4,794,001
`[11] Patent Number:
`[19]
`Ulllted States Patent
`Mehta et al.
`[45] Date of Patent:
`Dec. 27, 1988
`
`
`4,133,475 2/1979 Mcmnsii at al.
`424/21
`:-;::*:::‘;:::2;:
`.
`.
`tie}; in
`.
`424/19
`4,243,357
`2/1931 DeNeale at al.
`424/21
`4,248,858 2/ 1981 Gnley at a].
`424/21
`4,294,819 10/ 1981 Tencza, H ........
`424/14
`«£309,404
`1/ 1982 DeNea1e at al.
`.
`.. 424/2!
`4,309,405
`1/1932 Guley e: al.
`. . . . .
`. . . .. 424/21
`4,309,405
`1/1932 Guley et al.
`.
`. 424x21
`4,339,428 T/1932 Tencza, I
`424/21
`4,524,060
`6./1935 Mughal at al.
`........................ 424/22
`u;:§EI::fAEEi';:’°CUME“T5
`o
`nitc
`‘ gdom
`2039737
`8/1980 United Kingdom
`OTHER PUBLICATIONS
`.
`
`424/3'?
`354/193
`
`c;:’I;’r‘“f“§”§4°‘ 31" Ph“"“*‘°°"“°°~1 Technology, pp-
`'
`.
`‘
`.
`'
`Pnmmj: Examiner-—-fihep K. Rose
`"“°”“’J" A8‘-”“' 0’ ”*"”—’°h“ “’- ROW‘
`[57]
`ABSTRAC1‘
`A therapeutic Preparation consisting of mree groups of
`.
`.
`.
`.
`.
`.
`spheroids containing an active medicinal substance. The
`firs: group of spheroids is uncoated and rapidly disinte-
`gfiitesbigpon ingestinndto re1ea.se;fanIi1nitial dose ofmedici-
`11
`31:
`tame a seccn group 0 sp eroids is coated with
`a pH sensitive coftt
`provide a second dose and a third
`group of Spl-'1eI'OldS'lS coated with a pH independent
`coat to prowde a third dose. A powder blend of active
`medicinal substance may be substituted for the first
`group of unccated spheroids.
`.
`.
`.
`Th
`.
`.
`e therapeutic preparaitoii may be utilized as 21 mm-
`“"3 0*" 3’°“P5 °f 5Ph°T°1d5 1“ 3 Capsule-
`
`8 Claims, 6 Drawing Sheets
`
`Amerigen Ex. 1033, p. 1
`Amerigen Ex. 1033, p. 1
`
`.........
`
`.
`
`
`
`[541 FORMULATIONS PROVIDING THREE
`DISTINCTRELEASES
`Inventors: Atul M. Mehta. Ramsey. NJ.:
`Lizbeth A. Bachimd; Thomas W.
`Leonard, both of Plattsburgh, N.Y_;
`Rama N_ wane,’ Grand Isle, Vt,
`_
`_
`[73] Asslgnem American Home Products
`Corporation, New York, N.Y.
`[21] AppL No‘: 100,646
`:22] Filed:
`Sep. 24, 1937
`Related US. Application Data
`Division of Ser. No. 336,033, Mar. 4. 1986. Pat. No.
`4,728,512.
`hi h ‘
`'
`'
`-'
`-
`fS .N'.
`
`[75]
`
`[60]
`
`s1
`
`0
`er
`1§ss;,ca$3::::? m pm 0
`131,175. Mgy
`4;
`9
`Int. Ci.-s ......................... A61K 9 52; A61
`/
`A611; 9,358
`I
`[
`[52] U.S. Cl. .................................... 424/453; 424/453;
`424/457; 424/459; 424/461; 424/462
`[58] Field of Search ............... 424/458, 453, 457, 459,
`424 461,
`/
`462
`
`[55]
`
`R°fB|'l'-“C35 Cited
`U5_ 1:ATENT DOCUMENTS
`_
`
`
`
`9,1950 Swinmky
`3,951,792
`7/1952 3,113,.
`3.044333
`1/1963 Mayron . .. . . . . . , , ,
`3,074,852
`1/1964 Heimlich et al.
`3,119,742
`3,I'!5,52l 3/1965 Hershberg .......
`£325,365
`5/196.‘, Hmko ____H
`3,558,768
`1/1911 Klippel . .......
`3.B35.22l 9/ l9T4 Full:-erth et al.
`3.859.431
`I/1975 Newton at al.
`
`.
`
`U 157,32
`__ 15-,-/32
`. . . . .. 167/32
`424/19
`424/14
`167/32
`. . . . .. 424/21
`.... .. 424/19
`424/3‘!
`
`

`
`U.S. Patent
`
`Dec. 27, 1988
`
`Sheet 1 of 6
`
`4,794,001
`
`24
`
`I8
`
`I6
`
`IoI2:4
`
`
`
`‘run:{nouns}
`
`FlG.l
`
`I00
`
`90
`
`999556
`G0 7 6
`'51-
`F'Ifl-I
`
`0
`
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`
`3SV3'l3H “lo
`
`Amerigen Ex. 1033, p. 2
`Amerigen Ex. 1033, p. 2
`
`

`
`U.S. Patent
`
`Dec. 27, 1933
`
`Sheet 2 of 6
`
`4,794,001
`
`FIG.2
`
`30
`
`26
`
`24
`
`20
`
`W
`
`M
`
`loM‘!
`
`
`
`nut:(MINUTES)
`
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`90
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`30
`
`20
`
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`
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`
`G3SV313H %
`
`Amerigen Ex. 1033, p. 3
`Amerigen Ex. 1033, p. 3
`
`

`
`US. Patent
`
`Dec. 27, 1933
`
`Sheet 3 of6
`
`4,794,001
`
`13'
`(‘U
`
`(‘U
`TU
`
`D‘
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`
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`
`Amerigen Ex. 1033, p. 4
`Amerigen Ex. 1033, p. 4
`
`

`
`U.S. Patent
`
`Dec.27,1988
`
`Sheet 4 of6
`
`% 4,794,001
`
`FIG.4
`
`IE
`
`IS
`
`I4
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`I0I2
`
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`nu:(nouns)
`
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`
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`
`Amerigen Ex. 1033, p. 5
`Amerigen Ex. 1033, p. 5
`
`

`
`US. Patent
`
`Dec. 27, 1933
`
`Sheet 5 of 6
`
`4,794,001
`
`FlG.5
`
`20
`
`M
`
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`
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`GI
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`«.9
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`(1lWHl'3N03 1010HVHd0Hd
`
`Amerigen Ex. 1033, p. 6
`Amerigen Ex. 1033, p. 6
`
`

`
`U.S. Patent
`
`Dec. 27, 1933
`
`Sheet 6 of 6
`
`4,794,001
`
`28
`
`24
`
`I6
`
`I2
`
`
`
`TIHEIHOURSI
`
`FIG.6
`
`¢n:nr--uaunq-m~-
`
`("IN/BN1 ‘IJNOIJ
`
`'I0'|0HVBd0l:Id
`
`Amerigen Ex. 1033, p. 7
`Amerigen Ex. 1033, p. 7
`
`

`
`1
`
`4,794,001
`
`FOR.M'ULATIONS PROVIDING THREE DIS'I'INCI'
`RELEASES
`
`This is a division of application Ser. No. 336,033, filed
`Mar. 4, 1986, now U.S. Pat. No. 4,723,512, which is a
`continuation-in-part of application Ser. No. 731,175,
`filed May 6, 1985, now abandoned.
`
`5
`
`BACKGROUND OF THE INVENTION
`
`10
`
`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 sequential,
`timed release of medicinal substances into a patient's
`system are lrnown 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. 2.809.913 discloses inert drug coated
`nonpareils which are enteric coated with a shellac-
`stearic acid mixture. 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
`“Spausule," nonenteric coated spheroids designed for
`sustained release. U.S. Pat. No. 3,835,221 discloses oral
`delayed action “globules” coated with a mixture of
`polyvinylacetate and ethyl cellulose, useful as an “inert
`carrier core.” F. W, Goodhart et al., Pharmaceutical
`Technology, page 64-11, April 1984, discloses the eval-
`uation of Eudragit 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 hali‘-life
`resulting in sub-
`therapeutic plasma levels. Also, with many patients, 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.
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`The present invention provides 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
`short elimination half-lives. This system results in supe-
`rior oral bipavailability as compared to a continuous
`
`65
`
`2
`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 presysternic metabolism or
`have a relatively short elimination half life that nor-
`mally would be administered in divided doses two or
`more times a day. Such medicinal agents include the
`cardiovascular drugs such as propranolol hydrochlo-
`ride, isosorbide dinitrate, isosorbide-5-mononitrate, pel-
`rinone (see U.S. Pat. No. 4,505,910). acifran (see U.S.
`Pat. No. 4,244,958) verapamil hydrochloride, quinidine
`sulfate,
`the cerebral activators such as vinpocetine,
`Ay-30109 (see U.S. patent application Ser. No. 811,551,
`filed Dec. 20, 1985 by Jirkovsky et al., entitled 6,?,8,9-
`Tetrahydro-10-mel.hylpyrido[1,2-a]indole-9-Amines
`and Derivatives Thereof (AI-IP-8723);
`the analgesics
`such as those disclosed and claimed in U.S. patent appli-
`cation Ser. No. 726,197, filed Apr. 22, 1935, the antihis-
`tarriines such as chiorpheniramine and bromophenira-
`mine; and the decongestants such as pseudoephedrine
`and phenylpropanolamine.
`In the case of medicinal agents having a significant
`pH dependent solubility profile, weak organic acids
`such as citric, tartaric, Eumaric 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 pH
`sensitive coated spheroids containing a second dose of
`the medicinal substance and the third group of spher-
`oids 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
`pharmaceutical 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. (b) the
`second group of spheroids comprises the medicinal
`substance in admixture 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 spheroids 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
`consisting of hydroxypropyl methylcellulose and hy-
`droxypropyl methylcellulose containing as a disinte-
`\
`
`Amerigen Ex. 1033, p. 8
`Amerigen Ex. 1033, p. 8
`
`

`
`3
`grant sodium carboxymethylcellulose, such as Ac-
`DiSol, or sodium starch glycolate such as Explotab,
`wherein the AcDiSol is present to the extent of 10% to
`60% by weight of the hydroxypropyl methylcellulose
`and the Explotab is present to the extent of 10% to 60%
`by weight of the hydroxypropyi methyl cellulose and
`an (i) overcoat comprising a neutral copolymer of poly-
`methacrylic acid esters such as Eudragit E30D contain-
`ing metallic stearates wherein the Eudragit E30D is
`present to the extent of 5% to 12% by weight of the
`uncoated spheroids and the metallic stearate is present
`to the extent of 9% to 16% by weight of the Eudragit
`E30D solids and preferably about 12.5% by weight of
`the Eudragit E30D solids.
`A separate and distinct aspect of the present inven-
`tion reiates to the double coated spheroids used as the
`third dose of the active medicinal substance.
`
`Suitable pharmaceutical excipients for the powder
`blend of the medicinal substance include lactose, micro-
`crystalline cellulose, 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.
`Eudgragit S is available as a lacquer solution in isopro-
`pyl alcohol and as a solvent free solid. It is known as
`methacrylic acid copolymer. Type B, N.F.
`Eudragit E30D 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
`30% (28.5%-31.5%) aqueous dispersion. Both Eudragit
`S and Eudragit E'.30D are available from Rohm Pharma,
`D-6103 Weiterstadt 1, Dr.-Otto-Rohm-Str. 2-4, West
`Germany.
`Metalic stearates include zince stearate, calcium stea-
`rate and magnesium stearate.
`Explotab is a trade name for sodium starch glycolate.
`Sodium starch glycolate is the sodium salt of a carbony-
`methyl ether of starch. It is available from Edward
`Mendell Co.,
`Inc., Route 52, Carmel, NY. 10512,
`U.S.A.
`AcDiSol is a trade name for carboxyrnethylcellulose
`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 methylceliulose for
`use in the present invention are the Methocel brand,
`made by Dow Chemical Comany, Midland, Mich.,
`U.S.A., grades E. 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 rnethylcellu-
`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 viscocity of about 4-000 cps.
`Methocel F is a grade of hydroxypropyl methylcellu-
`lose containing about 2'.-' to 30% methoxyl content and
`from about 4.0 to 7. 5% hydroxypropoxyl content calcu-
`lated on the dried basis. Methocel K is a grade of hy-
`droxypropyl methylcellulose containing about 19 to
`25% methoxyl content and from about 4 to 12% hy-
`droxypropoxyl content calculated on the dried basis.
`
`10
`
`{S
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`4,794,001
`
`4
`The preferred grade of hydroxypropyl methylcellu-
`lose for use in the present invention is hydroxypropyl
`methylcellulose USP, 2910, 4000 cps (METHOCEL
`E4MP) which is a propylene glycol ether of methylce1-
`lulose containg 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 rnicrocrystalline cel-
`lulose is, for example, the material sold as Avicel-PI-L
`101 (available from FMC Corporation, American Vis-
`cose DivisioI1,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 and effective thick-
`ness to provide a maximum release of medicinal sub-
`stance in a period of 2 to 6 hours after ingestion, and (c)
`the third group of spheroids comprising coated spher-
`oids contains medicinal substance in a spheroid core
`coated with an undercoat of hydroxypropyl methylcel-
`lulose and an overcoat of a neutral copolymer based on
`polymethacryiic acid esters containing metallic stea-
`rates. the coats having an effective thickness to provide
`a maximum 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-
`non.
`
`the uncoated
`In the first four of these examples,
`spheroids were made in accordance with the teachings
`of U.S. Pat. No. 4,138,475 in the following manner:
`Propranolol hydrochloride (60 kg.) and microcrystal-
`line cellulose (Avicel-PI-I-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 extrudates 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 68 cm.) rotated at 300 to 400 r.p.rn. 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.
`
`EXAMPLE 1
`
`The finished dosage form consists of a hard gelatin
`capsule containing a power blend of propranolol hydro-
`chloride and two types of spheroids. The formulation
`
`Amerigen Ex. 1033, p. 9
`Amerigen Ex. 1033, p. 9
`
`

`
`4,794,001
`
`6
`Eudragit E 30 D suspension containing calcium stea-
`rate was sprayed on the Methocel E4MP coated
`spheroids using peristaltic pump
`The spheroids were dried
`4. Manufacture
`
`Capsules were filled with the powder blend, pH-sen-
`sitive coated spheroids and coated spheroids on an en-
`capsulating machine capable of dual filling powders and
`spheroids.
`
`EXAMPLE 2
`
`The finished dosage form consists of a hard gelatin
`capsule containing 3 types of spheroids. The formula-
`tion particulars are based on 160 mg propranolol I-ICI
`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 HCl)
`(2) pH sensitive coated spheroids to provide a second
`dose (pH) 5.5) e.g. 60 mg propranolol HCl
`(3) Coated spheroids to provide a third dose (4-10
`hours post ingestion) e.g. 70 mg propranolol HCl
`1. Uncoated Splieroids (prepared as described previ-
`ously)
`2. Alternate pH Sensitive Coated Spheroids
`Polyvinyl Acetate Phthalate (PVAP) system:
`(a) Formula-(based on 3 kg uncoated spheroids)
`
`
`
`Ingredients
`Uncoeted Spheroids (60%
`wxw propranolol HCI)
`0.30 kg
`Polyvinyl Acetate Phthalate (PVAP), NP
`0.0.! kg
`Triethyl Citrate, NF
`Slearic Acid. NP
`0.06 kg
`
`Methanol, Anhydrous, NF
`2.61 kg
`
`Quantity
`3.00 kg
`
`(in) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`The PVAP solution was applied using a peristaltic
`.
`n
`The spheroids were dried
`3. Coated Spheroitis (prepared as described above in
`Example 1)
`
`EXAMPLE 3
`
`1. Uncoated Spheroids (prepared as described above}
`2. pH Sensitive Coated Spheroids (prepared as de-
`scribed above in Example 1)
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
` Quantityfliatch
`Undercoat Ingredients
`Uncoated Spheroids (60%
`wfw propranolol HCI)
`Hydroxypropyl inefliylceliulose, USP.
`2910. 4-000 cps [Methocel E4MP)
`Methylene Chloride. NF
`Methanol, Anhydrous, NF
`Overcoat Ingredients
`0.600 kg
`Eudragit E 30 D (aqueous dispersion)
`0.0125 kg
`Calcium Stearate. NF
`0.002 kg
`Simethieone Emulsion USP
`Water. USP. Purified 0.300 kg
`
`
`0.0'l'S kg
`
`4.93? kg
`1.963 kg
`
`3.0 kg
`
`(b) Process for applying undercoat
`
`Amerigen Ex. 1033, p. 10
`Amerigen Ex. 1033, p. 10
`
`5
`
`15
`
`20
`
`15
`
`30
`
`35
`
`5
`particulars are based on 160 mg propranolol hydrochlo-
`ride per capsule, although they can be designed to pro-
`vide other dosage strengths.
`The propranolol hydrochloride powder blend (or
`first group of spheroids) provides the loading dose, (e.g.
`25 mg propranolol HCl).
`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. 65 mg propranolol HCl.
`(2) Coated spheroids to provide a third dose (4-10
`hours post ingestion} e.g. 70 mg propranolol HCl.
`1. Powder Blend
`
`(:1) Formula
`
`
`
`Quantity
`Ingredient
`30 mg/capsule
`Propranolol HCI, USP
`54 rng./capsule
`Lactose. USP
`Microcrystalline cellulose. NF
`15 mg/capsule
`
`Magnesium stearatc. NF
`1 mg/capsule
`
`2. pH Sensitive Coated Spheroids
`(i) Eudragit S System:
`(a) Formula (based on 3 kg uncoated spheroids)
`
`
`
`Quantity
`3.00 kg
`
`Ingredients
`Uncosted spheroids (60%
`wfw Propranolol HCl)
`Methacrylic Acid Copolymer, Type B, NF
`Eudragit S
`0.112 kg
`Ti-iacetin, USP
`Methylene Chloride. NF
`1.99 kg
`Isopropyl Alcohol. USP
`L64 kg
`
`Water
`050 kg
`
`0.75 kg
`
`(b) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`The Eudragit S solution was applied using a peristal- 40
`tic pump
`The spheroids were dried
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
`45
`
`
`
`Quantity
`
`Undereoat In
`
`ients
`
`3.00 kg
`
`0.075 kg
`
`Unooated Spheroids (60%
`wfw propranolol HCi)
`Hydroitypropylmethylcellulose.
`USP. 2910. 4000 cps. (e.g..
`Methocel sum
`Methylene Chloride, NF
`Methanol. Anhydrous. NF
`Overcoat Ingredients
`Eudragit E 30 D (Aqueous
`Dispersion)
`0.030 kg
`Calcium Stearate. NF
`Siluethicone Emulsion, USP
`' 0.0025 kg
`
`Water. USP. Purified
`0.500 kg
`
`4.98? kg
`2.963 kg
`
`[.00 kg
`
`50
`
`'
`55
`
`60
`
`(In) Process for applying undercoat
`The uncoated spheroids were placed in a fluidized-
`bed coater
`
`Methocel E4MP solution was sprayed using a peri- 65
`stalfic pump
`The spheroids were dried
`(c) Process for applying overcoat
`
`

`
`4,794,001
`
`8
`
`
`Fm gm"?
`second gm“? Third group
`0; sphemigs
`p,op,,,.mg.,|
`of spheroids
`of spheroids
`[or powder)
`Hydrochloride
`5 mg per capsule % of dose
`% of dose
`% of dose
`
`an M
`:23: :2 in
`:3: 2
`in :2
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`_
`,
`_
`_
`Examples of in vitro release profiles are given In
`FIGS. 1-4. FIG. 1 represents the dissolution profile of
`the composite capsule formulation comprised of three
`separate doses, produced in Example 3. The dissolution
`profile was obtained using the United States Pharmaco-
`peia Apparatus I at 37° C. and 100 RPM. The-dissolu-
`tion media was varied with time beginning with 0.lN
`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 represents the dissolution profiles of the first
`dose uncoated spheroids produced in Examples 2, 3 and
`4 vs the powder blend of the first dose in Example 1.
`The dissolution profiles were obtained using the United
`States Pharrnacopeia Apparatus I at 37° C. and 100
`RPM. The dissolution media was 0.lN HCI.
`FIG. 3 represents the dissolution profile of the second
`dose Eudragit S coated spheroids produced in Example
`1, 2. 3 and 4. The dissolution profile was obtained using
`the United States Pharmacopeia Apparatus I at 37° C.
`and 100 RPM. The dissolution media was varied with
`time beginning with 0. lN HCl 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 'i'.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 (FIG. 1) vs
`a total of 160 mg propranolol hydrochloride admin-
`stered in four divided doses of 4-0 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
`mortohydrate (10.0 kg) were blended together in a 450
`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 63 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
`
`Amerigen Ex. 1033, p. 11
`Amerigen Ex. 1033, p. 11
`
`7
`The uncoated spheroids were placed in a fluidized
`bed coater
`Methocel E4MP solution was applied using a peri-
`stalfic pump
`The spheroids were dried
`r«=> Process for -was
`Eudragit E 30 D suspension containing calcium stea-
`rate was sprayed on the Methocel E4MP coated
`spheroids using a peristaltic pump
`The spheroids were dried
`The three types of spheroids are categorized as:
`(I) Uncoated spheroids to provide a loading dose
`(e.g. 30 mg propranolol HCl)
`(2) pH sensitive coated spheroids to provide a second
`dose (pH 6.5) e.g. 60 mg propranolol HCl
`(3) Coated spheroids to provide a third dose (4-10
`hours post ingestion) eg. 70 mg propranolol HCI
`EXAMPLE 4
`
`1. Uncoated Spheroids (prepared as described above)
`2. pH Sensitive Coated Spheroids (prepared as de-
`scribed above in Example 1)
`3. Coated Spheroids
`(a) Formula
`
`
`
`Quantityfflutch
`
`'
`
`3.00 kg
`
`Undercoal Ingredients
`Urtcoated Spheroids (60%
`w./w Propranolol HCl)
`Hydroxypropylmethylcellulose.
`USP. 2910. 4-CH1} cps (E-l-MP)
`Methylene Chloride. NF
`Methanol. Anhydrous, NF
`Overcoat Ingredients
`0.550 kg
`Eudragit E in D (Aqueous Dispersion)
`0.021 kg
`Calcium Stearate. NF
`0.002 kg
`Simetjiicone Emulsion, USP
`
`Water, USP. Purified 0.1115 kg
`
`0.075 ltg
`
`4.937 kg
`2.963 kg
`
`(b) Process for applying undercoat
`The uncoated spheroids were placed in a fluidized
`bed coater
`
`45
`
`Methocel E4-MP solution was applied using a peri-
`staltic pump
`The spheroids were dried
`(c) Process for applying overcoat
`Eudragit E 30 D suspension containing calcium stea-
`rate was sprayed on the Methocel E4-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 proparanolol I-ICI)
`(2) pH sensitive coated spheroids to provide a second
`dose (pH) 6.5) e.g. 60 mg propranolol HCl
`(3) Coated spheroids to provide a third dose (4-10
`hours post ingestion) e.g. 70 mg propranolol HCl
`The finished dosage form consiso‘. 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:
`
`50
`
`55
`
`60
`
`65
`
`

`
`4,794,001
`
`10
`-continued
`.
` ._e.j
`Quantity j
`
`5
`
`Overcoat Ingredients
`Eudragit E 30 D (Aqueous
`Dispersion)
`0.030 kg
`Calcium Stearate. NF
`0.0025 kg
`Siniethioone Emulsion. USP
`
`Water, USP. Purified 0.500 kg
`
`1.00 kg
`
`9
`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, (eg. 5 mg vin-
`pocetine).
`The second and third types of spheroids are catego-
`rized as:
`
`(1) pH sensitive coated spheroids to provide a second
`dose (pl-l‘>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
`1. Powder Blend
`(a) Formula
`
`
`
`Quantity
`ingredient
`S mg./capsule
`Vinpocetine
`0.! mg/capsule
`Sodium Lauryl Sulfate, NF
`3 ntg/capsule
`Sodium Starch Glycolate. NF
`6 mg/capsule
`Glutamic Acid, NF
`7 mg/capsule
`Starch. NF
`62 mg/capsule
`Lactose, USP
`13 mg/capsule
`Microcrystalline celluiose. NF
`
`Magnesium stearate. NF 1 mg,/capsule
`
`(b) Procedure
`1. Blend the Vinpocetine. Lactose. Microcrystalline
`Cellulose. Starch, Glutamic Acid, Sodium Starch
`Glycolate, Talc Triturate and the Sodium Lauryl
`Sulfate into the PK blender for 20 minutes with
`intensifier bar running.
`2. Pass the Step #1 blend through a Fitz Mill using a
`{#13 screen, medium speed. knives 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.
`2. pH Sensitive Coated Spheroids
`(i) Eudragit S System:
`(a) Formula (based on 3 kg uncoated spheroids)
`
`
` Ingredients Quantity
`Uncoated Spheroids (10%
`mo kg
`wXw VlJ1pOCE!.l.l'I.e]
`Methaeryljc Acid Copolyrner, Type B. NF
`Eudragit S
`0.112 kg
`Triacetin. NF
`[.99 kg
`Methylene Chloride. NF
`1.64 kg
`[supropyl Alcohol NF
`
`Water. USP. Purified 0.50 ltg
`
`(175 kg
`
`(b) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`The Eudragit S solution was applied using a peristal-
`tic pump
`The spheroids were dried
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
` Quantity
`Underooat Ingredients
`Uncoated Spheroids (24%
`wifw vittpocetine
`Hydroxypropylmethylcellulose.
`USP. 2910. 4000 cps. (e.g.,
`Methooel EAMP)
`Methylene Chloride. NF
`Methanol, Anhydrous. NF
`
`3.00 kg
`
`0.015 kg
`
`4.98‘! kg
`2.963 kg
`
`(b) Process for applying undercoat
`The uncoated spheroids were placed in a fluidized
`bed coater
`
`Methocel E4MP solution was sprayed using a peri-
`staltic pump
`The spheroids were dried
`(c) Process for applying overcoat
`Eudragit E 30 D suspension containing calcium stea-
`rate was sprayed on the Methocel E4MP coated
`spheroids using a peristaltic pump
`The spheroids were dried
`4. Manufacture
`
`Capsules were filled with the powder blend, pl-I sen-
`sitive coated spheroids and coated spheroids on an en-
`capsulating machine capable of dual filling powders and
`spheroids.
`
`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 he designed to provide other
`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 vinpocetine
`(3) Coated spheroids to provide a third dose (4-10
`hours post ingestion) e. g. 13 mg vinpocetine
`I. Uncoated Spheroids {prepared as described above
`in Example 5 except that 5% of the microcrystalline
`cellulose was replaced with Avicel RC 581)
`2. Alternate pl-I Sensitive Coated Spheroids
`Polyvinyl Acetate Phthalate (PVAP) system:
`(a) Formula-(based on 3 kg uncoated spheroids)
`
`
`
`Ingredients
`Llnooated Spheroids 00%
`wfw vinpocetine I-lCl)
`0.30 kg
`Polyvinyl Acetate Phthaiate (PVAP), NF
`0.03 kg
`Triethyl Citrate. NF
`Stearlc Acid. NF
`0.06 kg
`
`Methanol Anhydrous, NF
`2.61 kg
`
`Quantity
`3.00 kg
`
`IS
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`(b) Process
`Uncoated spheroids were placed in a fluidized bed
`CD813?!’
`
`65
`
`The PVAP solution was applied using a peristaltic
`PUMP
`The spheroids were dried
`3. Coated Spheroids (prepared as described above in
`Example 5)
`Other dosage strenghts of vinpocetine can be formu-
`lated as follows:
`
`Amerigen Ex. 1033, p. 12
`Amerigen Ex. 1033, p. 12
`
`

`
`11
`
`
`4,794,001
`
`12
`Uncoated spheroids are placed in a fluidized bed
`coater
`
`The Eudragit S solution is applied using a peristaltic
`Pl1'1"P
`The spheroids are dried
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
` Quantity
`Undercoat Ingredients
`Uneoated spheroids (30%
`wfw isosorbide dinitrate
`Hydrnxypropyl methylcellulose.
`USP. 1930. -I000 cps. (e.g..
`Methocel E4MP)
`Methylene Chloride. NF
`Methanol. Anhydrous. NF
`Overcoat Ingredients
`Eudragit E 30 D (Aqueous
`Dispersion)
`0.030 kg
`Calcium Stearate, NF
`0.0025 kg
`Simethicone Emulsion. USP
`
`Water. USP, Purified 0.300 kg
`
`4.98? kg
`1.963 kg
`
`1.00 kg
`
`3.00 kg
`
`0.015 kg
`
`(b) Process for applying undercoat
`The uncoated spheroids are placed in a fluidized bed
`coater
`
`Methocel E4-MP solution is sprayed using a peristaltic
`13111