`h p
`n ert e aperwor k R d e uct1on A ct o
`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
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`PTO/AIA/15 (03-13)
`Approved for use through 01/31/2014. OMB 0651-0032
`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`d
`II
`f . f
`I
`d'
`I
`I'd OMB
`I
`b
`1995, no persons are requ1re
`to respon
`to a co ect1on o 1n ormat1on un ess 1t 1sp1ays a va 1
`contra num er.
`d
`Attorney Docket No.
`First Named Inventor
`
`I os51 99-0996
`I Amir SHOJAEI
`
`Title CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`(ONLY FOR NEW NONPROVISIONAL APPLICATIONS UNDER
`37 CFR 1.53(8))
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`Express Mail Label No. I
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`APPLICATION ELEMENTS
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`56
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`Both the claims and abstract must start on a new page.
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`assignee, person to whom the inventor is under an obligation to assign, or person who otherwise shows sufficient proprietary
`interest in the matter. See 37 CFR 1.46(b).
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`I
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`0 The address associated with Customer Number: I
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`18. CORRESPONDENCE ADDRESS
`20277
`
`I OR D Correspondence address below
`
`Name
`
`Address
`
`City
`
`Country
`
`Signature
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`Name
`(Print/Type)
`
`/Paul M. Zagar/
`
`Paul M. Zagar
`
`I State I
`I Telephone I
`
`I Email
`
`I
`
`Date
`
`I Zip Code I
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`Registration No.
`(Attorney/Agent)
`
`I September 26, 2014
`52,392
`I
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`I hereby certify that this paper (along with any paper referred to as being attached or enclosed) is being transmitted via the Office electronic filing
`system in accordance with 37 CFR § 1.6(a)(4).
`
`Dated: September 26, 2014
`
`Signature: /Hiroko Lavietes/
`
`OM_ US 55283553-1.085199.0996
`DRAFT 9/26/14
`
`Page 1 of 322
`
`KVK-TECH EXHIBIT 1030
`
`
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`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of Invention:
`
`CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`First Named Inventor/Applicant Name:
`
`Amir SHOJAEI
`
`Filer:
`
`Paul Michael Zagar/Hiroko Lavietes
`
`Attorney Docket Number:
`
`085199-0996
`
`Filed as Large Entity
`
`Utility under 35 USC 111 (a) Filing Fees
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`Description
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`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USD($)
`
`Basic Filing:
`
`Utility application filing
`
`Utility Search Fee
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`Utility Examination Fee
`
`1011
`
`1111
`
`1311
`
`1
`
`1
`
`1
`
`280
`
`600
`
`720
`
`280
`
`600
`
`720
`
`Pages:
`
`Claims:
`
`Miscellaneous-Filing:
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`Late Filing Fee for Oath or Declaration
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`1051
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`1
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`140
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`140
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`Petition:
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`Page 2 of 322
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`Description
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`Fee Code
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`Quantity
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`USD($)
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`Patent-Appeals-and-Interference:
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`Post-Allowance-and-Post-Issuance:
`
`Extension-of-Time:
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`Miscellaneous:
`
`Total in USD ($)
`
`1740
`
`Page 3 of 322
`
`
`
`Electronic Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`20258571
`
`14498130
`
`International Application Number:
`
`Confirmation Number:
`
`5887
`
`Title of Invention:
`
`CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`First Named Inventor/Applicant Name:
`
`Amir SHOJAEI
`
`Customer Number:
`
`20277
`
`Filer:
`
`Paul Michael Zagar/Hiroko Lavietes
`
`Filer Authorized By:
`
`Paul Michael Zagar
`
`Attorney Docket Number:
`
`085199-0996
`
`Receipt Date:
`
`26-SEP-2014
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`15:36:55
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`Application Type:
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`Utility under 35 USC 111 (a)
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`Authorized User
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`yes
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`$1740
`
`2084
`
`500417
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`Document Description
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`I
`
`File Name
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`I
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`File Size( Bytes)/ I Multi 'I Pages
`(ifappl.)
`Message Digest
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`Page 4 of 322
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`yes
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`Warnings:
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`2
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`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New A~~lications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing date of the application.
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`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
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`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
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`New International A~~lication Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 181 0), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/R0/1 OS) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`Page 6 of 322
`
`
`
`085199-0996
`
`CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`BACKGROUND OF THE INVENTION
`
`Traditionally, drug delivery systems have focused on constant/sustained drug output with
`
`the objective of minimizing peaks and valleys of drug concentrations in the body to optimize
`
`drug efficacy and reduce adverse effects. Reduced dosing frequency and improved patient
`
`compliance can also be expected for constant/sustained release drug delivery systems, compared
`
`to immediate release preparations. However, for certain drugs, sustained release delivery is not
`
`suitable and is affected by the following factors:
`
`First pass metabolism: Some drugs, such as B-blockers, B-estradiol, and salicylamide,
`
`undergo extensive first pass metabolism and require fast drug input to saturate metabolizing
`
`enzymes in order to minimize pre-systemic metabolism. Thus, a constant/sustained oral method
`
`of delivery would result in reduced oral bioavailability.
`
`Biological tolerance: Continuous release drug plasma profiles are often accompanied by a
`
`decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal
`
`nitroglycerin.
`
`Chronopharmacology and circadian rhythms: Circadian rhythms in certain physiological
`
`functions are well established. It has been recognized that a symptom or disease onset can occur
`
`during specific time periods of the 24 hour day, e.g., asthma and angina pectoris attacks are most
`
`frequently in the morning hours (Lemmer, B, J Controlled Release. 199t 16:63-74; Lemmer B,
`
`Pulsatile Drug Delivery: Current Applications and Future Trends (R Gurney, HE Junginger, NA
`
`Peppeas, eds.) 1993; 11-24).
`
`Local therapeutic need: For the treatment of local disorders such as inflammatory bowel
`
`disease, the delivery of compounds to the site of inflammation with no loss due to absorption in
`
`the small intestine is highly desirable to achieve the therapeutic effect and to minimize side
`
`effects.
`
`Gastric irritation or drug instability in gastric fluid: For compounds with gastric irritation
`
`or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate
`
`gastric irritation and chemical instability in gastlic fluid.
`
`1
`
`Attorney docket No. 20342!1202653-USS
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`Page 7 of 322
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`
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`Drug absorption differences in various gastrointestinal segments: In general, drug
`
`absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining
`
`in the large intestine. Compensation for changing absorption characteristics in the
`
`gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery
`
`system to pump out the drug much faster when the system reaches the distal segment of the
`
`intestine, to avoid the entombment of the drug in the feces.
`
`Pulsed dose delivery systems, prepared as either single unit or multiple unit formulations,
`
`and which are capable of releasing the drug after a predetermined time, have been studied to
`
`address the aforementioned problematic areas for sustained release preparations. These same
`
`factors are also problematic in pulsed dose formulation development. For example,
`
`gastrointestinal transit times vary not only from patient to patient but also within patients as a
`
`result of food intake, stress, and illness; thus a single-unit pulsed-release system may exhibit
`
`higher variability compared to a multiple unit system. Additionally, drug layering or core making
`
`for multiple unit systems is a time-consuming and hard-to-optimize process. Particularly
`
`challenging for formulation scientists has been overcoming two conflicting hurdles for pulsatile
`
`formulation development, i.e., lag time and rapid release.
`
`Various enteric materials, e.g., cellulose acetate phthalate, hydroxypropyl
`
`methylcellulose phthalate, polyvinyl acetate phthalate, and the EUDRAGIT® acrylic polymers,
`
`have been used as gastroresistant, enterosoluble coatings for single drug pulse release in the
`
`intestine (Xu X and Lee P, Pharm Res. 1993; 10(8):1144-1152). The enteric materials, which are
`
`soluble at higher pH values, are frequently used for colon-specific delivery systems. Due to their
`
`pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as
`
`well as inter- and intra-subject variability are major issues for using enteric coated systems as a
`
`time-controlled release of drugs.
`
`A retarding, swellable hydrophilic coating has been used for oral delayed release systems
`
`(Gazzaniga et al., Eur J Pharm Biopharm. 1994; 40(4):246-250; Gazzaniga et al., S.T.P. Pharma
`
`Sciences. 1996; 5(1):83-88). It was demonstrated that lag time was linearly correlated with
`
`coating weight gain and drug release was pH independent.
`
`Hydroxypropyl methylcellulose barriers with erodible and/or gellable characteristics
`
`formed using press coating technology for tablet dosage forms have been described to achieve
`
`2
`
`Attorney docket No. 2034211202653-USS
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`Page 8 of 322
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`
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`time-programmed release of drugs (Conte et al., Biomaterials. 1993; 14(13):1017-1023). Barrier
`
`formulation variables (such as grade of hydroxypropyl methylcellulose, water-soluble and water(cid:173)
`
`insoluble excipients) significantly altered the lag time and the release rate from the center cores.
`
`Special grades of hydroxypropyl methylcellulose, e.g., METOLOSE® 60SH, 90SH
`
`(Shin-Etsu Ltd., Japan), and METHOCEL® F4M (Dow Chemical Company, USA) have been
`
`used as a hydrophilic matrix material to achieve bimodal drug release for several drugs, i.e.,
`
`aspirin, ibuprofen, and adinazolam (WO 87/00044 ). Bimodal release is characterized by a rapid
`
`initial release, followed by a period of constant release, and then by a second rapid drug release.
`
`Tablets or capsules coated with a hydrophobic wax-surfactant layer, made from an
`
`aqueous dispersion of carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and
`
`hydroxypropyl methylcellulose have been used for rapid drug release after a predetermined lag
`
`time. However, even though a two-hour lag time was achieved for the model drug theophylline
`
`at a higher coating level ( 60% ), three hours were required for a complete release of theophylline
`
`after the lag time. (Walia et al., Pharm Dev Tech. 1998; 3(1):103-113)
`
`A sustained-release drug delivery system is described in U.S. Pat. No. 4,871,549. When
`
`this system is placed into dissolution medium or the gastrointestinal tract, water influx and the
`
`volume expansion of the swelling agent cause the explosion of the water permeable membrane.
`
`The drug thus releases after a predetermined time period.
`
`The OROS® push-pull system (Alza Company) has been developed for pulsatile delivery
`
`of water-soluble and water-insoluble drugs (Theeuwes, Drug Dev Ind Pharm. 1983; 9(7):1331-
`
`1357; Theeuwes F, Novel Drug Delivery and Its Therapeutic Application (LF Prescott and WS
`
`Nimmos eds.) 1989; 323-340), e.g. the OROS-CT® system and is based on the swelling
`
`properties of an osmotic core compartment which provides a pH-independent, time-controlled
`
`drug release.
`
`The PULSINCAP® dosage form releases its drug content at either a predetermined time
`
`or at a specific site (e.g., colon) in the gastrointestinal tract (WO 90/09168). The drug
`
`formulation is contained within a water-insoluble capsule body and is sealed with a hydrogel
`
`plug. Upon oral administration, the capsule cap dissolves in the gastric juice and the hydrogel
`
`plug swells. At a controlled and predetermined time point, the swollen plug is ejected from the
`
`PULSINCAP® dosage form and the encapsulated drug is released. A pulsatile capsule system
`
`3
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`Attorney docket No. 2034211202653-USS
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`Page 9 of 322
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`
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`containing captopril with release after a nominal5-hr period was found to perform, reproducible
`
`in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no
`
`measurable amounts of the drug were observed in the blood, possibly due to instability of the
`
`drug in the distal intestine. (Wilding et al., Pharm Res. 1992;9(5):654-657)
`
`ADDERALL® is an immediate release composition, which includes a mixture of four
`
`amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine
`
`aspartate monohydrate and amphetamine sulfate. This combination of amphetamines is
`
`indicated for the treatment of Attention Deficit Hyperactivity Disorder in children from 3-10
`
`years of age.
`
`One disadvantage of immediate release-only treatments for children is that two separate
`
`doses are administered, one in the morning and one approximately 4-6 hours later, commonly
`
`away from home under other than parental supervision. This requires a second treatment, which
`
`is time-consuming, inconvenient and may be problematic for those children having difficulties in
`
`swallowing tablet formulations. ADDERALL XR® met the need for a dosage form, which can
`
`be administered once, in place of the two oral doses which are needed using the conventional
`
`drug delivery formulations of the prior art. See U.S. Patent Nos. 6,322,819 and 6,605,300; co(cid:173)
`
`pending Reissue Application Nos. 11/091,010 and 11/091,011.
`
`There are currently two medications (ADDERALL XR® and STRATTERA™) approved
`
`by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD in adults.
`
`ADDERALL XR® is a mixed amphetamine salts medication. STRATTERA TM is an
`
`atomoxetine (a norepinephrine reuptake inhibitor) medication. Long acting stimulant
`
`preparations, such as ADDERALL XR® and CONCERT A® (methylphenidate), are designed to
`
`provide a duration of effect up to 12 hours. However, clinicians have noted that a proportion of
`
`patients treated with these formulations require additional treatment with a short-acting stimulant
`
`to extend the daily therapeutic effect. For patients taking long-acting stimulant formulations who
`
`require duration of clinical benefit beyond 10-12 hours, clinicians have augmented the morning
`
`long-acting formulation, typically at 8-10 hours post-dose, with a dose of the same immediate(cid:173)
`
`release (IR) medication. Typically, the dose of theIR medication is smaller than the long-acting
`
`dose. This augmentation strategy is most relevant to the "longer day demands" of adult and
`
`adolescents, rather than school age, pediatric patients.
`
`4
`
`Attorney docket No. 2034211202653-USS
`
`Page 10 of 322
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`
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`Thus, a need exists for a once-daily, long-acting oral composition that provides effective
`
`treatment of ADHD, without supplementation, for patients with longer day demands (e.g., 14-16
`
`awake hours).
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a long-acting amphetamine pharmaceutical composition,
`
`which includes an immediate release component, a delayed pulsed release component and a
`
`sustained release component, to meet the therapeutic needs for ADHD patients with longer-day
`
`demands. The present invention fills the need for once-daily longer-day treatment of ADHD by
`
`providing an amphetamine pharmaceutical composition that is bioequivalent to an equal dosage
`
`of ADDERALL XR® followed by an IR amphetamine composition 8 hours later.
`
`The addition of a second delayed pulsed release formulation, having a lag time of about 8
`
`hours, to ADDERALL XR® cannot, as one might expect, meet the recognized need for a once(cid:173)
`
`daily long-acting amphetamine composition that meets a patient's longer day requirements (i.e.,
`
`a once-daily amphetamine composition that is bioequivalent to ADDERALL XR® plus an
`
`immediate release amphetamine composition administered 8 hours later). A delayed pulsed
`
`formulation having a lag time of about 8 hours would be unsuitable because it would release the
`
`active agent in the distal gastrointestinal tract (the colon), resulting in decreased absorption of the
`
`active agent.
`
`Unexpectedly, it has been discovered that a sustained release formulation administered in
`
`combination with immediate release and delayed pulsed release components similar to those
`
`present in ADDERALL XR® can mimic the bioavailability of an equivalent total amphetamine
`
`dosage provided by ADDERALL XR® followed by an immediate release amphetamine
`
`composition 8 hours later. However, the "usual" or "typical" construction for a sustained release
`
`formulation is not suitable. Typically, a sustained release formulation is constructed with a
`
`delayed release coating overlaying a sustained release coating. Such a usual or typical sustained
`
`release construction results in a Tmax that is too early after administration to a patient to result in
`
`a composition that meets the longer-day requirements for the treatment of ADHD. For example,
`
`the dissolution profiles for a typical sustained release formulation (PD0149-124) and a sustained
`
`release formulation of the present invention (PD0149-120) are illustrated in FIG. 1. PD0149-
`
`124 has a typical sustained release formulation construction, wherein the immediate release bead
`
`5
`
`Attorney docket No. 2034211202653-USS
`
`Page 11 of 322
`
`
`
`of Example 1 (see Examples 1 and 2, infra) is coated with a sustained release coating
`
`(SURELEASE®), the sustained release coating is coated with a delayed release coating
`
`(EUDRAGIT® FS30 D), and the delayed release coating is coated with a protective layer
`
`(OPADRY®). PD0149-120 is an embodiment of a sustained release formulation of the present
`
`invention. PD0149-120 has a construction wherein the immediate release bead of Example 1 is
`
`coated with a delayed release coating (EUDRAGIT® FS30 D), the delayed release coating is
`
`coated with a protective coating (OPADRY®), and the protective coating is coated with a
`
`sustained release coating (SURELEASE®). As illustrated in FIG. 1, PD0149-120 provides a
`
`later Tmax relative to a typically-constructed sustained release formulation, PD0149-124.
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`According to the present invention, an atypical, counter-intuitive construction for a
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`sustained release amphetamine formulation, when administered in combination with an
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`immediate release formulation and a delayed pulsed release formulation, is bioequivalent to
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`ADDERALL XR® followed by an immediate release amphetamine formulation administered 8
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`hours later. A sustained release formulation of the present invention comprises at least one
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`amphetamine salt layered onto, or incorporated into, a core; a delayed release coating layered
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`onto the amphetamine core; a sustained release coating layered onto the delayed release coating;
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`and, optionally, a protective coating. See FIG. 2. In a preferred embodiment, the delayed release
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`component is pH dependent.
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`A sustained release pharmaceutical formulation of the present invention can comprise
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`about 10% to about 150% of the amphetamine dosage of the immediate release mixed
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`amphetamine salt composition and/or an extended release mixed amphetamine salt composition.
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`For example, the sustained release formulation can be administered, in the same or different
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`dosage forms, with theIR and delayed pulsed release components of ADDERALL XR® in an
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`amphetamine dosage ratio of 1:1:1 (e.g., 10 mg immediate release amphetamine, 10 mg delayed
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`pulsed release amphetamine, 10 mg sustained release amphetamine). Thus, in this example, the
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`sustained release composition comprises about 33% of the total amphetamine dose. In another
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`example, a patient with ADHD and insomnia can be administered a reduced amount of the
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`sustained release composition, e.g., 10 mg immediate release amphetamine, 10 mg delayed
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`pulsed release amphetamine, and 5 mg sustained release amphetamine (the sustained release
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`composition comprises 20% of the total amphetamine dose). Thus, according to the present
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`invention, a clinician can adjust the sustained release formulation dosage to meet the needs of an
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`individual patient suffering from ADHD.
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`The pharmaceutical composition of the present invention, comprising an immediate
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`release amphetamine component, a delayed pulsed release amphetamine component and a
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`sustained release amphetamine component, delivers, in a single dose, mixed amphetamine salts
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`to a patient with a pharmacokinetic profile similar to a 2-dose treatment with a currently
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`available commercial extended release composition (i.e., ADDERALL XR®) plus an immediate
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`release composition administered about eight hours after the ADDERALL XR®. See, for
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`example, FIG. 9. This similarity in bioequivalence is surprising because it would be expected
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`that some part of the drug delivered by the delayed release components of compositions of the
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`present invention (i.e., the delayed pulsed release and/or the sustained release components)
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`would be lost (i.e., not absorbed) in the colon. The FDA package insert and labeling for
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`ADDERALL XR® (Shire US, Inc.) are hereby incorporated by reference in their entirety.
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`Preferred amphetamine salts are those in ADDERALL XR®, i.e., dextroamphetamine
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`sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine
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`sulfate. However, the invention is not limited to these salts. Other amphetamines and
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`amphetamine salts can be used in the pharmaceutical compositions of the present invention
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`including, for example, amphetamine base, chemical and chiral derivatives thereof; other
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`amphetamine salts; and mixtures of the foregoing.
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`The three components comprising the extended release amphetamine composition of the
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`invention release doses of the active ingredients at varying, pre-determined times to provide for
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`full day treatment (i.e., about 14 hours to about 16 hours) of conditions such as ADHD. A
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`treatment for ADHD, which can be delivered in a single dosage is especially beneficial to
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`adolescents and adults who typically have longer daily waking hours compared to children.
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`The compositions of the present invention comprise an immediate release component, a
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`delayed pulsed release component, and a sustained release component. In embodiments of the
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`invention, delayed pulsed release and/or sustained release can be provided by an enteric coating.
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`In a particular embodiment, the immediate release component, delayed pulsed release
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`component and sustained release component each contain equal amounts of active ingredient.
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`In one embodiment, the immediate release, delayed pulsed release and sustained release
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`components of the composition are present on the same core. In another embodiment, the
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`immediate release and delayed pulsed release components are present on different cores. In a
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`further embodiment, the delayed pulsed release and sustained release components are present on
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`different cores. In a preferred embodiment, the immediate release, delayed pulsed release and
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`sustained release components are present on different cores. See FIG. 3.
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`In yet another embodiment, the amphetamine salt is coated onto a core. In a further
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`embodiment, the amphetamine salt is incorporated into a core.
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`It is contemplated that compositions of the present invention can include a combination
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`of the hereinabove referred to cores (one or more cores that include three components on the
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`same core, one or more cores that include two of the three components on the core, and one or
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`more cores that include one of the three components on the core).
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`In an embodiment of the present invention, a pharmaceutical composition is provided in
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`which there is immediate release of drug, a delayed pulsed release of drug, and a sustained
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`release of drug, and wherein the drug includes one or more amphetamine salts and mixtures
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`thereof. In a preferred embodiment, the delayed pulsed release of drug begins about one hour
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`after oral administration of the composition to a patient in the fasted state and the sustained
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`release of drug begins about four hours to about six hours after oral administration to a patient in
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`the fasted state.
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`Surprisingly, amphetamine salt pharmaceutical compositions of the present invention
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`deliver about bioequivalent drug levels to a patient in either a fasted state or fed state. Thus, an
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`amphetamine salt composition according to the present invention does not exhibit a food effect.
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`This is surprising because it would be expected that some of the drug delivered by delayed
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`release would be released earlier in the presence of food (especially fatty food) due to the
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`increase in gastric pH that accompanies the ingestion of food.
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`A pharmaceutical composition according to the present invention includes:
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`(a)
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`(b)
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`(c)
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`an immediate release bead comprising an amphetamine salt;
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`a first delayed release bead comprising an amphetamine salt; and
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`a second delayed release bead comprising an amphetamine salt;
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`wherein the first delayed release bead provides pulsed release of the mixed amphetamine salt and
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`the second delayed release bead provides sustained release of the mixed amphetamine salt.
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`A pharmaceutical composition of the present invention provides a patient with at least
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`about 14 hours to about 16 hours of effective therapy for Attention Deficit Hyperactivity
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`Disorder (ADHD).
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`In an embodiment of the invention, the d-amphetamine Cmax after administration of a 37.5
`
`mg amphetamine pharmaceutical composition to a human patient is about 50 ng/ml.
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`In another embodiment, the d-amphetamine area under the curve from time 0 to the last
`
`measured time (AUCo-tast) after administration of a 37.5 mg amphetamine pharmaceutical
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`composition to a human patient is about 1058 ng·hr/ml.
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`Further, according to an embodiment of the present invention, the d-amphetamine area
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`under the curve from time 0 to time infinity (AUCo-inf) after administration of a 37.5 mg
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`amphetamine pharmaceutical composition to a human patient is about 1085 ng·hr/ml.
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`In an embodiment, the present invention provides a pharmaceutical composition, wherein
`
`the d-amphetamine Tmax is about 8.2 hours after administration of a 37.5 mg amphetamine
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`pharmaceutical composition to a human patient.
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`In a particular embodiment, the [-amphetamine Cmax after administration of a 37.5 mg
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`amphetamine pharmaceutical composition to a human patient is about 15 ng/ml.
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`In a further embodiment, the [-amphetamine area under the curve from time 0 to the last
`
`measured time (AUCo-tast) after administration of a 37.5 mg amphetamine pharmaceutical
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`composition to a human patient is about 354 ng·hr/ml.
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`In another embodiment, the [-amphetamine area under the curve from time 0 to time
`
`infinity (AUCo-inf) after administration of a 37.5 mg amphetamine pharmaceutical composition to
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`a human patient is about 373 ng·hr/ml.
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`Further, in an embodiment of the present invention, the [-amphetamine Tmax is about 8.4
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`hours after administration of a 37.5 mg amphetamine pharmaceutical composition to a human
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`patient.
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`In a further embodiment, a protective layer is provided over at least one enteric coating.
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`In another embodiment, a protective layer is provided between the amphetamine salt and at least
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`one enteric coating. A protective layer can also be provided over the sustained release coating
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`according to the present invention.
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`In a particular embodiment, the amphetamine salt is selected from the group consisting of
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`dextroamphetamine
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`sulfate,
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`dextroamphetamine
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`saccharate,
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`amphetamine
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`aspartate
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`monohydrate, amphetamine sulfate, and mixtures thereof.
`