-. ·~ '-
`'·
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`\
`v 1·.1
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`PTO/SB/16 (08.{)3)
`Approved for use through 7/31/2006. OMB 0651.{)032
`U.S. Patent and Trademarl< Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperworl< Reduction Ad. of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c).
`I Express Mail Label No.
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`Given Name (first and middle [If any) )
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`Family Name or Surname
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`Residence
`(City and either State or Foreign Country)
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`INVENTOR(S)
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`separately numbered sheets attached hereto
`Additional inventors are being named on the
`TITLE OF THE INVENTION(500 characters max}
`MODIFIED RELEASE FORMULATIONS OF MEMANTINE ORAL DOSAGE FORMS
`
`Direct all correspondence to:
`
`0 Customer Number:
`
`l
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`CORRESPONDENCE ADDRESS
`07278
`
`I
`
`OR
`Adda C. Gogoris
`DFirmor
`Individual Name DARBY & DARBY P .C.
`P.O. Box 5257
`Address
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`City
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`New York
`us
`0 Specification Number of Pages 0
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`INY
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`[Telephone [(212) 527-7700
`ENCLOSED APPLICATION PARTS (check all that apply)
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`G]Application Data Sheet. See 37 CFR 1.76
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`0 Applicant claims small entity status. See 37 CFR 1.27.
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`DA check or money order is enclosed to cover the filing fees.
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`04-0100 8
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`DThe Director is hereby authorized to charge filing
`fees or credit any overpayment to Deposit Account Number:
`D Payment by credit card. Form PT0-2038 is attached.
`The invention was made by an agency of the United States Government or under a contract with an agency of the
`United States Government
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`and the Government contract number are:
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`Respectfully submitted,
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`SIGNATURE
`TYPED OR
`PRINTED NAME
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`Sandra S. Lee
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`Date
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`June 17, 2004
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`TELEPHONE
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`03269/0200817 -USO
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`USE ONLY FOR RUNG A PROVISIONAL APPUCA TION FOR PATENT
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`rtV :\03269\0200817us0\00203425. DOC IWUDIIIIIDIIJIDIIIIJDIIDIIIIIID}
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`IPR2015-00410
`Petitioners' Ex. 1008
`Page 1
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`

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`I
`-. 1'-
`~ · I
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`Application No. (if known):
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`Attorney Docket No.: 03269/0200817-USO
`
`·•·· .. . -~
`
`Certificate of Express Mailing Under 37 CFR 1.10
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`I hereby certify that this correspondence is being deposited with the United States Postal Service as
`
`Express Mail, Airbill No. eV
`• us in an envelope addressed to:
`41 8 2 6 8 4 8 7
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`on
`
`June 17, 2004
`Date
`
`AVt..S
`Typed or printed n~me of person signing Certificate
`
`Note: Each paper must have its own certificate of mailing, or this certificate must identify
`each submitted paper.
`
`Provisional Application For Patent Cover Sheet (1 page};
`Specification (31 pages, including 5 pages of Claims and 1 page of
`Abstract};
`Drawings (9 sheets, Figures 1-9};
`Application Data Sheet (2 pages}; and
`Return postcard.
`
`IPR2015-00410
`Petitioners' Ex. 1008
`Page 2
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`... ··
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`5
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`EXPRESS MAll CERTIFICATE
`
`Date -
`----,-,---- - Label No. ---.,....------:,-
`1 hereby certify that. on the date indicated above, this paper or fee
`was deposited with the U .S. Postal Service & that it was addressed
`for delivery to the Mail Stop Provisional Patent Application,
`Commissioner for Patents. PO BOX 1450, Alexandria, VA 22313·
`1450 by "Express Mail Post Office to Addressee· service.
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`Name (Print)
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`PLEASE CHARGE ANY DEFICIENCY UP TO $300.00 0 R CREDIT ANY
`EXCESS IN THE FEES DUE WITH THIS DOCUMENT TO OUR
`DEPOSIT ACCOUNT NO. 04 - 0100
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`File No.: 03269/0200817-USO
`
`MODIFIED RELEASE FORMULATIONS
`OF MEMANTINE ORAL DOSAGE FORMS
`
`. FIELD OF THE INVENTION
`
`The present invention is directed to pharmaceutical solid, oral dosage fonns which
`
`exhibit a modified release profile. The invention is particularly suitable for once a day solid oral
`
`pharmaceutical dosage fonns in which the active ingredient is memantine, releasing a
`
`therapeutically effective amount of the active ingredient over an extended time period.
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`BACKGROUND OF THE INVENTION
`
`Solid oral drug compositions or preparations have various release profiles such as a
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`modified or extended release profile as referenced by USP XXIII (CDER, FDA, Rockville, MD)
`
`or an immediate release profile as referenced by FDA guidelines (Dissolution Testing of
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`Immediate Release Solid Oral Dosage Forms, issued 8/1997, Section IV-A). For example, in the
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`15
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`dissolution testing guideline for modified release profiles, material dissolves over an extended
`
`period and its dissolution is measured over time. A minimum of three time points is
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`recommended and should cover early, middle and late stages of the dissolution profile. The last
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`measurement should be at a time point where at least 80 % of the drug is dissolved (Guidance for
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`Industry, "Extended Release Oral Dosage Forms: Development, Evaluation, and Application of
`In Vitro/In Vivo Correlations", Food and Drug Administration, CDER, September 1997, Page
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`20
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`17). Adequate sampling should be performed, for example, at 1, 2 and 4 hours and every two
`
`hours thereafter until 80% of the drug is released (Guidance for Industry, SUPAC-MR:
`
`Modified Release Solid Oral Dosage Fonns," Food and Drug Administration, CDER, September
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`{W:\03269\0200817us0\00140289.DOC *032690200817USO*}
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`IPR2015-00410
`Petitioners' Ex. 1008
`Page 3
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`2
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`1997, Page 6). The preferred dissolution apparatus is USP apparatus I (basket) or II (paddle),
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`used at compendially recognized rotation speeds, e.g., 100 rpm for the basket and 50-75 rpm for
`
`the paddle (Guidance for Industry, "Extended Release Oral Dosage Forms: Development,
`
`Evaluation, and Application of In VItro/In Vivo Correlations", Food and Drug Administration,
`
`5 CDER, September 1997, Page 4).
`
`Modified release solid oral dosage forms permit the sustained release of the active
`
`ingredient over an extended period oftime in an effort to maintain therapeutically effective
`
`plasma levels over similarly extended time intervals and/or to modify other pharmacokinetic
`
`properties of the active ingredient. Immediate release solid dosage forms permit the release of
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`10 most or all of the active ingredient over a short period of time, such as 60 minutes or less, and
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`make rapid absorption of the drug possible. A multiphase release profile (i.e., a composition
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`containing at least an immediate release formulation and at least one modified release
`
`formulation) may be employed to attain one or more combinations of release rates to attain more
`
`specific therapeutic objectives such as a portion of drug releasing immediately, followed by an
`
`15
`
`extended release. However, modulation of the release rate of an active ingredient does not
`
`necessarily ensure that long-lasting effec6ve blood level concentrations will be consistently
`
`achieved or that the pharmacological effect will be based solely on the release of the drug.
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`Sustained release formulations for drugs have become increasingly avai lable. This is true
`
`especially when the particular drug is relatively soluble. Various formulation techniques have
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`20
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`been used for providing a sustained release formulation of soluble drugs. In many such
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`formulations, a drug-containing particle is coated by one or more release retardant layers or films
`
`or is dispersed within a continuous matrix such as a polymeric matrix. The coating layer or the
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`matrix comprises a relatively insoluble material or materials, and the release of the drug is
`
`controlled by means of the resistance of the coating layer or matrix against the diffusion of the
`
`25
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`drug there through. The release of the drug from such formulations is driven, e.g ., by the
`
`gradient of the drug concentration resulting from penetration of, e.g., gastric fluid, by diffusion
`
`into the formulation.
`
`One or more film-forming polymers may be employed to provide sustained release of the
`
`active substance by controlling its rate of diffusion across the film barrier(s). However, such an
`
`30
`
`approach is compromised if, during ingestion of the oral dosage form, the film is prematurely
`
`breached, as by chewing, splitting or abrasion, thereby releasing an excessive amount of active
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`IPR2015-00410
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`3
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`ingredient, which can result in undesirable effects from excessive single-shot drug release, and in
`
`failure of the dosage form to remain effe.ctive for the required duration.
`
`In the more common matrix-controlled release approach, lipophilic substances, e.g.,
`
`higher alcohols, waxes, or insoluble thermoplastic materials, are employed. The release is
`
`5
`
`controlled by the rate of diffusion of the active ingredient into the surrounding medium and, if
`
`the matrix itself is degradable, by the rate of its degradation. One of the disadvantages is that a
`
`complete release of drug from the matrix is frequently not achieved in practice. Another
`
`drawback is that dose proportionality of the dosage forms is not readily achieved, thus, requiring
`
`different compositions for different strengths. Thus, the matrix composition to formulate a 20
`
`10 mg sustained release dosage form may well be different from the matrix composition to
`
`formulate a 40 mg sustained release dosage form.
`
`U.S. Patent No. 5,382,601 provides solid phannaceutical dosage forms containing
`
`memantine, which exhibit an extended two-phase release profile, with a portion of the drug being
`
`released immediately, followed by a sustained release of the remainder. The matrix of this
`
`15
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`formulation contains both a water-soluble and a water-insoluble salt of casein, preferably sodium
`
`and calcium caseinate. However, casein has an unpleasant taste; it is associated with undesirable
`
`effect of exacerbating some side effects as disclosed in U.S. Patent No. 6,413,556; and displays
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`instability in varying pH. Another concern regarding casein is the possibility of Bovine
`
`Spongiform Encephalitis (BSE) contamination since casein is an animal-derived milk protein.
`
`20
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`A general method of modified release for N-methyl-D-aspartate (NMDA) receptor
`
`antagonists, including memantine, was described in U.S. Patent No. 6,194,000. This method
`
`also involves preparing an instant release component and a modified release component to arrive
`
`at the final formulation. The patent discloses the formulations consisting of encapsulated beads
`
`previously coated using organic solvent-based systems. However, this patent does not
`
`25
`
`specifically disclose compositions containing memantine.
`
`Currently, a dosing regimen ofmemantine of twice a day is employed using immediate
`
`release tablets. This may be undesirable because patient compliance decreases as the frequency
`
`of taking a drug increases. Moreover, administration of an immediate-release tablet can lead to
`
`greater frequency of adverse events due to a faster rate of absorption. For pain treatment, it is
`
`30
`
`very important to maintain the pain relief without additional discomfort. There is therefore an
`
`existing and continual need for a once a day modified release formulation containing memantine
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`{W:\03269\0200817us0\00140289.DOC *032690200817USO*}
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`IPR2015-00410
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`4
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`or a pharmaceutically acceptable salt of memantine with reliable slower absorption over a
`
`targeted period of time.
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`SUMMARY OF THE INVENTION
`
`According to the present invention, it has now been found that memantine, and its salts,
`
`5
`
`including the hydrochloride salt as well as other pharmaceutically acceptable salts of memantine
`
`can be formulated into a modified release fonn with slower absorption and therefore possible
`
`improved tolerability. The formulation of the present invention includes memantine
`
`hydrochloride, a pharmaceutically acceptable polymeric carrier (coating and/or matrix), and one
`
`or more excipients to be administered in a once a day oral dosage form.
`
`10
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`Specifically, the present invention provides a dosage form which slowly releases the
`
`active agent at a release rate of from about 70 to about 80% in about 4 hours to about 24 hours
`
`following entry of the dosage form into a use environment. In one embodiment, the dosage form
`
`is released to this extent over 6 hours of entry into the use environment, i.e., the gastric fluids.
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`Alternatively, the dosage form is released to this extent over 12 hours of entry into the use
`
`15
`
`environment.
`
`For a 12-hour, 80% release formulation, the active ingredient, e.g., memantine
`
`hydrochloride, in the oral dosage form of the present invention is usually present in amounts
`
`from about 1.0% w/w to about 20.0% w/w, preferably from about 1.6% w/w to about 20.0%
`
`w/w, most preferably from about 2.5% w/w to about 20% w/w. Alternatively, the active
`
`20
`
`ingredient may be measured as mg per tablet, ranging from about 10 to about 80 mg per tablet.
`
`Preferably, the tablets contain 10 mg, 20 mg, 40 mg or 80 mg active ingredient.
`
`For a 6-hour release formulation, the active ingredient is usually present in amounts from
`
`about 1.0% w/w to about 35% w/w, preferably from about 1.6% w/w to about 35.0% w/w, most
`
`preferably from about 5.0% w/w to about 35.0% w/w. The active ingredient would therefore be
`
`25
`
`present from about 10 mg to about 80 mg per tablet. Preferably, the tablets contain 10 mg, 20
`
`mg, 40 mg, or 80 mg active ingredient.
`
`In one embodiment of the present invention, the polymeric carrier is a polymeric matrix.
`
`Preferably, the polymeric matrix contains hydroxypropyl methylcellulose. The hydroxypropyl
`
`methylcellulose, in 12-hour formulations is present in amounts from about 50% w/w to about
`
`30
`
`80% w/w, more preferably in amounts from about 68% w/w to about 77% w/w. In 6-hour
`
`{W:\03269\0200817us0\00140289.DOC *032690200817USO*}
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`IPR2015-00410
`Petitioners' Ex. 1008
`Page 6
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`

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`5
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`fonnulations, the hydroxypropropyl methylcellulose is present in amounts from about 20% w/w
`
`to about 70% w/w, preferably from about 54% w/w to about 65% wlw.
`
`The fonnulations of the present invention may further comprise a filler. Preferably, the
`
`filler is lactose monohydrate. In 12-hour fonnulations, the lactose monohydrate is present in
`
`5
`
`amounts from about 5% w/w to about 50% w/w, more preferably from about 5% w/w to about
`
`25% w/w, most preferably from about 6.9% wlw to about 15% w/w. In 6-hour fonnulations, the
`
`lactose monohydrate is present in amounts from about 5% wlw to about 50% wlw, more
`
`preferably from about 5% wlw to about 71% w/w, most preferably from about 7% w/w to about
`
`24%w/w.
`
`10
`
`The fonnulations of the present invention may further comprise a lubricant, preferably
`
`magnesium stearate. In 12-hour formulations, the magnesium stearate is present in amounts
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`ranging from about 0.8% w/w to about 1.2% w/w, preferably from about 0.9% w/w to about
`
`1.1% w/w. In 6-hour fonnulations, the magnesium stearate is present in amounts ranging from
`
`about 0.~% to about 0.6% w/w, preferably in an amount of about 0.5% w/w.
`
`15
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`The fonnulations ofthe present invention may also contain one or more additional
`
`carriers, excipients, fillers, stabilizing agents, binders, colorants, glidants and lubricants.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 shows the dissolution rates for the scaled up batches of 10, 20, and 40 mg
`
`memantine HCL tablets after two months of storage conditions at 40°C/75%RH. Dissolution is
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`20
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`shown as percent dissolved over time (hours). The open diamond represents the 40 mg strength;
`
`the open square represents the 20 mg strength; and the open triangle represents the 1 0 mg
`
`strength. These open shapes represent measurements at 6 months. The corresponding colored
`
`shapes represent the baseline measurements.
`
`Figure 2 shows the dissolution rates for the scaled up batches of 10, 20, and 40 mg
`
`25 memantine HCL tablets after six months of storage conditions at 40°C/75%RH. Dissolution is
`
`shown as percent drug released over time (hours). The open diamond represents the 40 mg
`
`strength; the open square represents the 20 mg strength; and the open triangle represents the 10
`
`mg strength. These open shapes represent measurements at 6 months. The corresponding
`
`colored shapes represent the baseline measurements.
`
`{W:\03269\0200817us0\00140289.DOC *032690200817USO *}
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`IPR2015-00410
`Petitioners' Ex. 1008
`Page 7
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`6
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`Figure 3 shows the stability of dissolution profiles for a 6 hour release formulation up to
`
`4 months at 40°C/75%RH. The dissolution profiles show the percentage of drug dissolved for
`
`various batches over time (hours).
`
`Figure 4 shows the stability of dissolution profiles for a 12 hour release formulation up to
`
`5
`
`4 months at 40°C/75%RH. The dissolution profiles show the percentage of drug dissolved for
`
`various batches over time (hours).
`
`Figure 5 depicts the mean plasma concentrations of memantine following administration
`
`of20 mg modified release tablets in comparison to two 10 mg immediate release tablets
`
`administered four hour apart in young healthy male and female subjects over time (hours).
`
`1 0
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`Treatment A (closed circle) represents the immediate release formulation. Treatment B (open
`
`circle) represents a modified release formulation. Treatment C (inverted triangle) also represents
`
`a modified release formulation.
`
`Figure 6 depicts the mean plasma concentrations of memantine following admini_stration
`
`of 20 mg modified release tablets of the present invention and two 10 mg immediate release
`
`15
`
`tablets administered four hours apart in young healthy male and female subjects on a semi-log
`scale. Treatment A (closed circle) represents the immediate release formulation. Treatment B
`
`(open circle) represents a modified release formulation. Treatment C (inverted triangle) also
`
`represents a modified release formulation.
`
`Figure 7 depicts a truncated 24-hour profile of mean plasma concentrations of memantine
`
`20
`
`following administration ofmemantine 20 mg modified release tablets ofthe present invention in
`
`comparison to two 10 mg immediate release formulation tablets administered four hours apart in
`
`young healthy male and female subjects. Treatment A (closed circle) represents the immediate
`
`release formulation. Treatment B (open circle) represents a modified release formulation.
`
`Treatment C (inverted triangle) also represents a modified release formulation.
`
`25
`
`Figure 8 shows the dose proportionality of drug dissolution of time (hours) for 10 mg
`
`(circular), 20 mg (oral), and 40 mg (oral) modified release memantine tablets.
`
`Figure 9 presents the dissolution data as percent drug dissolved over time (hours) for
`
`using monohydrate and anhydrate forms of lactose in 40 mg modified release memantine tablets.
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`{W:\03269\0200817us0\00140289.DOC *032690200817USO*}
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`IPR2015-00410
`Petitioners' Ex. 1008
`Page 8
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`7
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`DETAILED DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, a pharmaceutical composition is provided for
`
`the once daily administration ofmemantine or a pharmaceutically acceptable salt thereof,
`
`preferably its HCl salt, or derivatives thereof, to a human or animal, where the composition
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`5
`
`includes memantine in oral solid dosage forms, preferably tablets.
`
`In the present invention, the pharmaceutical compositions comprise a therapeutically
`
`effective amount ofmemantine (free base) or a pharmaceutically acceptable salt thereof,
`
`preferably the HCl salt, one or more release modifiers in the form of polymeric coatings and
`
`matrices, as well as, optionally, one or more carriers, excipients, anti-adherants, fi llers,
`
`10
`
`stabilizing agents, binders, colorants, glidants, and lubricants (all pharmaceutically acceptable).
`
`Memantine (1-amino-3,5-dimethyladamantane), which is an analog of 1-amino(cid:173)
`
`cyclohexane (disclosed, e.g., U.S. Patent Nos. 4,122,193; 4,273,774; 5,061,703), is a
`
`systemically-active uncompetitive NMDA receptor antagonist having low to moderate affinity
`
`for the receptor and strong voltage dependency and rapid blocking/unblocking kinetics. These
`
`15
`
`pharmacological features allow memantine to block sustained activation of the receptor under
`
`pathological conditions and to rapidly leave the NMDA channel during normal physiological
`
`activation of the channel. Memantine and pharmaceutically acceptable salts thereof (e.g., the
`
`HCl salt, MW 215.77) is approved in the U.S. for treatment of Alzheimer's disease. Memantine
`
`is currently being investigated for its therapeutic potential in patients with neuropathic pain, and
`
`20
`
`is currently approved outside the United States as an oral formulation for both Alzheimer's and
`
`Parkinson's Disease and has been available commercially since 1982.
`
`According to the invention, memantine may be used in the form of a pharmaceutically
`
`acceptable salt. Suitable salts of the compound include, but are not limited to, acid addition salts,
`
`such as those made with hydrochloric, methylsulfonic, hydrobromic, hydroiodic, perchloric,
`
`25
`
`sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic,
`
`fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic,
`
`ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic,
`
`cyc1ohexanesulfarnic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic
`acid. In a preferred embodiment, the salt is memantine hydrochloride (C12H21N·HCl, MW
`
`30
`
`215.77). The term "salts" can also include addition salts of free acids or free bases. All ofthese
`
`salts (or other similar salts) may be prepared by conventional means. All such salts are
`
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`IPR2015-00410
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`8
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`acceptable provided that they are non-toxic and do not substantially interfere with the desired
`
`pharmacological activity.
`
`In addition, it is possible to use any form ofmemantine, including polymorphs, hydrates
`
`and solvates as welJ as amorphous forms of memantine.
`
`5
`
`In a preferred embodiment of the invention, the active ingredient is memantine
`
`hydrochloride.
`
`In one embodiment, the memantine is formulated as a 12-hour formulation, the active
`
`ingredient is present in amounts ranging from about 1% w/w to about 20% w/w, preferably from
`about 1.6% to about 20% w/w, most preferably from about 2.5% w/w to about 20% w/w. In a
`preferred embodiment, the active ingredient is present in amounts of about l 0 mg to about 80 mg
`
`10
`
`per tablet.
`
`In an alternate embodiment, the memantine is formulated as a 6-hour formulation, where
`
`the active ingredient is present in an amount ranging from about 1% w/w to about 35% w/w,
`
`preferably from about 1.6% w/w to about 35% w/w, most preferably from about 5% w/w to
`
`15
`
`about 35% w/w. In another preferred embodiment, the active ingredient is present in amounts of
`
`about 1 0 mg to about 80 mg per tablet.
`
`To achieve the desired modified release rates, the modified release dosage form may be
`
`formulated as a polymeric coating or matrix. In a preferred embodiment, the modified release
`
`dosage form is formulated as a matrix.
`
`20
`
`Depending upon the hydrophilic or hydrophobic nature of the matrix, it may be a material
`
`that swells upon contact with gastric fluid to a size that is large enough to promote retention in
`
`the stomach while the subject is in the digestive state. The digestive state is induced by food
`
`ingestion and begins with a rapid and profound change in the motor pattern of the upper
`
`gastrointestinal (GI) tract. The change consists of a reduction in the amplitude of the
`
`25
`
`contractions that the stomach undergoes and a reduction in the pyloric opening to a partially
`
`closed state. The result is a sieving process that allows liquids and small particles to pass
`
`through the partially open pylorus while indigestible particles that are larger than the pylorus are
`
`retropelled and retained in the stomach. In other words, biological fluids migrate through the
`
`matrix and dissolve the active ingredient which is released by diffusion through the matrix
`
`30 which, simultaneously .modulates the release flow. The controlled-release matrix in these
`
`embodiments of the invention is therefore selected as one that can swell to a size large enough to
`
`{W:\03269\0200817us0\00140289.DOC *0326 902 00817USO* }
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`IPR2015-00410
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`Page 10
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`9
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`be retropelled and thereby retained in the stomach, causing the prolonged release of the drug to
`
`occur in the stomach rather than in the intestines. Disclosures of oral dosage forms that swell to
`
`sizes that will prolong the residence time in the stomach are found in U.S. Pat. Nos. 5,007,790,
`
`5,582,837, and 5,972,389, as well as International (PCT) Patent Application WO 98/55107 and
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`5 WO 96/267 18. Each of the documents cited in this paragraph is incorporated herein by reference
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`in its entirety.
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`In compositions comprising a hydrophilic matrix, the matrix is composed of an insoluble
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`hydrophilic polymer. This polymer is chosen from cellulose esters, carboxyvinyl esters, or
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`acrylic or methacrylic esters. On contact with biological fluids, the matrix becomes hydrated and
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`10
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`swells, forming a very dense network of polymers, through which polymers the soluble active
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`principles diffuse. Furthermore, lipids, in particular glyceryl esters, can be added in order to
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`modulate the matrix swelling. In addition, these compositions include numerous adjuvants, often
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`expensive adjuvants, at high concentrations, which greatly increases the cost of the composition.
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`These compositions are obtained by granulation and then compression of the mixture formed of
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`15
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`the polymer, active principles and various adjuvants. These techniques often involve the use of
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`organic solvents, which it is subsequently essential to recover in order to prevent them from
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`dispersing into the atmosphere. In addition, traces of toxic solvents can remain in the final
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`product, which traces necessarily have to be quantified.
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`In the compositions comprising a hydrophobic matrix, the matrix is composed of a lipid
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`20 matrix agent of natural origin, for example beeswaxes, which is highly innocuous. However, its
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`composition varies from one batch to another and its stability over time is not very satisfactory.
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`As above, these compositions are generally obtained by granulation, by a wet or solvent route,
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`and then compression, involving high proportions of each of the constituents.
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`In general, swellable matrices contain binders that are water-swellable polymers, and
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`25
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`suitable polymers are those that are non-toxic, that swell in a dimensionally unrestricted manner
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`upon imbibitions of water, and that release the drug gradually over time. Examples of polymers
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`meeting this description include, but are not limited to the following: cellulose polymers and
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`their derivatives including, but not limited to, hydroxymethyl cellulose, hydroxyethyl cellulose,
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`hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, and
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`30 microcrystalline cellulose polysaccharides and their derivatives, polyalkylene oxides,
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`polyethylene glycols, chitosan, poly( vinyl alcohol), xanthan gum, maleic anhydride copolymers,
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`IPR2015-00410
`Petitioners' Ex. 1008
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`poly(vinyl pyrrolidone), starch and starch-based polymers, maltodextrins, poly (2-ethyl-2-
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`oxazoline), poly(ethyleneimine), polyurethane hydrogels, crosslinked polyacrylic acids and their
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`derivatives.
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`Further examples are copolymers of the polymers listed above, including block
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`5
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`copolymers and graft polymers. Specific examples of copolymers are PLURONIC® and
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`TECTONIC®, which are polyethylene oxide-polypropylene oxide block copolymers available
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`from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA. Further examples are
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`hydrolyzed starch polyacrylonitrile graft copolymers, commonly known as "Super Slurper" and
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`available from lllinois Com Growers Association, Bloomington, Ill., USA.
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`10
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`In the present invention, particularly preferred polymers are poly( ethylene oxide),
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`hydroxypropyl methyl cellulose, and combinations of poly( ethylene oxide) and hydroxypropyl
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`methyl cellulose. Most preferred is hydroxypropyl methyl cellulose. In the 12-hour modified
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`release formulations, the polymer is present in amounts ranging from about 50% w/w to about
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`80% w/w, preferably from about 68% to about 77% w/w. In the 6-hour modified release
`formulations, the polymer is present in amounts ranging from about 20% w/w to about 70% w/w,
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`15
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`preferably from about 54% w/w to about 65% w/w.
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`The prolongation in the time of maximum plasma concentration values (T max) as
`
`compared to immediate release, is related to the in vitro dissolution release rate of the drug. The
`
`in vitro dissolution release rate of the drug depends on the composition of the matrix. By using
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`20
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`different cellulosic matrices, in-vitro release rates (drug dissolution of more than about 70% to
`
`about 80 %) can be manipulated anywhere from about 4 hours to 24 hours. The formulations
`
`have a time of maximum plasma concentration (average T max) ranging from between about 8 to
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`about 24 hours, preferably from about 10 to about 20 hours and an in vitro release rate of more
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`than about 70% to about 80% in about 6 to about 12 hours. Preferably, the formulations have a
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`25
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`release rate of about 30% to about 60% in about 2 to about 6 hours. More preferably, the
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`formulations have a release rate of about 10 % to about 50 % within the first hour following
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`entry into a use environment followed by extended release; more preferably, the formulations
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`have a release rate of about 10% to about 35% within the first hour. All of the drug from the
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`modified release formulation does not release memantine immediately , such as more than 80 %
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`30
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`in about 15 to about 30 minutes within the first hour following entry into a use environment.
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`This is important so as to prevent dose dumping.
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`Petitioners' Ex. 1008
`Page 12
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`11
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`Tablets in accordance with this invention can be prepared by conventional mixing,
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`comminution, and tabletting techniques that are well known in the pharmaceutical formulations
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`industry. The modified-release tablet, for example, may be fabricated by direct compression by
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`punches and dies fitted to a rotary tabletting press, ejection or compression molding, granulation
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`5
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`followed by compression, or forming a paste and extruding the paste into a mold or cutting the
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`extrudate into short lengths. Preferably, the process used for preparing tablets is direct
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`compression of the blend. This process is also preferred economically, because it involves fewer
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`unit operations involving inexpensive equipment. Ordinarily, direct blending is a difficult
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`process, and problems such as blend segregation, low compressibility and low content uniformity
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`10
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`can occur. However, the formulations described in this invention do not exhibit any such
`
`problems.
`
`Fillers such as lactose are used to modify the dissolution pattern. When hydroxypropyl
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`methylcellulose or ethyl cellulose are used, the dissolution rates can be much slower than the
`
`modified release rate targeted. The slow release is because hydrophobic matrix tablets that are
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`15
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`formed release the drug by mechanism of polymer erosion. Since the erosion from a
`
`hydrophobic matrix is very slow, the dissolution rate of the readily soluble active ingredient is
`
`also slow. Lactose, however, is also an important filler ingredient useful in improving the
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`powder flow and compressibility for memantine HCl tablets.
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`In one preferred embodiment for 12 hour release formulations, lactose monohydrate is
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`20
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`present in amounts ranging from about 5% w/w to about 50% w/w, preferably from about 5%
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`w/w to about 25% w/w, most preferred from about 6.9% w/w to about 15% w/w.
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`In a preferred embodiment for 6 hour release formulations, lactose monohydrate is
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`present in amounts ranging from about 5% w/w to about 75% w/w, preferably from about 5%
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`w/w t