,·('--·
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`•
`
`1111111111m1111111m1rn 111111111111111m111111111m 11111
`
`(43) International Publication Date
`15 September 2005 (15.09.2005)
`
`PCT
`
`(10) InternationaJ Publication Number
`WO 2005/084666 Al
`
`{Sl) Intemetlooal Patent Clesslficatlon7:
`
`A61K3V41
`
`{21) Intemeilonel Appllceiloo Number:
`PCT/US200S/006043
`
`{22) lntemetlonel FWng Date: 28 February 2005 (28.02.2005)
`
`(25) FIUng Language:
`
`{26) Publication Language:
`
`English
`
`English
`
`{30) Priority Date:
`60/549,420
`
`2 March 2004 {02.03.2004) US
`
`{71) Applicant (for all designated States except US):
`ABEILLE PHARMACElITICALS, INC. [US/US]; 116
`Village Boulevard, Suite 200, Princeton, NJ 08540-5700
`(US).
`
`(72) Inventor; end
`{75) Inventor/Appllcent (for US only): BORSADIA, Suresh
`{US/US]; Abeille Phannaceuticals, Inc., 116 Village
`Boulevard, Suite 200, Princeton, NJ 08540-5700 (US).
`
`-
`-
`iiiiii
`_
`_
`-
`
`=
`= Jackson, P.O. Box 88, Hopewell, NJ 08525 (US).
`
`{74) Agent: JACKSON, Arthur; Law Offices of Arthur E.
`
`(81) Designated States (unless otherwise indicalt!d, for every
`Ir.ind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY. BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, Il.., IN, IS, JP, KE,
`KG, ICP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SO, SK, SL, SM, SY, TJ,
`TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA,
`ZM,ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`Ir.ind of regional protection available): ARTPO (BW, GH,
`GM, KE, LS, MW, 'MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE. BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, m. rs. IT, LT, LU, MC, NL, PL. PT. RO,
`SE. SI, SK. TR), OAPI (BF, BJ, CF, CG, CI. CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Publlshed:
`with inlemational search n!pon ·
`before the expiration of the time limit for amending the
`claims and to be republished in the evenl of IT!Ceipr of
`amendments
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gaume .
`
`< {54) Title: CO-FORMULATIONS OF KITS OFBIOACI1VE AGENTS
`.....c
`
`\C {57) Abstract: Provided, among other things, is a fonnulation or kit comprising: (a) a phannaceutically effective dosage of one
`~ or more a glucose-levekontrolling bioactive agents selected from an a-glucodase inhibitor, sulfonylurea, meglitinide, thiazolidine(cid:173)
`"'i" diones, biguanide, insulin, dual PPAR al"( agonist, PPARy agonist or insulin secretagogue; and (b) a pharmaceutically effective
`Q0 dosage of (i) one or more of an antihypertensive bioactive agent selected from an ACE inhibitor, calcium channel blocker, beta
`Q blocker, angiotension Il receptor antagonist or diuretic, or (ii) one or more of an anti-dyslipidemia bioactive agent selected from a
`ln HMG-CoA reductase inhibitor, bile acid sequestrant, fabric acid derivative, sterol, cholesterol absorption inhibitor, MTP inhibiior
`Q or nicotinic acid derivative; wherein: in the case of (i) a combination of a first bioactive agent of group (a) that is metfonnin with
`Q
`a second bioactive agent of group (b), or (ii) a combination of a first bioactive agent of group (a) that is a thiamlidinedione or dual
`N PPAR a ly agonist with an angiotension Il receptor antagonist, one or more of the following applies: (I) one of the first bioactive
`O agent or the second bioactive agent is formulated for sustained release, and the other is formulated for immediate release, each for(cid:173)
`:>- mulated for once-a-day dosing; or (Il) the co-formulation or kit comprises (A) a biguanide and a thiazolidinedione and (B) one or
`~ more group (b) bioactive agents.
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`Co-formulations or Kits of Bioactive Agents
`
`(1)
`
`The present invention relates to the use of multi-bioactive agent administration
`
`products having two or more different bioactive agents indicated for two or more
`
`r
`
`different disease conditions to an individual in need of such bioactive agents; More
`
`specifically, the invention relates to co:-formulations or kits of two or more different
`
`bioactive agents for treating diabetes and its co-morbidities (including co-existing
`disease conditions), including hypertension, dyslipidemia, cardiovascular disease, and
`
`nephropathy
`(2)
`According to studies cited in Merck Manual, only about half of patients who
`
`leave a physician's office with a prescription take the medicament as directed. The most
`common reason given for noncompliance is forgetfulness. Other reasons for
`noncompliance with medicament regimens include lack of understanding or confusion
`about dosing. Older persons with cognitive impairment often find the dosing regimen
`complex, and difficult to remember and to follQw.
`(3)
`Current therapeutic regimens for individuals having two or more separate
`
`disease conditions typically involve treatment with two or more different and distinct
`bioactive agents, which often need to be given at separate times. The individuals need to
`talce each bioactive agent at its required time for maximum therapeutic effect.
`Individuals who must take multiple bioactive agents on multiple schedules to treat more
`than one disease condition often find thi~ multi-bioactive agent administration regimen
`
`very confusing and even more difficult to follow. Multi-bioactive agent administration is
`especially difficult for elderly patients who often have several co-existing conditions
`needing therapeutic treatment.
`Various solutions have been suggested for improving patient compliance with
`[ 4]
`medication dosing, including intervention by the physician and/or pharmacist. However,
`
`it is generally accepted that the best possible dosing regimen for patient compliance is a
`simplified regimen, especially a once-daily dosing regimen.
`
`There is recent evidence based on prospective and retrospective analysis that
`[ 5]
`comorbidity of hyper-lipidemia and diabetes is prevalent and could benefit from
`
`concomitant treatment with an anti-dyslipidemia agent and a glucose controlling agent.
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`[6]
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`Co-administration of these bioactive agents however is often difficult since the
`
`glucose lowering agent often needs to be dosed multiple times a day and the anti(cid:173)
`
`dyslipidemia agent is typically administered once a day, preferably at night time. A
`
`single administration of anti-diabetic bioactive agent can be achieved by formulating the
`
`bioactive agent in a sustained release dosage form. However, addition of the anti(cid:173)
`dyslipidemia agent in the same sustained release dosage form could inappropriately
`
`control the second bioactive agent's release such that it would be difficult to achieve
`
`therapeutic levels.
`
`[7]
`
`. United States Patent 6,660,300 to Timmins et al describes a delivery system
`
`wherein Metfonnin and optionally a hypolipidemic agent are administered in a biphasic
`
`system .. The delivery system's two phases are: an inner solid particulate phase of
`
`granules containing a highly water soluble pharmaceutical with hydrophilic and
`
`· hydrophobic polymers, and an outer solid continuous phase in which the inner solid
`particulate phase granules are dispersed. The outer solid continuous phase is formed of
`
`an extended release material with hydrophobic polymers or materials. Since both phases
`
`in the described system contain hydrophobic polymers, it is likely to control the release
`
`of not only highly soluble Metfonnin which requires an .extended release profile, but will
`
`also inhibit the release of any hypolipidemic agent, leading to sub-therapeutic levels of
`
`the hypolipidemic agent.
`
`[8]
`
`WO 2004/017896 A2, to Waldstreicher et al, describes a combination bioactive
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`agent th~y for the treatment of hypertension and type 2 diabetes mellitus, Metabolic
`
`Syndrome, or a pre-diabetic condition in a patient in need of such treatment. The
`
`invention describes the use of combinations of pharmaceutically active compounds that
`
`are dual agonists of the alpha and gamma subtypes of the peroxisome pro liferators
`
`activated receptor (PPAR.a/-y) with Angiotensin II Type I receptor (A-2) antagonists. The
`
`invention does not specifically address the combinations of other bioactive agents for
`
`treatment of diabetes and comorbidities, particularly where the bioactive agents have
`
`distinct treatment regimens.
`
`[9]
`
`What is needed then is a multi-bioactive agent administration product for
`
`concurrently treating two distinct disease conditions each of which has distinct treatment
`
`options and different treatment regimens.
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`Summarv of the Invention
`Provided, among other thingS, is a fonnulation or kit comprising:
`
`[10]
`
`(a) a pharmaceutically effective dosage of one or more a glucose-level-controlling
`
`bioactive agents selected from an a-glucodase inhibitor, sulfonylurea, meglitinide,
`
`thiazolidinediones, biguanide, insulin, dual PP ARs:Jiy agonist, PPAR:y agonist or
`
`insulin secretagogue; and
`
`(b) a pharmaceutically effective dosage of (i) one or more of an antihypertensi ve
`
`bioactive agei;it selected from an ACE inht'bitor, calcium channel blocker, beta
`
`blocker, angiotension II receptor antagonist or diuretic, or (ii) one or more of an anti(cid:173)
`
`dyslipidemia bioactive agent selected from a HMG-CoA reductase inhibitor, bile acid
`
`sequestrant, fibric acid derivative, sterol, cholesterol absorption inhibitor, MTP.
`
`inhibitor or nicotinic acid derivative;
`
`wherein:
`in the case of (i) a combination of a first bioactive agent of group (a) that iS metformin
`with a second bioactive agent of group (b), or (ii) a combination of a first bioactive
`
`agent of group (a) that is a thiazolidinedione or dual PP AR.a/y agonist with an
`
`angiotension II receptor antagonist, one or more of the following applies:
`
`(I) one of the first bioactive agent or the second bioactive agent is formulated for
`
`sustained release, and the other is formulated for immediate release, each
`
`formulated for once-a-day dosing; or
`
`(II) the co-formulation or kit comprises (A) a biguanide and a thiazolidinedione
`and (B) one or more group (b) bioactive agents.
`
`[11]
`
`The multi-bioactive agent administration product may be a co-formulation or a
`... -
`-
`- . --
`kit. The kit may comprise, for example, daily dosing for 7, 14, 21, 28 or more· days.
`In certain embodiments, such a co-formulation is a capsule wherein
`
`[12) .
`
`one or more group (a) bioactive agents are formulated in sustained release beads
`
`comprised within the capsule; and
`
`one or more group (b) bioactive agents in a more immediate release form are
`
`comprised within the capsule.
`In certain embodiments, such a co-formulation is a compression fonnulation
`
`[13)
`
`wherein
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`one or more group (a) bioactive agents are formulated in sustained release form ·
`comprised within a portion of the compression formulation; and
`one or more group (b) bioactive agents in a more immediate release form are
`
`comprised within another portion of the compression formulation.
`In certain embodiments, such a co-fo~ulation is a suspension formulation
`
`[14)
`
`wherein
`
`one or more group (a) bioactive agents are formulated in sustained release form
`
`comprised within particles that are suspended or adapted to be suspended in a
`
`liquid; and
`
`one or more group (b) bioactive agents are dissolved in the liquid ..
`
`The instructions for the co-formulation may pro-vi.de that it should be shaken
`
`immediately prior to use (to suspend particles). Particles may be beads, such as
`
`described below. Bead and liquid density can be selected to increase bead propensity to
`
`remain in suspension.
`In certain embodiments the invention provides, among other things, methods of
`[15]
`treating diabetes or its co-morbidities. One such method is for delivering in the co(cid:173)
`
`formulation a glucose-level-controlling bioactive agent and a second bioactive agent fo:r
`
`treating a co-morbidity of diabetes, the glucose-level-controlling bioactive agent having
`a first dosing regimen and the second bioactive agent having a second, distinct dosing
`regimen, wherein the co-formulation provides a phannacokin:etic profile of the glucose(cid:173)
`
`level-controlling bioactive agent that mimics the first dosing regimen and a
`
`pharmacokinetic profile of the second bioactive agent that mimics the second dosing
`
`regimen.
`
`Brief Description of the Drawings
`
`Figure 1 is an embodiment _of a kit of "the invention.
`
`Figure 2 is another embodiment of a k:it of the invention.
`Figure 3 is a further embodiment of a kit of the invention.
`
`Figure 4 shows dissolution profiles or formulations of the invention.
`
`[16)
`
`[17] ·
`
`[18]
`
`[19)
`
`Detailed Description of the Invention
`
`Dual Release Embodiments
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`[20]
`
`In certain embodiments, the invention provides methods and co-formulations
`
`for delivering in the co-formulation a glucose-level-controlling bioactive agent and a
`
`second bioactive agent for treating a co-morbidity of diabetes, the glucose-level(cid:173)
`
`controlling bioactiv.e agent having a first dosing regimen and the second bioactive agent
`
`having a second, distinct dosing regimen, wherein the co-formulation provides a
`
`phannacokinetic profile of the glucose-level-controlling bioactive agent that mimics the
`
`first dosing regimen and a pharmacokinetic profile of the second bioactive agent that
`
`mimics the second dosing regil:nen.
`The present invention provides, in one embodiment, a novel method of
`
`[21]
`
`concurrently treating diabetes and co-morbidities, such as hypertension or dyslipidemia,
`
`by utilizing a multi-bioactive agent administration product to deliver a glucose level
`
`controlling bioactive agent, such as one which requires a controlled release dosage form,
`
`and a second bioactive agent, such as one which requires an immediate release dosage
`
`form, such as an anti-dyslipidemia bioactive agent or an anti-hypertension bioactive
`
`agent, in a single product. The multi-bioactive agent administration product of the
`
`present invention may comprise a co-formulation or a kit. An exemplary co-formulation
`
`is provided wherein a glucose-le'Vel-controlling bioaetive agent is formulated as a
`controlled release product and an another bioactive agent is delivered in an immediate
`release formulation in the same overall dosage form. The multi-bioactive agent
`
`administration product of the invention may also comprise a kit, wherein each individual
`
`bioactive agent may be formulated.in a separate dosage form but their presentation
`
`together in a single kit enhances patient compliance and improves the ease of bioactive
`
`agent administration over talcing each bioactive agent separately from a separate bottle.
`
`The present invention also provides, in one embodiment, a co-formulation of a
`[22]
`first highly water soluble bioactive agent in a controlled release dosage form using a
`
`blend of hydrophobic and hydrophilic polymers to provide controlled release of the
`
`bioactive agent where needed, with a second immediate release bioactive agent, and a
`
`method of formulating such co-formulation.
`
`[23]
`
`While coating techniques using a core-coat combination are lmown in the
`
`formulation of pharmaceutical agents, these techriiques have typically been applied to
`
`control the release of either a single active ingredient or as a method to prevent
`
`interaction between two bioactive agents. Thus, the invention provides an ability to
`
`deliver two such bioactive agents in a single daily dosage form or single dosage
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`combination (in a kit), one with an otherwise typical once a day dosing regimen and
`
`another with an otherwise typical more frequent dosing during the day. This invention
`
`also provides formulating techniques to provide a single dosage form wherein the
`
`pharmacokinetic profiles of each of the included b:ioactive agents will mimic their
`respective single dose or multidose equivalents. In. this way, multiple bioactive agents
`may be administered in a single dosage form, even. when each bioactive agent bas its
`
`own. specific and distinct dosing regimen different from the other bioactive agent(s) in
`
`the single dosage form.
`In one aspect the invention provides a co-formulation of an glucose level
`
`[24)
`
`controlling bioactive agent with an anti-dyslipidetnia bioactive agent or with another
`
`bioactive agent directed against a co-moibidity of diabetes. A glucose level controlling
`
`bioactive agent, such as for example Metformin.H Cl, which needs to be dosed multiple
`
`times a day and is given in large doses, is in this embodiment formulated. in controlled.
`
`release form, such as, for example, controlled release beads. The co-administered second
`agent (e.g., anti-dyslipidemia) is, in some embodiments, required in an amount that is
`only a fraction of the dose of the anti-diabetic and may need to be dosed only once daily.
`
`Common problems which can be expected with c<>-formulating two such bioactive
`
`agents having such different dosing regimens inch.::ide content uniformity, uneven
`
`layering and limiting the release of the bioactive agent requiring once a day dosing.
`
`These problems are overcome by the present invention by controlling the coating on the
`
`controlled release cores of the high dose bioactive agent, and either coating or admixing
`
`the low dose bioactive agent with the controlled re lease core for immediate release. The
`
`result is a single dosage form which can be administered once a day to address both
`
`conditions.
`In certain embodiments, a controlled release aspect of the co-formulation
`
`[25)
`
`utilizes, at least in part, beads comprising the bioactive agent to be released in a
`
`controlled fashion. Such beadS may comprise, for example, pharmaceutically acceptable
`
`components such as water soluble gums or polymers, water insoluble polymers,
`
`polymers with pH dependent solubility, natural clays, synthetic clays, waxes,
`
`triglycerides, mixtures thereof, and the like. The selection of excipients may be
`
`sufficient to provide all or a substantial portion of "the controlled release characteristics.
`
`Or, materials used to coat or embed the beads may provide 811 or a substanti.al of
`
`controlled release characteristics.
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`[26)
`
`Such gums or polymers can be, for example, alginates, alkyl celluloses,
`
`hydroxyalkylcelluloses, alkyl hydroxyalkylcelluloses, carboxyalkylcelluloses,
`
`carrageenan, guar gum, agar, gum arabic, .gum ghatti, gum karaya, gum tragacanth,
`
`locust bean gum, pectins, polyacrylamide, polyacrylic acid, polyethylene glycol,
`poly( ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, starch, tamarind gum,
`xanthum gum, cross linked polyacrylic acid (Carbomers), mixtures thereo~ and the like.
`
`(Alkyl in the foregoing can be, for example, Cl-C3 alkyl.) Such clays can be, for
`
`example, kaolins, serpentines, 8mectites (montmorillo:nites), bentonites, illites,
`
`glaticonite, chlorites, vermiculites, mixed-layer clays, attapulgite, saponite, sepiolite,
`
`synthetic clays (such as, for example, synthetic smectic clays, silicates, fluorosilicates),
`
`mixtures·. thereof, or the like.
`
`[27]
`
`Such beads may comprise, for example, pharmaceutically acceptable diluents or
`
`multifunctional excipients such as lactose, sucrose, de::xtrose, mannitol, sorbitol, starch,
`
`microcrystalline cellulose, d.Ibasic calcium phosphate, calcium carbonate and calcium
`
`sulfate, including different grades of the above mentie>ned diluents or multifunctional
`
`excipients, coprocessed excipients such as Prosolv SY-ICC (silicified microcrystalline
`
`cellulose, with intimate contact and even distribution of colloidal silicon dioxide on
`rnicrocrystalline cellulose surfaces, from JRS Pharma Ltd., Surrey, UK), mixtures
`
`thereof, or the like.
`In embodiments where such cores are coated,, coatirigs may be obtained from,
`
`[28]
`
`for example, and as appropriate, polymer dispersions in aqueous solution or organic
`solvent. Coating methods can include, for example, fl -uid bed coating, pan coating, hot(cid:173)
`
`melt coating in a high shear granulator, or the like. Coating polymers can include, for
`example, those above listed with respect to components of the core. In certain ·
`
`embodiments, the polymers include water irisoluble polymers, or mixtures of water
`
`soluble and water insoluble polymers, or mixtures of two or more of enteric polymers,
`
`water soluble and water insoluble polymers. The coatings can include, for example,
`
`plasticizers such as, for example, acetyltributyl citrate (ATBC), acetyltriethyl citrate
`
`(ATEC), dibutyl phthalate (DBP), dibutyl sebacate (Dl3S), diethyl phthalate (DEP),
`
`tributyl citrate (TBC), mixtures thereof, and the like.
`In certain embodiments, a more immediate release form of one or more other
`
`[29)
`
`bioactive agents is coated over the beads (which are, for example, formulated for
`
`sustained release of one or more first bioactive agents) . Or, the beads are embedded in
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`compressed formulation of the second bioactive agent(s) and appropriate excipients for
`
`such a compression formulation.
`
`For bead coatings intended to provide sustained release properties, a coating
`[30]
`can provide, for example, a weight .gain of from one of following lower values to one of
`
`the following upper values. Lower values can be, for example, 5, 6, 7, 8, 9, 10, and so
`
`forth by intervals of 1to49% w/w. Upper values-can be, for example, 6, 7, 8, 9, 10, and
`
`so forth by intervals of 1 to 50% w/w.
`
`[31]
`
`Bead sizes after coating can be, for example, from one of following lower
`
`values to one of the following upper values. Lower values can be, for example, 75, 100,
`
`125, 150, and so forth by intervals of 25 to 500 microns. Upper values can be, for
`
`example, 150, 175, 200, and so.forth by intervals of25 to 2000 microns. For example,
`
`ranges can be 75-2000 microns, 125-1500 microns, or 500-1200 microns. Bead size can
`
`be measured by sieve analysis.
`
`(32]
`
`In certain embodiments, a more sustained release fonn is compounded in one
`
`portion of a compression tablet or other compression product, and a more immediate
`
`release form is compounded in another portion;
`
`(33]
`
`Dissolution is measured in 900 ml of pH 6.8 phosphate buffer using a USP 1
`
`dissolution apparatus at 37°C and 100 rpm. More immediate release forms can, for
`
`example, provide 90% dissolution in 60 minutes or less, 55 minutes or less, 50 minutes
`
`or less, 45 minutes or less, 40 minutes or less, 35 minutes or less, 30 minutes or less, 25
`
`minutes or less, or 20 minutes or less. More sustained release forms can, for example,
`
`provide a target dissolution in 2 hours or more, 2.5 hours or more, 3 hour8 or more, 3.5
`
`hours or more, 4 hours or more, 5 hours or more, 6 hours or more, 7 hours or more, or 8
`
`hours or more. The target dissolution for more sustained release can be, for example,
`
`70% or more, 75% or more, 80% or more, 85% or more or 90% or more.
`
`Intermediate layers in beads or in compression formulations may be used to
`(34)
`separate compositions that are less stable or otherwise less compatible when in direct
`contact Thus, a composition containing no active or a third bioactive agent may
`
`separate compositions of a first bioactive agent and of a second bioactive agent.
`
`Kits
`
`[35]
`
`Kits also provide a convenient way to deliver two or more bioactive agents
`
`targeted at treating diabetes and its co-morbidities. Kits can be of several compositions
`
`and forms which aim at providing advantages of patient compliance, improved visibility
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`for patients with limited vision and aid in remembering the last dose taken, :and patient
`
`counseling by phamiacist or physician.
`
`[36)
`
`Examples of such kits include prepackaged bioactive agents as in Figures 1-3 or
`
`can be packaged by the pharmacists in an appropriate configuration using ~isting
`marked containers. In the kit embodiments illustrated in Figures 1, a first bi<:>active agent
`1 is contained in a first compartment 2 and a second bioactive agent 3 is eontained in a
`
`second compartment 4.
`
`[37]
`
`The kits may be marked by the physician or pharmacist with the days of the
`
`week, as illustrated in Figure 2, or with the days of the month to help the pa"tient
`remember if she has taken her medications each day.
`
`[38]
`
`The kits may also be appropriately labeled to indicate whether eacll kit contains
`
`an individual bioactive agent to be taken more than once a day or multiple bioactive
`
`agents, each taken daily.
`
`[39)
`
`The kits may also be marked with "morning" and "afternoon" marlcings, as
`
`necessary, along with days of the week or month.
`The compartments of the kits may be color coded to reflect an indi. vidual color
`
`[40]
`
`for each single bioactive agent or multiple bioactive agent application.
`The compartments of the kits may also be color coded to reflect an. individual
`color for diabetic bioactive agent, cardiovascular bioactive agent and multi-bioactive
`
`[41)
`
`agent combination.
`
`[42]
`
`The kit may be marked with detailed directions on how to take the medication
`
`to serve as a reminder to patients on proper dosing.
`
`[43]
`
`Each kit may contain more than two different bioactive agents, as shown in
`
`Figure 3, which contains a first bioactive agent 1, a second bioactive agent 3, arid a third
`
`bioactive agent 5.
`
`Definitions
`
`[44)
`
`The following terms shall have, for the purposes of this application, the
`
`respective meanings set forth below.
`
`• bioactive agent
`
`[45]
`
`A bioactive agent is a substance such as a chemical that can act on. a cell, virus,
`
`tissue, organ or organism, including but not limited to drugs {i.e., pharmace-uticals) to
`create a change in the functioning of the cell, virus, organ or organism to acliieve a
`
`pharmaceutical or therapeutic effect.
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`• co-formulation
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`[46]
`
`Two or more bioactive agents are co-formulated into a co-formulation if a
`
`single dosage form contains the two or more bioactive agents. The two (or more)
`
`bioactive agents may be intimately adinixed, provided no significant stability issues are
`thereby created. Alternatively, the two bioactive agents may be in separate initial
`formulations (such as particles including time release particles) so long as the initial
`
`formulations are physically linked, such as, for example, by compression or containment
`
`in a capsule. In one example, two bioactive agents can be in distinct regions of a dosage
`form, so long as the two regions are physically linked sufficiently so that the typical
`
`mode of administration would be concurrent. Further examples of co-formulation
`
`include suspension forms, in which the suspension form contains particles containing the
`
`two or more bioactive agents (in separate particles or the same particles), or in which one
`bioactive agent is in substantially particle form and another is in substantially dissolved
`form.
`
`•kit
`
`[47)
`
`A kit of two or more bioactive agents means that the two or more bioactive
`
`agents are packaged to visually or tactilely indicate an appropriate sequence for
`
`administering the bioactive agents to a single patient.
`• dosage form
`Dosage form refers to the manner in which a single unit dose of one or more
`
`[48]
`
`bioactive agent(s) is provided for administration to a patient.
`
`• pharmacoldnetic profile
`
`[49]
`
`The pharmacokinetic profile of a bioactive agent is the characteristic data for
`
`the bodily absorption, distribution,·metabolism, and excretion of that bioactive agent.
`
`• dosing regimen
`
`[50]
`
`Dosing regimen refers to the proper amount of a bioactive agent and the
`
`schedule on which the bioactive agent is to be taken by a patient in need of the bioactive
`
`agent.
`
`• dyslipidemia
`
`[51)
`
`Dyslipidemia refers to a disorder of lipid metabolism, and includes various
`
`conditions characterized by abnormal concentrations of one or more lipids or other
`
`associated markers (e.g., the macromolecular complexes formed by the lipid and
`
`apolipoprotein(s) that allow lipids to circulate in blood, such as Low Density
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`Lipoproteins {LDL), Very Low Density Lipoproteins (VLDL), and Intermediate Density
`
`Lipoproteins {IDL)); apoliproteins; and the like). [Note: Cholesterol is primarily carried
`
`by Low Density Llpoproteins (LDL), and is commonly referred to as "bad" cb.olesterol,
`since elevations in LDL cholesterol correlate closely to the risk of coronary heart disease.
`
`Cholesterol is also associated with the High Density Lipoproteins (HDL), corr:nnonly
`
`referred to as "good" cholesterol, since HDL associates with cholesterol deposited in the
`arterial wall and atherosclerotic plaques for reverse cholesterol transport to the liver. It is
`
`therefore desirable to lower _elevated levels of LDL cholesterol and to concurrently
`
`increase levels of HDL cholesterol.] Dyslipidemia includes elevated concentrations of
`
`total cholesterol, LDL cholesterol, VLDL and/or IDL cholesterol, which may be
`
`accompahled by low concentrations of HDL. Anti-dyslipidemic agents inclucl.e bioactive
`
`agents that decrease the concentrations of total, LDL, VLDL and IDL cholesterol, and/or
`
`increase the concentration of HDL cholesterol.
`
`• effective amount
`
`[52]
`
`The meaning of "effective amount" will be recognized by clinicians but
`
`includes an amount effective to reduce, ameliorate or eliminate one or more symptoms of
`the disease sought to be treated or the condition sought to be avoided or treated, or to
`
`otherwise produce a clinically recognizable change in the pathology of the disease or
`
`condition:
`
`• treating diabetes
`[53]
`Treating diabetes shall include treating metabolic syndrome, obesity with
`
`propensity for diabetes, other pre-diabetic conditions and the co-morbidities o:f such
`
`conditions so long as the treated condition allows a meaningful interpretation :for
`
`"effective amount" with respect to the bioactive agents in question.
`
`Exemplary Bioactive agents
`
`Nonlimiting examples of glucose-level-controlling bioactive agents vvhich may
`(54]
`be suitable -for use in the present invention in therapeutically effective doses, i:nclude
`
`compounds selected from a.-glucodase inhibitors {A), thiazolidinediones (B), biguanides
`
`(C), insulin, PPARcx/y agonists {D), PPARy agonists (E), or insulin secretagog;ues {F)
`
`{such as, without limitation. sulfonylureas {F-1), meglitinides {F-2), and d-phenylalanine
`
`derivatives/analogs {F-3)). Further nonlimiting examples of such compounds, along with
`
`exemplary amounts for their inclusion in a formulation, include:
`
`Acarbose {20, 50 & 100 mg) {from 10 to 200 mg) {A);
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`Acetohexamide (250 & 500 mg) (from i 00 to 1000 mg) (F-1 );
`Chlorpropamide (100 & 250 mg) (from 50 to 500 mg) (F-1);
`
`Gliclazide (80 mg) (from 40 to 160 mg) (F-1);
`GJimepiride (1, 2 & 4 mg) (from 0.5 to 10 mg) (F-1 );
`
`Glipizide (2.5, S & 10 mg) (from 1to20 mg) (F-1);
`
`Glyburide (1.25, 1.S, 2.S. 3 S & 6 mg) (from O.S to 20 mg) (F-1);
`Insulin (from 0.1 to 3.0 U/kglday);
`Metformin HCl (500, 850 & 1000 mg) (from 100 to 2000 mg) (C);
`
`Miglitol (25, SO & 100 mg) (from 10 to 200 mg) (A);
`
`Nateglinide (60 & 120 mg) (from 30 to 200 mg) (F-3);
`
`Pioglitazone HCl (15, 30 & 45 mg) (from 5to100 mg) (B);
`
`Repaglinide (O.S, 1 & 2 mg) (from 0.2 to S mg) (F-2);
`
`