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`PCT/IB02/04 101
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`administering the unit dose into the oral cavity of a patient or(b) dispensingthe unit dose into
`
`. an intermediate receptacle and thereafter administering the unit dose into the oral cavity of the
`
`patient.
`
`[0038]
`In certain embodiments, the invention provides a drug formulation for
`gastrointestinal deposition comprising a non-compressed free flowing plurality of particles
`
`comprising a drug and a pharmaceutically acceptable excipient, the particles having a mean
`
`diameter of greater than 10 pm to about 1 mm.
`
`[0039]
`
`In certain embodiments, the particles of the invention comprise at least about 40%
`
`drug; at least about 50% drug; at least about 60% drug; at least about 80% drug; or at least
`
`about 90% drug.
`
`I
`
`[0040]
`
`In certain embodiments, the invention provides a method for delivery of a drug
`
`comprising delivering the multiparticulates disclosed herein comprising‘ drug particles via the
`
`use of a multiple unit dosing device comprising a housing and an actuator, the device upon
`
`actuation delivering a unit dose of the multiparticulates disclosed herein, and thereafier re-
`
`using said device to deliver additional unit doses ofthe multiparticulates at appropriate
`
`dosing intervals.
`
`[0041]
`
`In certain embodiments of the invention, greater than about 80% ofthe unit dose is
`
`"deposited in the gastrointestinal tract, preferably greater than about 90% or greater than about
`
`95%,or greater than about 99% and most preferably, about 100% of the unit dose is deposited
`
`in the gastrointestinal tract.
`
`[0042]
`In preferred embodiments of the invention, the unit dose comprises a discreet
`collection of multiparticulates. For purposes of the invention, a “discreet collection" means
`
`that the multiparticulates are in the form of a non—compressed free flowing unit and not
`dispersed in a cloud or mist, which effectively minimizes inhalation of the active agent into
`
`the lungs of the patient. The unit dose can be, e.g., from about 0.01 mg to about 1.5 g,
`
`8
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1501
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1501
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`PCTlIB02l04l01
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`depending on the dose of the active agent being delivered. For example, the unit dose can be
`
`from about 1 mg to about 100 mg or from about 10 mg to about 50 mg. Preferably, the unit
`
`dose is administered to the tongue, most preferably towards the front of the tongue behind the
`
`teeth, where it can be easily swallowed with or without the need for an additional fluid.
`
`However the invention does contemplate delivery to any portion of the tongue, taking— into
`
`account, e.g., the taste sensations of different sections of the tongue and/or individual patient
`
`preference associated with comfort, e.g. mouth position.
`
`Incertain embodiments of the invention, the mean diameter of the drug particles is-
`[0043]
`of a size which minimizes their capacity to be inhaled into the lower lung. Typically, the
`mean particle size of the drug particles (or agglomerates) is greater than 10 um, preferably
`greater than about 50 pm or greater than about 75 pm. In certain embodiments ofthe
`
`invention, the mean particle size range of the drug particles is from about 100 um to about 1
`mm, preferably from about 50 pm to about 500 um . In preferred embodiments, greater than
`80% ofthe drug particles have the above disclosed diameter (not mean diameter), e.g. 80% of
`
`the drug particles have a diameter of greater than 10 pm, or a diameter of from about 100 pm
`
`to about 1 mm. In other embodiments, greater than about 90% of the drug particles have the
`
`above disclosed diameter.
`
`[0044]
`
`In certain embodiments of the invention, the mean diameter of the drug particles
`
`does not vary by greater than about 20%, preferably not greater than about 15% and most
`
`preferably not greater than about 10%.
`
`[0045]
`
`In certain embodiments of the invention, the multiparticulates comprise a
`
`pharmaceutically acceptable excipient. The excipient preferably does not comprise more than
`
`about 60% by weight of the formulation; more preferably not more than about 50%; more
`
`preferably not more thanuabout 40% by weight by weight; more preferably not more than
`
`about 20% by weight multiparticulates by weight, and most preferably not more than about
`
`10% by weight of the formulation.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1502
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1502
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`[0046]
`
`In certain embodiments of the invention, the multiple doses of=the drug formulation
`
`disclosed herein are contained in a reservoir. The reservoir can contain an amount of
`
`multiparticulates to provide any number of unit doses, e.g. from about 2 doses to about 400
`
`doses. For ease in patient compliance, the reservoir has a sufficient quantity of to provide e.g.
`
`a days supply, a months supply or a years supply of doses, e.g. 30 or 365 for once daily
`
`dosing for a month or year, respectively.
`
`. [0047]
`
`In order to aid in patient compliance, certain embodiments of the invention include a
`
`counter or indicator to display the number of doses remaining in the system or the number of
`
`doses actuated.
`
`[0048]
`
`. In certain embodiments of the invention, the unit doses are individually metered
`
`prior to actuation, e.g., in the form of capsules or blisters, wherein each blister contains one
`
`individual unit dose. The system can be capable of containing any multiple of pre-metered '
`
`unit doses, e.g. from about 2 to about 400 blisters.
`
`[0049] The invention is also directed to methods of delivery (e.g., in vivo administration
`
`and ex vivo dispensing) and methods of treatment utilizing any of the disclosed embodiments .
`
`directed to compositions of matter. The invention is also directed to methods of preparation
`
`of all of the disclosed embodiments.
`
`[0050] The invention is also directed to methods of providing a therapeutic effect to a
`
`patient comprising administering to the patient a unit dose of a drug utilizing the systems and .
`
`formulations disclosed herein. The invention is also directed to methods of preparing the
`
`systems and devices.
`
`[0051] For purposes of the present invention, thelterm “device” refers to an apparatus
`
`capable of delivering a unit dose of drug.
`
`10
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1503
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1503
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`[0052] The term “system" refers to a drug delivery device in combination with the disclosed
`multiparticulate drug having the specifications disclosed herein, e.g. drug particle size,
`
`_ excipient type, etc.
`
`[0053] The term “discreet collection" refers to a non-compressed free flowing unit of
`
`multiparticulates with minimal particulate matter being dispersed in the surrounding
`
`environment (e.g., as a cloud or mist).
`
`[0054] The term “drug” refers to any agent which is capable of providing a therapeutic
`
`effect to atpatient upon gastrointestinal deposition. This encompasses all drugs which are
`
`intended for absorption for a systemic effect (regardless of their actual bioavailability) as well
`
`as drugs intended for a local effect in the gut and /or oral cavity, e. g. nystatin, antibiotics or
`
`local anesthetics.
`
`[0055] The term “particle size” refers to the diameter of the particle.
`
`[0056] The term “deposition" means the deposit of the unit dose at the intended point of '
`
`absorption and/or action. For example, gastro-intestinal deposition means the intended
`
`deposit of the unit dose in the gastrointestinal system for e.g., absorption for a systemic effect
`
`or to exert a local effect. Pulmonary deposition means the intended deposit of drug into the
`
`lungs in order to provide a pharmaceutical effect, regardless that the unit dose may enter the
`
`oral cavity prior to pulmonary deposition.
`
`[0057] The term “dispense”, when used in connection with the devices and systems of the
`
`present invention, means that the device or system delivers the unit dose ex vivo with the
`
`intent of subsequent administration to a mammal. For example, the device or system can
`
`dispense the unit dose into a food, a liquid, a spoon, or another intermediate receptacle.
`
`[0058] The term “administer", when used in connection with the devices and systems of the
`
`present invention, means that the device or system delivers the unit dose in viva, i.e., directly
`
`11
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1504
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1504
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`PCT/[B02/04101
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`into the gastrointestinal tract of a mammal.
`
`[0059] The term “deliver" is meant to cover all exvivo and in viva delivery, i.e., dispensing
`
`and administering, respectively.
`
`[0060] The term “patient" refers to humans as well as other mammals in need of a
`
`therapeutic agent, e.g., household pets or livestock. This term also refers to humans or
`mammals in need of or receiving prophylactic treatment.
`
`[0061] The term “functional coat” means a coating on a drug particle which provides a
`
`controlled release of the drug (e.g., a sustained release), a delayed release of the drug (e.g., via
`an enteric coating), taste masking, salivary stimulation, a moisture‘ barrier, texture
`
`modification, minimization of surface asperities, chip resistance, pliability or any
`
`combination of any of the foregoing.
`
`[0062]
`
`In certain embodiments, the particulates are defined functionally with respect to the
`
`fact that they are of a size such that an effective dose cannot be delivered into the lower lung
`
`of a human patient. However, this definition should be understood to mean that a small
`
`percentage of drug (but not an amount effective to render a therapeutic effect) may in fact be
`
`inadvertently delivered to the lungs of the patient. Also, this definition is meant to define the
`particles, but not to limit the use ofthe invention to the treatments ofhumans only. The
`A
`invention may be used for delivering doses of drugs to other mammals as well.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0063]
`
`Fig.1 is a graph of adhesion vs. humidity for standard powders.
`
`[0064] Fig. 2 is a graph of adhesion vs. humidity for powders of the present invention.
`
`[0065] Fig. 3 is a dissolution profile of Indomethacin & 4% PVP K-30 wet granulation in a
`
`pH 6.8 phosphate buffer made in accordance with an embodiment of the present invention.
`
`[12
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1505
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1505
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`[0066]
`
`Fig. 4 is a pH 6.8 phosphate buffer dissolution profile ‘of-Indomethacin & 10%
`
`PEG6000 melt granulation made in accordance with an embodiment of the present invention. '
`
`[0067]
`
`Fig. 5 is a .1 N Hydrochloric Acid dissolution profile of Indomethacin & 10%
`
`PEG6000 & 15% Acryl-eze melt granulation made in accordance with an embodiment of the
`
`present invention.
`
`[0068] Fig. 6 is a pH 6.0 phosphate bufifer dissolution profile ofIndomethacin &'10%
`PEG6000 & 15% Acryl-eze melt granulation made in accordance with an embodiment of the
`
`present invention.
`
`[0069]
`
`Fig. 7 is a .1 N Hydrochloric Acid dissolution profile of Indomethacin & 15%
`
`Sureteric & 10% PEG6000 melt granulation made in accordance with an embodiment of the
`
`present invention.
`
`[0070]
`
`Fig. 8 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin & 15%
`
`Sureteric & 10% PEG6000 melt granulation made in accordance with an embodiment of the
`
`present invention.
`
`[0071]
`
`Fig. 9 is a .1 N Hydrochloric Acid dissolution profile of Indomethacin & 15%
`
`Sureteric melt granulation made in accordance with an embodiment-of the present invention.
`
`[0072]
`
`Fig. 10 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin & 15%
`
`Sureteric melt granulation made in accordance with an embodiment of the present invention.
`
`[0073]
`
`Fig. 11 is a .1 N Hydrochloric Acid dissolution profile of Indomethacin & 15%
`
`Sureteric & 10% Lustre Clear melt granulation made in accordance with an embodiment of
`
`the present invention.
`
`[0074]
`
`Fig. 12 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin & 15%
`
`13
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1506
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1506
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`PCT/[B02/04101
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`Sureteric & l0% Lustre Clear melt granulation made in accordance with an embodiment of
`
`the present invention.
`
`[0075]
`
`Fig. 13 depicts the particle size distribution for the fonnulations made in accordance
`
`with an embodiment of the present invention.
`
`DETAILED DESCRIPTION
`
`[0076]
`
`In general, it has been recognized in the art that dry powder inhalation or insufflation
`
`formulations must consist ofparticles of a size of about 2 microns in diameter in order for the
`
`particles, when inhaled, to reach the peripheral or “deep” lung, including alveoli. Particles
`
`larger than 10 microns in diameter are not able to reach the deep lung when inhaled because
`they are collected on the back ofthe throat and upper airways in humans. Therefore, known 0
`powder delivery systems have been formulated with particle sizes of less than 10 microns in
`
`order for the particles to reach the intended site of action, the pulmonary system. Known
`
`powder delivery devices have not contemplated delivery of particles from a multi-dose
`delivery device to achieve gastrointestinal deposition, and therefore have avoided the use of
`
`drug particles having a large size, e.g. greater than 10 microns. By virtue of the invention
`
`disclosed in Applicants copending application, PCT/lB0l/00251, it has been a surprising ‘
`
`discovery that drug particles greater than 10 microns can be delivered from a multi-use drug
`delivery device for gastrointestinal deposition in a patient in order to minimize the inhalation
`ofthe drug particles into the lungs, in order to have substantially all ofthe dose deposited in.
`the gastrointestinal system. By virtue of the present invention, it has been surprisingly
`discovered that powders that can be used in such devices can be functionally coated in order
`
`to provide desired characteristics with respect to their use in the device, e.g., increased
`flowability and decreased bridging (disclosed in more detail below) as well as characteristics
`
`of the powder itself, e.g. an acceptable weight variability. The powders can be used in the
`
`device or can be administered without the use of the device, e.g., by using a sachet.
`
`[0077]
`
`In preferred embodiments, the drug formulation for gastrointestinal deposition of the
`
`invention comprising a non-compressed free flowing plurality ofparticles comprising a core
`
`14
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1507
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1507
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`comprising a drug and a phannaceutically acceptable excipient-, with the core overcoated with
`
`a functional coating.
`
`[0078]
`
`In preferred embodiments, the core of the invention comprises drug coated with the
`
`excipient and a functional coat overcoating the excipient coat, thus providing a dual coated
`powder. The dual coated powder has improved functionality as a multiparticulate dosage
`form.
`
`[0079]
`
`In other preferred embodiments, the core of the invention comprises drug
`
`interdispersed with the excipient and a functional coat overcoating the core. In these
`
`embodiments, the core can be prepared by wet granulation or by melt granulation. It has been
`
`surprisingly found that preparing the core by wet granulation or melt granulation results in a
`
`decreased fraction of fine particles in the resultant dosage form.
`
`[0080] Depending on the choice of the initial excipient overcoat, single coated particles can
`
`have a surface area whichis not smooth, with a significant degree of rugosity and surface
`
`asperities. Such particles have significant associated problems which decrease the usefiilness
`‘and benefits of multiparticulate dosage forms.
`
`[0081] For example, the presence ofsurface asperities on the surface ofthe particles
`
`provides gaps and cavernous areas which promote the coalescence of water onto the surface -
`
`of the particles. The accumulation of water onto the surface of the particles promoted
`
`cohesiveness of the particles which is undesirous in the multiparticulate dosage form of the
`
`present invention, e.g., due to decreased flowability. Accordingly, the use of the present
`
`invention may not be able to be used to full benefit in areas which have increased humidity.
`
`This is relevant not only by the geographic location of use, e.g., a tropical area, butalso
`
`relevant by the workplace, e.g. air conditioned buildings which may result in increased
`
`humidity. The functional overcoat can be provided in order to provide a relatively smooth
`surface area with minimal rugosity and surface asperities. The overcoated particles can then
`be resistant to the deleterious effects of moisture and humidity of the functionality of the
`
`.15
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1508
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1508
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`multiparticulate dosage form. The moisture resistant overcoat- may have the added benefit of
`
`protecting the stability of the drug contained therein.
`
`[0082] Another functional problem associated with particles with increased rugosity and
`
`surface asperities is the presence of points or protrusions which rise from the surface of the
`
`particle and increase cohesiveness by multiple pathways.
`
`[0083] One reason for increased adhesion between particles due to surface points or
`
`protrusions is due to physical interlocking between adjacent particles in the formulation. The
`
`protrusions of one particles can interlock between a “valley” in another particle.
`
`Alternatively, protrusions can actually interlock due to “jigsaw” type characteristics of the
`
`protrusions. The resultant is agglomeration of particles and decreased flowability of the
`
`formulation. An overcoat which smooths the surface can minimize asperities and rugosity
`
`and increase the functionality of the formulation.
`
`[0084] Another reason for increased adhesion between particles due to surface points or
`
`protrusions is due to the fact that charge tends to gather at these points and protrusions. Thus,
`
`the existence of localized charge can increase electrostatic forces between the particles and
`promote agglomeration and adhesion. An overcoatwhich smooths the surface ofthe
`
`underlying particle and decreases asperities and rugosity can decrease accumulation and
`
`adhesion due to electrostatic forces. Electrostatic forces can also be minimized by coating a
`
`substrate with a conductive polymer, disclosed in more detail below.
`
`[0085] The concept of rugosity of particles can be quantified by a rugosity index. The
`
`calculation of the rugosity index involves the concept of a “convex hull”. A convex hull is a
`
`minimum enveloping boundary fitted to an outline of the measured particle that is nowhere
`
`concave. The rugosity index is defined as the perimeter ofthe particles outline divided by the
`
`perimeter of the convex hull. According to this index, certain embodiments of the
`multiparticulates ofthe present invention can have a mean rugosity index ofbetween 1.0 and
`
`1.5, more preferably from about 1.0 to about 1.2. In other embodiments, greater than 80% of
`
`16
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1509
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1509
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`the particles of the invention have a rugosity index within the disclosed mean range.
`
`In other
`
`embodiments, greater than 90% of the particles of the invention have a rugosity index within
`
`the disclosed mean range.
`
`[0086] Another calculation index which can be used in the present invention is a roundness
`
`index. When the particles of the present invention are coated as disclosed herein, certain
`
`embodiments will exhibit a roundness of the particles. The roundness index can be calculated.
`
`as the square of the perimeter of the particles outline divided by 41t(cross-sectional or
`
`projection area of particle outline). ‘According to this index, certain embodiments of the
`
`multiparticulates of thepresent invention can have a mean roundness index of between .70
`and 1.0, more preferably from about .85 to about 1.0. In other embodiments, "greater than
`
`80% of the particles of the invention have a roundness index within the disclosed mean range.
`
`In other embodiments, greater than 90% of the particles of the invention have a roundness
`
`index within the disclosed mean range.
`
`[0087]
`
`In certain embodiments of the invention, flowability is improved by virtue of the
`
`functional coatings, without the need for certain flow aids known in the art such as the
`
`inclusion of silicone dioxide. The use of silicone dioxide is not preferred in the present
`
`invention because this compound is not suited for inhalation, should a patient accidentally or
`
`inadvertently have aspiration into the lungs of a fiaction of the unit dose.
`
`[0088] Adhesion and agglomeration also leads to the concept of bridging which is
`
`particularly problematic with respect to the use of the multiparticulate formulation disclosed
`
`herein in multiple unit dosing devices. When multiple unit doses of the multiparticulates of
`
`the present invention are stored in containers, e.g., reservoirs, and unloaded therefrom
`
`through an opening or openings in the bottom of the container, the containers are often
`
`designed to have very steep walls adjacent the opening to aid the outward flow of the
`
`multiparticulates. Nevertheless the multiparticulates can become clogged and will have
`
`reduced or no flow out of the container. This phenomenon is generally termed "bridging"
`
`since the bulk material tends to assume a curved or cupola-like shape. It is known that
`sometimes vibrating or knocking the container walls from outside is sufficient to break the
`
`17
`
`Patent Owner, UCB Pharma GmbH_— Exhibit 2007 - 1510
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1510
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`wo 03/020241
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`integrity of the bridge enable the flow to return to normal. Sometimes, however, such .
`vibrating or knocking results in container wall vibrations which further compact the material
`resulting in an even more rigid and indestructible bridge being formed, or the shaking and
`
`vibrating of the container can break or damage the dosing device.
`
`[0089] One aspect of the present invention is formulating the mean particles size of the
`particulates to have a diameter which can minimize or possibly eliminate bridging when the
`formulation is included in a system in a multiple unit dosing device (e.g., a hopper base
`
`device). The multiple unit dosing devices as disclosed herein and in PCT/[B01/00251 may be
`susceptible to bridging which could result in reduced flow and inaccurate dosing. It has been
`discovered that bridging can be significantly reduced if the particles size of the
`multiparticulates are" no greater than 1/14th or _l/15th the diameter of the exit opening in the
`reservoir or container ofthe bulk fonnulation. The typical opening of a multiple unit dosing
`device is about 7 mm, thus, a preferred particle size of the present invention is a mean
`particles size ofless than about 500 micrometers. Ifthe mean particle size of the
`multiparticulates are significantly greater than 1/14th the size of the diameter of the exit
`opening, the resultant bridging and reduced flow will increase. For example, bridging may be
`more problematic if the mean particle size of the formulation is 1.5 mm in a dosing device
`with a 7 m exit. Bridging is also increased if the particulates have asperities and
`protrusions due to interlocking as discussed above. With interlocking, the particles cannot
`move relative to each other in the direction of an applied driving force component, such as
`
`gravity, due to the presence of a force such as a frictional force component which is larger
`than the driving force component and normal thereto and which urges the particles against
`each other. The frictional force component that holds the particles together is proportional to
`
`the coefficient of friction of the particular bulk material. Thus, materials having relatively
`large coeflicients of friction have a relatively large tendency to bridge. The inclusion of a
`coating or overcoating which smooths the surface of the multiparticulates will result in
`decreased bridging due to decreased interlocking.
`'
`
`[0090] The -multiparticulates of the present formulation, when in motion are known to have
`a relatively smaller coefficient of friction than at rest. The present invention is therefore
`directed to devices which reduce the coefficient of friction between multiparticulates by
`
`producing relative motion therebetween in order to reduce bridging effects. This can be
`accomplished, for example, by the inclusion of a internal rake or lever which agitates and
`
`18
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1511
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1511
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`, moves the particles within the device upon actuation, or .by a vibrating mechanism which is
`
`preferably activated upon actuation.
`
`[0091] The present invention is therefore directed to particles having a novel size range,
`which are dependent on a number of factors. In order to reduce pulmonary inhalation, the
`
`mean diameter of the particles are preferably greater than about 10 micrometers and
`
`preferably greater than about 50 micrometers and the mean diameter of the multiparticulates t.
`are preferably less than about 500 micrometers as a typical dosing device will have an exit
`
`opening of about 7 mm. However, this range is not meant to be limiting as the dosing devices
`(e.g., hopper base devices) can have different size openings and the formulations of the
`
`present invention may be used without the device.
`
`[0092]
`-As bridging and aspiration will depend on the actual size of the particles in
`proximity to each other, mean particles size is only one factor to consider, as the actual
`
`particles in proximity to each other may wind up being very large or very small, despite the
`
`mean particles size of the entire batch.
`
`[0093] Accordingly; with respect to aspiration, it is preferred that greater than 90% of said
`
`particles have a diameter-of greater than about 10 um. Preferably, greater than 95% of said
`
`particles have a diameter of great than about 10 pm. More preferably, greater than 99% of
`said particles have a diameter of greater than about 10 um.
`
`[0094]
`
`In other embodiments, greater than 90% ofsaid particles have a diameter ofgreater
`
`than about 50 um. Preferably, greater than 95% of said particles have a diameter of great
`than about 50 pm. More preferably, greater than 99% ofsaid particles have a diameter of
`
`greater than about 50 pm.
`
`[0095]
`
`In other embodiments, greater than 90% of said particles have a diameter of less
`
`than about 500 um. Preferably, greater than 95% of said particles have a diameter ofless
`than about 500 pm. More preferably, greater than 99% of said particles have a diameter of
`
`greater than about 500 um. ,
`
`19
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1512
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1512
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`rrcr/11302/04101
`
`[0096]
`In other embodiments, greater than 90% of said particles have a diameter of greater
`than about 50 pm and greater than 90% of said'particles have a diameter of less than about
`
`I 500 um. . Preferably, greater than 95% of said particles have a diameter of great than about
`
`50 pm and greater than 95% of said particles have a diameter of less than about 500 pm.
`
`More preferably, greater than 99% of said particles have a diameter of greater than about 50
`pm and greater than 99% of said particles have a diameter of greater than about 500 pm.
`i
`
`[0097]
`
`In order to achieve the desired lower limit of the particles size of the present
`
`invention the invention, in certain embodiments is directed to a method of preparation I
`.
`comprising air jet sieving particles to remove fine particles. In particular embodiments, the
`
`invention is directed to a method ofpreparing a multiparticulate drug formulation for
`gastrointestinal deposition comprising preparing a non—compressed fi'ee flowing plurality of ‘
`particles comprising a core comprising a drug and a pharmaceutically acceptable excipient as
`
`disclosed herein and air jet sieving the particles to separate the cores from fine particles; and
`
`thereafier overcoating said core with a functional coating as disclosed herein. The invention
`
`is also directed to compositions obtained using these methods.
`
`[0098] The compositions of multiparticulates obtained using airjet sieving and methods
`
`thereof are not limited to the particular embodiments disclosed herein. Air jet sieving can be
`
`used for any composition of multiparticulates intended for oral use in order to remove fine
`
`particles (e.g., particles which may be aspirated into the lungs). Accordingly, the present
`invention is directed to compositions and methods ofpreparing a multiparticulate
`
`formulations for oral delivery comprising preparing a multiparticulate composition and air jet
`
`sieving the composition to remove particles of less than about 10 pm, less than about 50 pm
`
`or less than about 100 pm. In preferred embodiments, particles larger than about 500 pm or
`
`larger than about 1 mm are also removed from the composition. Preferably, multiple unit
`doses ofthe composition are then placed in an oral delivery device capable ofmetering aiunit
`dose of the composition for oral delivery. These compositions can be coated (e.g. for
`
`sustained release or tastemasking) before air jet sieving, afler air jet sieving or not coated at
`
`20
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1513
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1513
`
`

`
`W0 03/020241
`
`PCT/[B02/04101
`
`all. The coated embodiments can be single or multiple coated (e.g., as disclosed herein).
`
`[0099] The use of an air jet sieve is beneficial as the standard sieving techniques used with
`screens and meshes may not separate all ofthe desired fine particles as the fine particles may
`
`adhere to the surface of larger particles and thus not separate during the sieving process. The
`
`air jet sieving process utilizes a negative pressure to draw particles below a particular size
`
`-
`
`-range down through an appropriate screen or mesh. In another embodiment, there is a
`
`combination of a downward negative pressure and an upward positive pressure which
`
`facilitates the de-agglomeration of the different particle sizes. In other embodiments, the
`
`upward pressure can be introduced upwards fi'om a rotating wand. An apparatus utilizing a
`
`negative downward pressure and an upward positive pressure through a rotating wand is a
`
`Micron Air Jet Sieve MAJS I/II manufactured by Hosakawa.
`
`[0100]
`
`In order to facilitate swallowing of a unit dose of the present formulation, excipient
`
`should be kept to a minimum in order to reduce the mass of the dose. Therefore, in preferred
`
`embodiments of the present invention, the drug particles comprise at least about 40% drug, at
`
`least about 50% drug, at least about 60% drug, at least about 80% drug, or at least about 90%
`
`drug.
`
`[0101]
`
`In preferred embodiments, the core comprises drug coated with eytcipient; drug
`
`‘interdispersed in excipient; a combination thereof or drug coated onto excipient, e.g., drug
`
`coated inert beads. The core of drug and excipient is then overcoated with a functional
`
`coating. This is not limiting however, as it is contemplated that single coated particles and
`
`cores containing only drug (with at least one coating) are contemplated by the invention, as
`
`long as the desired functional characteristics are met. In preferred embodiments, the core is
`
`formed by mixing drug with excipient (e.g. a binder such as polyvinylpyrrolidone) to form a
`
`granulate which is then sieved and coated with further excipient (e.g. ethylcellulose). These
`
`cores can then be co_ated with a functional coating (e.g. microcrystalline cellulose).
`
`[0102]
`
`In certain embodiments, wet granulation techniques can be used to prepare cores
`
`21
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`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1514
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1514
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`

`
`W0 03/020241
`
`PCTIIB02/04101
`
`with the drug interdispersed in excipient. Utilizing wet granulation in preparing -the core
`
`. reduces any resultant fine particles in the final formulation. Reducing the fine particles
`
`results in an oral formulation which has decreased potential for pulmonary deposition due to
`
`the presence" of respirable fine particles. The application of the functional coat of the
`
`invention results in a further decrease in respirable fine particles.
`
`.
`
`[0103]
`
`In certain embodiments, melt granulation techniques can be used to prepare the
`
`cores with the drug interdispersed in excipient. In c