111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008039009B2
`
`c12) United States Patent
`Rastogi et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,039,009 B2
`Oct. 18, 2011
`
`(54) MODIFIED RELEASE FORMULATIONS OF
`MEMANTINE ORAL DOSAGE FORMS
`
`(75)
`
`Inventors: Suneel K. Rastogi, Island Park, NY
`(US); Niranjan Rao, Belle Mead, NJ
`(US); Antonia Periclou, Jersey City, NJ
`(US); Wattanaporn Abramowitz,
`Hillsborough, NJ (US); Mahendra G.
`Dedhiya, Pomona, NY (US); Shashank
`Mahashabde, Kendall Park, NJ (US)
`
`(73) Assignee: Forest Laboratories Holdings Limited
`(BM)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1377 days.
`
`(21) Appl. No.: 11/155,330
`
`(22) Filed:
`
`Jun.16,2005
`
`(65)
`
`Prior Publication Data
`
`US 2006/0051416Al
`
`Mar. 9, 2006
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/581,242, filed on Jun.
`17,2004.
`
`(51)
`
`Int. Cl.
`A61K9/00
`(2006.01)
`A61K 311015
`(2006.01)
`(52) U.S. Cl. ........................................ 424/400; 514/766
`(58) Field of Classification Search .................. 424/400;
`514/766
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
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`8/1994 Lipton
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`12/1996 Shell
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`2/2001 Smith eta!.
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`7/2002 Bathurst et a!.
`6,444,702 B1
`9/2002 Wang et al.
`6,479,553 B1
`1112002 McCarthy
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`2005/0245617 A1
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`112006 Yang eta!.
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`6/2006 Went eta!.
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`3/2007 Dedhiya et a!.
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`
`EP
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`0284849 A1
`10/1988
`W0-96/26718
`9/1996
`W0-98/55107
`12/1998
`WO 02/45710 A1
`6/2002
`OTHER PUBLICATIONS
`
`Hartmann et a! 'Tolerability of memantine in combination with
`cholinesterase inhibitors in dementia therapy' International Clinical
`Psychopharmacology, 18(2), p. 81-85, 2003.*
`Tariot et al 'Memantine Treatment in Patients with Moderate to
`Severe Alzheimer's Disease Already Receiving Donepezil' JAMA,
`291(3), p. 317-324, Jan. 2004.*
`International Search Report mailed on Oct. 6, 2005 for corresponding
`Application No. PCT/US2005/021260.
`Parsons et al., Neuropharmacology; 38(6):735-767 (1999).
`FDA Guidelines (Dissolution Testing of Immediate Release Solid
`Oral Dosage Forms, issued, Section IV-A) (Aug. 1997).
`Guidance for Industry, "Extended Release Oral Dosage Forms:
`Development, Evaluation, and Application of In Vitro/In Vivo Cor(cid:173)
`relations", Food and Drug Administration, CDER, p. 17, (Sep. 1997).
`Guidance for Industry, "Extended Release Oral Dosage Forms:
`Development, Evaluation, and Application of In Vitro/In Vivo Cor(cid:173)
`relations," Food and Drug Administration, CDER, p. 4 (Sep. 1997).
`Guidance for Industry,: "Modified Release Solid Oral Dosage
`Forms," Food and Drug Administration, CDER, p. 6, (Sep. 1997).
`Multisource Pharmaceutical Products: Guidelines on Registration
`Requirements to establish Interchangeability, Quality Assurance and
`Safety: Medicines, Essential Drugs and Medicines Policy, World
`Health Organization, 1211 Geneva 27, Switzerland, pp. 11-12
`(2004).
`U.S. Pharmacopoeia and National Formulary, USP XXIV I NF 19,
`Chapter 1088, pp. 2051-2056 (2000).
`U.S. Pharmacopoeia and National Formulary, USP XXIV I NF 19,
`Chapter 711, pp. 1941-1943 (2000).
`Reisberg Barry eta!: "Memantine in moderate-to-severe Alzheimer's
`disease." The New England Jouunal of Medicine. Apr. 3, 2003, vol.
`348, No. 14, Apr. 3, 2003, pp. 1333-1341, XP009054230, ISSN:
`1533-4406, abstract. Suzuki Rie eta!: "Comparison of the effects of
`MK -80 1, ketamine and memantine on responses of spinal dorsal horn
`neurones in a rat model ofmononeuropathy", PAIN, vol. 91, No. 1-2,
`Mar. 2001, pp. 101-109, XP002346013, ISSN: 0304-3959, abstract,
`p. 107, col. 2, paragraph 2 & p. 108, col. 1, paragraph 3.
`First Action Interview Pilot Program Pre-Interview Communication
`for U.S. Appl. No. 111424,024 mailed Dec. 17, 2009.
`Response to Pre-Interview Communication for U.S. Appl. No.
`111424,024, filed Jan. 6, 2010.
`Interview Summary, date of interview Jan. 22, 2010 for U.S. Appl.
`No. 111424,024 mailed Feb. 1, 2010.
`
`(Continued)
`
`Primary Examiner- Brandon Fetterolf
`Assistant Examiner- Christopher R Stone
`(74) Attorney, Agent, or Firm- Chareles S. Ryan; Michael
`Ciraolo
`
`ABSTRACT
`(57)
`The present invention provides pharmaceutical compositions
`given once daily containing at least one therapeutically active
`ingredient selected from the group consisting of memantine
`and a pharmaceutically acceptable salt of memantine, and a
`pharmaceutically acceptable polymeric matrix carrier. The
`dosage forms of the invention sustain the release of the thera(cid:173)
`peutically active agent from about 4 to about 24 hours when
`said dosage form is exposed to aqueous solutions. following
`entry of said form into a use environment, wherein said dos(cid:173)
`age form has a dissolution rate of more than about 80% after
`passage of about 6 hours to about 12 hours following said
`entry into said use environment.
`
`23 Claims, 10 Drawing Sheets
`
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`US 8,039,009 B2
`Page 2
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`OTHER PUBLICATIONS
`First Action Interview Office Action Sunnnary for U.S. Appl. No.
`111424,024 mailed Feb. 1, 2010.
`Interview Sunnnary, date of interview Feb. 16, 2010 for U.S. Appl.
`No. 111424,024 mailed Feb. 24, 2010.
`Response to First Action Interview Office Action Sunnnary for U.S.
`Appl. No. 111424,024, filed Feb. 16,2010.
`
`Final Office Action for U.S. Appl. No. 111424,024 mailed Jun. 3,
`2010.
`Response to Final Office Action for U.S. Appl. No. 111424,024, filed
`Aug. 18, 2010.
`International Search Report mailed on Oct. 19, 2006 for PCT/
`US2006/022841 corresponding to U.S. Appl. No. 111424,024.
`* cited by examiner
`
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`This application claims priority under 35 U.S.C. §119,
`based on U.S. Provisional Application Ser. No. 60/581,242
`filed Jun. 17, 2004, which is hereby incorporated by reference
`in its entirety.
`
`FIELD OF THE INVENTION
`
`BACKGROUND OF THE INVENTION
`
`US 8,039,009 B2
`
`1
`MODIFIED RELEASE FORMULATIONS OF
`MEMANTINE ORAL DOSAGE FORMS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`The present invention is directed to pharmaceutical solid,
`oral dosage forms which exhibit a modified release profile.
`The invention is particularly suitable for once-a-day solid oral
`pharmaceutical dosage forms in which the active ingredient is
`memantine, releasing a therapeutically effective amount of
`the active ingredient over an extended time period.
`
`2
`tently achieved or that the pharmacological effect will be
`based solely on the release of the drug.
`Sustained release formulations for drugs have become
`increasingly available. This is true especially when the par(cid:173)
`ticular drug is relatively soluble. Various formulation tech(cid:173)
`niques have been used for providing a sustained release for(cid:173)
`mulation of soluble drugs. In many such formulations, a
`drug-containing particle is coated by one or more release
`retardant layers or films or is dispersed within a continuous
`10 matrix such as a polymeric matrix. The coating layer or the
`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 drug there through. The release of the drug from such
`15 formulations is driven, e.g., by the gradient of the drug con(cid:173)
`centration 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 control-
`20 ling its rate of diffusion across the film barrier(s). However,
`such an 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
`Solid oral drug compositions or preparations have various
`amount of active ingredient, which can result in undesirable
`release profiles such as a modified or extended release profile
`as referenced by USP XXIII (CDER, FDA, Rockville, Md.) 25 effects from excessive single-shot drug release, and in failure
`or an immediate release profile as referenced by FDA guide(cid:173)
`of the dosage form to remain effective for the required dura-
`tion.
`lines (Dissolution Testing of Immediate Release Solid Oral
`Dosage Forms, issued August 1997, Section IV-A). For
`In the more common matrix-controlled release approach,
`lipophilic substances, e.g., higher alcohols, waxes, or
`example, in the dissolution testing guideline for modified
`release profiles, material dissolves over an extended period 30
`insoluble thermoplastic materials, are employed. The release
`anditsdissolutionismeasuredovertime.Aminimumofthree
`is controlled by the rate of diffusion of the active ingredient
`time points is recommended and should cover early, middle
`into the surrounding medium and, if the matrix itself is
`and late stages of the dissolution profile. The last measure(cid:173)
`degradable, by the rate of its degradation. One of the disad(cid:173)
`ment should be at a time point where at least 80% of the drug
`vantages is that a complete release of drug from the matrix is
`is dissolved (Guidance for Industry, "Extended Release Oral 35
`frequently not achieved in practice. Another drawback is that
`dose proportionality of the dosage forms is not readily
`Dosage Forms: Development, Evaluation, and Application of
`In Vitro/In Vivo Correlations", Food and Drug Administra(cid:173)
`achieved, thus, requiring different compositions for different
`strengths. Thus, the matrix composition to formulate a 20 mg
`tion, CDER, September 1997, Page 17). Adequate sampling
`should be performed, for example, at 1, 2 and 4 hours and
`sustained release dosage form may well be different from the
`every two hours thereafter until 80% of the drug is released 40
`matrix composition to formulate a 40 mg sustained release
`(Guidance for Industry, SUPAC-MR: Modified Release Solid
`dosage form.
`Oral Dosage Forms," Food and Drug Administration, CDER,
`U.S. Pat. No. 5,382,601 provides solid pharmaceutical
`September 1997, Page 6). The preferred dissolution appara-
`dosage forms containing memantine, which exhibit an
`tus is USP apparatus I (basket) or II (paddle), used at com(cid:173)
`extended two-phase release profile, with a portion of the drug
`being released immediately, followed by a sustained release
`pendially recognized rotation speeds, e.g., 100 rpm for the 45
`of the remainder. The matrix of this formulation contains both
`basket and 50-75 rpm for the paddle (Guidance for Industry,
`a water-soluble and a water-insoluble salt of casein, prefer(cid:173)
`"Extended Release Oral Dosage Forms: Development,
`ably sodium and calcium caseinate. However, casein has an
`Evaluation, andApplication ofln Vitro/In Vivo Correlations",
`unpleasant taste; it is associated with undesirable effect of
`Food and Drug Administration, CDER, September 1997,
`Page 4).
`50 exacerbating some side effects as disclosed in U.S. Pat. No.
`Modified release solid oral dosage forms permit the sus(cid:173)
`6,413,556; and displays instability in varying pH. Another
`concern regarding casein is the possibility of Bovine Spongi(cid:173)
`tained release of the active ingredient over an extended period
`form Encephalitis (BSE) contamination since casein is an
`of time in an effort to maintain therapeutically effective
`plasma levels over similarly extended time intervals and/or to
`animal-derived milk protein.
`A general method of modified release for N-methyl-D(cid:173)
`modifY other pharmacokinetic properties of the active ingre- 55
`dient. Immediate release solid dosage forms permit the
`aspartate (NMDA) receptor antagonists was described in U.S.
`release of most or all of the active ingredient over a short
`Pat. No. 6,194,000. This method also involves preparing an
`period of time, such as 60 minutes or less, and make rapid
`instant release component and a modified release component
`absorption of the drug possible. A multiphase release profile
`to arrive at the final formulation. The patent discloses a pellet
`(not a bead) consisting of a coated core, the coating being any
`(i.e., a composition containing at least an immediate release 60
`formulation and at least one modified release formulation)
`suitable coating using organic solvent-based systems. How-
`may be employed to attain one or more combinations of
`ever, not all NMDA antagonists act in the same mauner, and
`release rates to attain more specific therapeutic objectives
`this patent does not specifically disclose compositions con(cid:173)
`such as a portion of drug releasing immediately, followed by
`taining memantine.
`an extended release. However, modulation of the release rate 65
`Currently, a dosing regimen of memantine of twice a day is
`of an active ingredient does not necessarily ensure that long(cid:173)
`employed using immediate release tablets. This may be unde(cid:173)
`lasting effective blood level concentrations will be consis-
`sirable because patient compliance decreases as the fre-
`
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`US 8,039,009 B2
`
`3
`quency 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 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 formu(cid:173)
`lation containing memantine or a pharmaceutically accept(cid:173)
`able salt of memantine with reliable slower absorption over a
`targeted period of time.
`
`SUMMARY OF THE INVENTION
`
`10
`
`4
`tain the lactose monohydrate as filler. In 12-hour formula(cid:173)
`tions, the lactose monohydrate is present in 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%
`w/w to about 15% w/w. In 6-hour formulations, the lactose
`monohydrate is present in amounts from about 5% w/w to
`about 80% w/w, more preferably from about 5% w/w to about
`71% w/w, most preferably from about 7% w/w to about 24%
`w/w.
`In another embodiment, the dosage forms contain the
`microcrystalline cellulose as filler in amounts from about 5%
`w/w to about 80% w/w, more preferably from about 5% w/w
`to about 71% w/w, most preferably from about 7% w/w to
`about 40% w/w.
`In yet another embodiment, the dosage forms contain the
`dicalcium phosphate dihydrate as filler in amounts from
`about 5% w/w to about 80% w/w, more preferably from about
`5% w/w to about 71% w/w, most preferably from about 7%
`w/w to about 40% w/w.
`The formulations of the present invention may further
`comprise a lubricant, preferably magnesium stearate. In
`12-hour formulations, the magnesium stearate is present in
`amounts 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 formulations, the magnesium stearate is present in
`amounts ranging from about 0.4% to about 0.6% w/w, pref-
`erably in an amount of about 0.5% w/w.
`The formulations of the present invention may also contain
`one or more additional carriers, excipients, fillers, stabilizing
`30 agents, binders, colorants, glidants and lubricants.
`
`According to the present invention, it has now been found
`that memantine, and its salts, including the hydrochloride salt
`as well as other pharmaceutically acceptable salts of meman- 15
`tine can be formulated into a modified release form with
`anticipated improvements in tolerability. The formulation of
`the present invention includes memantine or a pharmaceuti(cid:173)
`cally acceptable salt thereof, a pharmaceutically acceptable
`polymeric carrier (coating and/or matrix) that substantially 20
`contributes to the modification of the release of memantine,
`and one or more excipients to be administered in a once-a-day
`oral dosage form.
`Specifically, the present invention provides a dosage form
`which slowly releases the active agent at a release rate of from 25
`at least about 70% to about 80% in about 4 hours to about 24
`hours following entry of the dosage form into a use environ(cid:173)
`ment. In one embodiment, the dosage form is released to this
`extent over 6 hours from entry into the use environment, e.g.,
`the gastric fluids. Alternatively, the dosage form is released to
`this extent over 12 hours from entry into the use environment.
`For a 12-hour release formulation, at least 70%, preferably
`at least 80% of the active ingredient, e.g., memantine hydro(cid:173)
`chloride, is released after about 12 hours following entry into
`the use environment, but not before such time. In the 12-hour 35
`oral dosage form of the present invention, the active ingredi(cid:173)
`ent 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 ingredient may be mea- 40
`sured as mg per tablet, ranging from about 5 to about 80 mg
`per tablet. Preferably, the tablets contain 7 mg, 10 mg, 20 mg,
`28 mg, 40 mg or 80 mg active ingredient. Alternatively, the
`active ingredient in the use of seeds may be up to 100 mg.
`For a 6-hour release formulation, at least 70% preferably at 45
`least 80% of the active ingredient is released after about 6
`hours following entry into the use environment, but not before
`such time. In the 6-hour oral dosage form of the present
`invention, the active ingredient is usually present in amounts
`from about 1.0% w/w to about 35% w/w, preferably from 50
`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 present from about 5 mg to about 80 mg
`per tablet. Preferably, the tablets contain 7 mg, 10 mg, 20 mg,
`28 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 is a swellable matrix that contains hydroxypropyl
`methylcellulose. The hydroxypropyl methylcellulose, in
`12-hour formulations is present in amounts from about 50% 60
`w/w to about 80% w/w, more preferably in amounts from
`about 68% w/w to about 77% w/w. In 6-hour formulations,
`the hydroxypropyl methylcellulose is present in amounts
`from about 20% w/w to about 70% w/w, preferably from
`about 54% w/w to about 65% w/w.
`The formulations of the present invention may further
`comprise a filler. In one embodiment, the dosage forms con-
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the dissolution rates for the scaled up batches
`of 10, 20, and 40 mg memantine HCL tablets after six months
`of storage conditions at 40° C./75% RH. Dissolution is 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 10 mg
`strength. These open shapes represent measurements at 6
`months. The corresponding filled shapes represent the base-
`line measurements.
`FIG. 2 shows the dissolution rates for the scaled up batches
`of 10, 20, and 40 mg memantine HCl tablets after six months
`of storage conditions at 40° C./75% RH. Dissolution is shown
`as percent drug released overtime (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 filled shapes represent the base(cid:173)
`line measurements.
`FIG. 3 shows the stability of dissolution profiles for a 6
`hour release formulation up to 6 months at 40° C./75% RH.
`The dissolution profiles show the percentage of drug dis-
`55 solved for various batches overtime (hours). The age of each
`sample is indicated in FIG. 3.
`FIG. 4 shows the stability of dissolution profiles for a 12
`hour release formulation up to 6 months at 40° C./75% RH.
`The dissolution profiles show the percentage of drug dis(cid:173)
`solved for various batches overtime (hours). The age of each
`sample is indicated in FIG. 4.
`FIG. 5 depicts the mean plasma concentrations of meman(cid:173)
`tine following administration of 20 mg modified release tab(cid:173)
`lets in comparison to two 10 mg immediate release tablets
`65 administered four hour apart in young healthy male and
`female subjects overtime (hours). Treatment A (closed circle)
`represents the immediate release formulation. Treatment B
`
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`US 8,039,009 B2
`
`10
`
`5
`(open circle) represents a modified release formulation.
`Treatment C (inverted triangle) also represents a modified
`release formulation.
`FIG. 6 depicts the mean plasma concentrations of meman(cid:173)
`tine following administration of 20 mg modified release tab(cid:173)
`lets of the present invention and two 10 mg immediate release
`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. Treat(cid:173)
`ment B (open circle) represents a modified release formula-
`tion. Treatment C (inverted triangle) also represents a modi(cid:173)
`fied release formulation.
`FIG. 7 depicts a truncated 24-hour profile of mean plasma
`concentrations of memantine following administration of
`memantine 20 mg modified release tablets of the present 15
`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. 20
`Treatment C (inverted triangle) also represents a modified
`release formulation.
`FIG. 8 shows the dose proportionality of drug dissolution
`over time (hours) for 1 0 mg (X data points), 20 mg (circular
`data points), and 40 mg (diamond data points) modified 25
`release memantine tablets. The 10 mg tablet is a circular
`shaped tablet, whereas the 20 mg and 40 mg tablets are oval
`shaped tablets. The shape of the tablet is critical to obtain the
`desired diffusion characteristics.
`FIG. 9 presents the dissolution data as percent drug dis- 30
`solved over time (hours) for using monohydrate and anhy(cid:173)
`drate forms of lactose in 40 mg modified release memantine
`tablets.
`FIG. 10 shows the dissolution profiles of modified release
`memantine tablets prepared for doses 7 mg and 28 mg using
`three different fillers-lactose monohydrate, dicalcium phos(cid:173)
`phate and microcrystalline cellulose. The data show that each
`work about the same dissolution. The shape of the data points
`for each composition is indicated in FIG. 10.
`
`6
`215.77) is approved in the U.S. for treatment of Alzheimer's
`disease. Approval of memantine is currently sought for the
`indication of neuropathic pain (wherein memantine has dem(cid:173)
`onstrated activity in in vitro models), and is currently
`approved outside the United States as an oral formulation for
`both Alzheimer's and Parkinson's Disease.
`According to the invention, memantine may be used in the
`form of a free base or 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, sulfu(cid:173)
`ric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyru(cid:173)
`vic, malonic, succinic, maleic, fumaric, maleic, tartaric, cit(cid:173)
`ric, benzoic, carbonic cinnamic, mandelic, methanesulfonic,
`ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic,
`p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-ami(cid:173)
`nosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid.
`In a preferred embodiment, the salt is memantine hydrochlo(cid:173)
`ride (C 12H21N.HC1, MW 215.77). The term "salts" can also
`include addition salts of free acids or free bases. All of these
`salts (or other similar salts) may be prepared by conventional
`means. All such salts are 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 salts and free base form
`of memantine (collectively referred to as memantine ), includ(cid:173)
`ing polymorphs, hydrates and solvates as well as amorphous
`forms of memantine.
`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, wherein the active ingredient has at
`least about 70-80% dissolution after about 12 hours. The
`active ingredient is present in amounts ranging from about
`35 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 ingre(cid:173)
`dient is present in amounts of about 10 mg to about 80 mg per
`tablet.
`In an alternate embodiment, the memantine is formulated
`as a 6-hour formulation, wherein the active ingredient has at
`least about 70-80% dissolution after about 6 hours. 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
`45 about 35% w/w, most preferably from about 5% w/w to about
`35% w/w. In another preferred embodiment, the active ingre(cid:173)
`dient is present in amounts of about 10 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 coat(cid:173)
`ing or matrix. In one preferred embodiment, the modified
`release dosage form is formulated as a matrix.
`Depending upon the hydrophilic (erodable or non-erod(cid:173)
`able) or hydrophobic nature of the matrix, the matrix 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. In addition to these diffu(cid:173)
`sion based matrices, the matrix may also be in an erodable
`form. 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 contractions that the stom(cid:173)
`ach 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
`
`40
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, a pharmaceutical
`composition is provided for the once-daily administration of
`memantine or a pharmaceutically acceptable salt thereof,
`preferably its HCl salt, or derivatives thereof, to a human or
`animal, where the composition includes memantine in oral
`solid dosage forms, preferably tablets.
`In the present invention, the pharmaceutical compositions
`comprise a therapeutically effective amount of memantine 50
`free base or a pharmaceutically acceptable salt thereof, pref(cid:173)
`erably 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, fillers, stabilizing
`agents, binders, colorants, glidants, and lubricants (all phar- 55
`maceutically acceptable).
`Memantine (1-amino-3,5-dimethyladamantane), which is
`an analog of 1-amino-cyclohexane (disclosed, e.g., U.S. Pat.
`Nos. 4,122,193; 4,273,774; 5,061,703), is a systemically(cid:173)
`active uncompetitive NMDA receptor antagonist having low 60
`to moderate affinity for the receptor and strong voltage depen(cid:173)
`dency and rapid blocking/unblocking kinetics. These phar(cid:173)
`macological features allow memantine to block sustained
`activation of the receptor under pathological conditions and
`to rapidly leave the NMDA charmel during normal physi- 65
`ological activation of the channel. Memantine and pharma(cid:173)
`ceutically acceptable salts thereof (e.g., the HCl salt, MW
`
`IPR2015-00410
`Petitioners' Ex. 1007
`Page 15
`
`

`

`US 8,039,009 B2
`
`7
`other words, biological fluids migrate through the matrix and
`dissolve the active ingredient which is released by diffusion
`through the matrix which, simultaneously, modulates the
`release rate. The controlled-release matrix in these embodi(cid:173)
`ments of the invention is therefore selected as one that can
`swell to a size large enough to be retropelled and thereby
`retained in the stomach, causing the prolonged release of the
`drug to occur in the stomach rather than in the intestine.
`Disclosures of oral dosage forms that swell to sizes that will
`prolong the residence time in the stomach are found in U.S. 10
`Pat. Nos. 5,007,790, 5,582,837, and 5,972,389, as well as
`International (PCT) Patent Application WO 98/55107 and
`WO 96/26718. Each of the documents cited in this paragraph
`is incorporated herein by reference in its entirety.
`In compositions comprising a hydrophilic matrix, the 15
`matrix is composed of an insoluble hydrophilic polymer. This
`polymer is chosen from cellulose esters, carboxyvinyl esters,
`or acrylic or methacrylic esters. On contact with biological
`fluids, the matrix becomes hydrated and swells, forming a
`network of polymers, through which polymers the soluble 20
`active principles diffuse. Furthermore, lipids, in particular
`glyceryl esters, can be added in order to modulate, or lessen,
`the matrix swelling and rate of diffusion.
`However, in the present invention, lipids are not needed to
`modulate the diffusion of the matrix. Rather, the composi- 25
`tions of the claimed invention work with the normal rate of
`gastric diffusion, controlled in part by the thickness of the
`tablet. In addition, compositions with lipids may include
`numerous adjuvants, often expensive adjuvants, at high con(cid:173)
`centrations, which greatly increases the cost of the composi(cid:173)
`tion. Furthermore, such compositions are obtained by granu(cid:173)
`lation and then compression of the mixture formed of the
`polymer, active principles and various adjuvants. These tech(cid:173)
`niques often involve the use of organic solvents, which it is
`subsequently essential to recover in order to prevent them 35
`from dispersing into the atmosphere. In addition, traces of
`toxic solvents can remain in the final product, which traces
`necessarily have to be quantified.
`In general, swellable matrices contain binders that are
`water-swellable polymers, and suitable polymers are those 40
`that are non-toxic, that swell in a dimensionally unrestricted
`manner upon imbibitions of water, and that release the drug
`gradually over time. Examples of polymers meeting this
`description include, but are not limited to the following: cel(cid:173)
`lulose polymers and their derivatives including, but not lim- 45
`ited to, hydroxymethyl cellulose, hydroxyethyl cellulose,
`hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
`carboxymethylcellulose, and microcrystalline cellulose
`polysaccharides and their derivatives, polyalkylene oxides,
`polyethylene glycols, chitosan, poly( vinyl alcohol), xanthan 50
`gum, maleic anhydride copolymers, poly( vinyl pyrrolidone ),
`starch and starch-based polymers, maltodextrins, poly
`(2-ethyl-2-oxazoline ), poly( ethyleneimine ), polyurethane
`hydrogels, crosslinked polyacrylic acids and their deriva(cid:173)
`tives.
`Further examples are copolymers of the polymers listed
`above, including block copolymers and graft polymers. Spe(cid:173)
`cific examples of copolymers are PLURONIC® and TEC(cid:173)
`TONIC®, which are polyethylene oxide-polypropylene
`oxide block copolymers available from BASF Corporation,
`Che