(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`\
`
`(43) International Publication Date
`10 November 2016 (10.11.2016)
`
`WIPO!|PCT
`
`(51)
`
`International Patent Classification:
`A61J 1/14 (2006.01)
`B65D 25/08 (2006.01)
`AG61K 9/14 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/IB2016/052486
`
`(81)
`
`(22)
`
`International Filing Date:
`
`2 May 2016 (02.05.2016)
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`(25)
`
`(26)
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`(30)
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`(7)
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`(72)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`PCT/IB2015/053209 1 May 2015 (01.05.2015)
`PCT/IB2015/055780 30 July 2015 (30.07.2015)
`15/133,826
`20 April 2016 (20.04.2016)
`
`English
`
`English
`
`IB
`IB
`US
`
`(84)
`
`Applicant: SUN PHARMACEUTICAL INDUSTRIES
`LIMITED [IN/IN]; Sun House, Plot No. 201 B/1, Western
`Express Highway, Goregaon (E), Mumbai, Maharashtra
`400 063 (IN).
`
`Inventors: BHARGAVA,Rahul, G-73, Sarita Vihar, New
`Delhi, Delhi 110076 (IN). MITTAL, Bhupesh Kumar;
`House No. 1/439, Kala Kua, Housing Board, Alwar, Ra-
`jasthan 301001 (IN). RAMARAJU, Kalaiselvan;
`s/o
`Ramaraju, Udayampatty, Kattukulam Post, Tiruvellerai
`
`(10) International Publication Number
`WO 2016/178132 Al
`
`VIA, Trichirapalli, Tamil Nadu 621009 (IN). KUMAR,
`Ashish; House No. 79/11, Gali No. 04, Nehru Park, Ba-
`hadurgarh, Jhajjar, Haryana 124507 (IN).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FL GB, GD, GE, GH, GM, GT,
`HN, HR, HU,ID,IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NL NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG,US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW,SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DF,
`DK, EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM,ML, MR,NE,SN, TD, TG).
`
`[Continued on next page]
`
`(54) Title: DUAL-CHAMBER PACK FOR EXTENDED RELEASE SUSPENSION COMPOSITIONS
`Figure 1: Schematic diagram of the components of a dual-chamber pack with a
`powderfor suspension prefilled in the plunger,
`
`(57) Abstract: The present invention relates to a dual-cham-
`ber pack comprising a first chamber prefilled with a suspen-
`sion base and a second chamberprefilled with a powderfor
`suspension comprising an active ingredient, wherein upon
`activation of the dual-chamberpack, the contents of both the
`chambers are mixed to form an extended release suspension
`composition which is characterized by having no substantial
`change in the in-vitro dissolutionrelease profile ofthe active
`ingredient upon storage for at least seven days.
`
`
`
`
`
`Overcap - |, Tamper evidentband - 2. Plunger- 3. Plug - 4, Breakable polymeric
`membrane- 5. Openingofthe comiainer- 6, Container- 7.
`
`WO2016/178132AX[IMVINIAININMINIATANIINUTTTAMMIEAN
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`

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`WO 2016/178132 AL UAUUIITNANEIMERETETUUT CANTONNAA
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`Published: —__before the expiration of the time limit for amending the
`
`— with international search report (Art. 21(3))
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
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`

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`WO 2016/178132
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`PCT/IB2016/052486
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`DUAL-CHAMBERPACK FOR EXTENDED RELEASE SUSPENSION
`
`COMPOSITIONS
`
`Field of the Invention
`
`The present inventionrelates to a dual-chamber pack comprising a first chamber
`
`prefilled with a suspension base and a second chamberprefilled with a powderfor
`
`suspension comprising an active ingredient, wherein uponactivation of the dual-chamber
`
`pack, the contents of both the chambers are mixed to form an extended release suspension
`
`composition which is characterized by having no substantial change in the in-vitro
`
`dissolution release profile of the active ingredient upon storage for at least seven days.
`
`Background of the Invention
`
`Extended release solid compositions are preferred dosage forms over immediate
`
`release solid compositions, especially for active ingredients showing fluctuationsin the
`
`plasma concentration and for active ingredients having short half-lrves. Extended release
`
`solid compositions can be in the form of tablets or capsules, wherein the release of the
`
`active ingredient is controlled by using a reservoiror a matrix system. However, extended
`
`release solid compositions suffer from certain drawbacks such as difficulty in swallowing,
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`particularly for certain groups of patients, e.g., pediatrics and geriatrics, resulting in poor
`
`patient compliance. Further, high doses of active ingredients lead to large-sized
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`10
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`15
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`compositions which aggravates this problem. Also, there remains a tendencyto divide
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`20
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`extended release solid compositions such as tablets into small pieces in orderto facilitate
`
`administration, which may ultimately lead to inaccurate dosing and/or dose dumping. In
`
`viewofall this, extended release liquid compositions provide the best alternative over
`
`extended release solid compositions. Extended release liquid compositions are casy to
`
`administer, thereby leading to enhanced patient compliance. Additionally, extended
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`25
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`release liquid compositions provide a unique advantage of having a flexible dosing
`
`regimen.
`
`Extended release liquid compositions are conventionally administered as powder
`
`for suspensions which are to be reconstituted by the end users at the time of administration
`
`using household pre-boiled and cooled water. Alternatively, the diluent or purified wateris
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`30
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`supplied separately along with the bottle having the extended release powder for
`
`suspension. These conventional packs lack patient compliance and may lead to
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`WO 2016/178132
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`PCT/1B2016/052486
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`contamination due to improper quality of water. Further, there remains a possibility of
`
`dosing errors if the diluent or water is not added to the marked level.
`
`US. Patent No. 3,156,369; U.S. Patent No. 3,603,469: U.S. Patent No. 3,840,136;
`
`and U.S. Patent No. 4,982,875 disclose the use of dual-chamberpacks for separately
`
`storing two compositions in two compartments which can be admixedat the timeofuse.
`
`The two compartments are separated by a breakable membrane whichis ruptured by the
`
`depression of a plungerso that the one composition gets released into another and is
`
`mixed. However, there remains a possibility that the membrane fragments may get
`
`detached andfall into the final product. This maylead to undesirable contamination and
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`10
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`can pose serious health hazards. Furthermore, the dual-chamber packs disclosed in the
`
`prior art have a limited capacity for the compartments which may not be suitable for high-
`
`dose drugs or for drugs which require chronic administration. Also, the liquid composition
`
`may get permeated into the solid composition across the membrane during storage which
`
`can lead to the agglomeration of the solid composition. This may result in poor flow of the
`
`solid composition, thus affecting the content uniformity of the final product. Also, the
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`liquid composition on permeation can affect the stability of moisture-sensitive active
`
`ingredients.
`
`The present invention provides a patient compliant dual-chamber pack with a
`
`significant improvement overthe prior art and which fulfills the unmet need of
`
`incorporating variety of active ingredients. The present dual-chamber pack can be suitable
`
`for anyclass of active mgredients including the high-dose active ingredients, active
`
`ingredients requiring chronic administration, and/or moisture-sensitive active ingredients.
`
`Further, the plunger used in the pack ofthe instant invention is designed in a way suchthat
`
`the breakable membrane remains adheredto the plug at the time ofactivation and
`
`membrane fragments do notfall into the final product. During activation, the pack ensures
`
`that the final product remains safe for the use of patients. The pack also ensures that the
`
`solid composition is completely released into the liquid composition thereby maintaining
`
`the content uniformityof the final product. Further, the pack also ensures that there is no
`
`permeation of moisture into the chamber having solid composition comprising the active
`
`ingredient, and the stability of the active ingredient remains unaffected during storage.
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`20
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`
`Apart from storage, there remains someof the complexities involved in
`
`formulating such reconstituted extended release powderfor suspension compositions.
`
`Uponreconstitution, the important prerequisite of these compositions is to provide the
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`WO 2016/178132
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`PCT/1B2016/052486
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`desired extended release ofthe active ingredient throughout its shelf life, as irregular
`
`release may lead to sub-therapeutic or toxic effects. Once reconstituted, the key hurdle
`
`remains to overcomethe leaching ofthe active ingredient from the coated cores into a
`
`suspension base during storage. The objective for a scientist remains to develop a
`
`formulation such that the release of the active ingredient into the suspension base during
`
`storage is avoided, and only whenthe suspension enters the gastrointestinal tract the
`
`release is allowed.
`
`The present invention offers the reconstituted suspension compositions which
`
`provide the desired extended release ofthe active ingredient throughout the shelf life of
`
`10
`
`the compositions. In the present invention, the suspension base prevents the leaching of
`
`the active ingredient from the coated cores and thus ensures substantially similar in-vitro
`
`dissolution release profile of the active ingredient throughoutthe shelf life of the
`
`compositions. This consistent in-vitro release then ensures a steady plasma concentration
`
`with no fluctuations throughout the shelf life of the compositions.
`
`The present invention thus provides a novel patient-compliant dual-chamber pack
`
`prefilled with solid and liquid compositions tn two chambers, which upon mixing forms a
`
`unique composition providing the desired extended release of the active ingredient
`
`throughout the shelf life of the composition. The compositionsprefilled in the dual-
`
`chamberpack remain stable during the storage.
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`20
`
`Summaryofthe Invention
`
`The present invention relates to a dual-chamber pack comprising a first chamber
`
`prefilled with a suspension base and a second chamber prefilled with a powder for
`
`suspension comprising an active ingredient, wherein upon activation of the dual-chamber
`
`pack, the contents of both the chambers are mixed to form an extended release suspension
`
`composition which is characterized by having no substantial change in the in-vitro
`
`dissolution release profile of the active ingredient upon storage for at least seven days. The
`
`pack allows the end-users ease of dispensing with only a few simple steps required for
`
`reconstitution. The pack is suitable from lowto high dose active ingredients, active
`
`ingredients required for chronic administration as well as moisture-sensitive active
`
`30
`
`ingredients. The pack ensures that the powder for suspension falls completely mto the
`
`suspension base thereby maintaining the content uniformity. The pack also ensures that
`
`final product remains free of any contamination from the pack components andis safe to
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`WO 2016/178132
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`PCT/1B2016/052486
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`the end-users. Further, the pack ensures the stability of the active ingredient during
`
`storage.
`
`Brief Description of the Drawings
`
`Figure 1: Schematic diagram of the components of a dual-chamberpack with a
`
`an
`
`powderfor suspension prefilled in the plunger
`
`Figure 2: Schematic diagram of the components of a dual-chamberpack with a
`
`powderfor suspension prefilled in the reservoir
`
`Figure 3: Schematic diagram for the biphasic connector — top view and front view
`
`Figure 4: Schematic diagram representing the assembly of a dual-chamber pack
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`10
`
`with a powderfor suspension prefilled in the reservoir
`
`Figure 5: Schematic diagram representing the functioning of a dual-chamber pack
`
`with a powderfor suspension prefilled in the reservoir
`
`Detailed Description of the Invention
`
`A first aspect ofthe invention provides a dual-chamber pack comprising;
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`15
`
`(a) a first chamberprefilled with a suspension base; and
`
`(b) a second chamberprefilled with a powder for suspension comprising an
`
`active ingredient;
`
`wherein uponactivation of the dual-chamberpack, the contents of both the chambers are
`
`mixed to form an extended release suspension composition whichis characterized by
`
`20
`
`having no substantial change in the in-vitro dissolution release profile of the active
`
`ingredient upon storage for at least seven days.
`
`According to one embodiment of the above aspect, the powder for suspension
`
`prefilled in the second chamberis present in a volume ranging from about 0.5 cc to about
`
`500 ce.
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`25
`
`According to another embodiment of the above aspect, the first chamber comprises
`
`of a container and the second chamber comprises of an overcap, a plunger, and a plug with
`
`a breakable polymeric membrane. The plungeris prefilled with the powder for suspension
`
`in a volumeranging from about 0.5 cc to about 30 cc.
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`According to another embodiment of the above aspect, the first chamber comprises
`
`of a container and the second chamber comprises of a reservoir, a biphasic connector, a
`
`plunger, and a plug with a breakable polymeric membrane. Thereservoiris prefilled with
`
`the powderfor suspension in a volumegreater than about 30 cc. Inparticular, the reservoir
`
`1s prefilled with the powder for suspension in a volume ranging from about 30 cc to about
`
`500 cc.
`
`According to another embodiment of the above aspect, the biphasic connector of
`
`the second chamber connects the reservoir to the container of the first chamber.
`
`According to another embodiment of the above aspect, the plunger ensures the
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`10
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`breakable polymeric membrane remainsattached to the plug during activation.
`
`According to another embodiment of the above aspect, the plunger comprise of one
`
`or more sharp projections with an essential continuous blunt area. In a preferred
`
`embodiment, the plunger comprise of one sharp projection with an essential continuous
`
`blunt area. The plunger can further have one or more grooves. The body of the plunger can
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`15
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`be in the form of a cylinderor a funnel.
`
`According to another embodiment of the above aspect, the plug is made up ofa
`
`polymeric material selected from the group comprising polyolefin, polyethylene,
`
`polypropylene, polyvinyl chloride, cyclic olefin polymer, cyclic olefin co-polymer,
`
`polyethylene terephthalate, polyethylene terephthalate - G, polypropylene, and
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`20
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`polycarbonate. In a preferred embodiment, the plug is made up of polyethylene.
`
`According to another embodiment of the above aspect, the plug additionally
`
`includes one or more moisture barrier additives.
`
`According to another embodiment of the above aspect, the moisture barrier
`
`additives are selected from the plastic additive group comprising of monomers and co-
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`25
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`polymersthat get activated through polymerization process to form an effective organic
`
`chemical.
`
`According to another embodiment of the above aspect, the moisture barrier
`
`additives improve the moisture barrier properties by up to 50%. In particular, the moisture
`
`barrier additives improve the moisture barrier properties by up to 30%.
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`WO 2016/178132
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`PCT/1B2016/052486
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`According to another embodiment of the above aspect, the plug with the breakable
`
`polymeric membrane prevents moisture permeation fromthe first chamber into the second
`
`chamber.
`
`According to another embodiment of the above aspect, the extended release
`
`suspension composition is a stable composition.
`
`A second aspect of the present invention provides a dual-chamber pack
`
`comprising:
`
`a)
`
`a first chamber in the form of a container(7) prefilled with a suspension
`
`base and provided with an opening (6) at an upper end;
`
`b)
`
`a second chamber comprising:
`
`(i)
`
`a overcap (1) optionally having a tamper evident band (2) fitted into
`
`a plunger (3);
`
`(11)
`
`the plunger(3) adapted to fit into a plug (4), having a topflat
`
`surface, prefilled with a powder for suspension comprising an active
`
`ingredient;
`
`(iii)
`
`the plug (4), with a breakable polymeric membrane (5), adapted to
`
`fit into the openimg (6) from a lower end and into the
`
`overcap (1) from the upper end; and
`
`wherein the overcap (1) has a means to exert pressure onto the plunger(3) so as to
`
`partially rupture the breakable polymeric membrane(5) of the plug and deliver the powder
`
`for suspension into the suspension base of the container (7); and wherein the powderfor
`
`suspension is mixed with the suspension base to form an extended release suspension
`
`composition which ts characterized by having no substantial changein thein-vitro
`
`dissolution release profile of the active ingredient upon storage forat least seven days.
`
`According to one embodimentof the above aspect, the plungeris prefilled with the
`
`powderfor suspension in a volume ranging from about 0.5 cc to about 30 cc.
`
`According to another embodimentof the above aspect, the plunger may be opened
`
`at both the ends. In this case, the plungeris fitted into the overcap first, and then the
`
`powderfor suspensionis prefilled into the plunger whichis then fitted with a plug.
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`According to another embodiment of the above aspect, the plunger comprise of one
`
`or more sharp projections with an essential continuous blunt area. In a preferred
`
`embodiment, the plunger comprise of one sharp projection with an essential continuous
`
`blunt area.
`
`The overcap exerts pressure onto the plunger whenit is screwed during activation
`
`of the dual-chamberpack.
`
`A third aspect of the present invention provides a dual-chamber pack comprising:
`
`a)
`
`a first chamber in the form of a container(8) prefilled with a suspension
`
`base provided with an opening (7) at an upper end;
`
`b)
`
`a second chamber comprising:
`
`(i)
`
`a reservoir (1) adapted tofit into a plunger(2) prefilled with a
`
`powderfor suspension comprising an active ingredient; the plunger
`
`(2) is further adapted to fit mto a plug (3) having a top flat surface,
`
`(11)
`
`the plug (3), with a breakable polymeric membrane (4), adapted to
`
`fit into the biphasic connector (5) optionally having a tamper
`
`evident band (6) whichis further connected from the lower end to
`
`the opening (7) of the container(8);
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`10
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`15
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`wherein the reservoir (1) at the top of the second chamberhas a meansto exert pressure
`
`onto the plunger(2) so as to partially rupture the breakable polymeric membrane(4)of the
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`20
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`plug and deliver the powder for suspension into the suspension base of the container(8);
`
`the second chamberis replaced with a cap (9), and wherein the powderfor suspensionis
`
`mixed with the suspension base to form an extendedrelease suspension composition
`
`which is characterized by having no substantial change in the in-vitro dissolution release
`
`profile of the active ingredient upon storage for at least seven days.
`
`According to one embodiment of the above aspect, the reservoir is prefilled with
`
`the powderfor suspension in a volume greater than about 30 cc, particularly in a range
`
`from about 30 cc to about 500 cc.
`
`According to another embodiment of the above aspect, the plunger comprise of one
`
`or more sharp projections, wherein the plungeressentially has a continuousbluntarea. In a
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`30
`
`preferred embodiment, the plunger comprise of one sharp projection with a continuous
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`WO 2016/178132
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`blunt area. The bodyof the plungercan be in the form of a cylinder or a funnel. The funnel
`
`shaped plungerfurther helps to increase the capacity to incorporate high dose drugs.
`
`According to another embodimentof the above aspect, the plunger is opened at
`
`both the ends.
`
`According to another embodiment of the above aspect, the cap is a conventional
`
`cap or a child-resistant cap.
`
`According to another embodimentof the above aspect, the biphasic connector has
`
`a tampercvident band on the side connected to the containerof the first chamber and
`
`grooves on anotherside for locking with the reservoir of the second chamber.
`
`According to another embodiment of the above aspect, the reservoir exerts
`
`pressure onto the plunger whenit is screwed during activation of the dual-chamberpack.
`
`A fourth aspect of the present invention provides a method of providing an
`
`extended release suspension composition stored in a dual-chamber pack, comprising the
`
`stepsof:
`
`(a)
`
`providing a first chamber comprising a container (7), a second chamber
`
`comprising an overcap (1), a plunger (3), a plug (4) with a breakable
`
`polymeric membrane(5);
`
`(b)
`
`(c)
`
`prefilling the container (7) of the first chamber with a suspension base;
`
`prefilling the plunger(3) of the second chamber with a powderfor
`
`suspension compnising, an active ingredient,
`
`(d)
`
`fixing the plunger(3) into the plug (4) and mounting the plug on an
`
`opening (6) of the container (7) of the first chamber;
`
`(c)
`
`activating the dual-chamberpack by screwing the overcap (1) so that the
`
`plunger(3) partially ruptures breakable polymeric membrane(5) of the
`
`plug (4); and
`
`(f)
`
`shaking the container(7) to allow the mixing of the powder for suspension
`
`with the suspension base to obtain the extended release suspension
`
`composition which is characterized by having no substantial change in the
`
`in-vitro dissolutionrelease profile ofthe active ingredient upon storage for
`
`at least seven days.
`
`an
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`According to one embodiment of above aspect, the plungeris prefilled with the
`
`powderfor suspension in a volume ranging from about 0.5 cc to about 30 cc.
`
`According to another embodiment of above aspect, the plunger may be openat
`
`both the ends. In this case, the plunger1s fitted into the overcap first, and then the powder
`
`5
`
`for suspension isprefilled into the plunger which is then fitted with a plug. Alternatively,
`
`the overcap may beprefitted with the plunger.
`
`The overcap may have a tamper-evident band which1s to be removedfirst to start
`
`the activation process.
`
`A fifth aspect of the present invention provides a method of providing an extended
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`10
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`release suspension composition stored in a dual-chamber pack, comprising the steps of:
`
`(a)
`
`providing a first chamber comprising a container (8), a second chamber
`
`comprising a reservoir (1), a plunger (2), a plug (3) with a breakable
`
`polymeric membrane (4), and a biphasic connector(5);
`
`(b)
`
`prefilling the container(8) of the first chamber with a suspension base to
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`15
`
`form a first chamber;
`
`(c)
`
`prefilling a reservoir (1) of the second chamber with a powder for
`
`(d)
`
`(e)
`
`(f)
`
`20
`
`suspension comprising an active ingredient;
`
`fixing the biphasic connector(5) into the reservoir (1);
`
`fixing the plunger(2) in the biphasic connector(5);
`
`mounting the plug (3) onto the plunger of the biphasic connector(5) to
`
`form the second chamber,
`
`(g)
`
`mounting the second chamberonto the opening (7) of the container (8) of
`
`the first chamber;
`
`(h)
`
`activating the dual-chamberpack by screwing the reservoir (1) of the
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`25
`
`second chamberso that the plungerpartially ruptures the circumference of
`
`(1)
`
`()
`
`a breakable polymeric membrane; and
`
`removing the second chamber and replacing it with a cap (9):
`
`shaking the container(8) to allow the mixing of the powder for suspension
`
`with the suspension base to obtain the extended release suspension
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`30
`
`composition which is characterized by having no substantial change in the
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`WO 2016/178132
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`PCT/1B2016/052486
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`in-vitro dissolution release profile of the active ingredient upon storage for
`
`at least seven days.
`
`According to one embodiment of the above aspect, the reservoiris prefilled with
`
`the powderfor suspension in a volume greater than about 30 cc, particularly in a range
`
`from about 30 cc to about 500 cc.
`
`According to another embodiment of above aspect, the biphasic connector has a
`
`tamper evident band on the side connected to the containerofthe first chamber and
`
`grooves on anotherside for locking with the reservoir of the second chamber. The tamper
`
`evident band is removedfirst to start the activation process.
`
`According to another embodimentof the above aspects, the powder for suspension
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`comprise of extended release coated cores of an active ingredient, optionally admixed with
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`one or more pharmaceutically acceptable excipients. The powder for suspension may
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`additionally have one or more osmogents, or one or more suspending agents. The core
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`may comprise ofa release-controlling agent in the form of a matrix withthe active
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`ingredient, which can be coated with a coating layer that remain insoluble in the
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`suspension base during storage.
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`According to another embodiment of the above aspects, the extended release
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`coated cores comprise a core comprising, an active ingredient and a coating laver over said
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`core comprising one or more release-controlling agents.
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`According to another embodiment of the above aspects, the core is m the form of a
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`bead, a pellet, a granule, a spheroid, or the like.
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`10
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`15
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`20
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`According to another embodiment of the above aspects, the active ingredientis
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`layered onto an inert particle to form the core.
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`Alternatively, the extended release coated cores comprise a core comprising an
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`active ingredient in a complexed or an ion-exchange resin form and a coating layer over
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`said core comprising one or more release-controlling agents.
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`According to another embodimentof above aspects, the release-controlling agentis
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`selected from the group comprising a pH-dependent release-controlling agent, a pH-
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`independent release-controlling agent, or mixtures thereof.
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`30
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`According to another embodiment of the above aspects, the extended release
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`suspension composition is characterized by having an osmolality ratio of at least about 1.
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`The term “powder for suspension,” as used herein, refers to a solid composition
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`comprising extended release coated cores of an active ingredient, optionally admixed with
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`one or more osmogents, one or more suspending agents, or pharmaceutically acceptable
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`excipients. The plungeror container of the second chamberof the present invention is
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`prefilled with the powderfor suspension.
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`The term “suspension base,” as used herein, refers to a medium whichis used to
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`suspend the coated cores of the active ingredient. The suspension base of the present
`
`invention comprises one or more suspending agents, one or more osmogents, and a
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`pharmaceutically acceptable vehicle. It may further comprise one or more
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`10
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`pharmaceutically acceptable excipients. The powder for suspension having coated cores
`
`of active ingredient maybe reconstituted with the suspension base having suspending
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`agents, osmogents, pharmaceutically acceptable excipients, and a pharmaceutically
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`acceptable vehicle. Alternatively, suspending agents, osmogents, or other
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`pharmaceutically acceptable excipients may be premixed with the coated cores which may
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`be reconstituted with the pharmaceutically acceptable vehicle. The pharmaceutically
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`acceptable vehicle may comprise of purified water or a mixture of purified water with one
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`or more suitable organic solvents, in particular purified water. The container ofthe first
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`chamberofthe present invention is prefilled with a pre-formed suspension base or a
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`pharmaceutically acceptable vehicle which forms the suspension base at the time of
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`reconstitution. The suspension base generates a hypertonic condition such that there is no
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`substantial change in the in-vitro dissolution release profile ofthe active ingredient upon
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`storage of the reconstituted extended release suspension compositionfor at least seven
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`days. The suspension base of the present invention has an osmolality of at least about |
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`osmol/kg of the suspension base.
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`The term “activation,” as used herein means a process which reconstitutes the
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`powderfor suspension with the suspension base. The activation can be done bythe end-
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`users such as patients, pharmacists, or caregivers. The activation process starts by either
`
`screwing the overcap or the reservoir.
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`20
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`25
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`The term “extended release,” as used hereim, refers to the release profile of the
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`30
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`active ingredient over an extended periodoftime, e.g., over a period of 4, 6, 8, 12, 24
`
`hours, or more.
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`The term “hypertonic condition,” as used herein, means the suspension base has
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`higher solute concentration which helps to generate high osmotic pressure such that there
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`is no significant leaching of active ingredient from the coated cores into the suspension
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`base. In the present invention, the solutes are osmogents /.e., pharmaceutically acceptable
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`inert water-soluble compoundsthat contribute towards generating hypertonic conditions in
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`the suspension base. Alternatively, a saturated solution of the active ingredient present in
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`the suspension baseor the external phase may prevent the substantial leaching of the
`
`active ingredient from the extended release coated cores.
`
`The term “osmolality ratio,” as used herem, meansthe ratio of the osmolality of
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`10
`
`the external phase to the osmolality of the internal phase. The external phase herein means
`
`the suspension base without the multiple extended release coated cores of the active
`
`mgredient. The internal phase herein means the extended release coated cores ofthe active
`
`ingredient. As the direct measurement of the osmolality of the internal phase i.e., coated
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`coresis difficult, the osmolality of the internal phase herein, is represented as the
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`osmolality of a solution which prevents significant leaching of the active ingredient from
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`the coated cores into the solution. The leaching ofthe active ingredient from the extended
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`release coated cores is determined bythe difference in the osmolalities across the coating
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`layer and the absence of any significant leaching from the extended release coated cores
`
`directs that the osmolality of the solution has become equal to the osmolality of the
`
`extended release coated cores. The osmolality ratio of the extended release suspension
`
`compositions of present inventionis at least about 1.
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`The term “osmolality,” as used herein, is expressed as number of moles of any
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`water-soluble compoundper kg of a liquid phase. The liquid phase can be a suspension
`
`base or a solution. In the present invention, the osmolality may be measured according to
`
`known methods, such as using a vapor pressure osmometer, a colloid osmometer, or a
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`freezing point depression osmometer such as Osmomat 030-D or Osmomat 3000, in
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`particular bya freezing point depression osmometer.
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`20
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`25
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`The term “inert particle,” as used herein, refers to a particle made from a sugar
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`sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic
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`30
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`calcium phosphate bead, a mannitol bead, a silica bead,a tartaric acid pellet, a wax based
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`pellet, and the like.
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`The term “substantial,” as used herein refers to any value whichlies within the
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`range as defined by a variation of up to +15 from the average value.
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`The term “about” as used herein, refers to any value which lies within the range
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`defined by a variation of up to +10% ofthe value.
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`The term “significant leaching,” as used herein means more than 20% ofthe active
`
`ingredient is leached out from the extended release coated cores into the solution.
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`The term “stable,” as used herein, refers to chemical stability, wherein not more
`
`than 5% w/w oftotal related substances are formed on storage at 40°C and 75%relative
`
`humidity (R.H.) or at 25°C and 60% R.H.for a period ofat least three monthsto the extent
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`10
`
`necessary for the sale and use of the composition.
`
`The term “osmogent,” as used herein, refers to all pharmaceutically acceptable
`
`inert water-soluble compoundsthat can imbibe water and/or aqucousbiological fluids.
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`The osmogent can be present in the suspension base or in the powderfor suspension or
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`both. Suitable examples of osmogents or pharmaceutically acceptable inert water-soluble
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`compoundsare selected from the group comprising carbohydrates such as xylitol,
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`mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose,
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`sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids
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`such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride,
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`sodium chloride, potas