FORMULATIONS PROVIDING THREE
`DISTINCT RELEASES
`Inventors: Atul M. Mehta, Ramsey, N.J.;
`Lizbetli A. Bachand; Thomas W.
`Leonard, both of Plattsburgh, N.Y.;
`Ronald N. Warner, Grand Isle, Vt.
`American Home Products
`Corporation, New York, NY.
`836,033
`
`Assignee:
`
`Appl. No.:
`Filed:
`
`Mar. 4, 1986
`
`[54]
`
`[75]
`
`1731
`
`1211
`
`1221
`
`1631
`
`[51]
`
`[52]
`
`I53]
`
`[56]
`
`United States Patent
`Mehta et al.
`
`[19]
`
`[11] Patent Number:
`
`4,728,512
`
`[45] Date of Patent:
`
`Mar. 1, 1988
`
`2/1981 De Nesle et al.
`........... 424/21
`4,248,857
`2/1981 Guley et a].
`424/21
`4,248,858
`
`4,294,819 10/1981 Tencza
`424/14
`
`1/1932 De Neslee
`.
`4,309,404
`424/21
`
`1/1982 Guleyetal.
`4,309,405
`424/21
`4,309,406
`1/1982 Guley et al.
`424/21
`4,339,428
`7/1982 Tencza ........
`424/21
`
`4,524,060
`6/1985 Mushal et a1.
`,. 424/22
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`1204580 9/1970 United Kingdom ............... 424/37
`
`8/1980 United Kingdom ............ 354/193
`2039737
`OTHER PUBLICATIONS
`
`Related U.S. Application Data
`Continuation-impart of Ser. No. 731,175, May 6, 1985,
`abandoned.
`
`Int. C1.4 ......................... A61K 9/52; A61K 9/54;
`A61K 9/53
`vs. c1. .................................... 424/453; 424/453;
`424/457; 424/459; 424/461; 424/462
`Field of Search ....................... 424/14, 16, 19—22,
`424/37, 453, 457, 458, 459, 461, 462
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,809,918 10/1957 Hermelin ...................... 424/19
`2,921,883
`1/1960 Reese et a1.
`424/19
`3,119,742
`1/1964 Heimlich et a1.
`424/ 19
`
`3/1965 Hershberg ......
`3,175,521
`424/ 14
`
`3,835,221 9/ 1974 Fulberth et a1.
`424/19
`3,859,431
`1/1975 Newton et al.
`424/37
`
`2/1979 Me Ainsh et a1.
`.
`4,138,475
`424/21
`
`4,173,626 11/1979 Dempski et a1.
`424/20
`.......................... 424/ 19
`4,248,856
`2/1981 Guley et a1.
`
`F. W. Goodhart et 3], Pharmaceutical Technology, pp.
`64-71, Apr. 1984.
`
`Primary Examiner—Shep K. Rose
`Attorney, Agent, or Firm—John W. Routh
`[57]
`ABSTRACT
`A therapeutic preparation consisting of three groups of
`spheroids containing an active medicinal substance. The
`first group of spheroids is uncoated and rapidly disinte-
`grates upon ingestion to release an initial dose of medici-
`nal substance :1 second group of spheroids is coated with
`a pH sensitive coat to provide a second dose and a third
`group of spheroids is coated with a pH independent
`coat to provide a third dose. A powder blend of active
`medicinal substance may be substituted for the first
`group of uncoated spheroids.
`The therapeutic preparation may be utilized as a mix-
`ture of groups of spheroids in a capsule.
`
`9 Claims, 6 Drawing Figures
`
`KVK-TECH EXHIBIT 1015
`
`KVK-TECH EXHIBIT 1015
`
`

`

`US. Patent
`
`Mar. 1, 1988
`
`Sheet 1 of 6
`
`4,728,512
`
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`US. Patent Mar. 1,1988
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`Sheet 3 of6
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`US. Patent Mar. 1, 1988
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`Sheet 4 of6
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`US. Patent
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`Mar. 1, 1988
`
`Sheet 5 of 6
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`US. Patent
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`

`1
`
`4,728,512
`
`FORMULATIONS PROVIDING THREE DISTINCT
`RELEASES
`
`BACKGROUND OF THE INVENTION
`
`This application is a continuation in part of applica-
`tion Ser. No. 731,175 filed May 6, 1985, now aban-
`doned.
`
`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 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. 2,809,918 discloses inert drug coated
`nonpareils which are enteric coated with a shellac-
`stearic acid mixture. US. Pat. No. 3,119,742 discloses
`coated drug crystals used as particulates for sustained
`release formulations. U.S. Pat. No. 2,921,883 discloses
`“Spansule,” 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—71, April 1984, discloses the eval-
`uation of Eudragit E 30D 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-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.
`
`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 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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`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 doses two or
`more times a day. Such medicinal agents include the
`cardiovascular drugs such as propranolol hydrochlo-
`ride, isosorbide dinitrate, isosorbide-S-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 6,7,8,9-
`Tetrahydro—10-methylpyrido[l,2—a]indole-9-Amines
`and Derivatives Thereof (AHP-8728); the analgesics
`such as those disclosed and claimed in U.S. patent appli-
`cation Ser. No. 726,197, filed Apr. 22, 1985, the antihis-
`tamines such as chlorpheniramine 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, 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 corn-prising 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-
`grant sodium carboxymethylcellulose,
`such as Ac-
`
`

`

`3
`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 hydroxypropyl methyl cellulose and
`an (i) overcoat comprising a neutral copolymer of poly-
`methacrylic acid esters such as Eudragit E3OD 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 relates 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 1:2. The mean molecular weight is 135,000.
`Eudragit S is available as a lacquer solution in isopropyl
`alcohol and as a solvent free solid. It is known as meth-
`acrylic 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 E30D are available from Rohm Pharma,
`D-6108 Weiterstadt 1, Dr.-Otto-Rohm-Str. 2—4, West
`Germany.
`Metalic stearates include zinc 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 carboxy-
`‘._,methyl ether of starch. It is available from Edward
`Mendel] Co.,
`Inc., Route 52, Carmel, NY. 10512,
`U.S.A.
`
`‘
`
`_
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`AcDiSol is a trade name for carboxymethylcellulose
`sodium. It is 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 Company, 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 methylcellu-
`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 methylcellu-
`lose containing about 27 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 or hy-
`droxypropyl methylcellulose containing about 19 to
`25% methoxyl content and from about 4 to 12% hy-
`droxypropoxyl content calculated on the dried basis.
`The preferred grade of hydroxypropyl methylcellu-
`lose for use in the present invention is hydroxypropyl
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4,728,512
`
`‘
`
`4
`methylcellulose USP, 2910, 4000 cps (METHOCEL
`E4MP) which is a propylene glycol ether of methylcel~
`lulose 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 corecoated 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.
`T
`,
`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-PH-lOl; 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.m. 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.
`
`EXAMPLELVI
`
`The finished dosage form consists of a hard gelatin
`capsule containing a powder blend of propranolol hy-_
`drochloride and two types of spheroids. The formula-
`tion particulars are based on 160 mg propranolol hydro-
`
`

`

`5
`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.
`25 mg propranolol HCl).
`The second and third types of spheroids are catego-
`rized as:
`
`4,728,512 '
`
`6
`Eudragit E30D suspension containing calcium ste-
`arate was sprayed on the Methocel E4MP
`coated spheroids using
`peristaltic pump
`The spheroids were dried
`4. Manufacture
`
`5
`
`(1) pH sensitive coated spheroids to provide a second
`dose (pH> 6.5) e.g. 65 mg propranolol HCl.
`010
`(2) Coated spheroids to provide a third dose (4-1
`hours post ingestion) e.g. 70 mg propranolol HCl.
`1. Powder Blend
`(a) Formula
`
`
`Ingredient
`Quantity
`Propranolol HCI, USP
`30 mg/capsule
`Lactose, USP
`54 mg/capsule
`Microcrystalline cellulose, NF
`15 mg/capsule
`Magnesium Stearate, NF
`1 rug/capsule
`
`20
`
`15
`
`2. pH Sensitive Coated Spheroids
`(i) Eudragit S System:
`(a) Formula (based on 3 kg uncoated spheroids)
`
`
`Ingredients
`Quantity
`Uncoated Spheroids (60%
`3.00 kg
`w/w Propranolol HCI)
`Methacrylic Acid Copolymer, Type B, NF
`Eudragit S
`0.112 kg
`Triacetin, USP
`1.99 kg
`Methylene Chloride, NF
`Isopropyl Alcohol, USP
`1.64 kg
`
`Water
`.
`0.50 kg
`
`0.75 kg
`
`25
`
`30
`
`35
`
`(b) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`The Eudragit S solution was applied using a peri- 4o
`staltic pump
`>
`The spheroids were dried
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
`
`45
`
`Quantity
`
`3.00 kg
`
`0.075 kg
`
`Undercoat Ingredients
`Uncoated Spheroids (60%
`w/w propranolol HCl)
`Hydroxypropyl methylcellulose,
`USP, 2910, 4000 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
`0.500 kg
`
`4.987 kg
`2.963 kg
`
`1.00 kg
`
`50
`
`55
`
`60
`
`(b) Process for applying undercoat
`The uncoated spheroids were placed in a fluidized
`bed coater
`
`Methoce1E4MP solution was sprayed using a peri- 65
`staltic pump
`The spheroids were dried
`(c) Process for applying overcoat
`
`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 HCl
`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 HC1
`1. Uncoated Spheroids (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
`Uncoated Spheroids (60%
`w/w propranolol HCI)
`0.30 kg
`Polyvinyl Acetate Phthalate (PVAP), NF
`0.03 kg
`Triethyl Citrate, NF
`0.06 kg
`Stearic Acid, NF
`
`Methanol. Anhydrous, NF 2.61 kg
`
`Quantity
`3.00 kg
`
`(1)) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`The PVAP solution was applied using a peristaltic
`pump
`The spheroids were dried
`3. Coated Spheroids (prepared as described above in
`Example 1)
`
`EXAMPLE 3
`
`l. 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)
`
`Quantity/Batch
`
`Undercoat In redients
`
`3.0 kg
`
`Uncoated Spheroids (60%
`w/w propranolol HCl)
`Hydroxypropyl methylcellulose, USP,
`2910, 4000 cps (Methocel E4MP)
`Methylene Chloride, NF
`Methanol, Anhydrous, NF
`Overcoat Ingredients
`0.600 kg
`Eudragit E 30 D (aqueous dispersion)
`0.0225 kg
`Calcium Stearate, NF
`0.002 kg
`Simethicone Emulsion USP
`Water, USP, Purified 0.300 kg
`
`
`0.075 kg
`
`4.987 kg
`2.963 kg
`
`

`

`7
`(b) Process for applying undercoat
`The uncoated spheroids were placed in a fluidized
`bed coater
`
`4,728,512
`
` 8
`
`Propranolol
`Hydrochloride
`mg per capsule
`40 to 240
`160
`
`First group
`of spheroids
`(or powder)
`% of dose
`10% to 30%
`12% to 20%
`
`_
`.
`Second group
`of spheroids
`% of dose
`20% to 75%
`35% to 45%
`
`Third group
`of spheroids
`% of dose
`10% to 60%
`35% to 45%
`
`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 0.1N
`HCl for O 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 Pharmacopeia Apparatus I, at 37° C. and 100
`RPM. The dissolution media Was 0.1N HCl.
`*
`
`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 0.1N 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 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
`Pharmacopeia 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 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 microcrys-
`talline cellulose (Avicel-PH—lOl); (80.0 kg.), citric acid
`monohydrate (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 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
`
`Methocel E4MP solution was applied using a peri-
`staltic pump
`The spheroids were dried
`(0) Process for applying overcoat
`Eudragit E30D suspension containing calcium ste-
`arate was sprayed on the Methocel E4MP
`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
`(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) e.g. 70 mg propranolol HCl
`EXAMPLE 4
`
`l. Uncoated Spheroids (prepared as described above)
`2. pH Sensitive Coated Spheroids (prepared as de-
`scribed above in Example 1)
`3. Coated Spheroids
`(a) Formula
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Quantity/Batch
`
`30
`
`3.00 kg
`
`Undercoat In redients
`Uncoated Spheroids (60%
`w/w Propranolol HCl)
`Hydroxypropyl methylcellulose,
`USP, 2910, 4000 cps (E4MP)
`Methylene Chloride, NF
`Methanol, Anhydrous, NF
`Overcoat Ingredients
`0.550 kg
`Eudragit E 30 D (Aqueous Dispersion)
`0.021 kg
`Calcium Stearate, NF
`0.002 kg
`Simethicone Emulsion, USP
`
`Water, USP, Purified 0.275 kg
`
`0.075 kg
`
`4.987 kg
`2.963 kg
`
`35
`
`(b) Process for applying undercoat
`The uncoated spheroids were placed in a fluidized
`bed coater
`
`45
`
`Methocel E4MP solution was applied using a peri-
`staltic pump
`The spheroids were dried
`'(c) Process for applying overcoat
`Eudragit E30D suspension containing calcium ste-
`arate was sprayed on the Methocel E4MP
`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
`(e.g. 30 mg propranolol HCl)
`(2) pH sensitive coated spheroids to provide a second
`dose (pH>6.5) e.g. 60 mg propanolol HCl
`(3) Coated spheroids to provide a third dose (4—10
`hours post ingestion) e.g. 70 mg propanolol HCl
`The finished dosage form consists of a hard gelatin
`capsule containing three types of spheroids containing
`propanolol hydrochloride. The formulation particulars
`are based on 160 mg propanolol hydrochloride per
`capsule, although they can be designed to provide other
`dosage strengths as follows:
`
`50
`
`55
`
`65
`
`

`

`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, (e.g. 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 (pH22 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
`
`
`Ingredient
`Quantity
`Vinpocetine
`5 mg/capsule
`Sodium Lauryl Sulfate, NF
`0.1 mg/capsule
`Sodium Starch Glycolate, NF
`3 mg/capsule
`Glutamic Acid, NF
`6 nag/capsule
`Starch, NF
`7 mg/capsule
`Lactose, USP
`62 mg/capsule
`Microcrystalline cellulose, NF
`13 mg/capsule
`
`Magnesium stearate, NF
`1 mg/capsule
`
`5
`
`10
`
`15
`
`20
`
`25
`
`(b) Procedure
`1. Blend the Vinpocetine, Lactose, Microcystalline
`Cellulose, Starch, Glutamic Acid, Sodium
`Starch Glycolate, Talc Triturate and the Sodium
`Lauryl Sulfate into the PK blender for 20 min- 30
`utes with intensifier bar running.
`2. Pass the Step #1 blend through a Fitz Mill using
`a #1B screen, medium speed, knives forward.
`3. Return the granulation from Step #2 to the PK
`blender and add the Magnesium Stearateand 35
`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)
`
`
`Quantity
`3.00 kg
`
`Ingredients
`Uncoated Spheroids (10%
`w/w Vinpocetine)
`Methacrylic Acid Copolymer, Type B, NF
`Eudragit S
`0.112 kg
`Triacetin, NF
`1.99 kg
`Methylene Chloride, NF
`1.64 kg
`Isopropyl Alcohol, NF
`
`Water, USP, Purified
`0.50 kg
`
`0.75 kg
`
`40
`
`45
`
`50
`
`(b) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`The Eudragit S solution was applied using a peri- 55
`staltic pump
`The spheroids were dried
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
`Quantity
`
`60
`
`Undercoat In redients
`
`Uncoated Spheroids (24%
`w/w vinpocetine
`Hydroxypropyl methylcellulose,
`USP, 2910, 4000 cps, (e.g.,
`Methocel E4MP)
`Methylene Chloride, NF
`
`55
`
`3.00 kg
`
`0.075 kg
`
`4.987 kg
`
`4,728,512
`
`10
`
`-continued
`
`Quantity
`2.963 kg
`
`Methanol, Anhydrous, NF
`mum.
`Eudragit E 30 D (Aqueous
`Dispersion)
`0.030 kg
`Calcium Stearate, NF
`0.0025 kg
`Simethicone Emulsion, USP
`
`Water, USP, Purified 0.500 kg
`
`1.00 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
`(0) Process for applying overcoat
`Eudragit E3OD suspension containing calcium ste-
`arate 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, pH 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 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. 5 mg vinpocetine)
`(2) pH sensitive 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
`1. Uncoated Spheroids (prepared as described above in
`Example 5 except that 5% of the microcrystalline
`cellulose was replaced in Avicel RCS81)
`2. Alternate pH Sensitive Coated Spheroids
`Polyvinyl Acetate Phthalate (PVAP) system:
`(a) Formula—(based on 3 kg uncoated spheroids)
`
`
`Ingredients
`Quantity
`Uncoated Spheroids (10%
`3.00 kg
`w/w vinpocetine HCl)
`0.30 kg
`Polyvinyl Acetate Phthalate (PVAP), NF
`0.03 kg
`Triethyl Citrate, NF
`Stearic Acid, NF
`0.06 kg
`
`Methanol Anhydrous, NF
`2.61 kg
`
`(b) Process
`Uncoated spheroids were placed in a fluidized bed
`coater
`
`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:
`
`

`

`11
`
`
`4,728,512
`
`Third group
`Second group
`First group of
`Vinpocetine
`of spheroids
`of spheroids
`spheroids (or
`mg per
`% of dose
`% of dose
`powder) % of dose
`capsule
`
`
`
`20% to 75%10% to 50%15 to 60 10% to 60%
`
`EXAMPLE 7
`
`12
`Uncoated spheroids are placed in a fluidized bed
`coater
`
`The Eudragit S solution1s applied using a peristal-
`tic pump
`The spheroids are dried
`_
`3. Coated Spheroids
`(a) Formula (based on 3 kg uncoated spheroids)
`
` Quantity
`
`3.00 kg
`
`0.075 kg
`
`4.987 kg
`2.963 kg
`
`WU
`
`ncoated Spheroids (30%
`w/w isosorbide dinitrate
`Hydroxypropyl methylcellulose,
`USP, 2910, 4000 cps, (e.g.,
`Methocel E4MP)
`Methylene Chloride, NF
`Methanol, Anhydrous, NF
`
`10
`
`15
`
`WE
`
`udragit E 30 D (Aqueous
`Dispersion)
`0.030 kg
`Calcium Stearate, NF
`0.0025 kg
`Simethicone Emulsion, USP
`
`Water, USP, Purified 0.500 kg
`
`1.00 kg
`
`(b) Process for applying undercOat
`The uncoated spheroids are placedin a fluidized
`bed coater
`
`Methocel E4MP solutionIS sprayed using a peri-
`staltic pump
`,
`The spheroids were dried
`(c) Process for applying overcoat
`Eudragit E3OD suspension containing calcium ste-
`arate