`Approved for use through 07/31/2006. OMB 0651-0032
`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`u d n erthe p aperwo rkR
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`fo
`
`f 99 eduction Act o 1
`I 20342/1202653-US8
`Attorney Docket No.
`I Amir Shojaei
`First Inventor
`
`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
`(ONLY FOR NEW NONPROVISIONAL APPLICATIONS UNDER
`37CFR 1.53(8))
`
`Title CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`Express Mail Label No. I
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`
`(Submit an original and a duplicate for fee processing)
`
`See 37 CFR 1.27.
`
`1. D Fee Transmittal Fonm (e.g., PTO/SB/17)
`2. D Applicant claims small entity status.
`3. 0 Specification
`4. 0 Drawing(s) (35 U.S. C. 113)
`
`ADDRESS TO:
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`ACCOMPANYING APPLICATION PARTS
`
`9. D Assignment Papers (cover sheet & document(s))
`
`Name of Assignee:
`
`I
`
`(when there is an assignee)
`
`Attorney
`
`publications, & other infom1ation
`
`I
`10. D 37 CFR 3.73(b) Statement DPowerof
`11. D English Translation Document (if applicable)
`12. D Information Disclosure Statement (PTO/SB/08 or PT0-1449)
`D Copies of foreign patent documents,
`13. D Preliminary Amendment
`14. D Return Receipt Postcard (MPEP 503)
`15. D Certified Copy of Priority Document(s)
`16. D Non publication Request under 35 U.S.C.122 (b)(2)(B)(i).
`
`(Should be specifically itemized)
`
`(if foreign priority is claimed)
`
`Applicant must attach fom1 PTO/SB/35 or equivalent.
`
`"Do'~' I
`
`I
`
`[Total Pages
`Both the claims and abstract must start on a new page
`(For infonnation on the preferred arrangement, see MPEP 608.01(a))
`10 1
`- - -
`- - -
`
`56
`
`1
`
`[Total Sheets
`
`5. Oath or Declaration
`
`[Total Sheets
`
`1
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`a. D
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`Newly executed (original or copy)
`
`b. D
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`A copy from a prior application (37 CFR 1.63(d))
`(for continuation/divisional with Box 18 completed)
`
`Signed statement attached deleting inventor(s) named in the
`prior application, see 37 CFR 1.63(d)(2)and 1.33(b).
`
`i. D DELETION OF INVENTOR(S)
`6. 0 Application Data Sheet. See 37 CFR 1.76
`7. D CD-ROM or CD-R in duplicate, large table or
`D Landscape Table on CD
`
`Computer Program (Appendix)
`
`8. Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a. -c. are required)
`
`a. Computer Readable Fom1 (CRF)
`
`i.
`
`D Computer Readable Fom1 (CRF)
`ii. D Transfer Request (37 CFR 1.821(e))
`ii. 0 Paper
`i. 0 CD-ROM or CD-R (2 copies); or
`c. D Statements verifying identity of above copies
`
`b. Specification Sequence Listing on:
`
`18. If a CONTINUING APPLICATION, check appropriate box, and supply the requisfte information below and in the first sentence of the
`specification following the title, or in an Application Data Sheet under 37 CFR 1. 76:
`
`0 Continuation D Divisional D Continuation-in-part (CIP)
`
`of prior application No.:
`
`Art Unft:
`
`Prior application information: Examiner
`
`0 The address associated with Customer Number.
`
`I
`
`07278
`
`I OR D Correspondence address below
`
`19. CORRESPONDENCE ADDRESS
`
`Name
`
`Joseph R. Robinson
`DARBY & DARBY P.C.
`
`Address P.O. Box 5257
`
`City
`
`Country
`
`Signature
`
`Name
`(Print/Type)
`
`I State I
`NY
`New York
`I Telephone I (917) 286-2910 I Email Address
`us
`ClfL--J---__ IL~ ~ -~-'Cw fl3/ '19-<o)
`.
`Jbteph R. Robinson
`
`Registration No.
`(Attorney/Agent)
`
`Date
`
`I Zip Code I 10150-5257
`
`May 12, 2006
`33,448
`
`Page 1 of 821
`
`KVK-TECH EXHIBIT 1005
`
`
`
`Application Data Sheet
`
`Application Information
`
`Application Type::
`
`Subject Matter::
`
`Suggested Group Art Unit::
`
`CD-ROM or CD-R?::
`
`Sequence submission?::
`
`Regular
`
`Utility
`
`1615
`
`None
`
`None
`
`Computer Readable Form (CRF)?::
`
`No
`
`Title::
`
`CONTROLLED DOSE DRUG DELIVERY
`
`Attorney Docket Number::
`
`20342/1202653-USS
`
`SYSTEM
`
`Request for Early Publication?::
`
`Request for Non-Publication?::
`
`Total Drawing Sheets::
`
`Small Entity?::
`
`Petition included?::
`
`Secrecy Order in Parent Appl.? ::
`
`Applicant Information
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence::
`
`State or Province of Residence::
`
`Country of Residence::
`
`Street of mailing address::
`
`City of mailing address::
`
`No
`
`No
`
`10
`
`No
`
`No
`
`No
`
`Inventor
`us
`Full Capacity
`
`Amir
`
`Shojaei
`
`Phoenixville
`
`PA
`us
`241 Rivercrest Drive
`
`Phoenixville
`
`Page# 1
`
`Initial 05/12/06
`
`Page 2 of 821
`
`
`
`PA
`State or Province of mailing address::
`Postal or Zip Code of mailing address:: 19460
`
`Correspondence Information
`
`Correspondence Customer Number::
`
`07278
`
`Representative Information
`
`Representative Customer Number::
`
`07278
`
`Domestic Priority Information
`
`Foreign Priority Information
`
`Assignee Information
`
`Assignee name::
`
`SHIRE LLC
`
`Street of mailing address::
`City of mailing address::
`State or Province of mailing address::
`Postal or Zip Code of mailing address::
`
`9200 Brookfield Court
`Florence
`KY
`41 042
`
`Page# 2
`
`Initial 05/12/06
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`Page 3 of 821
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`
`
`Attorney Docket No. 20342/1202653-USS
`(PATENT)
`
`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. 1991; 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 gastric fluid.
`
`1
`
`Attorney docket No. 2034211202653-USS
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`Page 4 of 821
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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
`
`Page 5 of 821
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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
`
`Attorney docket No. 2034211202653-USS
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`Page 6 of 821
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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 7 of 821
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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 8 of 821
`
`
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`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.
`
`According to the present invention, an atypical, counter-intuitive construction for a
`
`sustained release amphetamine formulation, when administered in combination with an
`
`immediate release formulation and a delayed pulsed release formulation, is bioequivalent to
`
`ADDERALL XR® followed by an immediate release amphetamine formulation administered 8
`
`hours later. A sustained release formulation of the present invention comprises at least one
`
`amphetamine salt layered onto, or incorporated into, a core; a delayed release coating layered
`
`onto the amphetamine core; a sustained release coating layered onto the delayed release coating;
`
`and, optionally, a protective coating. See FIG. 2. In a preferred embodiment, the delayed release
`
`component is pH dependent.
`
`A sustained release pharmaceutical formulation of the present invention can comprise
`
`about 10% to about 150% of the amphetamine dosage of the immediate release mixed
`
`amphetamine salt composition and/or an extended release mixed amphetamine salt composition.
`
`For example, the sustained release formulation can be administered, in the same or different
`
`dosage forms, with theIR and delayed pulsed release components of ADDERALL XR® in an
`
`amphetamine dosage ratio of 1:1:1 (e.g., 10 mg immediate release amphetamine, 10 mg delayed
`
`pulsed release amphetamine, 10 mg sustained release amphetamine). Thus, in this example, the
`
`sustained release composition comprises about 33% of the total amphetamine dose. In another
`
`example, a patient with ADHD and insomnia can be administered a reduced amount of the
`
`sustained release composition, e.g., 10 mg immediate release amphetamine, 10 mg delayed
`
`pulsed release amphetamine, and 5 mg sustained release amphetamine (the sustained release
`
`composition comprises 20% of the total amphetamine dose). Thus, according to the present
`
`6
`
`Attorney docket No. 2034211202653-USS
`
`Page 9 of 821
`
`
`
`invention, a clinician can adjust the sustained release formulation dosage to meet the needs of an
`
`individual patient suffering from ADHD.
`
`The pharmaceutical composition of the present invention, comprising an immediate
`
`release amphetamine component, a delayed pulsed release amphetamine component and a
`
`sustained release amphetamine component, delivers, in a single dose, mixed amphetamine salts
`
`to a patient with a pharmacokinetic profile similar to a 2-dose treatment with a currently
`
`available commercial extended release composition (i.e., ADDERALL XR®) plus an immediate
`
`release composition administered about eight hours after the ADDERALL XR®. See, for
`
`example, FIG. 9. This similarity in bioequivalence is surprising because it would be expected
`
`that some part of the drug delivered by the delayed release components of compositions of the
`
`present invention (i.e., the delayed pulsed release and/or the sustained release components)
`
`would be lost (i.e., not absorbed) in the colon. The FDA package insert and labeling for
`
`ADDERALL XR® (Shire US, Inc.) are hereby incorporated by reference in their entirety.
`
`Preferred amphetamine salts are those in ADDERALL XR®, i.e., dextroamphetamine
`
`sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine
`
`sulfate. However, the invention is not limited to these salts. Other amphetamines and
`
`amphetamine salts can be used in the pharmaceutical compositions of the present invention
`
`including, for example, amphetamine base, chemical and chiral derivatives thereof; other
`
`amphetamine salts; and mixtures of the foregoing.
`
`The three components comprising the extended release amphetamine composition of the
`
`invention release doses of the active ingredients at varying, pre-determined times to provide for
`
`full day treatment (i.e., about 14 hours to about 16 hours) of conditions such as ADHD. A
`
`treatment for ADHD, which can be delivered in a single dosage is especially beneficial to
`
`adolescents and adults who typically have longer daily waking hours compared to children.
`
`The compositions of the present invention comprise an immediate release component, a
`
`delayed pulsed release component, and a sustained release component. In embodiments of the
`
`invention, delayed pulsed release and/or sustained release can be provided by an enteric coating.
`
`In a particular embodiment, the immediate release component, delayed pulsed release
`
`component and sustained release component each contain equal amounts of active ingredient.
`
`7
`
`Attorney docket No. 2034211202653-USS
`
`Page 10 of 821
`
`
`
`In one embodiment, the immediate release, delayed pulsed release and sustained release
`
`components of the composition are present on the same core. In another embodiment, the
`
`immediate release and delayed pulsed release components are present on different cores. In a
`
`further embodiment, the delayed pulsed release and sustained release components are present on
`
`different cores. In a preferred embodiment, the immediate release, delayed pulsed release and
`
`sustained release components are present on different cores. See FIG. 3.
`
`In yet another embodiment, the amphetamine salt is coated onto a core. In a further
`
`embodiment, the amphetamine salt is incorporated into a core.
`
`It is contemplated that compositions of the present invention can include a combination
`
`of the hereinabove referred to cores (one or more cores that include three components on the
`
`same core, one or more cores that include two of the three components on the core, and one or
`
`more cores that include one of the three components on the core).
`
`In an embodiment of the present invention, a pharmaceutical composition is provided in
`
`which there is immediate release of drug, a delayed pulsed release of drug, and a sustained
`
`release of drug, and wherein the drug includes one or more amphetamine salts and mixtures
`
`thereof. In a preferred embodiment, the delayed pulsed release of drug begins about one hour
`
`after oral administration of the composition to a patient in the fasted state and the sustained
`
`release of drug begins about four hours to about six hours after oral administration to a patient in
`
`the fasted state.
`
`Surprisingly, amphetamine salt pharmaceutical compositions of the present invention
`
`deliver about bioequivalent drug levels to a patient in either a fasted state or fed state. Thus, an
`
`amphetamine salt composition according to the present invention does not exhibit a food effect.
`
`This is surprising because it would be expected that some of the drug delivered by delayed
`
`release would be released earlier in the presence of food (especially fatty food) due to the
`
`increase in gastric pH that accompanies the ingestion of food.
`
`A pharmaceutical composition according to the present invention includes:
`
`(a)
`
`(b)
`
`(c)
`
`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
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`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
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`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
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`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
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`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
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`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.
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`In a more particular embodiment,
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`the amphetamine
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`salt
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`IS a mixture 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, and amphetamine sulfate.
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`In an aspect of the present invention, the pharmaceutical composition does not exhibit a
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`food effect.
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`The present invention encompasses methods for treating ADHD, which compnse
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`administering the amphetamine salt pharmaceutical composition of the present invention to a
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`patient suffering from ADHD.
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`The delayed pulsed release and sustained release components retard or delay the release
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`of the pharmaceutically active ingredient(s) for a specified time period ("lag time") until a
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`predetermined time. For example, a delayed pulsed release component having an enteric coating
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`layer retards or delays the release of the pharmaceutical active or drug for a lag time, then
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`releases the drug rapidly and completely, i.e., a pulsed release. In one embodiment of a delayed
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`pulsed release, the entire dose is released within about 30-60 minutes following a lag time after
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`administration of the composition. In another example, a sustained release component having an
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`enteric release coating retards or delays the release of the pharmaceutical active or drug for a lag
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`time and then the release of the drug is sustained (i.e., release of the entire dose takes greater
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`than about 60 minutes).
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`The delay or lag time will take into consideration factors such as transit times, food
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`effects, inflammatory bowel disease, use of antacids or other medicaments, which can alter the
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`pH of the GI tract.
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`According to the present invention, the lag time for the delayed pulsed release component
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`can be pH dependent or pH independent. In an embodiment of the invention, the lag time for the
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`delayed pulsed release component is only time-dependent, i.e., pH independent. In a preferred
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`embodiment, the lag time is pH dependent.
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`According to the present invention, a lag time can be about 1 hour to about 14 hours.
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`Multiple dose formulations can have more than one lag time. In a preferred embodiment, the
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`delayed pulsed release component has a lag time of about 60 minutes and the sustained release
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`component has a lag time of about 4 to about 6 hours.
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`In one aspect, the present invention is directed to a composition that provides for enteric
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`release of at least one pharmaceutically active amphetamine salt, including at least one
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`pharmaceutically active amphetamine salt that is coated with an enteric coating wherein (1) the
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`enteric release coating has a defined minimum thickness and/or (2) there is a protective layer
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`between the at least one pharmaceutically active amphetamine salt and the enteric release coating
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`and/or (3) there is a protective layer over the enteric release coating.
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`In attempting to provide for delayed pulsed release of an amphetamine salt, applicants
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`found that use of an enteric release coating as generally practiced in the art did not provide the
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`desired release profile. Using the typical amount of enteric coating ( 10 to 15 wt %) for the
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`delayed pulsed release component resulted in undesired premature leakage of the drug from the
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`delivery system into the upper gastrointestinal tract, and drug delivery at the desired, more distal
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`location in the gastrointestinal tract was reduced. Thus, this coating did not meet the
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`requirements for a drug release profile, which provides full beneficial therapeutic activity at the
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`desired time.
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`Applicants found that using a thicker application of enteric coating on the delayed pulsed
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`release component allowed for the delayed release pulsed dose to be released only, and
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`completely, at the appropriate time in the desired predetermined area of the gastrointestinal tract,
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`i.e