Unitecl States Patent [19]
`Yamamoto et al.
`
`[7 5]
`
`Inventors: Taizo Yamamoto. Osaka; Seinosuke
`Matsuura, Souralru-gun; Kazukiyo
`Akai, Kashihara. all of Japan
`
`[73] Assignee: Japan Elauco Co., Ltd •. Osaka. Japan
`
`[21] Appl. No.: 797,622
`
`[221 Fiied:
`
`Feb. 7, i99i
`
`Related U.S. AppliC3tion Data
`
`[63] Continuation-in-part of Ser. No. 548,265, Oct 25, 1995,
`abandoned.
`Foreign Application Priority Data
`
`[30]
`
`[JP]
`[JP]
`
`Japan .................................... 6-3235Sl
`Japm .................................... 6-333965
`
`Deo. 1, 1994
`Deo 16, 1994
`lnL CI.6
`....................................................... A61K 9/48
`[51]
`[52] U.S. CL .......................... 4W451; 424/452; 4241455;
`424/494
`[58] Field or Search ..................................... 4241451. 494.
`4241452. 455
`
`Refertnces Cited
`
`U.S. PATENT DOCUMENfS
`
`11111111111~ 11111111111111111111111 illi I Iii Ii
`
`lJS005756 i 23A
`[11! Patent Number:
`[45] Date of Patent:
`
`5,756,123
`May 26, 1998
`
`4,993,137
`5,032,074
`5264223
`5.43i,9i7
`
`2/1991 Muto et al ............................... 291451
`7/1991 Muto et at ........................... ,, 4251272
`11/1993 Yamamoto et al ..................... 4241451
`7/i995 Yam,.moto et al ..................... 4241451
`
`FOREIGN PxrENT DOCUMThTS
`
`411994 European Pat. Off ..
`0592130
`2029402
`6/1970 Gennany.
`Japan.
`47-4310
`211972
`Japan.
`61-100519
`5/1986
`62-266060 11/1987
`Japan
`Japm
`3-279325 1211991
`Primary F..xa.miner-Amy Hulina
`Attorn£); Agenl'., or Finn-Birch, Stewart. Kolasch & Birch.
`LLP
`
`[57]
`
`ABSTRACT
`
`A capsule shell compnsing 79.6-98.7% by weighi of a
`hydroxypropylmethyl cellulose. 0.03-0.5% by weight of
`cmageenan. and 0.14-3.19% by V/eight of a potassi!.!m .i.on
`and/or a calcilllll is prepared by drying an solution compris(cid:173)
`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 0.05-0.6% by weight of
`a potassium ion and/or calciwn ion as a co-gelling agent.
`The capsule shell e::r.hibits disintegrating ability equivalent to
`gelatin shells without degrading that ability even under
`special conditions containing much calcium ions.
`
`3,617,5&8 1111971 Langman ................................ 264/486
`4,001;211
`111977 Sarkar ....................................... 536184
`
`8 Claims, 2 Drawing Sh«ts
`
`FIRST FLUID
`
`• GEL.4.T!N CA.PSlJLE
`
`o
`
`INVENTIVE CAPSULE
`
`~
`
`"' z
`;:
`~ w
`!;;:
`w
`(,) a:
`w
`"'
`
`u
`
`10
`
`20
`
`30
`
`GO
`
`70
`
`eo
`
`90
`
`40
`
`so
`TIME, MIN.
`
`TEVA_MS_0045324
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 1
`
`

`
`lT.S. Patent
`
`May 26, 1998
`
`Sheet 1 of 2
`
`5,756,123
`
`S:I~ 1 I A)
`
`I
`
`• ~ •
`•
`
`' ' " " " /
`
`.. --·. ,_,
`FIG_ 1 (R)
`
`FIG.1 (C)
`
`-
`
`- - - -
`
`-
`
`'
`
`-
`
`I
`
`d
`
`/'
`lt<
`~~ 'i '"
`~
`~
`~
`)Jl~
`tJr?
`~ I
`\,.../ ~ ~ .
`.
`
`' -
`
`TEVA_MS_0045325
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 2
`
`

`
`lJ.S. Patent
`
`May 26, 1998
`
`Sheet 2 of 2
`
`5,756,123
`
`FIG.2
`
`FIRST FLUID
`
`• GELATIN CAPSULE
`
`o
`
`INVENTIVE CAPSULE
`
`...J
`
`G
`~
`::i:
`(,)
`<( w
`~ z
`w
`(,) cc
`w
`c..
`
`o~~~-..-~-r-~-.----.~-..-~-r-~..-----,.
`0
`10
`20
`30
`40
`50
`60
`70
`80
`90
`
`TIME, MIN.
`
`FIG.3
`
`SECOND FLUiO
`
`...J
`
`0 z s: u
`<( w
`!z
`(,) cc
`w
`c..
`
`i.i..i
`
`• GELATiN CAPSULE
`o INVENTIVE CAPSULE
`
`TIME. MIN.
`
`TEVA_MS_0045326
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 3
`
`

`
`5.756.123
`
`1
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation-in-part of copending
`application Ser. No. 08/548265 filed on Oct. 25, 1995 the
`entire contents of which are hereby incorporated by refer(cid:173)
`ence.
`
`B_A.CKGROTJND OF THE INVFNTION
`
`2
`molding pins In either of these metJiod:s, it is difficult to
`produce capsule shells having a low water contenL
`Additionally. these methods require a special apparatus or
`operation of heating the molding pins or immersing the
`5 molding pins with cellulose coating in hot water.
`Unfortunately, it is impossible to utilize the current manu(cid:173)
`facturing apparatus for gelatin capsules without a substantial
`change.
`To solve these problems. the applicant previously pro-
`io posed in U.S. Pat. No. 5.264,22.1· 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
`15 geiatin capsuies and can be pro<lucr;::d by utilizing the cwtent
`manufacturing apparatus for gelatin capsules as such.
`However, through the continuing rescarc.i1i works of t'le
`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-
`25 siurn ion as a ccr-ge.lling agent. Shells of this preferred
`f0nnulation take a long time to disintegrate under special
`conditions where calciwnions are present Then, if a capsule
`of this composition filled with drugs is administered after
`having a food or beverage containing much calcium ions. for
`example. milk. then the capsule is retarded from dislntegra·
`tion. Then the drugs are not fully released or absorbed within
`a proper ti..ue. failing to ffilly exert their pharrn..aceutical
`effect. Therefore, it is desired to further improve the prcp(cid:173)
`erties of the capsule based on a water·soluble cellulose
`35 derivative.
`
`30
`
`20
`
`1. Field of the Invention
`1 ·rus invention relates to a capsuie sneu ror forming
`medical hard capsules. More particularly. it relates to such a
`capsule she!! usL11g hydroxypropyhnethyl cellulose as a
`base.
`2. Prior Art
`Medical hard c.apsules are conventionally formed fi:om
`cornoositions comprising gelatin as a base with a plasticizer
`such- as glycerin ~d smbitot opaque agent. dye. pigment
`and other additives blended therein. After molding pins are
`inune:rsed in a gelatin aqueous solution with such compo(cid:173)
`nents blended and withdrawn therefrom. the gelatin solution
`.adhering to the pin::. is dried, obtai!iJng capsule shells.
`The shell-forming compositions based on gelatin have the
`prOOlem 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(cid:173)
`tered on drug filling. Also, as the water content lowers due
`to drying during shelf storage, shells can contract to loosen
`the cap-body engage.iuent of capsules.
`For gelatin capsules, it is thus critical to maintain the
`water oontent 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 fill to lower its titer. degrade its quality, and change its
`color, and inversely. the capsule shell can be insolubilized if
`the Un.lg fill is susceptible to hydrolysis or is a mixture of
`interacting ingredients. Therefore. there is a demand to have 40
`capsules hai;:f'!d on a suhrun~ other than gelatin so that the
`material of capsules can be selected in accordance with a
`particular drug fill.
`Medical capsules using a base other than gelatin are
`known in the art. Typically, capsules based on water- soluble 45
`cellulose derivative:; were P£oposcd. For exruuple, japanese
`Patent Publication (JP-B) No. 431011972 discloses a method
`for preparing capsules based on watr,r-soluhle ce11ulo~
`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 poly-vinyl alcotiol (P'"YA) blended therewith.
`The former shell-forming method involves the steps of
`L'?ll:nersin.g moldi!!g pi!!s in an. aqueous solution of water(cid:173)
`soluble cellulose derivative and heating the pins and hence,
`the coating adhered thereto for gelation. The coating is not
`gelled or solidified and can fall down from the pins if heating
`is insufficient. The coating can be wrinkled during gelation
`if the heating iemperature is iou high. Tu. the lattef method of
`preparing capsules from an aqueous solution of water(cid:173)
`so!uble cellulose de..riv~rive and PV_A., t.h:e water~solubJe
`cellulose derivative adhered to the molding pins is gelled by
`immersing it in hot water. Some of the gelled coating can be
`dissolved in the hot water at this JXtint, hindering formation
`of uniform shells. In addition, due to low jelly strength. the
`dried shells can be often cracked upon removal from the
`
`An object of the present invention is to provide a capsule
`shell based on a w·ater-soluble cellulose derivative which
`does not degrade its disintegration ability under special
`~onditions where much ca.lcium ions are presenl that is.
`exerts its performance under any condition.
`In connection with the capsule shell composition com(cid:173)
`prising hydroxypropylmethyl cellulose (to be abOCeviated as
`HPMC, hereinafter) as a water-soluble cellulose derivative
`base, carragccnan IUi a gelling agent, and a potassium ion as
`a co-gelling agent wherein the shapability of HPMC is
`Lm__provffi hy hlendi ng carrageenan as a gelling agent and
`gelling this carrageenan with the oo~gelling agent, we found
`so 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(cid:173)
`position as the gelling agent.
`Continuing research works, we have found that degrada-
`55 tion of t.lte dis~ntegration ability due to the presence of
`calcium ions is resttained 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:ffi-
`60 cient range to insure good Si'iapability. },.1orc particularly. by
`using a HPMC having a viscosity of 2.4 to 5.4 centistokes
`as mea.5Ured 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
`6' 18 to 28% by weight of the HPMC.0.01 to0.09% by weight
`of carrageenan and 0.05 to 0.6% by weight of a co-gelling
`agent. and d..-jing the aqueoos solution to form a capsule
`
`TEVA_MS_0045327
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 4
`
`

`
`5.756.123
`
`3
`she!! 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
`equivaient to conventionai gelatin capsules. A han1 capsule
`for pharmaceutical drugs of the capsule shell can be securely
`a.11d efficiently prodl!('ed according to the conventional
`immersion molding.
`Acoordine.lY. the present .invention provides a capsule
`shell comprising -79.6 to 98.7% -by weight of a
`hydroxypropyl-methyl cellulose, O.o3 to 0.5% by weight of
`c.arrageenan. and 0.14 to 3.19% by weight of a potassium ion
`and/or a calcium ion, said capsule shell being prepared by
`d..-,y'ing au aqueous soltU:ion comprising 18 to 28% by v1eight
`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, 0.01to0.09% 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 porassium and
`calcium ions as a co-gelling agent.
`
`BRIEF DESCRlPTION OF TIIE DRAWINGS
`
`FIGS. l(A). l(B) and l(C) sche..uatically illustrate L'ie
`gelation mechanism of carrageenan.
`F1G. 2 is <1 graph sho\vir.g the percent !eachi!lg of the
`contents from a capsule of Example 1 and a conventional
`gelatin capsule when they \\'ere immersed in the first solu(cid:173)
`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 conventionaJ
`gelatin capsule when they were immersed in the second
`solution prescribed in the Pha..T"uacoyocia of Japan.
`BEST MODE FOR CARRYING our THE
`INVENTION
`
`In a capsule she!! rons..isting esse.!!tiitlly 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
`P£oportion of the respective components such that the cap(cid:173)
`sule shell may rnalntain 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. AccordinR; to the invention. the
`HPNC sbOuld 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., preferabiy 3.0 to 4.6 centistokes at 20"=' C. As
`defined herein. the viscosity of HPMC is not the viscosity of
`HPMC itself. but the visco:s.ity of a 2% aqueous solution of
`HP.MC throughout the specification. With a viscosity of less
`than 2.4 centistokes, an immersion solution of HPMC from ss
`which a capsule shell is to be obtained by a dipping
`technique has a too low viscosity to shape the capsule shell.
`With a viscosiiy of mCll"e than 5.4 ceutistokes, an in-.n•etsion
`solution has a too high viscosity. which requires lo reduce
`Lhe a_rnount of HPMC blended which in turn. requires to 60
`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 cype HFMC (2% aqueous 65
`solution viscosity 3.0 centistokes at 20° C.) from Shin-Etsu
`Chemical Cc .. Ltd. These HP!>.1C products rnay b!: used
`
`4
`alone or suitahlv blended to form a mixture havine: a
`~i~-~sitY ~f-3.0 ~to 4.6 centistokes. Alternatively. such a
`EPMC product may be blended with another HPMC product
`having higher or iower viscosity (by itseif outside the scope
`5 of the invention) to form a mixture having an optimwn
`viS{"o:sity ~s defined .above.
`Carrageenan is blended as the gelling agent Carrageenan
`generally includes three types • .iota (t.), kappa (K) and lambda
`(A). Among these, i-carrageenan and lC-carrageenan having
`10 a gelling ability may be used. with the carrageenan being
`preferred.
`The co-gelling agent for assisting in gelation of carrag(cid:173)
`eenan is a potassium ion. a calcium ion or both. As a general
`rule. a calcium ion is used for t-carrageenan and a potassium
`ion is used for 1'-carrageenan. It is most preferred to use
`15 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 8nd potassium cilrate. The
`calcium ion may also be blended in the form of a water-
`20 soiubie compound sud::i as cah..:iwu (:blorid.¢.
`In the capsule shell of the invention containing the
`above-defined HF.MC base. c.a..rrageenan gelling agent and
`co-gelling agent in the above-defined proportion, there may
`be further blended various additives such as oolorirlg agents
`25 (e.g .• dyes and pigments). opaque agents. and flavors in
`conventional amounts.
`The c..psu.le shell of t.'ie present invention is prepfil"ed b}'
`drying an aqueous solution comprising the above-defined
`HPMCbase. carrageenan gelling agent, co-gelling agent and
`30 optional additives.
`The amount of HPMC blended in the aqueous solution is
`18 to 28% by weight. preferably 19 to 25% by v.·eig..11t.
`Several inconvenient problems occur if the amount of
`HPMC blended is outside this range. The capsule shell of the
`35 invention is prepared by dissolving the HPMC. ge_lling
`agent. co-gelling agent and optional additives in water to
`form an aqueous immersion solution, immersing moiding
`pins in the immersion solution, withdrawing the pins from
`the solution ""1th the solution adhering to !he ~.phery of
`40 the pins, and drying the adhering solution. If the amount of
`HPMC blended is le5' than 18% by weight, the l"'oportion
`of the gelling agent blended becomes relatively high. failing
`to achieve the object of the invention. If the amount of
`ltt'.MC biended is more than 28% by weight. the proportion
`45 of the gelling agent blended becomes relatively low. but the
`i..rn..'Il.ef"...ion so!!!tion has a too high viscosity to shape capsule
`shells by the dipping technique.
`The amount of carrageenan blended in the aqueous solu(cid:173)
`tion is 0.01to0.09% by weight.preferably 0.05 to 0.07% by
`so weight. H the amount of carrageenan blended is less than
`0.01 % by weight. no satisfactory degrt* of gel.ation is
`achieved and shells of :sufficient gage cannot be formed by
`the dipping tec}"lniqne. If the itmouJJt of ('".a.rrageenan blended
`exceeds 0.09% by weight. the capsule shell loses disinte(cid:173)
`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, preferabiy 0.06 to 0.1 %
`by weight in ionic amount. If the amount of co-gelling
`blended is less !.lian 0.05% by wcig.'1.t. !!O satisfactory
`gelatioo of carrageen.an is achieved and shells of sufficient
`gage cannot be formed by the dipping technique. If the
`amount of co-gelling agent blended exceeds 0.6% by
`weight. a gelled film forms in an aqueous immersion
`s.oiution, shell formation by the dipping technique is
`difficult.. and shells. even formed. are low in disintegration
`ability.
`
`TEVA_MS_0045328
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 5
`
`

`
`5
`Preferably. the aqueous so!uticn comprising t'1e above(cid:173)
`defined HPMC base, carrageenan gelling agent and
`co-~elling aioi;ent in the above-defined proportion has a
`visCosity-of 500 to 3000 centistok.es at 54° C., moce pref(cid:173)
`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 io the manufacture
`of conventional gelatin capsule Si'iells. ~l1orc pa. ...... ..icularly.
`medical hard capsules are prepared by blending the HPMC.
`gelling agent co-gelling agent and optional additives in 10
`water to form the above-defined aqueous solution or immer(cid:173)
`sion solution. once immersing molding pins in the immer(cid:173)
`sion solution. withdrawing the pins from the solution with
`the solution adhering to the periphery of the pins. drying the
`adhi::.i..ing solution to form capsuk: shells (body or cap) • .and 15
`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 2G
`dipping technique. the immersion solution in which shaping
`pins are immersed is preferabiy sec at a temperature of 48°
`to 55° C., especially 51° to 53° C. Outside this temperature
`range. the i.tn.onersion solution '111ou!d have a finely 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(cid:173)
`perature of 25° to 35° C. for 40 to 60 minutes. 'Through the
`drying step. the inunersion soiuiion adhering to the plus is
`concentrated to form hard shells around the pins. Other
`conditions rn"'y be the same as used in the man!!facture of
`conventional gelatin shells.
`The thus obtained caosule shell of the invention contains
`79.6 to 98.7% by welght, 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 potassiu..--n ion and/er a ca!ciu..-rn io!!
`as a co-gelling agent. It is noted that the capsule shell of the 4(J
`invention generally has a water content of about 1 to 8% by
`weight. preferably- I 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 45
`satisfactory disintegration ability e-ven in t.'lc presence of
`calcium ions is as follows.
`~11..s mentioned above, the shapability of HPMC is
`.improved by gelling carrageeoan as the gelling agent with
`the co-gelling agent. The gelation of carrageenan follows the 50
`mechanism schematically shown in FIG. 1 that cmageenan
`molecules form double helix structures with the aid of the
`co-gelling agent (t<IG. IB) to fonn a three-dimensionai
`network. If the thus gelled carrageenan comes in contact
`ivith i! .calcium .ion, the double heli~ stt1.Jcti.J.re.s increase to
`strengthen the three-dimensional network (FIG. IC). Also
`crosslinking occurs between adjacent sulfate groups in adja(cid:173)
`cent double helix structures to stabilize the three(cid:173)
`dimensional network. Then the gel increases its hardness to
`detract from wiubiiily o.r disintegration ability. However. in
`the capsule shell of the present invention. by using a HPMC
`havin{J a relativelv low viscositv as a base. increasinli! the
`p;:-opo'rtion ~-HP.MC us~d. in~easing the amount of the
`co-gelling agent blended. and minimizing the proportion of
`carrage.ena.n gelling agent within a sufficient range to insure 65
`good shapability. the amount of carrageenao relative to
`HPtv1C is set at a Vg_i low level. Theu even w·hen double
`
`35
`
`55
`
`fiJ
`
`5.756.123
`
`6
`he!i~ stti..Jctures of c:arrageenan increase upon contact v,:ith
`calcium ions and crosslinking occurs bet\Veen sulface groups
`in double helix structures, the interstice structure resulting
`from tangling of carrageenan molecules is maintained in a
`5 relatively coarse state so that strong gclation does not occur.
`In this way, satisfactory disintegration ability is maincained.
`
`The capsule shell of the invention containing the above(cid:173)
`defined HPMC baser carrageenan gelling agent and co(cid:173)
`gelling agent in the above-defined proportion exhibits sat(cid:173)
`isfactory disintegration ability even in an environment
`where calcium ions are present. In one preferred
`embodirneni, the CillJM.tle shell of 0.1 miu il1ick should
`preferably have an opening time within 4 minutes. more
`preferably 'vit.h.in 2~1:! winutes when im.111ersed in an aque(cid:173)
`ous solution of O.lM potassium chloride at 37° C. The
`potassium ion inhibits dissolution of carrageenan through a
`;imilar 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 ot·
`potassium ions can represent the dissolution of a shell in the
`presence of caicium ions. Tnen a shell having sai.isfactocy
`dissolution characteristics in an aqueous solution of polas-
`sium chloride will exhibit s.atisfacto:ry disi!:itegration ahility
`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(cid:173)
`tion time as defined above of more than 4 minutes will still
`30 have practically acceptable dissolution property in the pres(cid:173)
`ence of calcium ions.
`
`25
`
`The capsule shell of the invention has improved shap(cid:173)
`ability and disintegration ability comparable to conventional
`gelatin shells even in special conditions v,.·here much cal(cid:173)
`cium ions are present. HPMC capsules of the inventive shell
`will effectively disintegrate in the stonlach even when they
`are administered after drinking milk containing much cal-
`cium ions • .ac...11ieving equivalent performance to conven-
`tional gelatin capsules. Then the invention enables to take
`full advant.age of lWMC.-base hard capsules.
`
`EXAMPLE
`
`Examples of the invention are given below by way of
`illustration and not by way of limitation. Ail percents are by
`weight.
`
`Example I and Comparative Example 1
`
`Potassium chloride was dissolved in pure water at about
`75° C. With stirring. x:-carrageenan and a coloring agent
`(titanium oxide) were added to the solution and dissolved
`therein. With stirring. hydroxypropylmethyl cellulose
`(HPMC) was added w ihe soiution and dispersed therein.
`The solution was cooled to a temperature of 50° C. and
`fu ... nJ~er agitated for dissolving t.he HPMC therein, The solu(cid:173)
`tion was then allo"1ed to stand for deaeration. In this way.
`two .immersion solutions were obtained as shown in Table 1.
`
`A conventional capsule shell forming apparatus \Vas
`charged with the ilnmersion solution which was maintained
`at 52° C. The apparatus \\-'as operated in accordance with a
`conventional dipping technique to prepare No. 2 capsule
`shells of the shell composition shown in Tabie 1 having a
`thickness of 0.1 mm. In this way. two types of capsule shells
`-;,:ere obtained.
`
`TEVA_MS_0045329
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 6
`
`

`
`5,756,123
`
`8
`
`TABLE3
`
`'
`
`Gelatin
`Cvwpara.fr;;;; E;;;;;;.,,upk: l
`Example 1
`
`15
`
`3
`16
`3
`
`3
`18
`4
`
`av. 2.7
`'il.V. 16.3
`av. 3.3
`
`7
`
`TABLE I
`
`Example 1
`
`C'.urnp:iillliiv1=
`Example I
`
`TC-5R
`TC-SMW
`TC-SEW
`
`"K<arrageetHD.
`Potusiwn chiori&
`(poillllljiWll iou)
`Titanium oxide
`llPMC
`l:-carrageeuan
`Potassium chloride
`(potassium ion)
`Titacium oxide
`Water
`
`10%
`10%
`3.8 c5'
`0.00%
`0.11%
`(0.06%)
`0.77%
`90.63%
`0.36%
`0.50%
`(0.26%)
`3.51%
`5%
`
`16%
`
`6.D csi
`0.2%
`0.1%
`(O.D.5%)
`0.62%
`89.83%
`i.i2%
`0.56%
`(0.29%)
`3.49%
`5%
`
`Capsule shell
`
`Note: TC-5Rr TC-5MW and TC-5EW are trade names of
`HPMC manufactured by shin-Etsu Chemicai Co., Ltd.
`TC-5R has a viscosity of 6.0 centistokes; TC-5MW has a
`viscosity cf 4.5 centistokes; and TC-5EW !1as 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-5MW and TC-SEW.
`
`2s
`
`It is seen from Table 3 that the capsule shell of the
`lO invention exhibits dis.inte1Uation ability equivalent to the
`conventional gelatin capsu1e even in milk Containing much
`calcium ions.
`Next, the capsule of Example 1 and a conventional gelatin
`capsule were evaluated for disintegration ability in the first
`15 and second f!.uids prescribed io. the P!i.a..rrn...acopoeia. of Japan.
`Section 12. The capsules each were filled with 300 mg of a
`mixture of 20 parts by weight of acetaminophen and 280
`parts by weight of com starch. The capsules. were immersed
`in the first and second tluids. 'While stirring the test solution
`20 by rotating a paddle at 100 rpIT'.., t.'1.e percent !eact-.ing of t.°l?e
`contents was measured. The results are plotted in the graphs
`of FIGS. 2 and 3.
`It is seen from FIGS. 2 and 3 that lhe capsule of Example
`I has an equivalent disintegration ability to that of the
`conventionai geiatin capsuie in OOth ihe first and second
`fiuids 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. K-carrageenan was added to the solu(cid:173)
`tion and dissolved therein. With stirring. hydroxypropy!.TTI(cid:173)
`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 far dissolving the llPMC
`therein. The solution was then allowed to stand for deaera-
`tion. In ti.'iis way, rune irr-.mersion solu+Jcn:; "<:.'ere cbrain.ed as
`shown in Table 4.
`The immersion solution was maintained at 52° C. Nine
`types of capsule films of the shell composition shown in
`Table 4 having a thickness of 0.1 mm were prepared by
`conventional dipping rechnique from the immersion solu(cid:173)
`tions.
`The capsule shell fil.•r.s (10 m."ll..v.20 m.-rn) \Vere i.-on..TTiersed
`in milk at 37° C. The dissolving time was rneasmed by
`means of a dii;integration tester as prescribed in the Phar(cid:173)
`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 fJ..-n ·.vas si.T.i(cid:173)
`larly measured for dissolving time. with the results shown in
`Table 5.
`
`The capsules were filled with 0.3 g of corn starch and
`immersed in an aqueous solution of O.lM potassium chlo(cid:173)
`ride at 37° C. The opening time was measured by means of
`a disintegration tester as prescribed in the Pharmacopoeia of 30
`Japan. lbree measurements wae taken and an average was
`15 ralC'..tlated. The results are shown in Table 2 .• A.s a
`reference. a conventional gelatin capsule was similarly mea~
`sured for opening time. with the results shown in Table 2.
`
`TABLE 2
`
`c"""'°
`
`Geiarin
`Colllp"Mlltive Example 1
`Ex.ample 1
`
`Opening time (mill.)
`
`i.3
`4.2
`1.9
`
`i.5
`4.S
`2.2
`
`i.5
`6.8
`2.4
`
`;!."\', 1.4
`e.v. 5.2
`e.v. 2.2
`
`40
`
`Sepa..rately. t.~e capsules \I/ere filled \Vi!h 0.7 g of copper
`wire as a weight and immersed in milk at 37° C. The opening 45
`time was measured by means of a disintegration tester as
`prescnbed in the Pharmacopoeia of Japan. Three measure(cid:173)
`ments •,i,1ere taken and an average was calculated. The results
`are shown iii Table 3. As a rcfcrcncc. a conventional gelatin
`capsule was similarly measured fO£ opening time. with the
`results shown jn Table 3.
`
`TABLR4
`
`Ex"""1o
`
`Comoarative &amete
`
`No. 2
`
`No.3
`
`No. 4
`
`No. 5
`
`No. 2 No. 3 No.4
`
`No. 5 No.6
`
`lrnm('Jr&irm oohitio~
`
`"""""' """
`
`l(J>MC TC.SR
`TC·5MW
`TC-5EW
`ViscOJoSi.ry
`K-carrageenan
`Pota&sium chloride
`(poi:io»iw::u. ion)
`llPMC
`K~""""'°"'"
`Potassium chloride
`(potas&ium ion)
`
`28%
`3D !:st
`0.01%
`1.0%
`{0.5'%)
`95.55%
`0.00%
`3.42%
`(1.79%)
`
`16%
`
`10%
`
`18%
`
`16%
`
`10%
`16%
`25%
`25%
`10%
`6.0 (:!;~
`6.0<;:!it
`3.0 r;;sl
`4.5 cfil
`3.0 !:Si:
`3.8 est
`3.0c!!t
`4.5 C!!t
`0.20%
`0.1S%
`0.209b
`0.20%
`0.20%
`0.08%
`0.08%
`OJJ6%
`0.10%
`0.10%
`0.11%
`0.109b
`0.10%
`0.10%
`0.11%
`1.11%
`(0.06%) (0.06%) (0.06%) (0.05%) (0.05%) (0.05%) N\ nCn.\ (0.0S%)
`\V•V-'.""')
`98.33% 98.07% 97.97% 97.18% 97.18% 97.18% 98.01% 96.12%
`0.44%
`1.22%
`1.22%
`1.22%
`0.59%
`1.92%
`0.24% OA-0%
`0.60% o.~ 0.40%
`0.96%
`0.59%
`0.60%
`0.43%
`0.:53%
`(0.33%) (0.28%) (0.31%) (0.32%) (0.32%) (0.32%) (0.21%) (0.50%)
`
`TEVA_MS_0045330
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1004 - Page 7
`
`

`
`9
`
`10
`
`5.756.123
`
`TABLE 4-continued
`
`Example
`
`Comparative Exampic
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`1%
`
`Note: TC-SR, TC-5MW and TC-5EW are rrade nmnes of HPMC manufactured by Shm-Etsu. CnemicaJ Co., Lid. TI:..SR ks a •·isoos.itf
`of 6.0 rentistokcs: TC-SMW has a viscosity of 4.5 centistokes; and TC-:5EW has a viscosity of J.O centistoU5, as measuro:i in 2%
`~.q1_1enu..; solution at 20° C. The viscosity of Exatnple 4 is that of a 111 mixture Qf TC-5MW and TC-SEW.
`
`TABLE 5
`
`Film
`
`Di&.ulvilij t~ (mil-•. )
`
`No.2
`No.3
`No.4
`No~
`Comparative Exampie No.2
`No.3
`No A
`No.5
`No.6
`
`Gelatin
`
`4
`6
`7
`9
`
`"'
`
`25
`21
`14
`>6'.l
`3
`
`6
`8
`9
`
`'
`,.
`"'
`
`23
`i5
`>6'.l
`4
`
`5
`7
`9
`9
`28
`
`,.
`
`ZI
`15
`>6'.l
`s
`
`av. 4.7
`av. 6.3
`av. 8.0
`av. 9.0
`a .... 23.3
`av. 27.0
`av. 23.7
`av. 1,:._7
`
`av. 4.0
`
`It is seen from Table 5 that the capsule shell film of the
`invention exhibits disintegration ability even in milk con(cid:173)
`taining much calcium ions.
`
`Comparative Example 7
`
`Potassium chloride was dissolved in pure water at about
`75c C. With stirring. K-carrageenan and a coloring agent
`(thallium oxide) wac: added to the solution and dissolved
`therein. With stirring. hydroxypropylmethyl cellulose 35
`(HPMC) having a viscosity of 5.87 centistok.es as measured
`in a 2% aqueous solution at 20° C. was added to the solution
`and dispersed there.in. The solution was cooled to a tem(cid:173)
`perature of 50° C. and further agitated for dissolving the
`HPMC therein. The solution was then allowed to stand for 4(J
`lkacniliou. In tti.is way, an iawucrs