United States Patent [19]
`
`||l|||lllllllllll|||||l|||l|l|l|||||||||||l|||l||||||l|||||l|||||||l|||l||l
`US0O540'.7686A
`[11] Patent Number:
`
`5,407,686
`
`»
`
`Patel et al.
`
`[45] Date of Patent:
`
`Apr. 18, 1995
`
`
`
`[54] SUSTAINED RELEASE COMPOSITION FOR
`QRAL AD fl0N 01'.‘ ACTIVE
`INGREDIENT
`
`[75]
`
`I731 Asam-===
`
`‘
`Inventors: Satischandra P. Patel. Livingston;
`Vinayak T. Bhalm, Morris Plains,
`both of NJ.
`sidmk Laboratories, Inn. East
`Ha110\’Bfs N-1
`[2]] App; No_, 3;-£594
`_
`[221 Filed:
`
`Jnn.29. 1992
`
`Related U.S. Application Data
`
`-
`
`[63]
`
`.
`
`
`
`Continuation-in-part of Ser. No. 199,344-,'Nov. 27,
`1991' amdonm
`Int. CL6 ................................................ A61K 9/22
`[51]
`[52] U.S. Cl. .................................. .. 424/468; 424/494;
`'
`424/495; 424/480
`[53] Field ofsearch .............. .. 424/468, 476, 496, 475
`5
`Ref
`Ci
`[ 6]
`Emma
`ted
`US. PATENT DOCUMENTS
`3,133,863 S/1964 Tans-ey
`3’362'8s0
`1/1963 ‘lefffies
`3,492,397
`1/I970 Peters eta].
`3,792,157 2/1974 Sheth etal..
`zaffaroni "H
`3,943,254 4/I976 Zaffaroni
`3,993,072 ll/1976 Zalfaroni ...... ..
`4,016,330 4/197'.-' Theeuwes et al.
`4,138,475
`2/19‘.-'9 McAn.isl1 et a1.
`4,248,856 2/1931 Guley etal.
`4,248,858 2/1981 Guley et al.
`4.303.251 12/1981 Dunn
`4,309,405
`1/1932 Gale? 131 31-
`"'r399»4°5 V1932 GM‘? 91 31-
`4’359v172
`1/1933 5°h°‘ '3‘ 31-
`45459379 7/1934 snicker '3" 31'
`4’575’6m 3/1936 Gmtmxd 3‘ 3]‘
`
`424/-:65
`" 424/470
`1.424/495
`424/430
`
`424/423
`424/430
`123/260
`424/19
`424/2'1
`424/21
`424/I9
`424/21
`424/5’-1
`434/19
`424/19
`' 604/890
`
`5/1988 Tamas et al.
`4,743,023
`4,715,535 10/1988 Lowey
`4,784,358 11/1988 Ventouras
`4,736,503 ll/I983 Eclgren et al.
`4,824,678 4/I989 Lindahl et al.
`4,851,228
`7/1989 Zentner et al.
`4,853,249
`3/1939 Taltasltimaet al.
`izifiéfiii $1333
`4,394,223
`1/1990 Pigiet
`4,911,798 11/1990 Coiaet al.
`4,994,?-'9 2/1991 Aoki et ai.
`5,002,774
`3/1991 Agrewala etal.
`5,093,200
`3/1992 Watanabe et al.
`5,133.9‘.-'4
`'2'/1992 Paradissis at al.
`
`..
`
`424/405
`. 424/604
`424/468
`424/443
`-«:26/19
`. 424/456
`427/3
`: 33:23
`424/71
`424/440
`424/496
`424/468
`.
`424-/4T6
`.
`................ .. 424/475
`
`FOREIGN PATENT DOCUMENTS
`11$ :13.
`.
`5203330
`3,/1937 A t
`'
`0065505 12/1932 European pm“ Off_ _
`905000 9/3952 united Kingdom _
`
`OTHER PUBLICATIONS
`Sustained Release Medications, J. C. Johnson, Noyes
`Data Corporation, Park Ridge, N.J., 1980 pp. 3 and 4.
`Invoice #29944, Jul. 12, 1939, to Thompson Medical
`C°mP‘*“Y-
`Primary Exam:'::er—Th'<1rrnan K. Page
`.
`.
`.
`.
`’4””"‘"“ E"“’"""”‘w‘"’“m E‘ Be“‘t°“
`Artflrfley, Ageflb Hr F}-l7n‘SandIer,
`Bemsteifl
`
`&
`
`ABSTRACT
`[57]
`A sustained release tablet adapted to provide an initial
`immediate release of an active agent, a period of no
`release of the active agent, followed by a substantially
`constant, rate of release of the active agent. The tablet
`includes (a) a compressed tablet core containing an
`active agent, an insoluble binder and an insoluble; (b) a
`barrier coating formed over the tablet core, the barrier
`coating including a mixture‘oi‘ soluble and insoluble
`polymers and a plasticizer; (c) an active coati.ng'depos-
`ited over the barrier coating, the active coating includ-
`ing an active agent, a soluble polymer and a_ plastici_zer;
`and (5) 3 mm "°a““3 f°"m"-'5 °"°T the a°“"'° "°"““‘3-
`the film coating containing a soluble polymer and plasti-
`“zer-
`
`36 Claims, 3 Drawing Sheets
`
`
`
`'
`
`4’615’693 10/.1936 Guiuard t al_
`4,681,755 7/198? Colornboeet a.l.
`4,5345“; 3,1937 Bhuumi
`4,'.7U4,285 ll/1937 Alderman
`4,7l3,2.48 12/198'.-' Kjornaes et al.
`4,?21,6!9 1/I988 Panoz et a1.
`
`/39.’,
`424/436
`424/19
`. 424/4-63
`. 424/468
`424/459
`
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`Apr 18, 1995
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`5,407,686
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`

`
`1
`
`5,407,686
`
`SUSTAINED RELEASE COMPOSITION FOR
`ORAL ADMINISTRAITON OF ACITVE
`INGREDIENT
`
`REFERENCE TO RELATED APPLICATIONS
`
`5
`
`2
`(b) a barrier coating formed over the tablet core, the
`barrier coating comprising a mixture of soluble and
`insoluble polymers, and a plasticizer;
`(c) an active coating formed over the barrier coating,
`the active coating comprising the active agent, a
`Seluble P°1}'U1e1' and 3 P13-Weller; 311d
`(cl) a film coating fori'ned over the active coating, the
`This application is a Continuation-In-Part application
`Elm coating comprising a soluble polymer and a
`of application Ser. No. 07/799,344, filed Nov. 27, 1991,
`plasticizer.
`now abandoned the disclosure of which is incorporated 10
`The active agent is contained in the active coating in
`an amount of from about 1 to about 35% by weight of
`by ’°f°r°“°° in ll‘ entirety‘
`*1‘? ‘SE1 :10?-18° ‘l;'’l=ie‘11§°1;*I1%f~"-*i$ 388%‘ in the 5"?"
`BACKGROUND or TI-[E INVENTION
`tame
`re ease ta et.
`re era y,
`e active 21 exit
`is
`phenylpropanolamine hydrochloride, which ngay be
`1- Field °fthe1“"enl-1'0“
`The Present i1“"e11fi°n relate‘ to 3 eusteined release 15 present in the active coating in an amount of from about
`tablet designed or adapted to provide an immediate
`15 to about 33% by weight, of the total dosage weight
`ft‘-13359 Of 311 OOOVB 3831'“: 3 PBOOO Of DO 11313339 Of 311
`of the phenylpropanolamine hydrochloride in the tab-
`3OtiVe agent. fOl1OWOO bl? 3 Sllbetalllifi-“Y OOI1-51311‘ 1“e-
`let. Other active agents may be employed, however,
`lease of the active agent.
`including, but not limited to, to adrenergic agents, anti-
`2. Description of the Prior Art
`20 cholinergic agents; antispasmodic agents; curariform
`o'.-(ami11oe-
`Phenylpropanolamine
`hydrochloride
`agents; tranquilizers; muscle relaxants; antihistamines;
`thyl)benzy1 alcohol hydrochloride, also known as d1-
`hypotensive agents; cardioactive agents; angiotensin
`norephedrine
`hydrochloride,
`2-amino-1-pI1enyl-1-
`converting enzyme inhibitors; broncliodilators; ste-
`propanol hydrochloride, and ct-hydroxy-8-aminopro-
`roids; antibacterial agents; antimalarials; antibiotics;
`pylbenzene hydrochloride), is a well-known sympatho- 25 S€datiV¢5: and 3-Oalgefiiee
`mimetic amine. pheny1p1-opan0}amj_ne hydl-0311101-ide is
`The sustained release tablet of the present invention
`well documented asatherapeutic agent which is used as
`1133 3- WPIC3-l release P1'Ome Of the 3°31‘-"e agent “'1 the
`an anoreximt for comm} of obmiw In this capacity it
`tablet, as measured in the in-vitro dissolution method '
`has been marketed by, among othm, SBA pharmacem 30 utilizing U.§.P. XXII, basket method at 100 RPM in
`ticals, Inc. under the trademarks Anorexin ® and One-
`water at 37 C" 35 f°ll°“’5‘
`Span ®, and by Thompson Medical Company, Inc.
`under the trademark Dexatrim ®.
`Phenylpropanolamine hydrochloride is also a bron-
`chial dilator, and is accordingly used for the treatment 35
`of asthma, as well as being commonly employed as 3.
`decongestant for treatment of upper respiratory tract
`congestion. As an antiasthmatic, pheuylpropanolainine
`hydrochloride has been marketed by Eaton Laborato-
`ries under the trademark Rymed ®.
`U.S. Pat. No. 4,971,798 describes a slow-dissolving
`lozenge confection to provide slow sustained release of
`an antitussive, decongestant, antihistamine, or expecto-
`rant ingredient, which may be phenylpropanolamine.
`U.S. Pat. No. 4,894,223 describes a novel drug deIiv- 45
`ery system for decongestants. The delivery system,
`which may he used to deliver phenylpropanolamine
`hydrochloride, is in dry particulate form, and includes a
`hydrophobic matrix and a coat.
`It is an object of the present invention to provide a 50
`sustained release form of an active ingredient, such as
`Phenylpropanolamine hydrochloride, which is charac-
`‘°’l.’°‘l by immediate releilse of the active lngredienl’ a
`period of no release of active agent, followed by release 55
`.
`.
`.
`.
`.
`of the active ingredient at a umfortn constant rate, Inde-
`Pendent °f_tll‘? drug ‘_’°”c’emmtl9“ and/of gastrolmesll
`ml PH "'3*“at'°n dumlg the penod °f release
`SUMMARY OF THE INVENTION
`_
`_
`_
`_
`‘
`The object of the present invention is to provide 3.
`sustained release tablet adapted to provide an initial
`immediate 1‘e1-°-33¢ Of 31! 3-OOVO agent» 3 Pefied Of “O
`release of active agent, followed by a substantially con-
`stant, zero»-order rate of release of the active agent.
`The tablet of the present invention comprises:
`(a) a compressed tablet core comprising an active
`agent, an insoluble binder and an insoluble Fller;
`
`The sustained release tablet according to the present
`invention comprises:
`(a) a compressed tablet core comprising phenylpropa-
`110131135113 11YdfOOl1101'iC'Ie- ethlfl Cell‘-11059 and O31‘
`Oillm Wlfate;
`‘
`('3) 3‘! b?»!'1'ie1' OO-W35 fO1'O§|*‘-_d OVO1’ file tablet Ceres the
`heme‘ C03-‘mg ‘3°mF“5m3 3 ml-3‘-“'3 °f hYd"°"Y'
`propyl methyl cellulose, ethyl cellulose and glyc-
`eryl triacetate, wherein the hydroxypropyl methyl
`cellulose and the ethyl cellulose are utlllzed in 3
`ratio bl welghl of about 1:3;
`.
`.
`(Gig: a::;‘fe°0:On:fignl°r(l:;: iéifztigfirfliig:
`amine hydrochloride, hydiloxypropyl methyl cellu-
`lose and glyceryl triacetate, wherein the amount of
`phenylpmpanolamine hydrochloride in the active
`coating is from about 15 to about 33% by weight of
`the total dosage weight of the phenylpropanol-
`amine hY‘1I'?°111°11'd° in the tablet: fmd
`,
`(:1) a film coating formed over the active coating, the
`mm coating comprising hydmxypmpyl methfl
`ceuulose and g1yce,~y1t1-iacetate_
`The present invention also contemplates a method of
`preparing the move} sustained release ;ab1.:_-t ofthe 11-wen.
`65 tion. According to a preferred method, a sustained re»
`lease tablet adapted to provide an initial
`immediate
`release of an active agent, a period of no release of
`active agent, followed by a substantially constant, zero-
`
`, hm
`2 hours
`H 110"“
`3::
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`11-12 hours
`13-” ‘W5
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`Amerigen Ex. 1025, p. 5
`Amerigen Ex. 1025, p. 5
`
`

`
`5,407,686
`
`3
`order rate of release of the active agent is provided by
`a method which comprises:
`(a) forming a compressed tablet core comprising an
`active agent, an insoluble binder and a filler;
`(b) coating the tablet core with a barrier coating
`comprising a mixture of soluble and insoluble poly-
`mers, and a plasticizer;
`(c) coating the barrier coating with an active coating
`comprising an active agent, a soluble polymer and
`a plasticizer; and
`(cl) coating the active coating with a film coating
`comprising a soluble polymer and a plasticizer.
`The present invention also contemplates a method of
`inducing appetite suppression in a human, the method
`which comprises administering to the human a sus-
`tained release tablet adapted to provide an
`imme-
`diate release of phenylpropanolamine hydrochloride, a
`period of no release of active ingredient, followed by a
`substantially constant, zero-order rate of release of
`phenylpropanolamine hydrochloride,
`the tablet com-
`prising;
`(a) a compressed tablet core comprising phenylpropa-
`nolamine hydrochloride, ethyl cellulose and cal-
`cium sulfate;
`(b) a barrier coating formed over the tablet core, the
`barrier coating comprising a mixture of lrydroxy-
`propyl methyl cellulose, ethyl cellulose and glyc-
`eryl triacetate, wherein the hydroxypropyl methyl
`cellulose and the ethyl cellulose are utilized in a
`ratio by weight of about 1:3;
`(c) an active coating formed over the barrier coating,
`the active coating comprising phenyIpropanol-
`amine hydrochloride, hydroxypropyl methyl cellu-
`lose and glyceryl triacetate, wherein the amount of
`phenylpropauolamine hydrochloride in the active
`coating is from about 15 to about 33% by weight of
`the total dosage weight of the phenylpropanol-
`amine hydrochloride in the tablet; and
`(d) a film coating formed over the active coating, the
`film coating comprising hydroxypropyl methyl
`cellulose and glyceryl triacetate.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the release rate profile of Phenylpropa-
`nolamine Hydrochloride Sustained Release Tablet for
`Examples 1 and 2 according to the present invention
`showing immediate release, a period of no release, fol»
`lowed by constant release period.
`FIG. 2 shows the percent dissolved vs. time of Phen-
`ylpropanolamine Hydrochloride Sustained Release
`Tablet for Examples 1 and 2 according to the present
`invention showing immediate release, a period of no
`release, followed by constant release period.
`FIG. 3 shows in vivo data of the plasma concentra-
`tion of a Phenylpropanolamine Hydrochloride Sus-
`tained Release Tablet of phenylpropanolamine hydro-
`chloride on day 4 of treatment.
`DETAILED DESCRJPTION OF THE
`INVENTION
`
`In accordance with the present invention, a sustained
`release tablet is adapted to provide an initial immediate
`release of an active agent, a period of no release of
`active agent, followed by a substantially constant, zero-
`order rate of release of the active agent is provided. The
`tablet comprises:
`(a) a compressed tablet core comprising of an active
`agent. an insoluble binder and an insoluble filler;
`
`4
`(b) a barrier coating formed over the tablet core, the
`barrier coating comprising of a mixture of soluble
`and insoluble polymers and a plasticizer;
`(c) an active coating formed over the barrier coating,
`the active coating comprising the active agent, a
`soluble polymer and a plasticizer; and
`(d) a film coating formed over the active coating, the
`film coating comprising a soluble polymer and a
`plasticizer.
`Generally, sustained release dosage forms release
`their drug contents gradually after the drug makes
`contact with alimentary fluids, dampening the peaks
`and valleys observed with immediate release dosage
`forms. The drug concentration is also maintained in the
`body for longer periods of time, reducing the frequency
`of dosage. However, most sustained release products do
`not produce uniform blood concentration levels over a
`prolonged period of time. Initially,
`the rate of drug
`release increases rapidly, followed by an exponentially
`declining rate of release. This type of drug release is
`categorized as a first-order release mechanism.
`In contrast, the sustained release tablets of the present
`invention provide an initial immediate release of active
`agent and a period of no release of active agent, fol-
`lowed by a substantially constant rate of release. The
`sustained release tablet according to the present i.nven~
`tion provides initial immediate release of active agent,
`which is just sufficient to build initial concentration of
`active agent in the blood. In the period of no release, the
`blood concentration of active agent slowly declines to a
`desired level at which constant release period of the
`dosage form kicks in, providing substantially constant
`rate of release for a desired time period.
`A wide variety of medicaments which are orally
`administered in tablet form can be used in the sustained
`release tablet prepared according to this invention.
`These include, for example, adrenergic agents, such as
`ephedrine, desoxycphedrine, phenylephrine, epineph-
`rine and the like; cholinergic agents, such as, physostig-
`mine, neostigmine and the like; antispasmodic agents,
`such as atropine, methantheline, papaverine and the
`like; curariform agents, such as, chlorisondamine and
`the like;
`tranquilizers and muscle relaitants, such as
`iluphenazirxe, chlorpromazine, trifluoperazine, mephen-
`esin, meprobamate and the like; autihistamirres, such as
`dipheuhydramine,
`dimenhydrinate,
`tripelennamine,
`perphenazine, chlorprophenazlne, ch.lorprophenpyrida-
`mine and the like; hypotensive agents, such as rauwol-
`iia, reserpine and the like; cardioactive agents, bendro-
`flumethiazide, chlorothiazide, aminotrate, propranolol,
`nadolol, procainamide and the like, angiotensin con-
`verting enzyme inhibitors, such as, captopril, enalapril,
`and the like; bronchodilators, such as, phenylpropanol-
`amine hydrochloride, theophylline, and the like; ste-
`roids, such as, testosterone, prednisolone, and the like;
`antibacterial agents, e.g., sulfonamides, such as srrlfadia-
`zine, sulfamerazine, sulfamethazine, sulfisoxazole and
`the like, autimalarials, such as, chloroquine and the like;
`antibiotics such as the tetracyclines, nystatin, strepto-
`mycin, cephradine and other cepltalosporins, penicillin,
`semi-synthetic penicillins, griseofulvin and the like;
`. sedatives, such as chloral hydrate, phenobarbital and
`other barbiturates, glutethimide, antitubercular agents,
`such as isoniazid and the like; and analgesics, such as
`aspirin, acetaminophen, propoxyphene, meperidine and
`the like.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4-0
`
`45
`
`50
`
`S5
`
`60
`
`65
`
`These substances are frequently employed either as
`the free compound or in a salt form, for example, acid
`
`Amerigen Ex. 1025, p. 6
`Amerigen Ex._ 1025, p. 6
`
`

`
`5,407,686
`
`5
`addition salts or basic salts such as alkali metal salts.
`' Other therapeutic agents having the same or different
`physiological activity can also be employed in pharma-
`ceutical preparations within the scope of the present
`invention.
`
`is pheuylpropanolamine
`A preferred active agent
`hydrochloride, a known decongestant and appetite sup-
`pressant. Any commercially available forms of phenyl-
`propanolamine hydrochloride may he used in accor-
`dance with the present invention.
`In the present invention, the compressed tablet core
`contains active agent, insoluble binder and an insoluble
`filler and lubricant. The active ingredient in the core
`may contain any therapeutic agent, including any of
`those described above, however, preferably contains
`phenylpropanolamine hydrochloride. The active agent
`constitutes about 30 to 80% by weight of the core,
`preferably about 60% by weight of the core ingredient.
`The insoluble binder could be ethyl cellulose, cellulose
`acetate, cellulose tributarate, and is most preferably
`ethyl cellulose having a viscosity of 5 to 50 cps. The
`concentration of the insoluble binder varies between 2
`to 20% by weight, preferably about 15% by weight.
`The insoluble filler could be any insoluble excipient,
`organic or inorganic in nature, preferably calcium sul-
`fate. The concentration of the insoluble filler averages
`between 10 to 30% by weight, preferably about 20% by
`weight. The core contains a suitable lubricant, prefera-
`bly stearic acid and magnesium stearate.
`In the barrier coating, soluble and insoluble poly-
`mers, together with plasticizers, are utilized. The solu-
`ble polymer comprises hydroxpropyltuethylcellulose,
`hydroxypropylcellulose, hydroxyethylcellulose, me-
`thycellulose and carboxymethylcellulose. The pre-
`ferred soluble polymer forthe present invention is hy-
`droxypropylmethylcellulose, and preferably the hy-
`droxypropylmethylcellulose has a viscosity of 3 to 100
`cps, with the most preferred viscosity being 15 cps. The
`insoluble polymer of the present invention comprises
`ethyl cellulose, cellulose acetate, cellulose tributarate;
`the preferred insoluble polymer of this invention is
`ethyl cellulose. The viscosity range of ethyl cellulose is
`the range of S to 50 cps, with the preferred viscosity
`being 10 cps. The ratio of soluble polymer to insoluble
`polymer ranges from l:l to 1:10, preferably 1:3. The
`plasticizer added to the barrier coating consists of glyc-
`eryl triacetate, triethyl citrate, diethyl phthalate, poly-
`ethylene glycol, glycerin, castor oil and the like. The
`preferred plasticizer of the present invention is glyceryl
`triacetate. The concentration of the plasticizer in the
`barrier coating is about 5 to 20% by weight, preferably
`about 10% by weight, based on the total weight of the
`soluble and insoluble weight of the polymer in the bar-
`rier coating.
`The active coating is formed over the barrier coating,
`and comprises phenylpropanolamine hydrochloride,
`hydro:-typropylmethylcellulose. having a viscosity of 15
`cps, glyceryl
`triacetate, and polyvinyl pyrrollidone.
`The amount of phenylpropanolamine hydrochloride in
`the active coating is in the range of 15 to 33% on the
`basis of the total weight of phenylpropanolamirie hy-
`drochloride iii the tablet. The outer coating comprises
`hydroxypropylmethylcellulose, having a viscosity of 15
`cps, and glyceryl triacetate.
`The amounts of the above-indicated tablet compo-
`nents may be varied in accordance with principles
`known in the art to provide sustained release tablets
`having different release properties. For example, the
`
`6
`ratio of soluble polymer to insoluble polymer in the
`barrier coating may be varied. The blend of polymers
`and plasticizers in the barrier coating provides a mesh-
`like porous structure around the tablet core which ena-
`bles dissolution and diffusion of the active agent at a
`substantially constant, zero-order rate of release. Simi-
`larly, the thickness of each of the barrier, active, and
`film coatings may be manipulated so as to affect the
`initial release of active agent from the active layer as
`well as the subsequent sustained release of active agent
`from the tablet core. For example, increasing the thick-
`ness of the barrier coating will lower the rate of release
`of the active agent from the tablet core. Selection of a
`suitable thickness, based on the particular active agent
`and desired dosage levels, may be readily carried out by
`those of ordinary skill in the art.
`Thus, iii a preferred aspect of the present invention a
`sustained release tablet adapted to provide an initial
`immediate release of phenylpropanolamine hydrochlo-
`ride, a period of no release of phenylpropanolarnine
`hydrochloride, followed by a substantially constant,
`rate of release of phenylpropanolamine hydrochloride
`is provided by a tablet which comprises:
`(a) a compressed tablet core comprising phenylpropa-
`nolamine hydrochloride, ethyl cellulose and cal-
`cium sulfate;
`(b) a barrier coating formed over the tablet core, the
`barrier coating comprising a mixture of hydroxy-
`propyl methyl cellulose, ethyl cellulose and glyc-
`eryl trlacetate, wherein the hydroxypropyl methyl
`cellulose and the ethyl cellulose are utilized in a
`ratio by weight of about 1:3;
`(c) an active coating formed over the barrier coating,
`the active coating comprising phenylpropanol-
`amine hydrochloride, hydroxypropyl methyl cellu-
`lose and glyceryl triacetate, wherein the amount of
`phenylpropanolamine hydrochloride in the active
`coating is from about 15 to about 33% by weight of
`the total dosage weight of the phenylpropanol-
`amine hydrochloride in the sustained release tablet;
`and
`(d) a film coating formed over the active coating, the
`film coating comprising hydroxypropyl methyl
`cellulose and glyceryl triacetate.
`The tablets of the invention may also include those
`additional ingredients well-known in the pharmaceuti-
`cal art, such as colorants, film formers, preservatives,
`excipients,
`tableting lubricants, anti-adherents, and
`binders. Exemplary anti-adherents include silicon diox-
`ide and water. A preferred tableting lubricant used in
`the formulations of the invention comprises a mixture of
`stearic acid and magnesium stearate.
`The present invention also contemplates a method of
`preparing a sustained release tablet adapted to provide
`an initial immediate release of an active agent, a period
`of no release of active agent, followed by a substantially
`constant rate of release of the active agent, the method
`which comprises:
`(a) forming a compressed tablet core comprising an
`active agent, an insoluble polymer and a filler;
`(b) coating the tablet core with a barrier coating
`comprising a mixtLu'e of soluble and insoluble poly-
`mers, and a plasticizer;
`(c) coating the barrier coating with an active coating
`cornprinng an active agent, a soluble polymer and
`a plasticizer; and
`(cl) coating the active coating with a film coating
`comprising a soluble polymer and a plssticizer.
`
`5
`
`10
`
`15
`
`25
`
`30
`
`35
`
`45
`
`50
`
`S5
`
`60
`
`65
`
`Amerigen Ex. 1025, p. 7
`Amerigen Ex. 1025, p. 7
`
`

`
`5,407,686
`
`8
`(a) a compressed tablet core comprising phenylpropa-
`nolamine hydrochloride, ethyl cellulose and cal-
`cium sulfate;
`([3) a barrier coating formed over the tablet core, the
`barrier coating comprising a mixture of hydroxy-
`propyl methyl cellulose, ethyl cellulose and glyc-
`eryl triacetate, wherein the hydroxypropyl methyl
`cellulose and the ethyl cellulose are utilized in a
`ratio by weight of about 1:3;
`(c) an active coating formed over the barrier coating.
`the active coating comprising phenylpropanol-
`amine hydrochloride, hydroxypropyl methyl cellu-
`lose and glyceryl triacetate, wherein the amount of
`phenylpropanolamine hydrochloride in the active
`coating is from about 15 to about 33% by weight of
`the total dosage weight of the pheny1propanol-
`amine hydrochloride in the tablet; and
`(d) a film coating formed over the active coating, the
`film coating comprising hydroxypropyl methyl
`cellulose and glyceryl triacetate.
`It has been found that when phenylpropanolamine
`hydrochloride is administered according to the inven-
`tion, appetite suppression occurs immediately and is
`sustained for 12 to 24 hours.
`
`EXAMPLES
`
`The following examples are given to illustrate the
`invention, but are not deemed to be limiting thereon.
`The following examples illustrate the preparation of
`sustained release tablets in accordance with the present
`invention.
`
`Example 1
`Formulation of Sustained Release Tablet
`
`The below listed ingredients were utilized to prepare
`a phenylpropanolamine hydrochloride 75 mg sustained
`release tablet:
`
`7
`The tablet core is preferably formed according to
`techniques known in the art. These involve granulating
`a mixture comprising active agent and filler: with a solu-
`tion comprising insoluble polymer and organic solvent
`to form a granulated blend; drying the granulated blend 5
`to form a solid; and compressing this solid to form the
`core. A preferred organic solvent for the core granula-
`tion is isopropanoi. Drying temperatures in the range of
`30° to 40° C. are preferred, but any suitable range may
`be employed. Drying may be carried out in the blender 10
`utilized during granulation, in a fluid bed drier, or in a
`drying area/Lydon oven.
`The barrier coating is preferably formed by preparing
`a barrier coating solution comprising a mixture of solu-
`ble and insoluble polymers, plasticizer and organic sol-
`vent; and spray coating the barrier coating solution
`over the tablet core. The organic solvent used to pre-
`pare the barrier coating is preferably a solution compris-
`ing methylene chloride and methanol, employed in
`equal-volume amounts.
`Similarly, the active coating is preferably formed by
`a preparing an active coating solution comprising an
`active agent, a soluble polymer, a plasticizer and an
`organic solvent; and spray coating the active coating
`solution over the barrier coating. An equal-volume
`solution of methylene chloride and methanol is the
`preferred organic solvent used in forming the active
`coating.
`The film coating may be formed by any conventional
`technique known in the art, but preferably is formed by
`preparing a film coating solution comprising a soluble
`polymer, a plasticizer, and an organic solvent, along
`with coloring agents, opacifiers such as titanium dioxide
`and talc, perfumes, and the like; and spray coating the
`film coating solution over the active coating. Again, an
`equal volume solution of methylene chloride and meth-
`anol is the preferred organic solvent.
`Other coating techniques known in the art for form-
`ing tablet coatings may be employed instead of the
`preferred spray coating method. Exemplary alternative 40
`coating techniques include conventional pan coating
`and centrifugal liquid-bed coating methods. Upon oral
`administration, the film coating and active coating are
`dissolved by the action of gastrointestinal fluids to pro-
`vide an immediate release of the active agent contained 45
`in the active coating. The period of up to no release is a
`period of no release of active agent produced due to the
`special nature of the core and coating composition.
`Subsequently,
`the barrier coating permits the active
`agent to diffuse out of the tablet core at a substantially S0
`constant, zero-order rate of release.
`As indicated above, the sustained release tablets of
`the invention are advantageously usable with a wide
`variety of active agents. In a preferred embodiment, the
`active agent is phenylpropanolamine hydrochloride, an 55
`active agent which is desirably administered so as to
`achieve an immediate effect, a period of no release of
`active agent, followed by a constant rate of release over
`a prolonged period of time.
`Thus, the present invention contemplates a method of 60
`inducing appetite suppression in a human, the method
`which comprises administering to the human a sus-
`tained release tablet adapted to provide an initial imme-
`diate release of phenylpropanolamine hydrochloride, a
`period of no release of phenylpropanolamine hydro-
`chloride, followed by a substantially constant, zero-
`order rate of release of phenylpropanolamine hydro-
`chloride, the tablet which comprises:
`
`15
`
`25
`
`30
`
`35
`
`65
`
` INGREDIENTS Mg. Tablet % BY WEIGHT
`
`
`
`Core
`Phenylpropanolamine I-ICI
`U.S.P.
`Calcium Sulfate Anhydrous N.F.
`Ethyl Cellulose N.F.
`'Isopropyl Alcohol U.S.P.
`Stearic Acid N.F.
`llilagnesium Stearate ‘N.F.
`Barrier Coating
`Hydroxypropyl Methyl
`Cellulose U.S.P.
`Ethyl Cellulose N.F.
`Triacetirl U.S.P. (£10005 cc)
`‘Methylene Chloride N.F.
`‘Methanol N.F.
`Active Coating
`Phenylpropanolamine HC1
`U.S.P.
`Povidoue U.S.P.
`Hydroxypropyl Methyl
`Cellulose U.S.P.
`T1-iaeetin U.S.P. ((10025 cc)
`"lsopropy1 Alcohol U.S.P.
`‘Purified Water U.S.P.
`Film coating
`‘Methylene Chloride N.F.
`‘Methanol N.F.
`Triacetin U.S.P. (00004 cc)
`Hydroxypropyl Methyl
`Cellulose U.S.P.
`D & C “Yellow #10 Al Lake
`FD dc C Yellow #6 A1 Lake
`Titanium Dioxide U.S.P.
`
`60.000
`
`19.000
`15.500
`(0.012 cc)
`6.000
`0.500
`
`1.292
`
`3.318
`0.510
`(Q0536 cc)
`(£10586 cc)
`
`20.000
`
`1.244
`0.374
`
`2.865
`(0.02-$3 cc)
`(0.012-1 cc)
`
`((10572 cc)
`(CL0352 cc)
`0.464
`3.200
`
`0.160
`0.064
`0.960
`
`44.45
`
`14.0?
`1034
`0.01
`Ila.-t-5
`0.3?
`
`0.95
`
`2.33
`0.33
`0.04
`0.04
`
`14.32
`
`0.92
`0.28
`
`2.13
`0.02
`0.01
`
`0.04
`0.03
`0.35
`7.3‘!
`
`0.12
`0.05
`0.71
`
`Amerigen Ex. 1025, p. 8
`Amerigen Ex. 1025, p. 8
`
`

`
`5,407,686
`
`10
`Ezgut 5% by weight per tablet on a final weight
`is.
`3. Active coating: An active coating solution is pre-
`pared by mixing the active agent, soluble polymer,
`lasticizer, ovidone, organic solvent and water.
`P
`_
`P
`_
`The barrier coated tablet core from Step 215 spray
`coated wlth the active coating solution to provide
`an active coating having a desired weight gain to
`provide the desired weight percent of active agent
`in the active coating. which is preferably for phen-
`ylpropanolamine hydrochloride in the range of 15
`to 33% on the basis of the total weight of phenyl-
`propanolamine hydrochloride in the tablet.
`4. Film coating: A film coating solution is prepared
`by blending the soluble polymer, plasticizer, or-
`ganic solvent, titanium dioxide and colorant. The
`barrier/active coated tablet core from Step 3 is
`spray coated with the film coating solution to form
`a film coating having a desired thickness film coat-
`ing thickness.
`
`Example 4
`
`The thus formed tablets were tested by the in vitro
`dissolution method utilizing the U.S.P XXII basket
`method at 100 RPM in water at 37° C. The results of
`this test are illustrated in FIG. I wherein the release rate
`using the Example 1 formulation are depicted with the
`dotted line (“.”), and the release rate using the Example
`2 formulation are depicted with the crossed line (“-1- ”).
`Further, the results for Examples 1 and 2 are illus-
`trated in FIG. 2 where the % dissolved is plotted
`against time. The results of FIG. 2 are tabulated in
`Table l, wh.ich presents" the in vitro percent release of
`each of the 75 mg sustained release tablets of Example 1
`and Example 2.
`
`TABLE 1
`Phenylpropanolamiite Hydrochloride Sustained Release Tablets
`In-Vitro release rate in water USP Basket 100 RPM
`
`BX-
`AMPLE
`
`% RELEASE
`12
`10
`-1-
`2
`I
`I5
`8
`ER HR HR I-IR HR HR HR.
`
`Example: 1
`Example: 2
`
`24 M 37
`24.5
`24.9
`39.9
`
`50
`55.9
`
`63
`TL‘!
`
`1'5
`84.‘?
`
`83
`94.3
`
`
`
`H
`HR
`
`93
`104.1
`
`FIG. 2 and Table 1 illustrate that the sustained release
`tablet of the present invention exhibits an initial immedi-
`ate release of active agent upon administration, a period
`of no release of active agent, followed by a substantially
`constant, zero-order rate of release of the active agent.
`Release Rate Studies
`
`In-Vitro Release Profile:
`
`The in-vitro release profile of sustained release tablet
`was determined using U.S.P. XXII method, using rotat-
`ing basket at 100