity of the aqueous solu-
`tion increases, resulting in not only the difficult molding
`of a uniform capsule film by the immersion method but
`also the ready occurrence of gelatinized films on the
`wall face of the container in which the aqueous solution
`of the capsule base is contained, thereby causing trou-
`bles during the molding of a capsule film. Thus, the
`most appropriate concentration of the gelatinizing
`agent is 0.15 to 0.3% by weight.
`As to the concentration of the auxiliary for gelation,
`the use thereof less than or above the range described
`above brings about disadvantages as in the case of the
`gelatinizing agent. Therefore,
`the most appropriate
`concentration of such auxiliary for gelation is 0.05 to
`0.2% by weight.
`In accordance with the present. invention as in the
`case of the known hard capsules for pharmaceutical
`drugs, a coloring agent such as dye and pigment, an
`opaquer, a flavor and the like may be added to the
`aqueous solution depending on the need.
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`4
`The hard capsule for pharmaceutical drugs of the
`present invention can be produced according to the
`conventional immersion molding method as in the case
`of the known gelatin hard capsules. That is, a water-sol-
`uble cellulose derivative, a gelatinizing agent and an
`auxiliary for gelation, furthermore optionally a coloring
`agent, an opaquer, a flavor and the like, are com-
`pounded together with water to prepare an aqueous
`solution,
`in which an immersion molding pin is im-
`mersed to obtain a hard capsule according to the con-
`ventional method. The temperature of the aqueous solu-
`tion of the capsule base or the immersion solution is
`preferably adjusted to 48° to 55° C., especially to 50° to
`52° C. If the temperature of the immersion solution is
`outside of the range, the jelly viscosity of the immersion
`solution is changed slightly, with the result of no good
`attachment of the immersion solution to the molding pin
`during immersion molding. Thus, a uniform capsule
`film is difficult to obtain. Through subsequent processes
`comprising drawing out the immersion molding pin
`from the immersion solution, drying and detaching
`(removing) the film from the molding pin and cutting
`out the film, a hard capsule of a given size is obtained
`following the same processes as in the production of the
`known gelatin hard capsules by immersion method. In
`this case, the time requiring for the gelation of the im-
`mersion solution on the outer surface of the immersion
`
`molding pin is slightly longer, i.e. 30 to 60 seconds than
`that in the case of gelatin base which is 4 to 7 seconds.
`The thus obtained hard capsule film contains 5 to 25
`parts by weight, more preferably 13 to 17 parts by
`weight of the water-soluble cellulose derivative, 0.1 to
`0.5 parts by weight, more preferably 0.15 to 0.3 parts by
`weight of the gelatinizing agent and 0.01 to 0.5 parts by
`weight, more preferably 0.05 to 0.2 parts by weight of
`the auxiliary for gelation. More specifically, the film
`contains 92 to 94% by weight of the water-soluble cel-
`lulose derivative, 0.9 to 1.2% by weight of the gelatiniz-
`ing water and 0.5 to 0.6% by weight of the auxiliary for
`gelation. The water content in the capsule film is usu-
`ally in a range of 4 to 6% by weight of the capsule film.
`According to the present invention, the gelation of
`the aqueous solution or immersion solution can be car-
`ried out at room temperature, typically 22.5” to 25.5” C.
`without specific heating, and can form a flexible capsule
`film having a lower water content.
`EXAMPLES
`
`The present invention will now be described in de-
`tails with reference to examples hereinbelow, although
`the present invention is not restricted thereto.
`
`Example 1
`Into 19.55 liter of distilled water at about 70° C. was
`added and dissolved 18.4 g of potassium chloride (the
`concentration of the-auxiliary for gelation; 0.08% by
`weight), followed by addition of 39.1 g of kappa-car-
`rageenan (the concentration of the gelatinizing agent;
`0.17% by weight), which was dissolved under stirring.
`Into the solution was introduced 3.45 kg of hydroxy-
`propylmethyl cellulose (the concentration of the cellu-
`lose derivative; 15% by weight) under stirring, which
`was then dispersed in a hot bath. Then, the temperature
`of the solution was decreased down to 50° C., followed
`by dissolution of hydroxypropylmethyl cellulose under
`stirring, which was then left to stand for 7 hours prior to
`defoaming.
`
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`5,431,917
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`5
`The immersion solution (aqueous solution of the cap-
`sule base) thus prepared was charged into a known
`gelatin capsule production system based on immersion
`method, and while keeping the temperature of the im-
`mersion solution at 50° to 52° C., a hard capsule (Size
`No. 2) was obtained according to the conventional
`method. The following tests were conducted for evalu-
`ating the resulting capsule.
`
`6
`condition defined by Japanese Pharmacopoeia, using
`distilled water heated to 37°i-1° C.
`The results are shown in Table 3. The results indicate
`
`that the hard capsule of the present invention clearly
`shows a slower solubility than the gelatin hard capsule,
`but achieves the solubilization within 10 minutes as
`
`defined by the Pharmacopoeia, so no trouble may be
`caused thereby.
`
`TABLE 3
`,
`S°1“bm”‘i°“ “me
`minimum—maximum
`7 27 -9 45
`,
`,,
`,
`,,
`
`Average
`8 16
`,
`,,
`
`3'53"
`
`3'26"—4’45”
`
`,
`’
`Capsule
`Invention
`.
`pmduc,
`Control
`Product
`(Capsule number subjected to the test; 5)
`
`10
`
`20
`
`35
`
`Finger _ pressure
`.35,
`
`Test _ 1
`Assessment of Cracking of Empty Capsules
`_
`_
`_
`.
`.
`.
`The hard capsule obtained in the Example of the
`present invention and a gelatin hard capsule as a control
`capsule were left to stand under the condition of 12% 15
`RH for 4 days at 25° C. to decrease the water content in
`the individual films to 1.1% and 8.8%, respectively.
`Separately, the same hard capsules were dried at 105°
`C. for 2 hours to adjust the water content in the individ-
`ual films to 0%. By further subjecting the resulting
`samples to drop-weight impact test (wherein a 49.7 g
`weight is dropped down from the height of 20 cm) and
`The hard capsule obtained in the Example of the
`finger-pressure test, the state of cracking was observed.
`present invention and the control gelatin hard capsule
`The results are shown in Table 1. The results clearly
`were filled with corn starch, and then subjected to the
`indicate that the hard f3aPs“1° Of the Present i“V°“ti°n 25 disintegration test under the standard condition defined
`does not crack so readily as the gelatin hard capsule.
`by Japanese Pharmacopoeia, using a first Solution
`
`TABLE 1
`heated to 37°:1° C.
`_
`_
`_
`Drop _ weight
`As shown in Tables 4 and 5, the disintegration of the
`imam W
`hard capsule of the present invention is a bit slower than
`number of
`Wm,
`numb“ of
`water
`30 that of the control capsule, but the whole contents
`cracking
`Content of
`Cracking
`content of
`thereof were completely released within 3 to 5-minutes.
`
`C“P5“1°
`P“ 50
`°“P‘“‘°
`P" 10
`°“P‘“‘°
`Thus, it is confirmed thatvthe hard capsule ofthe present
`Invention
`0
`1.1%
`0
`0%
`invention is a hard capsule satisfactory for practical use.
`product
`Control
`46
`8.8%
`10
`0%
`
`product
`
`Test - 4
`
`Assessment of Disintegration Property
`
`TA
`
`BLE 4
`Cagule ogning time
`Average
`minimum—ma.ximum
`2'43"
`1'47"—4'14"
`,
`"
`0'57’ —l’08
`
`Test ' 2
`Assessment of Water Content in Equilibrium of Capsule 40
`Film
`
`Capsule
`Invention
`Product
`Control
`product
`
`1'0 ”
`
`The hard capsule obtained in the Example of the
`present invention and the control gelatin hard capsule
`were left to stand for 10 days under the condition of a 45
`humidity of 43% RH and a temperature of 25° C. After
`.
`.
`it was confirmed that the equilibrium was achieved, the
`water content in the capsule films was determined by
`.
`.
`.
`the method based on the loss in weight on drying, to
`examine the water content in equilibrium of the capsule 50
`films
`_
`_
`_
`The results are shown in Table 2. The results indicate
`that the hard capsule of the present invention clearly
`has a lower content than the gelatin hard capsule and
`thus is a lower water content capsule.
`TABLE 2
`water content in
`equilibrium
`4.3%
`139%
`
`55
`
`60
`
`Capsule
`Invention product
`Comm, product
`
`Test - 3
`
`Assessment of Solubility of Empty Capsules
`
`65
`
`The hard capsule obtained in the Example of the
`present invention and the control gelatin hard capsule
`were subjected to solubility test under the standard
`
`(Capsule numbc, 5.3,,-,c.,_.d .0 me R5,, 6)
`
`TABLE 5
`
`Capsule
`'
`
`contents
`T"“° f°’ ’°‘°“5° °°'“P1°“°“ °f
`.
`.
`.
`Average
`minimum—ma.ximum
`H
`_
`H
`I
`U
`I
`3 45
`2 5° '4 55
`2'03"
`l'58”—2'lS”
`
`Control
`product
`(Capsule number subjected to the test; 6)
`
`The hard capsule for pharmaceutical drugs of the
`present invention contains as the base material a water-
`soluble cellulose derivative and further a gelatinizing
`agent and an auxiliary for gelation, and has the follow-
`mg features’
`(1) A hard capsule of the lower content can be ob-
`tained, and furthermore, a capsule for pharmaceutical
`drugs with the film having an excellent mechanical
`strength can be provided.
`(2) Due to the lower water content in equilibrium in
`the capsule film, pharmaceutical agents which are likely
`to be subjected readily to adverse effects of water can
`be filled in the hard capsule as they are, so that the
`formulation thereof into a capsule is easily done.
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`7
`(3) Insolubility of the capsule film through the reac-
`tion with an aldehyde group or a carbonyl group never
`occurs.
`
`5,431,917
`
`(4) Because a gelatinizing agent and an auxiliary for
`gelation are used as auxiliary components of the base
`material, the hard capsule can be provided in inexpen-
`sive manner by using a hard capsule production system
`based on immersion method with no use of specified
`apparatuses or works.
`What is claimed is:
`
`1. A method for producing a hard capsule for phar-
`maceutical drugs, comprising
`preparing an aqueous solution of a capsule base con-
`taining a water-soluble cellulose derivative in the
`form of a cellulose ether in which some or all of the
`
`hydroxyl groups thereof are substituted with an
`alkyl group and/or a hydroxyalkyl group, a gelati-
`nizing agent and an auxiliary for gelation,
`immersing a capsule molding pin in the aqueous solu-
`tion of the capsule base,
`subsequently drawing out the molding pin from the
`aqueous solution of the capsule base,
`subjecting the aqueous solution of the capsule base
`attached to the outer surface of the molding pin to
`gelation at a temperature of 22.5° C. to 25.5° C.,
`and
`.
`forrggilfinz ‘gilgsule mm on the Outer Surface of the
`wherein the solution temperature of the aqueous solu-
`tion of the capsule base is 48° C. to 55° C.
`2. The method for producing a hard capsule accord-
`ing to claim 1, wherein the solution temperature of the
`aqueous solution of the capsule base is 50° C. to 52° C.
`3. The method for producing a hard capsule accord-
`ing to claim 1, wherein 5 to 25 parts by weight of the
`water-soluble cellulose derivative, 0.1 to 0.5 parts by
`weight of the gelatinizing agent and 0.01 to 0.5 parts by
`
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`8
`weight of the auxiliary for gelation are used in prepar-
`ing the aqueous solution of the capsule base.
`4. The method for producing a hard capsule accord-
`ing to claim 1, wherein the cellulose ether is selected
`from the group consisting of hydroxypropylmethyl
`cellulose, hydroxyethyl cellulose, hydroxypropyl cellu-
`lose, and hydroxyethylmethyl cellulose.
`5. The method for producing a hard capsule accord-
`ing to claim 1, wherein the cellulose ether is hydroxy-
`propymethyl cellulose.
`6. The method for producing a hard capsule accord-
`ing to claim 1, wherein the gelatinizing agent is carra-
`geenan and the auxiliary for gelation is a water-soluble
`compound containing potassium ion, ammonium ion or
`calcium ion.
`7. The method for producing a hard capsule accord-
`ing to claim 6, wherein the carrageenan is selected from
`the group consisting of kappa-carrageenan,
`iota-car-
`rageenan and ramda-carrageenan.
`8. The method for producing a hard capsule accord-
`ing to claim 3, wherein 13 to 17 parts by weight of
`water-soluble cellulose derivative is used in preparing
`the aqueous solution of the capsule base.
`9. The method for producing a hard capsule accord-
`ing to claim 3, wherein 0.15 to 0.3 parts by weight of the
`gelatinizing agent is used in preparing the aqueous solu-
`tion of the capsule base.
`.
`10. The method for producing a hard capsule accord-
`ing to claim 3, wherein 0.05 to 0.2 parts by weight ofthe
`auxiliary for gelation is used in preparing the aqueous
`solution of the capsule base.
`11. The method for producing a hard capsule accord-
`ing to claim 1, wherein the gelatinizing agent is selected
`from the group consisting of carrageenan, polysaccha-
`ride of tamarind seed, pectin, curdlan, gelatin, furcella-
`ran and agar, and the auxiliary for gelation is a water-
`soluble compound containing potassium ion, ammo-
`nium ion or calcium ion.
`*
`*
`*
`*
`*
`
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`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2022 - 5/5
`
`