(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:22)(cid:20)
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`US 7,163,693 BI
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`US. PATENT DOCUMENTS
`_
`.
`9:"1997 D1gen1s el :1].
`5.672.359 A
`5.074.530 A * 10.0997 Amidon et a].
`5.705.l89 A
`131998 Lehmann at al.
`5.750.143 A
`5."1998 Rashid ct :11.
`.-
`5.769.267 A
`@1998 Duynslager ct 31.
`5.770.224 A
`6-‘1998 Rashid d 21.
`.
`.
`11.-'1999 Cnson e1 :1].
`372001 Rashid
`39'2001 Crison ct :1].
`432002 Wurst et 31.
`10-12003 McAllister et :11.
`102004 McAllisler et al.
`77200]
`lIochIaIner ct 31.
`2!.7003 l'Iochmincr ct al.
`332003 McAlIisler et a1.
`42003 McAllislcrel a1.
`[032003 Miller et a].
`1072003 Miller 91 a].
`(#2004 McAllistcr at al.
`
`5.976.571 A
`6.200.600 Bl
`6.207.191 Bl
`6.367.228 B1
`”$1.456 S
`0403.518 5
`2001300086371 Al
`200370029558 Al
`200330049311 Al
`200370068369 Al
`200370194428 A1
`200330194430 Al
`2004.:‘0115256 Al
`
`424:472
`
`200470131668 A1
`2004-0166153 Al
`
`7:"2004 Hochrainer el :3].
`852004 McAllisler at al.
`
`‘
`FOREIGN PATENT DOCUMENTS
`.-
`6,1985
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`Page 2 of 20
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`Page 2 of 20
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`US. Patent
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`Jan. 16, 2007
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`Sheet 1 of5
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`US 7,163,693 Bl
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`US. Patent
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`Jan. 16, 2007
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`Sheet 2 of5
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`US. Patent
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`Jan. 16, 2007
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`US. Patent
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`Jan. 16, 2007
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`U.S. Patent
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`Jan. 16, 2007
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`Sheet 5 of 5
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`US 1163.693 B1
`
`1
`MULTI-COMPONENT PHARMACEUTICAL
`DOSAGE FORM
`
`This invention relates to phamtaceutical formulations.
`being a dosage form comprising two or ntore connected
`sub-units. particularly for oral desing.
`Various types of phanuaceutical dosage form are known
`for oral dosing. Phannaceutical capsules are well known.
`generally being intended for oral desing. Such capsules
`generally comprise an envelope wall of a phan'naceutically
`acceptable. e.g. orally ingestible. polymer material such as
`gelatin. although other materials for capsule walls. e.g.
`starch and cellulose based polymers are also known. Such
`capsules generally have soft walls made by making a film on
`a capsule former. which is then allowed to dry. Rigid walled
`capsules made by injection moulding are also known. see for
`example U.S. Pat. No. 4.576.284. U.S. Pat. No. 4.591.475.
`U.S. Pat. No. 4.655.840, U.S. Pat. No. 4.738.724. U.S. Pat.
`No. 4.738.817" and US. Pat. No. 4.790.881 (all to Warner
`Lambert). These disclose specific constructions of capsules
`made of gelatin. starch and other polymers, and methods of
`making them by injection moulding of hydrophilic polymer—
`water mixtures. U.S. Pat. No. 4.576.284 specifically dis-
`closes such capsules provided with a cap which closes the
`capsule. and which is formed in situ on the filled capsule by
`moulding. U .5. Pat. No. 4.738.724 discloses a wide range of
`rigid capsule shapes and parts.
`Multi—compartment capsules. including those of the type
`where each compartment has different drug release charac—
`teristics or for example contains a different drug substance
`or formulation are also known. for example in U .3. Pat. No.
`4.738.124(Wamer-Larnbert). U.S. Pat. No. 5.672.359 (Uni-
`versity of Kentucky). U .5. Pat. No. 5.443.461 (Alva Corp (J.
`W0 9516438 ((Tortecs Ltd). W0 90 l 2567 (I-lelminthology
`Inst). DEA—3727894. BE 900950 (Wanter Lambert). FR
`2524311. NI. 7610038 (Tapauhony NV). PR 28646 (Plurip-
`harm). US. Pat. No. 3.228.789 (Glassman). U.S. Pat. No.
`3.186.9l0 {Glassman} among others. U .8. Pat. No. 4.738.
`81? discloses a multicompartunent capsule with a similar
`construction to those of U.S. Pat. No. 3.228.789 and U .3.
`Pat. No. 3.186.910. made of a water-plasticised gelatin.
`Phamtaceutical dosage forms are also known which com—
`prise a matrix of a solid polymer. in which a drug substance
`is dispersed. embedded or dissolved as a solid solution. Such
`matrixes may be formed by an injection moulding process.
`This technology is discussed in Cuff G. and Raoul" F.
`Pharmaceutical Technology Jun. 1998 p 96—106. Some
`specific l'onnulations for such dosage forms are for example
`disclosed in U.S. Pat. No. 4.678.516: U.S. Pat. No. 4.806.
`33?: U.S. Pat. No. 4,764,378: U.S. Pat. No. 5.004.601; US.
`Pat. No. 5.135.252: US. Pat. No. 5.244.668; US. Pat. No.
`5.139.190: U.S. Pat. No. 5.082.655 among others; in which
`a polyethylene glycol (“PEG“) matrix is used and solid
`dosage [bulls are made by injection moulding.
`The content 01‘ the above-mentioned background publi-
`cations is incorporated herein by way of reference.
`It is an object of this invention to provide an alternative
`and improved pharmaceutical dosage fortu which provides
`inter alia greater flexibility in producing a dosage form
`adapted to a patient‘s specific administration requirement.
`and to ease of manufacture. Other objects attd advantages of
`the invention will be apparent from the following descrip-
`tion.
`
`According to this invention a multi~component dosage
`form is provided which comprises a plurality of drug sub-
`stance-containing sub-units each selected from capsule com-
`partments which can release their drttg substance in the
`
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`gastro-intestinal enviroruuent. and solid sub-units compris-
`ing a solid matrix of a polymer which contains a drug
`substance. the polymer being soluble. dispersible or disin-
`tegrable in the patient‘s gastro-intestinal environment to
`thereby release the drug substance.
`the sub-units being
`connected together in the assembled dosage form and being
`retained together by the connection at least prior to admin-
`istration to a patient, wherein the connection is provided by
`a weld between parts of the assembled dosage form.
`The connectable nature of these sub-units advantageously
`enables various sub-units having different drug release char-
`acteristics andi'or contents to be assembled and connected
`
`together to produce a dosage form. In a preferred form the
`sub—units have conunon interchangeable interconnectable
`parts so that the subunits oftlte invention may be assembled
`in various combinations using the same basic units of
`capsule compartments. solid sub-units. or of solid sub-units
`and capsule compartments. This can facilitate the rapid
`prototyping of a dosage form comprising a combination 01‘
`different drug substances in respective sub-units. auditor
`combinations of the same or dilTerent drug substances with
`diflerent release characteristics. whilst simplifying the for-
`mulation procedure.
`In a first embodiment of this invention the pharmaceutical
`dosage form comprises a plurality of capsule compartments
`each bounded and physically separated from at least one
`adjacent compartment by a wall made ot‘a phannaceutically
`acceptable polymer material, adjacent compartments being
`comtected together in the assembled dosage l'onn and being
`retained together by the connection at least prior to admin-
`istration to a patient. one or more of the compartments
`containing a drug substance. and wherein the connection is
`provided by a weld between parts of the assembled dosage
`form. suitably between immediately adjacent parts.
`first
`Suitably in the assembled dosage form of this
`embodiment there are at least two. for example three. such
`capsule compartments. Three or more such compartments
`may be linearly disposed in the assembled dosage form. e.g.
`in an arrangement comprising two end compartments at
`opposite ends of the line. and one or more intermediate
`compartments. Suitably there may be two such capsule
`compartments.
`In a second embodiment of this invention the pharma—
`ceutical dosage form comprises a plttrality of drugAcontain-
`ing sub-units comtected together in the assembled dosage
`form and being retained together by the connection at least
`prior to administration to a patient. at
`least one of the
`sub-units being a solid sub-unit comprising a solid matrix of
`a polymer which contains a drug substance. the polymer
`being soluble. dispersible or dishttegrable in the patient‘s
`gastro-intestiual enviromnent to thereby release the drug
`substance. and wherein the connection is provided by a weld
`between parts of the assembled dosage form.
`In one form of this second embodiment all ol‘the sub-units
`
`in the dosage form of this invention may be solid sub-units.
`e.g. two or more such solid sub—units. e.g. three such solid
`sub—units.
`In another form of this second embodiment. one or more
`of the sub-units comprise a solid sub-unit. and one or more
`ofthe other sub-units may comprises a capsule compartment
`bounded by a wall made of a pharmaceutical 1y acceptable
`polymer material. one or more of the said capsule compart-
`ments containing a drug substance.
`Suitably in the assembled dosage form there are at least
`two. for example three or more. e.g. four sub units. Such an
`assembled dosage form may comprise three or four sub-
`units comprising one. two or three solid sub-units. combined
`
`Page 8 of 20
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`

`3
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`US 1163.693 B1
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`two or three capsule sub-units.
`with independently one.
`Three or more such sub-tuiits may for example be linearly
`disposed in the assembled dosage fonn. eg. in an arrange-
`ment comprising two end sub-units at opposite ends of the
`line. and one or more intermediate sub-units. For example
`such an assembled dosage form may comprise a solid
`sub-unit connected to a capsule compartment: a solid sub—
`unit between two end capsule compartments: an end capsule
`compartment, an intermediate capsule compartment and an
`end solid sub-unit: an end capsule compartment. an inter-
`mediate solid sub-unit and an end solid sub-unit; or an
`intermediate capsule compartment between two end solid
`sub-units. An assembled dosage of four snch sub-units may
`comprise two end solid sub—units. an intermediate solid
`sub-unit and an intermediate capsule cotnpartment. Altern
`nately it may comprise two end solid sub-units with two
`intermediate capsule sub-units. or other combinations of
`sub-units.
`
`In one embodiment one or more. eg. all. of the sub-units
`may for example be substantially cylindrical, which term
`includes shapes which have a circular. oval or oblate circular
`cross section across the longitudinal axis. and shapes which
`have parallel or tapering e.g. with side walls which taper
`conically over at least part of their extent. Solid sub-units
`may also be substantially cylindrical in shape. Such sub-
`stantially cylindrical sub-units may be provided with con-
`neetable parts at one or both of their longitudinally disposed
`ends so that the assembled dosage form may also be overall
`ofa substantially cylindrical shape.
`A preferred form of the mold-component dosage form of
`this invention comprises two capsule compartments.
`The invention also provides individual sub-units. e.g.
`individual capsule cotnpartments or solid sub-units adapted
`for use in the assembled dosage form.
`in the assembled dosage form the adjacent sub~units_.
`whether capsule compartments. solid sub—tmits or combina—
`tions thereof. are connected together by tneans ofa weld at
`the area where two adjacent parts of the dosage form, e.g.
`sub-units. are in contact. e.g. a thermal weld. an ultrasonic
`or inductive weld. or an adhesive weld (cg. curable adhe-
`sives such as UV curable adhesive). A thermal weld may for
`example be achieved by bringing sub~units into adjacent
`contact and applying localised heating for example produced
`by directing a laser beam or a finejet of hot gas e.g. nitrogen
`at the area where two adjacent sub-units are in contact. [11
`thermal. inductive and ultrasonic welding normally localised
`fusion together of the tuaterials of adjacent parts of the
`dosage form which are in contact occurs, and on subsequent
`solidification of the materials a bond is formed between the
`
`adjacent parts. An adhesive weld may be achieved by
`applying an adhesive (e.g. curable adhesives such as UV
`curable adhesive] to parts of the dosage form which when
`the dosage form is assembled are in contact. and then
`causing or allowing the adhesive to set.
`The multi-component dosage form of the present inven-
`tion is particularly suited to fabrication using ultrasonic
`welding.
`Ultrasonic welding is a known technique involving the
`use of high frequency sound energy to soften or melt a
`thermoplastic material at the site where a joint with the
`material
`is required. A general description of ultrasonic
`welding is
`for example to be found in the publication
`“Ultrasonic Welding of Thennoplastics" (TWI Ltd.. Abing—
`ton. Cambridgeshire GB. (1997)). Parts to be joined are held
`together under pressure and then subjected to ultrasonic
`vibrations usually at a frequency of 20 40 kHz. The actual
`mechanism responsible for the generation of heat at thejoint
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`site is not well understood An ultrasonic welding machine
`comprises five main components. being a power supply. a
`control system. a welding head, fixturing to hold the parts to
`be welded. and a system to apply the required pressure. The
`power supply converts electricity into high frequency elcc-
`Lric power which drives a transducer, e.g. a piemelectric
`transducer. which converts electrical energy. e.g. from the
`mains supply.
`into mechanical.
`i.e. ultrasonic. energy.
`Between the transducer and the pans to be welded is located
`a booster and honi system. being a usually metallic com-
`ponent which serves to amplify the ultrasonic waves (the
`booster hom). transmit the clamping pressure. and deliver
`the sound energy to the part to be welded (the sonotrode or
`welding horn). For successful ultrasonic welding careful
`design of the parts to be welded and set up of the welding
`equipment is important.
`Adjacent parts of the dosage form of the invention. e.g. of
`adjacent sub-units may have features to facilitate the con-
`nection of the parts together. particularly to assist or supple-
`ment the weld.
`For example adjacent parts. eg. sub—units, of the dosage
`form of this invention may have substantially planar regions
`of their surface which may be brought into contact and then
`the weld may be formed. or may have regions of their
`surface of complementary. preferably interconnecting
`shapes. thereby facilitating connecting sub-units together by
`engagement of these complementary shaped parts.
`Preferably. additionally or alternatively adjacent sub—units
`may be provided with respectively inter~coru1ectable first
`and second connectable parts such that the first connectable
`part on one sub-unit may connect with the second connect-
`able pan on an adjacent part of the dosage form. e.g. an
`adjacent sub-unit
`in a suitable configuration. eg.
`in the
`above-mentioned linear configuration. This interconnection
`may contribute to the strength of bond achieved by the weld.
`or additionally or alternatively may help to hold adjacent
`parts of the dosage form together prior to and in readiness
`for the weld to be formed and contributes to the retention of
`
`the adjacent sub-units together. e.g. via a retaining friction.
`snap. screw or other kind of fit between the connectable
`parts. The conncetable parts may be such as to facilitate the
`assembly together of the subunits in preferred configurav
`tions, e.g.
`the comtectable part(s) on one or more one
`sub-unit may be such as to only cormect with a correspond-
`ing connectable part on other selected sub-units but not with
`non-corresponding connectable parts on other sub-units.
`Alternatively the comicctable parts on the sub-units may be
`common and interchangeable so that the sub-units may be
`connected together in a wide range of combinations. This
`means inter alia that otherwise different capsule compart—
`ments or solid sub-units may have mutually connectable
`parts so that the different capsule compartments or solid
`sub-units may be connected together in diflereiit combina-
`tions of solid sub-units or solid sub-units and capsule
`compartments.
`For example in one embodiment the respective first and
`second connectable parts may be respectively interlocking
`parts. For example the first or second pan may be a socket
`part. and the corresponding second or first connectable part
`may be a corresponding plug part which fits into the socket
`with a retaining friction. snap. screw or other kind of
`interlocking fit. If for example these plug and socket parts
`are common then any plug part on any solid sub-unit or
`capsule compartment may interconnect with any socket part
`on another solid sub—unit or capsule compartment.
`111 a friction fit for example the plug part may be slightly
`larger than the socket such that force needs to be applied
`
`Page 9 of 20
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`

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`5
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`6
`
`US 1163.693 B1
`
`against the natural resilience and contact friction of the plttg
`and socket parts to cattse the plug part to enter the socket.
`and similar force needs to be applied to separate them. In a
`snap fit for example the plug and socket parts may be
`respectively provided with a concavity and a corresponding
`convexity. such as a ridge and groove, which lock together
`as the parts are forced together against the natural resilience
`of the parts. Such a ridge and groove may for example
`comprise a co-operating circttrnlerential or part circumfer-
`ential bead and groove.
`for example located about
`the
`circumference of a connectable plug and socket part.
`Above-mentioned U.3. Pat. No. 4.576.284 and US. Pat.
`No. 4,738,724 for example.
`the contents of which are
`included herein in their entirety by way of reference. dis—
`close a range of interlocking parts of this general type by
`means of which capsule compartments may be made to
`interlock together. See for example FIGS. 1. 2 and 3 of U.S.
`Pat. No. 4,576,284 which discloses interlocking parts by
`means of which a cap may be retained on the mouth of a
`capsule. and FIGS. 4- 43 ol‘U.S. Pat. No. 4.738.724 which
`disclose numerous interlocking parts by means ofwhich part
`capsule shells may interlock and be retained together as an
`assembled complete capsule.
`The above-described first and second connectable parts
`facilitate assembly of sub-units together in various ways.
`For example in a dosage forth of the invention comprising
`a linear disposition of three or more e.g. four. sub-units. an
`intermediate sub—unit may be provided with one or more
`comiectable parts for example one at each end. which may
`connect with one or more connectable part on an adjacent
`intermediate sub-miit. An end sub-unit may be provided
`with one or more connectable pan which may connect with
`a connectable part on an adjacent
`intermediate sub-unit
`andt‘or with one or more connectable part on another end
`sub—unit. By means of this two end sub—units may connect
`together in a dosage form comprising two subunits. or two
`end sub-units may be connected to one or more intermediate
`sub-units. By ttsing common first and second connectable
`parts on the sub-units the various end and intermediate
`sub-units may be made such that they tnay be connected
`together
`in various combinations of assembled dosage
`forms.
`
`One or more sub—unit which is a capsule compartments
`may for example be substantially tubnshaped. i.e. having a
`base closed by a base wall. and side walls extending from the
`base wall (herein referred to as an “upwar " direction}. and
`an upper open mouth. With such a construction capsule
`compartments may connect together by the base of a first
`compartment fitting into the open mouth of an adjacent
`second capsule compartment. so as to close the mouth of the
`adjacent capsule compartment. and such that the base wall
`of the first compartment physically separates the compart-
`ments. In such a construction the base of the first compart-
`ment comprises a plug connectable part. and the mouth
`opening of the second compartment comprises a socket
`connectable part.
`One or more solid sub—unit may for example be shaped so
`as to [it as a plug into or a cap over the open mouth ofan
`adjacent capsule compartment so as to function as a closure
`for the mouth. Alternatively one or more solid sub-unit and
`the outer surface of the base wall ofa capsule compartment
`may be shaped so as to lit adjacent to and connect with each
`other. For example the base of such a tub-shaped capsule
`compartment may be provided externally with a plug or
`socket part and an adjacent solid sub—unit may be provided
`externally with a corresponding interconnecting socket or
`plug part. One or more capsule compartment may be formed
`
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`with a base part that can connect with the mouth opening of
`an adjacent capsule compartment so as to function as a
`closure for the mouth in the above-described manner.
`
`For example the base part of the first compartment may be
`shaped to engage with an adjacent solid sub-unit. c.g. by
`forming a socket engagement part on the adjacent part of the
`solid sub—unit which can engage the base of the capsule
`compartment. A weld between the sub-units may then be
`formed in the region of contact e.g. between the base of the
`first compartment or a solid sub-unit. and the mouth of the
`second compartment. Additionally or alternatively for
`example the sub-units may be provided with connectable
`parts to enable a retaining friction. snap, screw or other kind
`of interlocking fit.
`In such an assembly, a capsule compartment may have its
`mouth opening closed by the base wall of an adjacent
`compartment or by part of a solid sub-unit fitting into its
`open mouth in the marmer of a plttg closure. or over its
`mouth opening in the manner of a cap closure.
`Alternatively a capsule end compartment can be provided
`with some other type of closure for its mouth opening.
`particularly if it
`is connected by its base to an adjacent
`sub-unit. The closure may for example be made from the
`same. or a different. polymer than the polymer material of
`the compartment. This closure may for example comprise an
`over-cap for example fitting around the outer surface of the
`side walls of the compartment. as in the general manner
`disclosed in U.S. Pat. No. 4,196,565 or U.S. Pat. No.
`4.250.097 or altematively the closure may comprise a plug
`type of closure. Above-mentioned U.S. Pat. No. 4,576,284
`discloses some suitable types of closure for capsule com-
`partments which are suitable for use with the present inven-
`tion. The closure may be retained in place on the mouth
`opening of its compartment by a weld e.g. as described
`above. or additionally or alternatively the closure and mouth
`opening may be provided with features to enable a retaining
`friction. snap. screw or other kind of interlocking fit.
`Adjacent solid sub-units may for example have respective
`connectable plug and socket parts which can interlock to
`connect such adjacent parts together in the assembled dos-
`age limit.
`Ahemative ways of assembling and comiecting the sub
`units are encompassed within the scope of the invention.
`For example rather than having an open month which is
`closed by the presence of an adjacent compartment. one or
`more capsule compartments may be made closed and for
`example containing the drug substance. and may in this
`closed form connect in the manner described above with the
`one or more adjacent sub—units.
`For example one or more capsule compartments may be
`made in the form of two part compartment shells. each part
`compartment shell comprising a closed end and side walls
`and having a mouth opening opposite the closed end. which
`connect together. e.g. by the means discussed above. with
`their mouth openings facing. to lbrrn the capsule compart-
`ment. and one or both of the closed ends may have an
`external connectable part. One or both of the closed ends
`may connect with an adjacent sub-unit. which may be a solid
`sub-unit or a capsule compartment, e.g. by the means
`discussed above. For example if the dosage form comprises
`a linear assembly of sub-units one or both closed ends of an
`intermediate capsule compartment(s) may be connectable to
`an end sub—unit. For example each end sub-unit may be a
`substantially tub—shaped capsule compartment as described
`above and may have a mouth opening that is connectable to
`the closed end in the manner described above. or may be a
`solid sub-unit.
`
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`US 1163.693 B1
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`For example the dosage form may include one or more
`linker unit positioned between adjacent pairs ofsub-units. At
`least one weld in the dosage form may be between a sub-unit
`and such a linker unit. Such a linker unit may for example
`have connectable parts which are connectable to the above-
`mentioned first andfor second connectable parts on the
`adjacent sub—units. Suitably to facilitate a linear assembly of
`subunits in the dosage form a linker unit may have its
`connectable pans in opposite linear facing directions. Snit-
`ably such a linker unit may comprise a closure for the mouth
`opening of a capsule compartment, e.g. connecting with the
`capsule compartment in the manner ofa plug or a cap for its
`mouth opening. and having a connectable part enabling
`connection to an adjacent sub—unit. e.g. another capsule
`compartment.
`[11 a specific fon'n the linker may have one or two
`connectable parts which connect with the mouth opening of
`a capsule compartment. For example such a linker may have
`two connectable parts which are opposite facing plug parts
`and which can connect in a plug and socket manner with the
`mouth opening of two oppositely—facing capsule compart—
`ments to thereby form a capsule-linker-capsule assembly.
`Suitably welds, e.g. ultrasonic welds, may be formed
`between both of the capsule compartments and the linker
`between them in such a dosage form.
`When for example a capsule compartment has a closure
`for its mouth opening.
`then this closure may comprise a
`linker having one or more first andfor second connectable
`parts such that the first or second part on the closure may
`connect with mspectively the second or first part on an
`adjacent sub-unit in a suitable configuration.
`For example in one form such a closure may be provide
`with two oppositely-facing plug connectable parts which can
`connect with two socket connectable parts on adjacent
`sub—tuiits, e.g. the mouth openings of opposite—facing cap~
`sule compartments. Such a closure can thereby act as a
`linker between two capsule compartments with their mouth
`openings oppositely facing.
`in a capsule compartment-
`linker-capsule
`compartment
`linear
`arrangement.
`For
`example this arrangement may be an end compartment-
`linker—end compartment arrangement.
`Other ways in which such a linker may be used in a
`dosage form of the invention will be apparent. For example
`an intermediate capsule compartment may be in the form of
`a generally cylindrical shape with two oppositely facing
`open ends. and two linkers may connect via respectively one
`each of their connectable parts with an open end of the
`cylinder.
`leaving the other connectable part available for
`connection to respectively another subwunit.
`For forming an ultrasonic weld between adjacent parts of
`the dosage form ofthis invention, it is preferred that adjacent
`parts of the dosage form between which the ultrasonic weld
`is
`fanned. for example of adjacent contacting. capsule
`compartments andJ'or solid sub tutits. or of adjacent contact-
`ing parts ofa linker and a capsule compartment or solid unit.
`in particular of end capsule compartments with a linker in
`between. are profiled and dimensioned to facilitate an ultra—
`sonic shear joint. A shear joint is one type of weld structure
`which can be used in ultrasonic welding of polymer mate-
`rials. Adjacent parts to be brought into contact and welded
`are dimensioned and profiled to provide a small
`initial
`contact area. then a controlled interference occurs along the
`joint as the parts collapse together under the application of
`ultrasonic energy.
`For example a suitable profile is provided by plug and
`socket connectable parts comprising engaging tenon parts
`(cg. opposite facing complementary steps), where the
`
`length of one tenon is less than the length of the other tenon
`part. and under the ultrasonic welding operation the material
`of the parts can collapse until the tenon parts longitudinally
`engage.
`
`The multicomponcnt dosage form of this invention com-
`prising a capsule compartntcnt-linker-capsule compartment
`in a linear arrangement and connected together by means of
`at
`least one ultrasonic weld formed between a capsule
`compartment and the linker is a particular form of this
`invention. and some preferred features of this form are
`discussed below.
`
`ll]
`
`Advantageous features of the capsule compartments have
`been devised to facilitate assembly andi’or ultrasonic weld-
`ing of the dosage fonn ofthis invention.
`The wall of the capsule compartment is preferably ca.
`0.1—0.8 mm, especially 0.3—0.5 mm. thick. at least in the
`cylindrical side walls of the compartment. this thickness
`being generally found suitable as a minimum to reduce the
`risk of damage to the compartment by the ultrasonic energy
`during the welding operation. A thickness mansions mm
`is particularly preferred as a balance between strength for
`welding and drug content release. The end compartments in
`such a two compartment capsule are suitably each in the
`shape ofa cylinder having one open end and one closed end.
`The closed end is suitably closed by a generally rounded.
`e.g. hemispherical end wall, e.g. an open ended “bucket“ or
`“tub" shape. Suitably the side walls taper gently in a shallow
`conical fashion, the cross section being greatest at the open
`end (cmg inter alia to facilitate removal from an injection
`mould). Suitably the central part ofthe rounded end of such
`a bucket or tub shape may be flattened to facilitate the
`application of ultrasonic energy during the welding opera-
`tion.
`
`Preferably at least one, preferably both, of the connectable
`parts of the linker is a plug part which [it's in a plug-and-
`socket manner into the open end ofa capsule compartment.
`Therefore such a plug part is typically a cylindrical shape.
`corresponding closely to the internal shape of the open end
`ofa capsule compartment adjacent to the open end.
`Preferably the linker is in the form of a solid wall part with
`oppositely facing plug connectable parts, oppositely facing
`end surfaces ofthe plug parts extending generally transverse
`to the longitudinal direction of the linker. Preferably each
`plug part is a snug friction fit into the epen end of a capsule
`compartment. Preferably each plug part is provided with an
`abutment surface to define and limit the extent to which each
`
`plug part can extend into the open end of a capsule com-
`partmem by abutting against the rim of the open end of a
`capsule compartment when the plug part extends to a
`suitable extent into the capsule month.
`In a preferred construction. the linker comprises a gen-
`erally cylindrical solid body, its opposite facing ends being
`plug parts. with two oppositely facing abutment surfaces
`each being a surface ofa ledge formed around the circum-
`ference of the cylindrical body and generally planar in a
`plane perpendicular to the length direction. Such a ledge
`may typically be ring shaped with its plane perpendicular to
`the longitudinal direction of the capsule. With such a linker
`the assembled dosage form may comprise two capsule
`compartments each in the shape of a cylinder having one
`open end and one closed end (cg. the above-described tub
`or bucket shapes), with their open ends in an opposite facing
`relationship, with a linker between them with each of the
`opposite facing plug parts of the linker fitting in a plug—and—
`socket manner into the open end of a capsule compartment.
`with an ultrasonic weld fonned between a plug part andr‘or
`
`3U
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`35
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`4t]
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`45
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`50
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`55
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`6t;
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`65
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`US ?.163,693 B1
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`an abuttuent surface of the linker and the compartment wall
`in the vicinity of the open end. e.g. the rim ofthe open end.
`Another assembled dosage form may comprise three
`capsule compartments. two being end compartments each in
`the shape ol‘a cylinder having one open end and one closed
`end. with their open ends in an opposite facing relationship.
`with an intermediate compartment longitudinally between
`the two end compartments. with