United States Patent [19J
`Niirnberg et al.
`
`[75]
`
`[54) MEMANTINE-CONTAINING SOLID
`PHARMACEUTICAL DOSAGE FORMS
`HAVING AN EXTENDED TW0-8TAGE
`RELEASE PROFILE AND PRODUCTION
`THEREOF
`Inventors: Eberhard Niirnberg,
`Uttenreuth/W e1her; Erhard Seiller,
`Nidderau; Stefan Ritsert, Eberbach,
`all of Germany
`[73] Assignee: Merz + Co. GmbH & Co., Frankfurt
`am Main, Germany
`[21] Appl. No.: 96,952
`[22] Filed:
`Jul. 23, 1993
`Foreign Application Priority Data
`[30]
`Aug. 4, 1992 [DE] Germany ............................. 4225730
`Int. CJ.6 .•....................... A61K 9/38; A61K 9/64;
`[51]
`A61K 37/16
`[52] U.S. CI •.................................... 514/775; 530/360;
`424/465;424/469; 424/470
`[58] Field of Search ....................... 424/465, 469, 470;
`5141775; 530/360
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,594,467 7/1971 Christenson et al . ................. 424/19
`4,076,846 2/1978 Natsuka et al . ....................... 426/62
`4,122,193 10/1978 Scherm et al ....................... 424/330
`4,127,650 11/1978 Buehler .......... : .................... 424/184
`4,346,112 8/1982 Henkel et al ........................ 424/325
`4,665,081 5/1987 Doi et al ..
`4,816,177 3/1989 Nelson et al . ....................... 424/465
`4,853,377 8/1989 Pollack ................................ 514/161
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005382601A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,382,601
`Jan. 17, 1995
`
`4,897,380 1/1990 Pollack et al ......................... 514/23
`5,061,703 10/1991 Bormann et al .................... 514/212
`5,068,109 11/1991 Fo1dager et al .................... 424/441
`5,167,962 12/1992 Lew et al ............................ 424/426
`
`FOREIGN PATENT DOCUMENTS
`0447100 9/1991 European Pat. Off ..
`2207353A 2/1989 United Kingdom .
`
`OTHER PUBLICATIONS
`Pharm. Acta He1v. 66, No.4, 120-124 (1991), "Effect of
`Low-molecular Casein and Gelatin on Absorption of
`Ibuprofen after Oral and Rectal Administration"; S.
`Kimura, et al.
`Pharmaceutical Technology 9, 360-374 (1990), "Influ(cid:173)
`ence of Sodium Caseinate on the Dissolution Rate of
`Hydrochlorothiazide and Chlorothiazide", F. C. Millar,
`et al.
`Primary Examiner-Shep K. Rose
`Attorney, Agent, or Firm-Gordon W. Hueschen
`[57]
`ABSTRACT
`The present invention provides solid pharmaceutical
`compositions in dosage form containing an active ingre(cid:173)
`dient or principle, preferably memantine, which exhibit
`an extended two-phase release proftle and which are
`characterized by the presence of both a water-soluble
`and a water-insoluble salt of casein, preferably sodium
`and calcium caseinate, in the matrix thereof, in broad
`proportions and in a total amount between 5 and 98%
`by weight of the composition, and with a process for the
`production thereof.
`
`22 Claims, 3 Drawing Sheets
`
`IPR2015-00410
`Petitioners' Ex. 1009
`Page 1
`
`

`

`

`

`

`

`

`

`MEMANTINE-CONTAINING SOLID
`PHARMACEUTICAL DOSAGE FORMS HAVING
`AN EXTENDED 1WO-sfAGE RELEASE PROFILE
`AND PRODUCI'ION THEREOF
`
`45
`
`SUMMARY OF THE INVENTION
`
`1
`
`5,382,601
`
`2
`drotalc and magnesium aluminum oxide, thereby ensur(cid:173)
`ing that the active substance-provided that a gastric
`juice-resistant auxiliary agent is included-is not re~
`leased in the stomach but is rather rapidly released in
`5 the intestine. Such formulation will cause, on the one
`hand, a retarded release relative to the time of adminis(cid:173)
`BACKGROUND OF THE INVENTION
`tration but, on the other hand, due to the rapid dissolu-
`tion in the intestine, a high plasma concentration which
`1. Field of Invention
`is likely to result in undesirable side effects.
`The present invention is concerned with solid phar-
`maceutical compositions in dosage form which exhibit 10
`Pharm. Acta Helv. 66, No~ 4, 120-124 (1991) de-
`an extended matrix-controlled two-phase release profile
`scribes an ibuprofen formula containing casein or ge1a-
`tine which causes an elevated rate of dissolution and
`and which are characterized by the presence in the
`release, respectively, of the active substance.
`matrix of both a water-soluble and a water-insoluble salt
`Pharmaceutical Technology 9, 360-374 (1990) exam-
`of casein, preferably sodium and calcium caseinate,
`respectively, in a total amount between 5 and 98% by 15 ines the influence of the presence of sodium caseinate on
`weight of the composition, and with a process for the
`the rate of release of an active substance. Here, too, an
`production thereof. A part or all of the insoluble casein
`enhanced dissolution, in particular, of chlorothiazide
`salt may be replaced by a salt or solution of a polyvalent
`and hydrochlorothiazide, is reported.
`The EP-A 0 447 100 Patent discloses formulations
`including bivalent cation, e.g., the calcium cation,
`adapted to form the water-insoluble casein salt in situ. 20
`The invention is particularly suitable for the provision
`permitting controlled release in the stomach and in the
`of solid pharmaceutical dosage forms in which the ac-
`intestine in response to the enzymes contained therein.
`tive substance or principle is memantine.
`For this purpose, a gel matrix, e.g., of alginate or car-
`2. Background of the Invention and Prior Art
`boxymethyl cellulose, carragheenin, or the like is em-
`Solid oral drug compositions or preparations having 25 ployed, which contains imbedded therein a protein,
`a retarded release, so-called retarder or extended-
`such as calcium caseinate, and which comprises a fur-
`release preparations, are products from which the ac-
`ther drug or food substance which is bondable to the
`tive ingredient is released over an extended period of
`protein. Although a controlled release is enabled
`time and hence exhibit a prolonged effect, with resul-
`thereby, such effect is achieved by the incorporation of
`tant plasma levels being adapted to therapeutic require- 30 protein in a surrounding matrix-forming gel.
`ments. Also, a polyphase release profile can be em-
`GB-A 2 207 353 also describes formulations with a
`ployed to attain the desired therapeutic objectives.
`controlled release, containing calcium-free mixtures of
`However, this does not necessarily mean that long-last-
`alginic acid salts and caseinate. The protracted release
`ing effective blood level concentrations are consistently
`is, however, based on a surrounding gel-matrix princi"
`achieved. Moreover, systemic side effects and undesir- 35 pie of the type referred to above.
`able local effects within the gastrointestinal tract due to
`It is apparent to one skilled in the art that the avail-
`excessive local concentrations and resulting erratic
`able technology for effective and reliable extended re-
`plasma levels, respectively, are to be avoided.
`lease, especially multistage release pharmaceutical dos-
`In conventional procedures for the preparation of
`age forms, · still leaves much to be desired.
`solid pharmaceutical dosage forms having an extended- 40
`release profile or pattern, the active substance in the
`majority of cases is either given extended-release prop(cid:173)
`erties by the application of various coatings or by being
`embedded in a macromolecular substance from which it
`is slowly released.
`The most important control procedures for the re(cid:173)
`lease of an active pharmaceutical from a solid dosage
`form are the film-coating and the matrix procedures. In
`film coating procedures, film-forming polymers are
`employed to provide sustained release of the active 50
`substance in a diffusion-controlled manner. However,
`such an approach is disadvantageous if, during ingestion
`of the oral dosage form, the film is prematurely
`breached, as by chewing or abrasion, thereby releasing
`The invention then, comprises the following, inter
`an excessive amount of active ingredient, which can 55 alia, separately or in combination:
`result in undesirable effects from such excessive single-
`A solid pharmaceutical composition in dosage form
`shot drug release.
`having a mat~-controlled 7xtended two-stage release
`In the matrix-controlled release approach, lipophilic
`profile com~nsmg ~ eff~tlve ~ount of at l~t.one
`substances, e.g., higher alcohols, waxes, or insoluble
`pharm~ceut1cally~act1ve. mgred~ent or
`p~c1~le,
`thermoplasts, are employed, it being a disadvantage that 60 wherem the matnx conslSts essentially of a combmation
`synthetic polymers not only generally contain varying
`of a water-soluble salt of casein and a water-insoluble
`amounts of undesirable monomers but that moreover a
`salt of casein, the total water-soluble and water-insolu-
`complete release of drug from the matrix is frequently
`ble casein salt content comprising between 5% and 98%
`of the total weight of the pharmaceutical composition,
`not effected in practice.
`The U.S. Pat. No. 4,665,081 describes a nifedepin 65 all salts and cations being pharmacologically accept-
`formula for oral administration, which contains casein
`able; such a
`and inorganic additives selected from magnesium sili-
`composition wherein the water-soluble and water-
`cate, oxide, or aluminatemetasilicate, synthetic by-
`insoluble casein salts comprise between 10% and
`
`OBJECTS OF THE INVENTION
`It is accordingly an object of the present invention to
`provide a pharmaceutical dosage form which is charac(cid:173)
`terized by an extended controlled-release profile such
`that the active substance can be conveniently and reli(cid:173)
`ably released over an extended period in at least two (2)
`stages and a process for the production thereof. Other
`objects of the invention will become apparent hereinaf(cid:173)
`ter, and still others will be obvious to one skilled in the
`art to which the present invention pertains.
`
`IPR2015-00410
`Petitioners' Ex. 1009
`Page 5
`
`

`

`5,382,601
`
`3
`90% by weight of the pharmaceutical composition,
`preferably
`between 30% and 80% by weight; such a
`composition wherein the pharmaceutical composi(cid:173)
`tion comprises between about 5% and 95% of a 5
`water-insoluble casein salt based upon the total
`casein salt content, preferably
`between about 20% and 70% by weight; such a
`composition wherein the water-insoluble casein salt is
`calcium caseinate; such a
`composition wherein the water-soluble calcium salt is
`sodium caseinate; such a
`composition wherein the pharmaceutical composi(cid:173)
`tion comprises an enzyme; such a
`composition wherein the enzyme is pancreatin or 15
`pepsin or both, and such a
`composition wherein the active ingredient is meman(cid:173)
`tine.
`Moreover, a process for the preparation of a solid 20
`pharmaceutical composition in dosage form having a
`matrix-controlled two-stage release proflle comprising
`an effective amount of at least one pharmaceutically(cid:173)
`active ingredient or principle, wherein the matrix con(cid:173)
`sists essentially of a combination of a water-soluble salt 25
`of casein and a water-insoluble salt of casein, compris(cid:173)
`ing the step of compressing, granulating, extruding,
`pelletizing, or tabletting, in dry or wet manner, of a
`mixture comprising the at least one active ingredient in
`admixture with both a water-soluble and a water-insolu- 30
`ble salt of casein or, alternatively, a water-soluble salt of
`casein and a salt or solution of a polyvalent cation
`which is adapted to form a water-insoluble salt of casein
`in situ, the total water-soluble and water-insoluble ca(cid:173)
`sein salt content of the admixture in the fmal composi- 35
`tion comprising between 5% and 98% of the total
`weight of the pharmaceutical composition, all salts and
`cations being pharmacologically acceptable; such a
`process wherein the water-soluble and water-insolu(cid:173)
`ble casein salts are included in the mixture to the 40
`extent of between 10% and 90% by weight of the
`pharmaceutical composition, preferably
`between 30% and 80% by weight; such a
`process wherein between about 5% and 95% of a
`water-insoluble casein salt, based upon the total 45
`casein salt content, is mixed into the composition,
`preferably
`between about 20% and 70% by weight; such a
`process wherein the water-insoluble casein salt mixed
`into the composition is calcium caseinate, and such 50
`a process wherein the water-soluble casein salt is
`sodium caseinate; such a
`process wherein a water-soluble casein salt and a
`polyvalent cation salt is employed in the process, 55
`the percentage of the water-insoluble casein salt
`content to the fmal resultant casein salt content
`being between about 5% and 90%, preferably
`between 20% and 70%; such a
`process wherein the cations are calcium ions; such a 60
`process wherein the water-soluble casein salt em-
`ployed is sodium caseinate; such a
`process wherein an enzyme is also mixed into the
`pharmaceutical composition; such a
`process wherein the enzyme is pancreatin or pepsin 65
`or both; and such a
`process wherein the active ingredient mixed into the
`composition is memantine.
`
`4
`The Present Invention
`According to the practice of the present invention,
`the problem is solved by providing a solid pharmaceuti(cid:173)
`cal composition in dosage form containing a phar(cid:173)
`maceutically-effective amount of one or more active
`substances and the usual auxiliary agents and additives,
`but also a total of between 5 and 98%, preferably 10 to
`90%, and especially 30 to 80%-based on the total
`10 weight of the composition-of a combination of a
`water-soluble and a water-insoluble salt of casein. A
`pharmaceutical formulation of this type can then be
`treated in the usual way to provide a variety of solid
`dosage forms having a two-phase matrix-controlled
`extended release profile. This includes. the employment
`of procedures known in the pharmaceutical industry,
`such as compressing, granulating, extruding, pelletizing,
`and tabletting in dry or wet manner. It is of course also
`possible to combine a variety of procedures to provide
`the desired product formulation in any one of various
`forms such as tablets, dragees, pellets, granules, and the
`like. The amount of active substance present can be
`varied widely depending on the indication to be treated
`and the type of dosage form desired, for example, from
`0.01 to 90%, based on the total weight of the pharma-
`ceutical composition.
`Quite unpredictably, it has been found that the phar(cid:173)
`macokinetic properties of the solid dosage forms ac(cid:173)
`cording to the present invention are not affected by the
`manufacturing method employed or the variations aris(cid:173)
`ing in practice, e.g., the compression forces utilized.
`The casein employed can be a commercially available
`product, and the molecular weight and water content
`thereof may vary considerably, for example between
`MW 18000 and MW 30000 Daltons-depending upon
`the origin thereof, without detracting from its opera(cid:173)
`tiveness according to the present invention. Casein is of
`course a substance approved for use under food legisla-
`tion throughout the civilized world.
`A casein salt of a monovalent cation, such as lithium,
`potassium, ammonium, and preferably sodium, is used
`as the water-soluble casein salt.
`The water-insoluble caseinate is a salt of casein with
`a bi- or polyvalent cation, both referred to herein as a
`polyvalent cation. These include, e.g., calcium, magne(cid:173)
`sium, zinc, manganese, aluminum, iron, or mixtures
`thereof. Particularly preferred is calcium. The water(cid:173)
`insoluble caseinate can be used as such.
`In addition, it is possible to include in the composi•
`tion, containing a soluble casein salt, a physiologically(cid:173)
`compatible polyvalent cation, in the form of a salt
`thereof which is soluble in water or gastric fluid, op(cid:173)
`tionally in solution in water, in amounts such that a part
`of the soluble caseinate is converted to an insoluble
`caseinate, thereby transforming a part of the soluble
`casein salt to an insoluble casein salt in situ, as by gastric
`fluid upon ingestion. A part or all of the insoluble salt
`may be provided in this manner. Preferred cations are
`the chloride, gluconate, carbonate, lactate, and saccha(cid:173)
`rate cations and, in particular, calcium chloride, cal-
`cium gluconate, calcium hydrogen phosphate, calcium
`lactate, calcium D-saccharate, calcium levulinate, and
`their hydrates, or mixtures thereof, are preferred salts
`for providing the aqueous polyvalent, including biva(cid:173)
`lent, cation, which may be used as such or, if desired, be
`solvated by simple dissolution of the salt, e.g., in water,
`and optionally used in a normal granulation procedure.
`
`IPR2015-00410
`Petitioners' Ex. 1009
`Page 6
`
`

`

`5,382,601
`
`6
`5
`The weight/weight ratio of soluble to insoluble case(cid:173)
`first phase, i.e., in the stomach, as well as in the second
`inate is between 5 and 95%, preferably between 5 and
`phase, i.e., in the intestines where, after a slight delay, a
`90%, and more preferably between 20 and 70%, based
`renewed liberation of active ingredient is effected, the
`on the total caseinate content of the composition. Most
`remainder of the active ingredient being released over a
`preferred is a weight/weight ratio of between 30 and 5
`predetermined time period, thereby attaining an effec(cid:173)
`60%. The amounts of the aforementioned ionic com(cid:173)
`tive adaptation to the total active substance availability
`pounds and their solutions required for the production
`requirements, with the partial release in each stage re(cid:173)
`of the desired amount and ratio of insoluble caseinate in
`sulting in corresponding desirable plasma levels. Local
`situ are dependent on the type of cation, its counter-ion,
`excess concentrations of active substance are thus
`and the molecular weight of the casein employed, as 10
`avoided.
`will be readily understood by and as can be readily
`This two-phase pharmaceutically-active ingredient,
`determined by one skilled in the art since it involves
`e.g., drug or vitamin, liberation profile is substantially
`only basic chemistry.
`independent of the enzymes contained in the physiolog(cid:173)
`According to the invention, quite unpredictably and
`ical environment of the stomach and intestines, as
`advantageously, a controlled bi-phase matrix-controlled 15
`shown in the following examples, a result which hith(cid:173)
`extended rele~e of active pharmaceutical ingredient is
`erto has not been realizable by conventional dosage
`thus achieved with the specified combination of matrix(cid:173)
`formulations.
`forming substances alone and without the necessity of
`However, if a change in the release rate is required in
`any embedded or surrounding external protein.
`Common auxiliary agents and additives or excipients 20 one or the other of the two liberation phases which
`might be necessary or desirable in view of the type of
`which may be employed to complete the pharmaceuti-
`cal composition used as matrix are components well
`active substance employed, the physiology of the pa-
`tient, or the degree of seriousness of the ailment treated,
`known in the pharmaceutical industry. These include,
`enzymes such as pepsin and/or pancreatin can of course
`for example, tabletting aids, such as highly disperse
`silicic acid, magnesium stearate, microcrystalline cellu- 25 be included in the formulation in suitable amounts, as
`lose, lactose, talc, colorants such as iron oxides or quin-
`well as numerous other enzymes or polymer-enzyme
`oline yellow, pigments such as titanium dioxide and
`products such as neutral, acid, or alkaline protease, or
`calcium carbonate, glycerylmonostearate, glyceryl be-
`any of the foregoing enzymes insolubilized by attach-
`henate, sodium stearylfumarate, stearic acid, cetyl pal-
`ment to an ethylenemaleic acid or anhydride (EMA)
`mitate, long-chain partial glycerides, cellulose powder, 30 polymer (as in U.S. Pat. No. 3,751,561). This does not
`change the two-phase profile. It is only the rate ofliber-
`mannitol, calcium phosphate, silicon dioxide, colloidal
`silicon dioxide, silicon dioxide hydrate, and polyethyl-
`ation within the phases which can thus be slightly var-
`ene glycol, preferably of a molecular weight 1,500 to
`ied.
`6,000 Dalton, and the like.
`The mechanism of the extended two-stage release can
`Active ingredients or mixtures thereof, which can be 35 be explained as follows:
`The use of a water-insoluble caseinate, e.g., calcium
`used to provide an effective amount of the active phar-
`maceutical principle or ingredient in the compositions
`caseinate, results in the formation of a matrix tablet.
`of the invention, encompass innumerable pharmaceuti-
`The drug is released independently of the pH of the
`dissolution medium in a diffusion-controlled man-
`cally-active compounds which are suitable for ex-
`tremely varied fields of end-use application. They in- 40
`ner. In other words, due to the presence of the
`elude tranquillizers such as chlorpromazine and ben-
`insoluble caseinate, there is an extended release in
`zodiazepines such as diazepam; muscle relaxants such as
`both stages, the extent of retardation being depen-
`mephenesin; antihypertensive agents such as a-methyl-
`dent on the amount of insoluble caseinate in the
`dopa; -centrally-acting analgetics such as morphine;
`formulation, as shown in Study 5 and correspond-
`· FIG 5
`peripherally-acting analgetics such as paracetamol; non- 45
`. hl
`mg
`.
`.
`steroidal ant1p ogistics such as ibuprofen; local anes-
`In alkaline medium, the insoluble caseinate gradually
`becomes degraded, equivalent to an attenuation of the
`thetics such as benzocaine; spasmolytics such as papav-
`erine; prostaglandins such as PEG2, antibiotics such as
`penicillin and tetracycline; agents -influencing the de-
`matrix-effect. Subsequently, the retardation is dimin-
`mential syndrome such as memantine; anti-Parkinso- 50 ished and the drug release rate increases, which can be
`seen in the second stage, although also in this second
`nism therapeutic agents such as amantadine, L-dopa,
`selegiline, bromocriptine, and metixene; antimalarials
`stage drug release is extended.
`BRIEF DESCRIPTION OF THE DRAWINGS
`such as chloroquine; corticosteroids such as dexametha-
`sone; androgens such as methyltestosterone; estrogens
`Reference is now made to the accompanying draw(cid:173)
`such as ethinylestradiol; gestagens such as levonorges- 55
`ings, for a better understanding of the present invention,
`trel; sympathometics such as adrenalin; substances hav(cid:173)
`wherein:
`ing cardiovascular effect such as nitroglycerin; diuretics
`FIG. 1 is a graph of a biphasic drug liberation proflle
`such as hydrochlorothiazide; anthelmintics such as pra(cid:173)
`showing release of caffeine over a period of time in
`ziquantel: ,8-blockers such as timolo1; H2-blockers such
`accord with Study 1 of this application without enzyme
`as cimetidine: vitamins such as ascorbic acid, and the 60
`and with medium change after two hours.
`like. Effective amounts of such pharmaceutically-active
`FIG. 2 is the same according to Study 2 of this appli(cid:173)
`principles or ingredients are well known in the art.
`cation with enzyme and with medium change after two
`Most preferred is memantine.
`hours.
`The readily-produced formulations according to the
`FIG. 3 is a graph showing the biphasic release of
`invention, upon ingestion, advantageously result in a 65
`Memantine over a period of time in accord with Study
`controlled two-phase release of the active ingredient,
`with an amount of active substance adapted to the
`3 of this application without enzyme and with medium
`therapeutical goal being released and available in the
`change after two hours.
`
`IPR2015-00410
`Petitioners' Ex. 1009
`Page 7
`
`

`

`5,382,601
`
`8
`-continued
`Active Substances and Additives
`
`Aerosil200
`magnesium stearate
`
`Percent by Weight
`
`1.0
`1.0
`
`7
`FIG. 4 is the same as FIGS. 1 and 2, but in accord
`with Study 4 of this application without enzyme and
`with medium change after two hours, and
`FIG. 5 is a graph illustrating the dependence of drug
`release on the insoluble caseinate content of a dosage 5
`form. according to the invention, showing the percent
`caffeme released over a period of time with calcium
`caseinate content of the formulation varying from 0 to
`100%, this liberation profll.e being determined in a simu(cid:173)
`lated gastric environment at a pH of 1.2 without added 10
`enzyme.
`
`All components except for magnesium stearate are
`homogeneously distributed in a suitable mixer, e.g., a
`Diosna TM mixer, magnesium stearate then added, and
`the mixture passed through a screen of an average (U.S.
`Standard Sieve Series) mesh size of 300 p.m. After a
`further mixing of the compressed mass, tablets are pro(cid:173)
`duced on a suitable pelleting machine, having a mass of
`100 mg and a diameter of 6 mm, with a compression
`force of 8 kN being applied.
`Example 4
`
`SPECIFIC DESCRIPTION OF THE INVENTION
`The invention will now be described in greater detail
`with references to the following Examples, which are
`not to be construed as limiting.
`I. Production of the Drug Formulation
`Example 1
`Active Substances and Additives
`Percent by Weight
`~~~---------------------------20 ----~~~~~==~--~~~~~~-
`Active Substances and Additives
`Percent by Weight
`ibuprofen
`77.0
`sodium caseinate
`20.0
`calcium chloride + 2H20
`1.0
`Aerosil 200 ™
`1.0
`magnesium stearate
`1.0
`
`15
`
`memantine HCI
`20.0
`sodium caseinate
`46.8
`calcium caseinate
`31.2
`Aerosil 200 TM (fmely-divided Si02)
`1.0
`magnesium stearate
`1.0
`~----~------------~~----
`All components with the exception of magnesium
`stearate are homogeneously distributed in a suitable
`mixer such as a Diosna TM mixer; subsequently magne- 3
`.
`.
`0
`smm stearate IS added and the mixture passed through a
`s~reen of an average (U.S. Standard Sieve Series) mesh
`s1ze of 300 p.m. After a further mixing of the material to
`b~ compressed, tablets having a mass of 100 mg and a
`diameter of 6 mm are produced on a suitable tabletting
`f
`.
`~
`bin
`mac
`e, usmg a tOrce o compression of 8 kN.
`Example 2
`
`25
`
`35
`
`By spraying a suitable granulating liquid such as an
`ethanol/water mixture (v/v 3/2) or a colloid-containing
`granulating liquid such as gelatine/water (1/30), a crust
`granulate or an adhesive granulate is flrst produced
`from the ibuprofen.
`Th~ granulate is mixed with the remaining compo(cid:173)
`nents in a suitable mixer and is compressed, using a
`compression force of 15 kN, into tablets having a mass
`of 520 mg and a diameter of 12 mm.
`Example 5
`
`Percent by Weight
`Active Substances and Additives
`---~~~ein~e--~~~~~~~----~~~~~~---40
`20.0
`75.0
`3.0
`1.0
`1.0
`
`sodium caseinate
`calcium chloride X 2H20
`Aerosil 200 TM
`magnesium stearate
`
`45
`
`The caffeine and sodium caseinate components are
`mixed in a suitable fluidized bed granulation machine,
`such as the Aeromatic STREA 1 TM . The granulation
`of a 500 g batch is effected with 400 mi of an aqueous
`fluid containing 3 g calcium chloride dihydrate in dis- 50
`solved form at a pump rate of 10 ml/min, an inlet tem(cid:173)
`perature of 60° C., an outlet temperature of 32• C., and
`at an atomizing pressure on the binary nozzle of about 2
`bar. After a redrying of 10 min at 60° C. and a weak
`supply of fresh air, the granulate is separated from the 55
`coarse portion (> 1.0 mm) and from the fme portion
`( <?.15 mm) an~, after admixing with Aerosil and mag(cid:173)
`~esium stearate, 1s compressed using a force of compres(cid:173)
`SIOn of 8 kN into tablets having a weight of 100 mg and
`a diameter of 6 mm.
`Example 3
`
`60
`
`Active Substances and Additives
`piroxicam
`sodium caseinate
`calcium hydrogen phosphate + 2H20
`Avice) PH 102 TM -microcrystalline
`cellulose
`
`Percent by Weight
`
`65
`
`20.0
`65.0
`3.8
`9.2
`
`Active Substances and Additives
`memantine-HCI
`sodium caseinate
`calcium caseinate
`
`Percent by Weight
`20.0
`48.0
`32.0
`
`All components are homogeneously distributed using
`a suitable mixer and, in a mixing kneader, are then inti(cid:173)
`mately wetted with a suitable plasticizing liquid, such as
`purified water or an ethanol/water mixture (v /v 3/2) to
`an extent of about 60% v/v based on the solid portion.
`The resultant mass is !yo-extruded either on a screw
`extruder or on a distributing roll-type extruder with an
`apertured disk-diameter of 1.5 mm. The thus-obtained
`strands are divided and filleted on a spheronizer to form
`pellets of a diameter of 1.8 mm. Subsequently, the pel(cid:173)
`lets are either loaded into capsules or are compressed
`into tablets after admixing with 1% Aerosil and 1%
`magnesium stearate.
`II. Liberation or Release Tests
`The media used in all dissolution tests is either simu(cid:173)
`lated gastric fluid (pH 1.2) or simulated intestinal fluid
`(pH y.5). To more closely approach in vivo conditions,
`pepsm (gastric fluid) and pancreatin (intestinal fluid) are
`added. In the chapter "Test Solutions" of the U.S. Phar(cid:173)
`macopoea XXII, the compositions of the two media are
`exactly described as follows:
`"Gastric Fluid, Simulated, TS-Dissolve 2.0 g of
`sodium chloride and 3.2 g of pepsin in 7.0 mL of
`hydrochloric acid and sufficient water to make
`1000 mL. This test solution has a pH of about 1.2."
`
`IPR2015-00410
`Petitioners' Ex. 1009
`Page 8
`
`

`

`5,382,601
`
`9
`"Intestinal fluid, Simulated, TS-Dissolve 6.8 g of
`monobasic potassium phosphate in 250 mL of wa(cid:173)
`ter, mix, and add 190 mL of0.2N sodium hydroxide
`and 400 mL of water. Add 10.0 g of pancreatin,
`mix, and adjust the resulting solution with 0.2N 5
`sodiumhydroxide to a pH of 7.5±0.1. Dilute with
`water to 1000 mL."
`1. Retarded Release of an Active Substance in Re(cid:173)
`sponse to the Insoluble Caseinate Content
`The following basic formula is compressed:
`
`10
`
`10
`-continued
`magnesium stearate
`
`1.0
`
`It has been found that varying forces of compression
`within these ranges have no bearing or effect on the
`release profile.
`3. Addition of Polyvalent Salt to the Soluble Casein(cid:173)
`ate to Produce the Insoluble Caseinate In Situ
`The following basic matrix formulation is produced
`in the foregoing manner with admixture and/or granu(cid:173)
`lation and in accord with the foregoing conditions (see
`Examples 1-5):
`
`caffeine
`Ca-caseinate
`
`Aerosil200
`magnesium stearate
`NaCaseinate
`
`20.0
`0-78.0% (based on the
`total casein content)
`1.0
`1.0
`ad 100%
`
`15 -------------------------------------
`caffeine
`20.0
`65.0
`NaCaseinate
`Ca-salt, optionally in aqueous solution
`X
`Aerosil
`1.0
`magnesium stearate
`1.0
`Avice! PH 102
`ad 100%
`
`25
`
`35
`
`When completely converting a soluble caseinate, for
`example the NaCaseinate, to an insoluble, e.g., calcium,
`salt, the insoluble cation content can be readily deter(cid:173)
`mined, e.g., the calcium content is normally 1.5% to
`1.7% by weight, but can optionally be made even
`higher, so that an amount as suggested below according
`to the present invention can be readily determined and
`the desired amount of insoluble casein salt thereby cal(cid:173)
`culated and thus-provided.
`The following pharmaceutically-suitable calcium
`salts can, for example, be used in the foregoing formula(cid:173)
`tion to provide an insoluble casein salt in situ in a formu(cid:173)
`lation of the invention:
`
`Amount X employed in the Formula:
`calcium chloride X 2H20
`calcium gluconate X H20
`calcium carbonate
`calcium hydrogen phosphate X 2H20
`calcium lactate X 5H20
`calcium nitrate X 4H20
`calcium-D-saccharate
`calcium levulinate
`
`3.6
`10.9
`2.4
`4.2
`7.5
`5.8
`6.1
`7.5
`
`Eight different compressive masses of varying Na(cid:173)
`caseinate and Ca-caseinate proportions (added as such) 20
`are formulated by using the tabletting auxiliaries Aerosil
`and magnesium stearate. As no other auxiliaries are
`added, a true picture of the release properties is ob-
`tained.
`The total caseinate portion amounts to 78%. The
`pulverulent mixtures are compressed on an instrumen(cid:173)
`tized Exacta 1 TM at an adjusted speed of 30 strokes/(cid:173)
`min, using compressing tools of 6 mm, flat without
`facette, at a constant force of compression of 8 kN to 30
`form tablets having an individual weight of 100 mg.
`Dosage form products are obtained having a Ca case(cid:173)
`inate content of 0, 10, 20, 30, 40, 50, 70 and 100%, the
`liberation proflle of which is determined at pH 1.2 (sim-
`ulation of gastric environment).
`FIG. 5 shows the dependence of drug release on the
`insoluble caseinate, i.e., calcium caseinate, content of
`the dosage form, and thus the extent of retardation. The
`tablet formulations employed in this study correspond
`to the basic formula of II. 1 just hereinabove provided. 40
`The dissolution of 80% of total caffeine content oc(cid:173)
`curs in the case of20% Ca-caseinate (percentage