United States Patent
`
`[19]
`
`[11] Patent Number:
`
`4,904,476
`
`Mehta et a}_
`[45] Date of Patent:
`Feb. 27, 1990
`
`
`[54]
`
`1l;°IS.m.RMUI‘AwrnRE0INEs,sP§sOvmm
`
`G 1-mmg
`
`[75]
`
`Inventors: Atul M. Melita, Ramsey, N..I.;
`Lizbelh A. Bldlllldi TIIOIIIIS W.
`Leonard, both of Plattsburgh, N.Y.;
`nomad N Warner Grand Isle, Vt.
`'
`’
`[73] Assignee: American Home Products
`cw-==**~=»Y°=*~
`I2” APP!’ NM m’m
`22
`Filed:
`30 1988
`I
`1
`Sap‘
`'
`
`[60]
`
`Division of Sea; No. 100.646, (S481;2:‘. 1-;:;'.o§;t
`4-,794,(I]l, Wbic isadivisiouo
`.
`0.
`,
`’,
`.
`.
`4, 1986, Pat. No. 4,723,512, which i3acont1'.nuation-in-
`part of Ser. No. 731,175, May 6, 1935, abandoned.
`%4
`
`
`
`OTHER PUB1-1CAT10N3
`F. W.’ P’!
`- IT b
`If
`’
`‘’''"“’°‘°'“'°“
`9‘ "0 -"9 pp
`E;’)2_°‘:91;§;’
`'
`Primary Exami'ner—"l"hiirman K. Page
`Ammey, Agent’ or F:,mI_John WI Routh
`[51]
`Aas:m_4cr
`A therapeutic preparation consisting of three groups of
`spheroids containing an active medicinal substance. The
`first group of spheroids is ui-icoated end rapidly disinte-
`grates upon ingestion to release an initial dose of medici-
`[[31 substance 3 second group of
`'"""""'"'“"""'"""
`a pH sensitive coat to provide 8 second dose and a third
`157532
`§,;'?fC°:k:L, "
`
`stout! 01' 8P1_1°1'°id3_i'-°- coated with 8 PH 1nd¢IJ4=ndf=nt
`157/32
`..
`3:o44:93s 7/1962 Halley
`coat to provide a third dose. A powder blend of active
`167/82
`3,014,352
`1/1963 Mayrou
`medicinal substance may be substituted for the first
`157/32
`3,119,742
`1/1954 H¢1'm1i==31=’H11-
`group of “coated spheroids‘ Tm therapeutic prepm.
`. .... 424/14
`3,175,521
`3/1955 He:-shberg .. ......
`tion may be utilized as 3 mixture of groups of spheroids
`‘ 167/32
`3'325'365
`5/1957 H9fl"° ct 3]‘ '
`tag in a capsule
`3,558,768
`1/1911 K.'|.lppel
`.
`'
`_
`3,335,221 9/1974 Fulberth et
`.
`.. . . . .
`5i.
`. .... 424/3'.’
`,
`9,431
`1/1975 N€\VT-D
`_
`
`424/20
`3,233,415
`2/1919 McAin:he:t 41
`5 Claims. 6 Drnwlns Sheets
`
`424/461; 424/462
`424/456' 458' 461’ 462
`[581 Field "f Search
`[56]
`References Cited
`U_5_ PATENT DOCUMENTS
`
`
`
`l3tSS(I.|J'ITII|N PRIJFIE OF CDIFOEFE
`C.lPSI..ILE PHCDUCED IN El\‘.AH"|..E 3
`
`
`
`TIIE I HOURS!
`
`Amerigen Ex. 1034, p. 1
`Amerigen Ex. 1034, p. 1
`
`_ 64__-“
`
`4,173,626 ll/19'.-'9 Dempski em.
`
`4,243,255
`
`2/1932 Guley
`
`4,248,857 2/1981 Deiicale
`4,243,353 2/1931 Guley
`4,294,319 10/1931 Tencza
`3309.404
`1/1982 Deneale
`4,309,405
`1/1932 Guley . ......
`4,309,405
`1/1932 Giiley
`4,339,423
`1/1932 Tencza
`222,223 33:: :i,---
`,
`,
`rq
`e
`.
`FOREIGN PATENT DOCUMENTS
`1204530 9/1970 United Kingdom .
`
`424/19
`
`:32:
`
`
`
`_
`424/21
`424/14
`424/21
`. . . .. 424/21
`424/21
`424/21
`
`

`
`U.S. Patent
`
`Feb. 27, 1990
`
`Sheet 1 of6
`
`4,904,476
`
`man
`gm
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`Amerigen Ex. 1034, p. 2
`Amerigen Ex. 1034, p. 2
`
`

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`
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`
`Amerigen Ex. 1034, p. 3
`
`X
`
`
`

`
`U.S. Patent
`
`Feb. 27, 1990
`
`Sheet 3 of 6
`
`4,904,476
`
`DISSOLUTIONPROFlLE.0FSECONDDOSEINEXAMPLE
`
`I,2,3a4
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`
`Amerigen Ex. 1034, p. 4
`Amerigen Ex. 1034, p. 4
`
`

`
`US. Patent
`
`Feb. 27, 1990
`
`‘-Sheet 4 of 6
`
`4,904,476
`
`[4
`
`24,
`
`2'2
`
`20
`
`IS
`
`I6
`
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`
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`
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`
`
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`
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`
`6
`
`5
`
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`
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`
`Amerigén Ex. 1034, p. 5
`Amerigen Ex. 1034, p. 5
`
`

`
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`
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`
`Amerigen Ex. 1034, p. 6
`
`a.
`
`

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`Amerigen Ex. 1034, p. 7
`
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`
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`
`
`

`
`1
`
`4,904,476
`
`5
`
`I0
`
`20
`
`45
`
`50
`
`FORMUIAITONS PROVIDING THREE DISTINCT
`RELEASES
`
`This is a division of application Ser. No. 100,646, filed
`Sept. 24, I987 U.S. Pat. No. 4,794,001 which in tu.rn is a
`divisional of Ser. No. 836,033 filed Mar. 4-, 1936 and
`now U. S. Pat. No. 4,728,512 which in turn is a con-
`tinuation-in-part of application Ser. No. 731,175, filed
`May 6, 1985 now abandoned.
`.
`BACKGROUND OF THE INVENTION
`
`This invention relates to pharmaceutical preparations
`for oral administration encapsulated in a capsule dosage
`form and more particularly relates to such therapeutic
`preparations comprising coated pellets or spheroids
`which release a dose of an active medicinal substance at
`different times in the digestive system of a patient.
`Timed disintegration capsules for
`the sequtial,
`timed release of medicinal substances into a patients
`system are known in the art. Generally such capsules or
`tablets consist of particles containing the medicinal
`substance to be introduced into the system, and a coat-
`ing over the particles of a material which is resistant to
`disintegration for a selected period of time. Such coat-
`ing compositions are also referred to as enteric coating
`compositions, that is, compositions which are generally
`resistant to disintegration in the stomach, but which
`disintegrate in the intestine. Enteric compositions also
`include compositions which disintegrate slowly in the
`stomach such that the medicinal substance is not re-
`leased until the capsule or tablet has reached the intes-
`tine of the patient. For example, coatings comprising
`bees wax and glyceryl monostearate; bees wax, shellac
`and cellulose; and cetyl alcohol, mastic and shellac have
`been proposed for use as slow release or timed release
`coatings for medicinal substances. Release of the medic-
`inal substance by disintegration of the coating is gener-
`ally controlled by varying the thickness of the coating
`or by altering its composition.
`U.S. Pat. No. 2,309,918 discloses inert drug coated
`nonpareils which are enteric coated with a shellac-
`stearic acid mixttlre. U.S. Pat. No. 3,119,742 discloses
`coated drug crystals used as particulates for sustained
`release formulations. U.S. Pat. No. 2,921,883 discloses
`“SparIsule," nonenteric coated spheroids designed for
`sustained release. U.S. Pat. No. 3,835,221 discloses oral
`delayed action “globu1es" coated with a mixture of
`polyvinylacetate and ethyl cellulose, useful as an “inert
`carrier core." F. W. Goodhart et al., Pharmaceutical
`Technology, page 64-71, Apr. 1984, discloses the evalu-
`ation of Budragit E 30 D as an aqueous film forming
`dispersion for controlled release of phenylpropanol-
`amine hydrochloride.
`The prior art compositions have generally proved
`deficient in the case where the medicinal substance is
`extensively metabolized presystemically or has a rela-
`tively short elimination half-l.i.fe
`resulting in sub-
`therapeutic plasma levels. Also, with many patits, the
`coatings are not disintegrated to the extent necessary to
`release the medicinal substance until the tablet or cap-
`sule has reached the colon and the medicinal substance
`is discharged from the system rather than absorbed by
`the intestine.
`The present invention provided three repeated re-
`leases of a medicinal substance for once daily adminis-
`tration of those medicinal substances which are exten-
`sively metabolized presystemically or have relatively
`
`2
`short elimination half-lives. This system results in supe-
`rior oral bioavailability as compared to a continuous
`release system for a medicinal substance over a 6 to 24
`hour period. The present invention also provides the
`convenience of not requiring the administration of di-
`vided doses during a 24 hour period and results in better
`patient compliance.
`The medicinal agents useful in the invention are those
`that exhibit a significant presystemic metabolism or
`have a relatively short elimination half life that nor-
`mally would be administered in divided dosess two or
`more times a day. Such medicinal agents include the
`cardiovascular drugs such as propanolol hydrochloride,
`isosorbide dinitrate,
`isosorhide-5-mononitrate, pelri-
`none (see U.S. Pat. No. 4,505,910), acifran (see U.S. Pat.
`No. 4,244,958) verapamil hydrochloride, quinidine sul-
`fate, the cerebral activators such as vinpocetine, Ay-
`30l09 (see U.S. Pat. application Ser. No. 811,551, filed
`Dec. 20, 1985 by Jirkovsky et a1., entitled 6, 7, 8, 9-Tet-
`rahydro-l0-methylpy1'ido[1,2-a]indole-9-Amines
`and
`Derivatives Thereof (AI-IP-8'.-'28); the analgesics such as
`those disclosed and claimed in U.S. Pat. application Ser.
`No. 726,197, filed Apr. 22, 1935, the antihistamines such
`as chlorpheniramine and bromophenirarnine; and the
`decongestants such as pseudoephedrine and phenylpro-
`pauolamine.
`In the case of medicinal agents having a significant
`pH dependent solubility profile, weak organic acids
`such as citric, tartaric, fumaric and glutamic acids may
`be added to the spheroid formulation to facilitate drug
`dissolution throughout the gastrointestinal tract.
`The present invention also lies in the general area of
`timed disintegration coatings and represents a. substan-
`tial improvement over the prior art compositions in that
`the time of disintegration is readily controllable and
`easily adjusted for release of a medicinal substance.
`The present invention relates to a therapeutic compo-
`sition comprising a pharmaceutical gelatin capsule con-
`taining (i) a powder blend of a medicinal substance and
`two groups of spheroids each containing the medicinal
`substance or (ii) three groups of spheroids each contain-
`ing a medicinal substance,
`the alternative group of
`spheroids comprising uncoated spheroids containing a -
`loading dose of the medicinal substance. In each em-
`bodiment, the second group of spheroids comprises pl-I
`sensitive coated spheroids containing a second dose of
`the medicinal substuce and the third group of spheroids
`comprises double coated spheroids containing a third
`dose of the medicinal substance.
`A further preferred aspect of the present invention
`relates to a therapeutic composition consisting of a
`pltartttaceutical gelatin capsule containing three groups
`of spheroids wherein, (a) the first group of spheroids
`comprises an active medicinal substance admixed with
`non-water swellable microcrystalline cellulose, (13) the
`second group of spheroids comprises the medicinal
`substance in admisture with non-water swellable micro-
`crystalline cellulose and is coated with a copolymer
`based on methacrylic acid and methacrylic acid methyl
`ester such as Eudragit S to the extent of 20% to 30% by
`weight of uncoated spheriods or polyvinyl acetate
`phthalate to the extent of 5% to 15% by weight of
`uncoated spheroids and preferably to the extent of 10%
`by weight and (c) the third group of spheroids com-
`prises the medicinal substance in admixture with non-
`water swellable microcrystalline cellulose and is coated
`with (i) an undercoat to the extent of 2.5% to 5.5% by
`weight of uncoated spheroids selected from the group
`
`Amerigen Ex. 1034, p. 8
`Amerigen Ex. 1034, p. 8
`
`

`
`4,904,476
`
`45
`
`59
`
`60
`
`3
`consisting of hydroxypropyl methylcellulose and hy-
`droxypropyl methylcellulose containing as a disinte-
`grant sodium carboxymethylcellulose, such as Ac-
`Disol, or sodium starch glycolate such as Explotab,
`werein the AcDiSo1 is present to the extent of 10% to 5
`60% by weight of the hydroxypropyl methylcellulose
`and the Explotab is present to the extent of 10% to 60%
`by weight of the hydroxypropyl methyl celulose and an .
`(i) overcoat comprising a neutral copolymer of poly-
`Inethacrylic acid esters such as Eudragit EBOD contain- 10
`ing metallic stearates wherein the Eudragit E3013 is
`present to the extent of 5% to 12% by weight of the
`unccated spheroids and the metallic stearate is present
`to the extent of 9% to 16% by weight of the Eudragit
`moo solids and preferably about 12.5% by weight of 15
`the Budragit E30D solids.
`A separate and distinct aspect of the present inven-
`tion relates to the double coated spheroids used as the
`third dose of the active medicinal substance.
`Suitable pharmaceutical excipits for the powder
`blend of the medicinal substance include lactose. micro-
`crystalline celulose. starch, calcium phosphate, calcium
`sulfate, stearic acid, magnesium stearate and disinte-
`grants.
`Eudragit S is a copolymer, anionic in character, based
`on methacrylic acid and methacrylic acid methyl ester.
`The ratio of free carboxylic groups to the esters is ap-
`proximately l:2. The mean molecular weight is 135,000.
`Eudragit S is available as a lacquer solution in isopropyl
`alcohol and as a solvt free solid. It is known as meth-
`acrylic acid copolymer, Type B. NF.
`Eudragit E3013 is a copolymer, neutral in character,
`based on polymethacrylic acid esters. The mean molec-
`ular weight is 800,000. Eudragit E 30 D is available as a 35
`30% (28.5%-31.5%) aqueous dispersion. Both Eudragit
`S and Eudragit E30D are available from Rohm Pharma,
`D-6108 Wciterstadt 1, Dr. -Otto —Rohm-Str. 2-4, West
`Germany.
`Metalic stearates include zinc stearate, calcium stea-
`rate and magnesium stearatc.
`Explotab is a trade name for sodium starch glycolate.
`. Sodium starch glycolate is" the sodium salt of a carboxy-
`methyl ether of starch. It is available from Edward
`Mendell Co.,
`Inc., Route 52, Carmel N.Y. 10512,
`U.S.A.
`AcDiSol is a trade name for carboxymethylcellulose
`sodium. It is the sodium salt of a polycarboxymethyl
`ether of cellulose, available from FMC Corporation,
`200 Market St., Philadelphia, Pa. 19103, U.S.A.
`Other disintegrants such as Amberlite can be used
`instead of Explotab and AcDiSol.
`Suitable grades of hydroxypropyl methylcellulose for
`use in the present invention are the Methocel brand,
`made by Dow Chemical Comany, Midland, Mich., 55
`U.S.A., grades 13, F and K having a viscosity range of
`about 3500 to about 5600 cps and preferably a viscosity
`of about 4000 cps.
`Also suitable grades of hydroxypropyl methylce1lu-
`lose are the Metolose brand, made by Shin-Etsu Chemi-
`cal Co., Ltd.. grades 60 SH, 65 SH and 90 SH having a
`viscosity range of about 3500 to about 5600 cps and
`preferably a viscosity of about 4000 cps.
`Methocel F is a grade of hydroxypropyl methylce1lu-
`lose containing about 2".-' to 30% methoxyl content and 65
`from about -1.0 to 7.5% hydroxypropoxyl content calcu-
`lated on the dried basis. Methocel K is a grade of hy-
`droxypropyl methylcellulose containing about 19 to
`
`4
`25% methoxyl content and from about 4 to 12% hy-
`droxypropoxyl content calculated on the dried basis.
`The preferred grade of hydroxypropyl methylceI1u-
`lose for use in the present invention is hydroxypropyl
`methylcellulose USP, 2910, 4000 cps (METHOCEL
`E4-AMP) which is a propylene glycol ether of methyl-
`cellulose containing not less than 28.0% and not more
`than 30.0% methoxyl content, and not less than 7.0%
`and not more than 12.0% hydroxypropoxyl content.
`A suitable non-water swellable microcrystalline cel-
`lulose is, for example, the material sold as Avicel-PH-
`101 (available from FMC Corporation. American Vis-
`cose Division, Avicel Sales, Marcus Hook, Pa.., U.S.A.).
`The polyvinyl acetate phthalate, available from Col-
`orcon, Inc., is the standard grade.
`The spheroid coatings may further contain other
`pharmaceutically acceptable excipients such as binders,
`fillers, anti-adherents and the like.
`A still further preferred aspect of the present inven-
`tion relates to a therapeutic composition comprising a
`pharmaceutical hard gelatin capsule containing three
`groups of spheroids containing an active medicinal sub-
`stance, wherein (a) the first group of spheroids compris-
`ing uncoated spheroids contains the medicinal sub-
`stance for maximum release thereof within a period of
`two hours after ingestion, (b) the second group of spher-
`oids comprising coated spheroids contains the medici-
`nal substance in a spheroid core coated with a pH sensi-
`tive coat comprising a copolymer based on methacrylic
`acid and methacrylic acid methyl ester or polyvinyl
`acetate phthalate, the coat having an effective thickness
`to provide a maximum release of medicinal substance in
`a period of 2 to 6 hours after ingestion, and (c) the third
`group of spheroids comprising coated spheroids con-
`tains medicinal substance in a spheroid core coated with
`an undercoat of hydroxypropyl methylcellulose and an
`overcoat of a neutral copolymer based on polymeth-
`acrylic acid esters containing metallic stearates,
`the
`coats having an effective thickness to provide a maxi-
`mum release of medicinal substance 4 to 10 hours after
`ingestion.
`The following examples are by way of illustration of
`the preferred embodiments of the therapeutic prepara-
`tion of the present invention and its manner of prepara-
`tion.
`the uncoated
`In the first four of these examples,
`spheroids were made in accordance with the teachings
`of U.S. Pat. No. 4,133,475 in the following manner:
`Propanolol hydrochloride (60 kg.) and microcrystal-
`line cellulose (Avicel-PH-101; 40 kg.) were blended
`together in a 450 liter planetary mixer. Water (50 kg.)
`was added, and the mixer was run for 10 minutes until a
`homogeneous, plastic mass was obtained. The mass was
`extruded under pressure through a perforated cylinder
`to give cylindrical extruclates of nominally 1 mm. diam-
`eter.
`
`The damp extrudates (in batches of 15 to 20 kg.) were
`placed in a spheronizer in which the rotating disc (diam-
`eter 63 cm.) rotated at 300 to 43) r.p.n1. The rotation
`was continued for 10 minutes, and the resulting spher-
`oids were then dried at 60° C. in a fluidized bed drier.
`The dried spheroids were passed over a 1.4 mm. screen,
`and those which passed through were subjected to a 0.7
`mm. screen. The over-and under-sized spheroids were
`discarded.
`
`Amerigen Ex. 1034, p. 9
`Amerigen Ex. 1034, p. 9
`
`

`
`5
`
`EXAMLPLE 1
`
`4,904,476
`
`6
`
`EXAMPLE 2
`
`The finished dosage form consists of a hard gelatin
`capsule containing 3 types of spheroids. The formula-
`[ion pa;-ficulars are based on 160 mg propranolol HCI
`per capsule, although they can be designed to provide
`other dosage strengths.
`The three types of spheroids are categorized as:
`(1) Uncoated spheroids to provide a loading dose (e.g.
`30 mg propranolol HCI)
`eroids to rovide a second
`2 H sensitive coated s
`P
`P
`dose (PH 5_5) e_g. 50 mg pl-op,-amlo] [-10]
`(3) Coated spheroids to provide a third dose (4-10 hours
`post ingestion) e_g_ 79 mg Pmpranow HC1
`
`
`
`The finished dosage form consists of a hard gelatin
`capsule containing a. powder blend of propanolol hy-
`drochloride and WJO types Of spheroids. The f{‘.Il'l:I:I.l.l.la-
`tion particulars are based on 160 mg propanolol hydro-
`chloride per capsule. although they can be designed to
`provide other dosage strengths.
`The propranolol hydrochloride powder blend (or
`first group of spheroids) provides the loading dose, (e.g. 19
`25 E18 13093110101 HC1}
`,
`_
`I The second and third types of spheroids are catego-
`Mad 95‘
`_
`_
`_
`_
`(1) pH sensitive coated spheroids to provide a second
`dose (pH 6.5) e.g. 65 mg propranolol I-IC1.
`(2) Coated spheroids to provide a third dose (4-10 hours
`post ingestion) e.g. 70 mg propranolol HCI.
`
`5
`
`15
`
`
`
`.
`Quanutv
`
`Quantity
`d in described reviousl
`1. Uiicoeted S heroids
`2. Alternate pl-I Sensitive Coated Spiieroids
`2,0 M .yvinyl Acetate Phthalate (PVAP) system:
`ga} Formula - p on 3 kg uncoeted gplheroido)
`Ingredients
`Uncoated Spherotds (60%
`w./w propranolol HCJ)
`Polyvinyl Acetate Phthaiate (PVAP), NF
`Triethyl Citrate, NF
`Stearic Acid. NF
`Methanol, Anhydrous, NF
`.“_’)L"-33*’;
`Unooeted spheroids were placed in a fluidized bed coater
`The FVAP solution was applied using a peristaltic pump
`The spheroids were dried
`I
`_
`
`3. Coated Spheroids (prepared as described above 111 Example 1)
`
`3.00 kg
`
`0.30 kg
`0.03 kg
`0.05 kg
`2.6l kg
`
`EXAMPLE 3
`
`
`
`3.0 kg
`
`0.075 kg
`
`4-937 *8
`2.963 kg
`
`0.600 kg
`0.0215 kg
`0.00: kg
`0.300 kg
`
`35
`
`45
`
`55
`
`50
`
`Amerigen Ex. 1034, p. 10
`Amerigen Ex. 1034, p. 10
`
`25
`
`30
`
`30 mg/capstile
`54 mg/capsule
`15 ms/capsule
`1 ms/capsule
`
`‘ed mm d!
`
`
`3.00 kg
`0.75 kg
`
`c112 ks
`1.99 kg
`kk:
`
`.
`
`3.00 kg
`
`0.0?! kg
`
`4-93? its
`3353 ks
`
`1.00 kg
`0.030 kg
`°~°°?-5 3.!
`9-500 K!
`
`*-
`
`2.
`(0
`
`3.
`
`‘
`
`£°_W_;1s.=_B.1fl
`
`l..l...._.j°F°1:“‘“-'3
`L“.E!.';‘1i‘
`Propranolol HCI. USP
`Lactose, USP
`Microcrystullinc cellulose. NF
`Masnesium stcmte NF
`_
`EH Sensitive Coated Snhcroads
`Eudgasitufj 5)’-'fi¢m=
`3 k
`
` 391111 3 011 “W03 . .fl_.:)_i
`Ingredients
`Uncosted Spiteroids (60%
`wgw pmpnnugul Hal)
`Metlieeiylic Acid Copolyiner.
`r
`:r,.:.r ‘:3’
`Tnnoenn. USP
`Methylene Chloiide, NF
`fitwmwh
`I‘:Popropyl Alcohol. USP
`Q"-in
`eter
`1. Unooeted Spheroids gp.-eppged as described above}
`do
`-
`-
`-
`1
`-
`Uncoated spheroids were placed in a fluidized bed coater
`pH S¢l'll:1E:1u|'¢ Coated Spheroids (prepared as described above in
`40 1.
`The Eudmait 8 solution was appfiad using 3 Puimmc
`.
`""'
`'
`P‘-WP
`_
`3- Qfieléeo
`The spheroids were dried
`gag Formula [paced on 3 kg uncoated spheroids!
`Coated spheroids
`Urldercoll
`EH18
`gs] Formula §I_:ased on 3 kg uncoated gpheroidsl
`Uncoatod Spheroids (60%
`Underooat. Ingedients
`W/w iuopranoloi HC!)
`Unccned Spheroids (60%
`I-Iydmitypropyl nieihylcelluloce. USP.
`wprw pmp,-“D101 Hm)
`1910. 4000 CPS
`F/I'M?)
`Hydroxypropyl methylceiiulose,
`Mfiihlllfilfl Cli-l0l'ld=. NF
`USP. ZQIO. -l-DIX) cps. (e.g..
`Methanol,
`NF
`mmocd 5410112)
`50
`Methylene Chloride. NF
`Budregit E 30 D (aqueous dispersion)
`Methanol. Anhildrfil-I3. NF
`Calcium Steernte. NF
`Overcoat Ing£d1'ents
`Simethieone Emulsion use
`Eudragit E 30 D (Aqueous
`Water. USP.
`3539;,-31¢“)
`Process for a
`i
`unclerooat
`Calcium Stearatc. NF
`The uncoeted spheroids were placed in a fluidized bed coater
`Si-limb-i'=°l|= E91'«'-'5l°‘1- USP
`Methocel EAMP solution we applied using it peristaltic pump
`w3*¢1'- U53
`1-he sphfluids we dd“;
`undereoet
`l
`Process for at
`go; Process for spam‘g overcoat
`The unooeted spheroids were placed in I. fluidized lied coater
`Eudmgit E 30 D suspension containing calcium stearate was
`Muhocel 54311‘ solution was sprayed usius a Perimllic P1-W113
`.
`.
`sprayed on the Methocel Ed-MP coated spheroids using a
`The whmif “=1? <?1""=d
`Pmsmm Rump
`_
`y
`-
`{:1 Process‘ or app Egg overcoat _
`'11.; gpimggdg wag dried
`Eudrngit E. 30 D suspension containing calciuni steai-etc was
`The three types of spheroids are categorized as:
`SPn_I¥I=d_on the Methooei EAMP coated spheroids using a
`(1) Unconu.-d spheroids to provide a loading dose (e.g. 30 mg
`perutaluc sump
`_
`propranolol HCI)
`TJESIEICONWS WEN d-1134
`('2) pH sensitive coated spheroids to provide it second dose {pH 6.5)
`- uglufl
`65 e.g. 60 mg propranolol HC1
`Capsules were titled with the powder blend. pH-sensitive
`(3) Coated spheroids to provide a third dose (4-in hours post ingestion)
`coated spheroids and coated spheroids on an encapsulating
`machine capable of dual filling powders and spheroids.
`e.g. 70 rag propranolol HCl
`
`

`
`4,904,476
`
`EXAMPLE 4-
`
`3.00 kg
`
`0.075 kg
`
`-1.98‘.-' kg
`2.963 kg
`
`
` Quantityfflatch
`1. Uncooked
`heroids
`r
`ared as described above
`pH Sensitive Coated Sphecroids (prepared as described above in
`Example 1)
`3. Coated Spheroida
`gs) Formula
`Undercoat Ingridients
`Uncosted Splteroids (60%
`w/w Proprsnolol I-1C1)
`Hytlroxypropyl methyloellulosc.
`USP, 2910. 4000 cps (EAMP)
`Methylene Chloride. NF
`Methanol, Anhydrous. NF
`Overcoat Ittgggits
`Eudragit E 30 D (Aqueous Dispersion)
`Calcium Shear-ate, NF
`Simethicone Emulsion. USP
`Water, USP. liurified
`lg) Process for ggplflg undercoat
`The unconted spheroids were placed in a fluidized bed coater
`Methocel E-1-MP solution was applied using a peristaltic pump
`The spheroids were dried
`gel Process for applygg overcoat
`Eudragit E 30 D suspension containing calcium stearste was
`sprayed on the Methocel EA-MP coated spheroids using a
`peristaltic pump
`The spheroids were dried
`The three types of spheroids are categorized as:
`(1) Uncoated spheroids to provide a loading dose (eg. 30 mg
`propranolol HCl)
`(2) pH sensitive coated spheroids to provide a second dose (pH. 6.5)
`e.g. 60 mg propranolol HC1
`(3) Coated spheroids to provide a third dose (4-10 hours post ingestion)
`e.g. 70 mg propranolol HCI
`
`0.550 kg
`0.021 kg
`0.002 kg
`0.275 kg
`
`Examples of in vitro release profiles are given in FIG.
`1-4. FIG. 1 represents the dissolution profile of the 50
`composite capsule formulation comprised of three sepa-
`rate doses. produced in Example 3. The dissolution
`profile was obtained using the Unites States Pharmaco-
`peia Apparatus I at 37' C. and 100 RPM. The disssolu-
`tion media was varied with time beginning with 0.lN 55
`HCl for 0 to 2 hours. From 2 to 4 hours the media was
`pH 6.5 phosphate buffer and from 4 to 24 hours the
`media was pH 7.5 phosphate buffer.
`FIG. 2 representsthe dissolution profiles of the firs:
`dose uncoated spheroids produced in Examples 2, 3 and 60
`4 vs the powder blend of the first dose in Example 1.
`The dissolution profiles were obtained using the United
`States Pharnracopeia Apparatus I at 37° C. and 100
`RPM. The dissolution media was 0.114 HC1.
`FIG. 3 represents the dissolution profile of the second -65
`dose Eudragit S coated spheroid produced in Example
`1, 2, 3 and 4. The dissolution profile was obtained using
`the United States Pharmaceopeia Apparatus I at 37° C.
`
`10
`
`25
`
`30
`
`35
`
`4-0
`
`45
`
`8
`and 100 RPM. The dissolution media was varied with
`time beginning with 0.lN I-{Cl from 0 to 2 hours. From
`2 to 4 hours the media was pH 6.5 phosphate buffer and
`from 4 to 24 hours the media was pH 7.5 phosphate
`buffer.
`FIG. 4 represents the dissolution profile of the third
`dose produced in Example 3. The dissolution profile
`was obtained using a modification of the United States
`Pharrnacopeia Apparatus I. at 37" C.. 100 RPM, and
`water as the dissolution media.
`FIGS. 5 and 6 represent the in vivo profiles of pro-
`pranolol hydrochloride in two different human subjects
`dosed once a day with the composite capsule containing
`a total of 160 mg propranolol hydrochloride (H6. 1) vs
`a total of 160 mg propranolol hydrochloride adminis-
`tered in four divided doses of 40 mg each. The individ-
`ual components of the composite capsule are discernible
`as separate peaks in the plasma level profiles.
`EXAMPLE 5
`
`Vinpocetine hydrochloride (10.0 kg.) and rnicrocrys-
`talline cellulose (Avicel-PH-101); (80.0 kg.), citric acid
`monohydrate (10.0 kg) were blended together in a 4-50
`liter planetary mixer. Water (100 kg.) was added, and
`the mixer was run for 10 minutes until a homogeneous,
`plastic mass was obtained. The mass was extruded
`under pressure through a perforated cylinder to give
`cylindrical extrudates of nominally 1 mm. diameter.
`The damp extrudates (in batches of 15 to 20 kg.) were
`placed in a spheronizer in which the rotating disc (diam-
`eter 68 cm.) rotated at 300 to 400 r.p.m. The rotation
`was continued for 20 minutes. and the resulting spher-
`oids were then dried at 80° C. in a fluidized bed drier.
`The dried spheroids were passed over a 1.2 mm. screen,
`and those which passed through were subjected to a 0.5
`mm. screen. The over—and under-sized spheroids were
`discarded.
`The finished dosage form consists of a hard gelatin
`capsule containing a powder blend of vinpocetine and
`two types of spheroids. The formulation particulars are
`based on 30 mg per capsule, although they can be de-
`signed to provide other dosage strengths.
`The vinpocetine powder blend (or first group of
`spheroids) provides the loading dose, (e.g. 5 mg vin-
`pooetine).
`The second and third types of spheroids are catego-
`rized as:
`(1) p}! sensitive coated spheroids to provide a second
`dose (pH 6.5) e.g. 12 mg vinpocetine.
`(2) Coated spheroids to provide a third dose (4-10 hours
`post ingestion) e.g. 13 mg vinpocetine.
`
` Quantity
`1.
`Powder Blend
`
`gs; Formula
` .
`Vinpocetine
`Sodium Lauryl Sulfate, NF
`Sodium Starch Glycollte, NF
`Glutlmic Ac-id, NF
`Starch. NF
`Lactose. USP
`Microcrystalline cellulose, NF
`Magnesium stearale. NF
`19) Procedure
`1. Blend the Vinpooetine, Lactose, Microorystslline Cellulose.
`Starch, Glutsntic Acid. Sodium Starch Glyeolatc. Talc
`Triturate and the Sodium Lauryl Sulfate into the PK blender
`
`5 mg/capsule
`0.1 mg/capsule
`3 mg/capsule
`6 mgfcapsulc
`7 mg/capsule
`62 mg/capsule
`13 mg/capsule
`1
`rngfcapauie
`
`Amerigen Ex. 1034, p. 11
`Amerigen Ex. 1034, p. 11
`
`The finished dosage form consists of a hard gelatin
`capsule containing three types of spheroids containing
`propranolol hydrochloride. The formulation particulars
`are based on 160 mg propranolol hydrochloride per
`capsule, although they can be designed to provide other
`dosage strengths as follows:
`
`First group
`of spheroids
`(or powder)
`% of dose
`10% to 30%
`12% to 20%
`
`Second group
`of spheroids
`as of dose
`20% to 15%
`35% to 45%
`
`Third group
`of spheroids
`% of dose
`10% to 60%
`35% to 45%
`
`
`
`Proprsnolol
`Hydrochloride
`mg per capsule
`40 to 240
`160
`
`

`
`4,904,476
`
`10
`-continued
`with Avicel RC 581)
`2. Alternate EH Sensitive Coated Sgheroids
`Polyvinyl Acetate Phthalate (PVAP) system:
`ta} Formula - ghased on 3 kg uricoated spheroids)
`In
`'
`ts
`Uuccated Spheroids (10%
`w/w vinpocetine HCI)
`Polyvinyl Acetate Phthslate (PVAP). NF
`Triethyl Citrate, NP
`Stearic Acid. NF
`Methanol Anhydrous. NF
`Process
`Uneoated spheroids were placed in a fluidized bed coater
`The PVAP solution was applied using a peristaltic pump
`The spheroids were dried
`as described above in Exam le 5
`Coated S heroida
`Other dosage strengths of vinpocetine can he formulated
`as follows:
`
`3.00 kg
`
`0.30 kg
`0.03 kg
`0.06 kg
`2.61 kg
`
`Viripocetirte
`nagpercapsule
`15 to 60
`
`First group
`of spheroids
`(or powder)
`%ofdose
`10% to 50%
`
`
`
`Second group
`of spheroids
`‘liaofdose
`20% to 15%
`
`Third group
`of spheroids
`“flxofdosc
`10% to 60%
`
`EXAIMPLE T
`
`Isosorbide dinitrate as a 50% triturate with lactose
`(60 kg) and microcryatalline cellulose (Avicel PI-I-101)
`(40 kg) are blded together in a 450 liter planetary
`mixer. Water (50 kg.) is added, and the mixer is run for
`10. minutes until a homogeneous, plastic mass is ob-
`tained. The mass is extruded under pressure through a
`perforated cylinder to give cylindrical extrudates of
`nominally 1 mm. diameter.
`The damp extrudates (in batches of 15 to 20 kg.) are
`placed in a spheronizer in which the rotating disc (diam-
`eter 68 cm.) rotates at 300 to 400 r.p.m. The rotation is
`continued for 10 minutes, and the resulting spheroids
`are then dried at 60' C. in a fluidized bed drier. The
`dried spheroids are passed over a 1.4 mm. screen. and
`those which pass through are subjected to a 0.7 mm.
`screen. The over-and under-sized spheroids are dis-
`carded.
`The finished dosage form consists of a hard gelatin
`capsule containing a powder blend of isosorhide dini-
`trate and two types of spheroids. The formulation par-
`ticulars are based on 40 mg per capsule, although they
`can be designed to provide other dosage strengths.
`The isosorbide dinitrate powder blend (or first group
`of spheroids) provides the loading dose. (e.g. 14 mg
`isosorbide dinitrate (100%).
`The second and third types of spheroids are catego-
`rized as:
`
`(1) pH sensitive coated spheroids to provide a second
`dose (pH 6.5) e.g. 13 mg isosorbide dinitrate (100%).
`(2) Coated spheroids to provide 9. third dose (4-10 hours
`post ingestion) e.g. 13 mg isosorbide dinitrate (100%).
`
`1.
`
`Powder Blend
`
`ta) Formula
`In
`lent
`Isosorbide dinitrate (100%) USP
`Lactose, USP
`Mictoerystnlline cellulose. NF
`Magnesium mate, NF
`EH Semitive Coated Spheroids
`
`2.
`
`Quantity
`
`5 mg/capsule
`54 mg/capsule
`15 mycapaule
`1 rnglcspsuie
`
`Amerigen Ex. 1034, p. 12
`Amerigen Ex. 1034, p. 12
`
`25
`
`30
`
`40
`
`45
`
`S0
`
`EXAMPLE 6
`
`The finished dosage form consists of a hard gelatin
`capsule containing 3 types of spheroids. The formula-
`tion particulars are based on 30 mg vinpocetine per
`capsule, although they can be designed to provide other 55
`dosage strengths.
`The three types of spheroids are categorized as:
`(1) Uncoated spheroids to provide a loading dose (e.g. 5
`mg vinpocetine)
`(2) pH sensitive coated spheroids to provide a second
`dose (pH 5.5) e.g. 12 mg vinpooetine
`(3) Coated spheroids to provide a third dose (4-10 hours
`post ingestion) e.g. 13 mg vinpocetine
`
`Quantity
`1. Uncoated Spheroids
`prepared as described above in Example 5 except that
`5% of the microcrystalline cellulose was replaced
`
`65
`
`9
`continued
` Quantity
`for 20 minutes with intensifier bar rurtning.
`2. Fast: the Step #1 blend through a Fitz Mill using a #113
`screen. medium speed. Jtnivu forward.
`3. Return the granulation from Step #2 to the PK blender
`and add the Magnesium Stearate and blend for 2 minutes
`without the intensifier bar on.
`pH Sensitive Coated spheroids
`Eudragit S System:
`ta) Formtda {Q on 3 kg unooated gheroiclsg
`Inggedieots
`Uncooked Spheroids (10%
`wfw Vinpocetine)
`Methacrylic Acid Copolymer.
`Type B. NF
`Eudragit. S
`Triacctin