United States Patent [19]
`Yamamoto et al.
`
`US005756123A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,756,123
`May 26, 1998
`
`[54] CAPSULE SHELL
`
`[75] Inventors: Taizo Yamamoto. Osaka; Seinosuke
`Matsuura. Souraku-gun; Kazukiyo
`Akai. Kashihara. all of Japan
`
`[73] Assignee: Japan Elanco Co., Ltd.. Osaka. Japan
`
`[21] Appl. No.: 797,622
`[22] Filed:
`Feb. 7, 1997
`
`Related US. Application Data
`
`[63] Continuation-impart of Ser. No. 548,265, Oct 25, 1995,
`abandoned.
`Foreign Application Priority Data
`
`[30]
`
`Dec. 1, 1994
`JP
`Dec. 16,1994 [1P1
`6
`
`J
`12;:
`
`6-323581
`6333965
`
`2/1991 Muto et a1v ............................. .. 29/451
`4,993,137
`7/1991 Muto et a1. ....... ..
`425/272
`5,032,074
`5,264,223 11/1993 Yamamoto et a1.
`424/451
`5,431,917
`7/1995 Yamamoto et a1. .................. .. 424/451
`
`FOREIGN PATENT DOCUMENTS
`
`4/ 1994
`0592130
`European Pat. O?'. .
`6/1970
`2029402
`Germany .
`47-4310 2/1972
`Japan .
`61-100519
`5/1986
`Japan .
`62-266060 11/1987 Japan.
`3-279325 12/1991 Japan.
`Primary ExaminerwAmy Hulina
`Attorney, Agent, or Firm—Birch. Stewart. Kolasch & Birch.
`LLP
`
`ABSTRACT
`[57]
`A capsule shell comprising 79.6—98.7% by weight of a
`,
`hydroxypropyhnethyl cellulose. 0.03-0.5% by weight of
`carrageenan. and 0.l4—3.19% by weight of a potassium ion
`
`Int. Cl- . . . . .
`
`. . . . . . . . . . . . . . . . . . . . . . . . ..
`
`and/or 3
`
`is prepared by drying an solution comp?g
`
`[52] US. Cl. ........................ .. 424/451; 424/452; 424/455;
`424/494
`[58] Field of Search ................................... .. 424/451. 494,
`424/452, 455
`
`[5 6]
`
`References Cited
`
`U'S‘ PAW DOCUMENTS
`
`3,617,588 11/1971 Langman .............................. .. 264/486
`4,001,211
`1/1977 Sarkar ..................................... .. 536/84
`
`ing 18-28% by weight of hydroxypropylmethyl cellulose
`whose 2% aqueous solution has a viscosity of 2.4-5.4
`centistokes at 20° C. as a base. 0.01-0.09% by weight of
`carrageenan as a gelling agent. and ODS-0.6% by weight of
`a potassium ion and/or calcium ion as a co-gelling agent.
`The capsule shell exhibits disintegrating ability equivalent to
`gelatin shells without degrading that ability even under
`special conditions containing much calcium ions.
`
`8 Claims, 2 Drawing Sheets
`
`
`
`PERCENT LEACHING
`
`FIRST FLUID
`
`' GELATIN CAPSULE
`
`a INVENTIVE CAPSULE
`
`40
`
`510
`
`6'0
`
`1‘0
`
`60 do
`
`TIME , MIN.
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 1
`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 1 of 2
`
`5,756,123
`
`FIG.1 (A)
`
`FIG.1 (B)
`
`F|G.1 (C)
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 2
`
`

`

`US. Patent
`
`May 26, 1998
`
`Sheet 2 of 2
`
`5,756,123
`
`FIG .2
`
`FIRST FLUID
`
`° GELATIN CAPSULE
`
`o INVENTIVE CAPSULE
`
`100 -
`
`
`
`PERCENT LEACHING
`
`0
`
`10
`
`2'0
`
`I
`
`30 4b
`
`T
`
`so so 70
`
`I
`
`so
`
`T
`
`90
`
`TlME,MlN.
`
`FIG.3
`
`SECOND FLUID
`
`1001
`
`
`
`PERCENT LEACHING
`
`' GELATIN CAPSULE
`° ‘NVENTIVE CAPSULE
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 3
`
`

`

`5,756,123
`
`2
`molding pins. In either of these methods. it is di?icult to
`produce capsule shells having a low water content.
`Additionally. these methods require a special apparatus or
`operation of heating the molding pins or immersing the
`molding pins with cellulose coating in hot water.
`Unfortunately. it is impossible to utilize the current manu
`facturing apparatus for gelatin capsules without a substantial
`change.
`To solve these problems. the applicant previously pro
`posed in US. Pat. No. 5.264.223 a medical hard capsule
`having a low water content which is shaped from a capsule
`shell composition comprising a water-soluble cellulose
`derivative as a base. a gelling agent and a co-gelling agent.
`This capsule has equivalent performance to conventional
`gelatin capsules and can be produced by utilizing the current
`manufacturing apparatus for gelatin capsules as such.
`However. through the continuing research works of the
`inventors. it was found that this capsule is inferior to
`conventional gelatin capsules in solubility or disintegrating
`ability under certain conditions. More particularly. one pre
`ferred formulation of this capsule shell composition uses
`hydroxypropylmethyl cellulose as a water-soluble cellulose
`derivative base. carrageenan as a gelling agent and a potas
`sium ion as a co-gelling agent. Shells of this preferred
`formulation take a long time to disintegrate under special
`conditions where calcium ions are present. Then. if a capsule
`of this composition ?lled with drugs is administered after
`having a food or beverage containing much calcium ions. for
`example. milk. then the capsule is retarded from disintegra
`tion. Then the drugs are not fully released or absorbed within
`a proper time. failing to fully exert their pharmaceutical
`effect. Therefore. it is desired to further improve the prop
`erties of the capsule based on a water-soluble cellulose
`derivative.
`
`30
`
`35
`
`1
`CAPSULE SHELL
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`This application is a continuation-in-part of copending
`application Ser. No. 08/548265 ?led on Oct. 25. 1995 the
`entire contents of which are hereby incorporated by refer
`ence.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`This invention relates to a capsule shell for forming
`medical hard capsules. More particularly. it relates to such a
`capsule shell using hydroxypropylmethyl cellulose as a
`base.
`2. Prior Art
`Medical hard capsules are conventionally formed from
`compositions comprising gelatin as a base with a plasticizer
`such as glycerin and sorbitol. opaque agent. dye. pigment
`and other additives blended therein. After molding pins are
`immersed in a gelatin aqueous solution with such compo
`nents blended and withdrawn therefrom. the gelatin solution
`adhering to the pins is dried. obtaining capsule shells.
`The shell-forming compositions based on gelatin have the
`problem that the plasticity and other properties of shells
`largely depend on a water content. With a too low water
`content. shells are less resistant against shocks as encoun
`tered on drug ?lling. Also. as the water content lowers due
`to drying during shelf storage. shells can contract to loosen
`the cap-body engagement of capsules.
`For gelatin capsules. it is thus critical to maintain the
`water content constant. However. since the optimum Water
`content is as high as about 10 to 15% by weight. there is a
`likelihood that the water in the capsule shell can affect the
`drug ?ll to lower its titer. degrade its quality. and change its
`color. and inversely. the capsule shell can be insolubilized if
`the drug ?ll is susceptible to hydrolysis or is a mixture of
`interacting ingedients. Therefore. there is a demand to have
`capsules based on a substance other than gelatin so that the
`material of capsules can be selected in accordance with a
`particular drug ?ll.
`Medical capsules using a base other than gelatin are
`known in the art. Typically. capsules based on water- soluble
`cellulose derivatives were proposed. For example. Japanese
`Patent Publication (JP-B) No. 4310/1972 discloses a method
`for preparing capsules based on water-soluble cellulose
`ether from an aqueous solution of water-soluble cellulose
`ether. Japanese Patent Application Kokai (JP-A) Nos.
`100519! 1986 and 266060/ 1987 discloses to prepare capsules
`from an aqueous solution of water-soluble cellulose ether
`and polyvinyl alcohol (PVA) blended therewith.
`The former shell-forming method involves the steps of
`immersing molding pins in an aqueous solution of water
`soluble cellulose derivative and heating the pins and hence.
`the coating adhered thereto for gelation. The coating is not
`gelled or solidi?ed and can fall down from the pins if heating
`is insuf?cient. The coating can be wrinkled during gelation
`if the heating temperature is too high. In the latter method of
`preparing capsules from an aqueous solution of water
`soluble cellulose derivative and PVA. the water-soluble
`cellulose derivative adhered to the molding pins is gelled by
`irmnersing it in hot water. Some of the gelled coating can be
`dissolved in the hot water at this point. hindering formation
`of uniform shells. In addition. due to low jelly strength. the
`dried shells can be often cracked upon removal from the
`
`SUlVIlVIARY OF THE INVENTION
`
`- An object of the present invention is to provide a capsule
`shell based on a water-soluble cellulose derivative which
`does not degrade its disintegration ability under special
`conditions where much calcium ions are present. that is.
`exerts its performance under any condition.
`In connection with the capsule shell composition com
`prising hydroxypropylmethyl cellulose (to be abbreviated as
`HPMC. hereinafter) as a water-soluble cellulose derivative
`base. carrageenan as a gelling agent. and a potassium ion as
`a co-gelling agent wherein the shapability of IIPMC is
`improved by blending carrageenan as a gelling agent and
`gelling this carrageenan with the co-gelling agent. We found
`that the disintegration ability of this composition is degraded
`in the presence of calcium ions because the calcium ions
`inhibit dissolution of the carrageenan blended in the com
`position as the gelling agent.
`Continuing research works. we have found that degrada
`tion of the disintegration ability due to the presence of
`calcium ions is restrained by using a larger proportion of a
`EPMC having a relatively low viscosity as a base. increasing
`the amount of the co-gelling agent blended. and minimizing
`the proportion of carrageenan gelling agent within a su?i
`cient range to insure good shapability. More particularly. by
`using a HPMC having a viscosity of 2.4 to 5.4 centistokes
`as measured in a 2t aqueous solution at 20° C.. blending the
`HPMC with carrageenan as a gelling agent and a co-gelling
`agent in the water to form an aqueous solution comprising
`18 to 28% by weight of the HPMC. 0.01 to 0.09% by weight
`of carrageenan and 0.05 to 0.6% by weight of a co-gelling
`agent. and drying the aqueous solution to form a capsule
`
`45
`
`50
`
`55
`
`65
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 4
`
`

`

`5.756.123
`
`3
`shell comprising 79.6 to 98.7% by weight of the HPMC.
`0.03 to 0.5% by weight of carrageenan. and 0.14 to 3.19%
`by weight of a co-gelling agent. there is obtained a capsule
`shell which maintains satisfactory disintegration ability even
`in the presence of calcium ions and exerts performance
`equivalent to conventional gelatin capsules. A hard capsule
`for pharmaceutical drugs of the capsule shell can be securely
`and e?iciently produced according to the conventional
`immersion molding.
`Accordingly. the present invention provides a capsule
`shell comprising 79.6 to 98.7% by weight of a
`hydroxypropyl-methyl cellulose. 0.03 to 0.5% by weight of
`carrageenan. and 0.14 to 3.19% by weight of a potassium ion
`and/or a calcium ion. said capsule shell being prepared by
`drying an aqueous solution comprising 18 to 28% by weight
`of hydroxypropyl-methyl cellulose having a viscosity of 2.4
`to 5.4 centistokes as measured in a 2% aqueous solution at
`20° C. as a base. 0.01 to 0.09% by weight of carrageenan as
`a gelling agent. and 0.05 to 0.6% by weight of at least one
`ion selected ?'om the group consisting of potassium and
`calcium ions as a co-gelling agent.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIGS. 1(A). 1(3) and 1(C) schematically illustrate the
`gelation mechanism of carrageenan.
`FIG. 2 is a graph showing the percent leaching of the
`contents from a capsule of Example 1 and a conventional
`gelatin capsule when they were immersed in the ?rst solu
`tion prescribed in the Pharmacopoeia of Japan.
`FIG. 3 is a graph showing the percent leaching of the
`contents from a capsule of Example 1 and a conventional
`gelatin capsule when they were immersed in the second
`solution prescribed in the Pharmacopoeia of Japan.
`
`BEST MODE FOR CARRYING OUT THE
`INVENTION
`
`10
`
`20
`
`25
`
`35
`
`45
`
`4
`alone or suitably blended to form a mixture having a
`viscosity of 3.0 to 4.6 centistokes. Alternatively. such a
`EPMC product may be blended with another HPMC product
`having higher or lower viscosity (by itself outside the scope
`of the invention) to form a mixture having an optimum
`viscosity as de?ned above.
`Carrageenan is blended as the gelling agent. Carrageenan
`generally includes three types. iota (t). kappa (K) and lambda
`(7t). Among these. t-carrageenan and K-carrageenan having
`a gelling ability may be used. with the carrageenan being
`preferred.
`The co-gelling agent for assisting in gelation of carrag
`eenan is a potassium ion. a calcium ion or both. As a general
`rule. a calcium ion is used for i-carrageenan and a potassium
`ion is used for tr-carrageenan. It is most preferred to use
`K-carrageenan as the gelling agent and a potassium ion as the
`co-gelling agent. The potassium ion may be blended in the
`form of a Water-soluble compound such as potassium
`chloride. potassium phosphate and potassium citrate. The
`calcium ion may also be blended in the form of a water
`soluble compound such as calcium chloride.
`In the capsule shell of the invention containing the
`above-de?ned HRMC base. carrageenan gelling agent and
`co-gelling agent in the above-de?ned proportion. there may
`be further blended various additives such as coloring agents
`(e.g.. dyes and pigments). opaque agents. and ?avors in
`conventional amounts.
`‘The capsule shell of the present invention is prepared by
`drying an aqueous solution comprising the above-de?ned
`HPMC base. carrageenan gelling agent. co-gelling agent and
`optional additives.
`The amount of HPMC blended in the aqueous solution is
`18 to 28% by weight. preferably 19 to 25% by weight.
`Several inconvenient problems occur if the amount of
`HPMC blended is outside this range. The capsule shell of the
`invention is prepared by dissolving the HPMC. gelling
`agent. co-gelling agent and optional additives in water to
`form an aqueous immersion solution. immersing molding
`pins in the immersion solution. withdrawing the pins from
`the solution with the solution adhering to the periphery of
`the pins. and drying the adhering solution. If the amount of
`HPMC blended is less than 18% by weight. the proportion
`of the gelling agent blended becomes relatively high. failing
`to achieve the object of the invention. If the amount of
`HPMC blended is more than 28% by weight. the proportion
`of the gelling agent blended becomes relatively low. but the
`immersion solution has a too high viscosity to shape capsule
`shells by the dipping technique.
`The amount of carrageenan blended in the aqueous solu
`tion is 0.01 to 0.09% by weight. preferably 0.05 to 0.07% by
`weight. If the amount of carrageenan blended is less than
`0.01% by weight. no san'sfactcry degree of gelation is
`achieved and shells of su?icient gage cannot be formed by
`the dipping technique. If the amount of carrageenan blended
`exceeds 0.09% by weight. the capsule shell loses disinte
`gration ability in the presence of calcium ions. failing to
`achieve the object of the invention.
`The amount of co-gelling agent blended in the aqueous
`solution is 0.05 to 0.6% by weight. preferably 0.06 to 0.1%
`by weight in ionic amount. If the amount of co-gelling
`blended is ' less than 0.05% by weight. no satisfactory
`gelation of carrageenan is achieved and shells of su?icient
`gage cannot be formed by the dipping technique. If the
`amount of co-gelling agent blended exceeds 0.6% by
`weight. a gelled ?lm forms in an aqueous immersion
`solution. shell formation by the dipping technique is
`di?icult. and shells. even formed. are low in disintegration
`ability.
`'
`
`In a capsule shell consisting essentially of HPMC as a
`base. carrageenan as a gelling agent. a co-gelling agent for
`assisting in gelation of carrageenan and water. the present
`invention optimizes the viscosity of HPMC and the blending
`proportion of the respective components such that the cap
`sule shell may maintain satisfactory disintegration ability
`even under special conditions where much calcium ions are
`present.
`The HPMC used as the base may be a commercially
`available powder product. According to the invention. the
`I-[PNC should be a low viscosity one such that a 2% aqueous
`solution of HPMC has a viscosity of 2.4 to 5.4 centistokes
`at 20° C.. preferably 3.0 to 4.6 centistokes at 20° C. As
`de?ned herein. the viscosity of HPMC is not the viscosity of
`HPMC itself. but the viscosity of a 2% aqueous solution of
`HPMC throughout the speci?cation. With a viscosity of less
`than 2.4 centistokes. an immersion solution of HPMC from
`which a capsule shell is to be obtained by a dipping
`technique has a too low viscosity to shape the capsule shell.
`With a viscosity of more than 5.4 centistokes. an immersion
`solution has a too high viscosity. which requires to reduce
`the amount of HPMC blended which in turn. requires to
`increase the proportion of the gelling agent blended. failing
`to achieve the object of the invention.
`Such low viscosity EPMC is commercially available as
`TC-5M type HPMC (2% aqueous solution viscosity 4.5
`centistokes at 20° C.) and TC-SE type HPMC (2% aqueous
`solution viscosity 3.0 centistokes at 20° C.) from Shin-Etsu
`Chemical Co.. Ltd. These HPMC products may be used
`
`50
`
`55
`
`65
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 5
`
`

`

`6
`helix structures of carrageenan increase upon contact with
`calcium ions and cros slinln'ng occurs between sulfate groups
`in double helix structures. the interstice structure resulting
`from tangling of carrageenan molecules is maintained in a
`relatively coarse state so that strong gelation does not occur.
`In this way. satisfactory disintegration ability is maintained.
`The capsule shell of the invention containing the above
`de?ned HPMC baser carrageenan gelling agent and co~
`gelling agent in the above-de?ned proportion exhibits sat
`isfactory disintegration ability even in an environment
`where calcium ions are present. In one preferred
`embodiment. the capsule shell of 0.1 mm thick should
`preferably have an opening time within 4 minutes. more
`preferably within 24/: minutes when immersed in an aque
`ous solution of 0.1M potassium chloride at 37° C. The
`potassium ion inhibits dissolution of carrageenan through a
`similar mechanism to the inhibitory mechanism of the
`calcium ion and rather to a greater extent than the calcium
`ion. Then the dissolution of a shell in the presence of
`potassium ions can represent the dissolution of a shell in the
`presence of calcium ions. Then a shell having satisfactory
`dissolution characteristics in an aqueous solution of potas
`sium chloride will exhibit satisfactory disintegration ability
`comparable to that of conventional gelatin shells even in an
`environment where much calcium ions are present. It is thus
`understood that the shell of the invention having a dissolu
`tion time as de?ned above of more than 4 minutes will still
`have practically acceptable dissolution property in the pres
`ence of calcium ions.
`The capsule shell of the invention has improved shap
`ability and disintegration ability comparable to conventional
`gelatin shells even in special conditions where much cal
`cium ions are present. HPMC capsules of the inventive shell
`will effectively disintegrate in the stomach even when they
`are administered after drinldng milk containing much cal
`cium ions. achieving equivalent performance to conven
`tional gelatin capsules. Then the invention enables to take
`full advantage of HPMC-base hard capsules.
`
`20
`
`25
`
`30
`
`35
`
`5,756,123
`
`5
`Preferably. the aqueous solution comprising the above
`de?ned HPMC base. carrageenan gelling agent and
`co-gelling agent in the above-de?ned proportion has a
`viscosity of 500 to 3000 centistokes at 54° C.. more pref
`erably 800 to 2000 centistokes at 54° C.
`The capsule shell of the present invention is prepared by
`a well-known dipping technique as used in the manufacture
`of conventional gelatin capsule shells. More particularly.
`medical hard capsules are prepared by blending the HPMC.
`gelling agent. co-gelling agent and optional additives in
`water to form the above-de?ned aqueous solution or immer
`sion solution. once immersing molding pins in the immer
`sion solution. withdrawing the pins from the solution with
`the solution adhering to the periphery of the pins. drying the
`adhering solution to form capsule shells Goody or cap). and
`removing the shells from the pins. The shells are cut to a
`suitable size if necessary. A pair of body and cap shells are
`mated to form a capsule. In this way. the capsule shell of the
`invention is available in the form of a hard capsule.
`In shaping the capsule shell by the above-mentioned
`dipping technique. the immersion solution in which shaping
`pins are immersed is preferably set at a temperature of 48°
`to 55° C.. especially 51° to 53° C. Outside this temperature
`range. the immersion solution would have a ?nely varying
`jelly viscosity and thickly or thinly adhere to the pins. failing
`to form shells of uniform gage. Thereafter the immersion
`solution adhering to the pins is preferably dried at a tem
`perature of 25° to 35° C. for 40 to 60 minutes. Through the
`drying step. the immersion solution adhering to the pins is
`concentrated to form hard shells around the pins. Other
`conditions may be the same as used in the manufacture of
`conventional gelatin shells.
`The thus obtained capsule shell of the invention contains
`79.6 to 98.7% by weight. preferably 79.8 to 98.7% by
`weight of the HPMC as a base. 0.03 to 0.5% by weight.
`preferably 0.14 to 0.38% by weight of carrageenan as a
`gelling agent and 0.14 to 3.19% by weight. preferably 0.17
`to 0.5% by weight of a potassium ion and/or a calcium ion
`as a co-gelling agent. It is noted that the capsule shell of the
`invention generally has a water content of about 1 to 8% by
`weight. preferably 1 to 6% by weight. ensuring formation of
`hard capsules with a low water content.
`Though the invention is not bound to the theory. the
`reason why the capsule shell of the invention maintains
`satisfactory disintegration ability even in the presence of
`calcium ions is as follows.
`As mentioned above. the shapability of HPMC is
`improved by gelling carrageenan as the gelling agent with
`the co-gelling agent. The gelation of carrageenan follows the
`mechanism schematically shown in FIG. 1 that carrageenan
`molecules form double helix structures with the aid of the
`co-gelling agent (FIG. IE) to form a three-dimensional
`network. If the thus gelled carrageenan comes in contact
`with a calcium ion. the double helix structures increase to
`strengthen the three-dimensional network (FIG. 1C). Also
`crosslinking occurs between adjacent sulfate groups in adja
`cent double helix structures to stabilize the three
`dimensional network. Then the gel increases its hardness to
`detract from solubility or disintegration ability. However. in
`the capsule shell of the present invention. by using a HPMC
`having a relatively low viscosity as a base. increasing the
`proportion of HPMC used. increasing the amount of the
`co-gelling agent blended. and minimizing the proportion of
`carrageenan gelling agent within a sut?cient range to insure
`good shapability. the amount of carrageenan relative to
`HPMC is set at a very low level. Then even when double
`
`EXAMPLE
`
`Examples of the invention are given below by way of
`illustration and not by way of limitation. All percents are by
`weight
`
`Example 1 and Comparative Example 1
`
`Potassium chloride was dissolved in pure water at about
`75° C. With stirring. K-carrageenan and a coloring agent
`(titanium oxide) were added to the solution and dissolved
`therein. With stirring. hydroxypropylmethyl cellulose
`(HPMC) was added to the solution and dispersed therein.
`The solution was cooled to a temperature of 50° C. and
`further agitated for dissolving the HPMC therein. The solu
`tion was then allowed to stand for deaeration. In this way.
`two immersion solutions were obtained as shown in Table 1.
`A conventional capsule shell forming apparatus was
`charged with the immersion solution which was maintained
`at 52° C. The apparatus was operated in accordance with a
`conventional dipping technique to prepare No. 2 capsule
`shells of the shell composition shown in Table 1 having a
`thickness of 0.1 mm. In this way. two types of capsule shells
`were obtained.
`
`50
`
`55
`
`65
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 6
`
`

`

`7
`
`TABLE 1
`
`5.756.123
`
`8
`
`TABLE 3
`
`Example 1
`
`Comparative
`Example 1
`
`'
`Immersion solution l-IPMC
`
`Capsule shell
`
`TC-SR
`TC-SMW
`TC-SEW
`Viscosity
`“We”: ,
`P62323203)!”
`manium oxide
`HPMC
`ggta‘?gwn? _
`“slim? mde
`(potassium ton)
`manium om:
`water
`
`—
`10%
`10%
`3.8 cs!
`‘108%
`(36:53:)
`057%
`90.63%
`036%
`050%
`(0.26%)
`351%
`5%
`
`Capsule
`
`Opening time (min)
`
`Gelatin
`Comparative Example 1
`Example 1
`
`2
`15
`3
`
`3
`l6
`3
`
`3
`18
`4
`
`av. 2.7
`av. 16.3
`av. 3.3
`
`15
`
`16%
`-
`_
`6.0 est
`It is seen from Table 3 that the capsule shell of the
`01%
`(852;) w invention exhibits disintegration ability equivalent to the
`052%
`conventional gelatin capsule even in milk containing much
`89.83%
`Calcium ions
`112%
`Next. the capsule of Example 1 and a conventional gelatin
`056%
`capsule were evaluated for disintegration ability in the ?rst
`(0.29%)
`.
`.
`.
`.
`349%
`and second ?uids prescribed in the Pharmacopoeia of Japan.
`5%
`Section 12. The capsules each were ?lled with 300 mg of a
`mixture of 20 parts by weight of acetaminophen and 280
`parts by weight of corn starch. The capsules were immersed
`in the ?rst and second ?uids. While stirring the test solution
`20 by rotating a paddle at 100 rpm. the percent leaching of the
`contents was measured. The results are plotted in the graphs
`of FIGS. 2 and 3.
`It is seen from FIGS. 2 and 3 that the capsule of Example
`1 has an equivalent disintegration ability to that of the
`25 conventional gelatin capsule in both the ?rst and second
`?uids prescribed in the Pharmacopoeia of Japan. This sug
`gests that the hard capsules of the shell according to the
`invention are useful as medical capsules. Examples 2-5 and
`Comparative Example 2-6
`Potassium chloride was dissolved in pure water at about
`75° C. With stirring. tc-carrageenan was added to the solu
`tion and dissolved therein. With stirring. hydroxypropylm
`ethyl cellulose (HPMC) was added to the solution and
`dispersed therein. The solution was cooled to a temperature
`35 of 50° C. and further agitated for dissolving the HPMC
`therein. The solution was then allowed to stand for deaera
`tion. In this way. nine immersion solutions were obtained as
`shown in Table 4.
`The immersion solution was maintained at 52° C. Nine
`types of capsule ?lms of the shell composition shown in
`Table 4 having a thickness of 0.1 mm were prepared by
`conventional dipping technique from the immersion solu
`tions.
`The capsule shell ?lms (10 mm><20 mm) were immersed
`in milk at 37° C. The dissolving time was measured by
`means of a disintegration tester as prescribed in the Phar
`macopoeia of Japan. Three measurements were taken and an
`average was calculated. The results are shown in Table 5. As
`a reference. a conventional gelatin capsule ?lm was simi
`larly measured for dissolving time. with the results shown in
`Table 5.
`
`Note: TC-5Rr TC-SMW and TC-SEW are trade names of
`HIPMC manufactured by shin-Etsu Chemical Co.. Ltd.
`TC-SR has a viscosity of 6.0 centistokes; TC-SMW has a
`viscosity of 4.5 centistokes; and TC-SEW has a viscosity of
`3.0 centistokes. as measured in 2% aqueous solution at 20°
`C. The viscosity of Example I is that of a 1/1 mixture of
`TC-SMW and TC-SEW.
`
`The capsules were ?lled with 0.3 g of corn starch and
`immersed in an aqueous solution of 0.1M potassium chlo
`ride at 37° C. The opening time was measured by means of
`a disintegration tester as prescribed in the Pharmacopoeia of
`Japan. Three measurements were taken and an average was
`15 calculated The results are shown in Table 2. As a
`reference. a conventional gelatin capsule was similarly mea
`sured for opening time. with the results shown in Table 2.
`
`30
`
`TABLE 2
`
`Capsule
`
`Opening time (min)
`
`Gelatin
`Comparative Example 1
`Example 1
`
`1.3
`4.2
`1.9
`
`1.5
`4.5
`2.2
`
`1.5
`6.8
`2.4
`
`av. 1.4
`av. 5.2
`av. 2.2
`
`Separately. the capsules were ?lled with 0.7 g of copper
`wire as a weight and immersed in milk at 37° C. The opening
`time was measured by means of a disintegration tester as
`prescribed in the Pharmacopoeia of Japan. Three measure
`ments were taken and an average was calculated. The results
`are shown in Table 3. As a reference. a conventional gelatin
`capsule was similarly measured for opening time. with the
`results shown in Table 3.
`
`TABLE 4
`
`Example
`
`Oogmarative Exgple
`
`No. 2
`
`No. 3
`
`No. 4
`
`No. 5
`
`No. 2
`
`No. 3
`
`No. 4
`
`No. 5
`
`No. 6
`
`16%
`
`10%
`
`18%
`
`16%
`
`10%
`25%
`16%
`10%
`25%
`28%
`6.0 as!
`3.0 cst
`6.0 est
`4.5 cst
`3.0 est
`4.5 cst
`3.8 cst
`3.0 est
`3.0 cst
`0.01% 0.06% 0.08% 0.08% 0.20% 0.20% 0.20% 0.15% 0.11%
`1.0%
`0.11%
`1.11% 0.11% 0.10% 0.10% 0.10% 0.10% 0.10%
`(0.5%) (0.06%) (0.06%) (0.06%) (0.05%) (0.05%) (0.05%) (0.05%) (0.05%)
`95.55% 98.33% 98.07% 97.97% 97.18% 97.18% 97.18% 98.01% 96.12%
`0.03% 0.24% 0.40% 0.44%
`1.22%
`1. 22% l 22% 0.59% 1.92%
`3.42% 0.43% 0.53% 0.59% 0.60% 0.60% 0.60% 0.40% 0.96%
`(1.79%) (0.33%) (0.23%) (0.31%) (0.32%) (0.32%) (0.32%) (0.21%) (0.50%)
`
`Immersion solution RPMC TC-SR
`'IC-SMW
`TC—SEW
`Viscosity
`K-canageenan
`Potassium chloride
`(potassium ion)
`HPMC
`K-carrageenan
`Potassium chloride
`(potassium ion)
`
`Capsule shell
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1016 - Page 7
`
`

`

`9
`
`5,756,123
`
`10
`
`TABLE 4-continued
`
`m
`
`COBB-Lil“? Exggle
`
`No. 2
`
`No. 3
`
`No. 4
`
`No. 5
`
`No. 2
`
`No. 3
`
`No. 4
`
`No. 5
`
`No. 6
`
`Water
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`Note: TC-SR, TC-SMW and 'IC-SEW are trade names of HPMC manufactured by Shin-Etsu Chemical 00., Ltd. ‘PC-5R has a viscosity
`of 6.0 centistckes'. TC-SMW has a viscosity of 4.5 centistokes; and ‘PC-SEW has a viscosity of 3.0 centistokes. as measured in 2%
`aqueous solution at 20° C. The viscosity of Example 4 is that of a 1/1 mixture of TC-SMW and TC-SEW.
`
`TABLE 5
`
`Film
`
`Dissolving time (min.)
`
`Example
`
`No.2
`No.3
`No.4
`No.5
`Comparative Example No.2
`No.3
`No.4
`No.5
`No.6
`
`Gelatin
`
`4
`6
`7
`9
`28
`25
`21
`14
`>60
`3
`
`5
`6
`B
`9
`28
`28
`23
`15
`>60
`4
`
`av. 4.7
`5
`av. 6.3
`7
`av. 8.0
`9
`av. 9.0
`9
`av. 28.3
`28
`av. 27.0
`28
`av. 23.7
`27
`av. 14.7
`15
`>60 -
`5
`av. 4.0
`
`It is seen from Table 5 that the capsule shell film of the
`invention exhibits disintegration ability even in milk con
`taining much calcium ions.
`
`Comparative Example 7
`
`20
`
`25
`
`30
`
`35
`
`Potassium chloride was dissolved in pure water at about
`75° C. With stirring. K-carrageenan and a coloring agent
`(titanium oxide) were added to the solution and dissolved
`therein. With stirring. hydroxypropylrnethyl cellulose
`(HPMC) having a viscosity of 5.87 centistokes as measured
`in a 2% aqueous solution at 20° C. was added to the solution
`and dispersed therein. The solution was cooled to a tem
`perature of 50° C. and further agitated for dissolving the
`HPMC therein. The solution was then allowed to stand for
`deaeration. In this way. an immersion solution containing
`20% by weight of the EPMC. 0.08% by weight of
`K-carrageenan and 0.06% by weight of potassium ion was
`obtained
`A viscosity of the immersion solution was too high for the
`capsule shell having a thickness of 0.1 mm to be formed by
`the dipping technique.
`We claim:
`1. A capsule shell comprising 79.6 to 98.7% by weight of
`a hydroxypropylmethyl cellulose. 0.03 to 0.5% by weight of
`carrageenan. and 0.14 to 3. 19% by weight of a potassium ion
`andlor a calcium ion.
`
`said capsule shell being prepared by drying an aqueous
`solution comprising 18 to 28% by weight of
`hydroxypropyl-methyl cellulose having a viscosity of
`2.4 to 5.4 centistokes as measured in a 2% aqueous
`solution at 20° C. as a base. 0.01 to 0.09% by weight
`of carrageenan as a gelling agent. and 0.05 to 0.6% by
`weight of at least one ion selected from the group
`consisting of potassium and calcium ions as a
`co-gelling agent.
`2. The capsule shell of claim 1 Which comprises 1 to 8%
`by weight of water.
`3. The capsule shell of claim 1 wherein said carrageenan
`gelling agent is K-carrageenan and the co-gelling agent is a
`potassium ion.
`4. The capsule shell of claim 1 wherein the viscosity of the
`hydroxypropylmethyl cellulose is 3.0 to 4.6 oentistokes as
`measured in a 2% aqueous solution a