I|||||lllllllllllllllllllll|l|||||||||||l|||l|l|||I|lllllllllllllllllllllll
`US0054'?4'}'86A
`
`Umted States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,474,786
`
`Kotwal et al.
`
`[45] Date of Patent:
`
`Dec. 12, 1995
`
`[54] MULTILAYERED CONTROLLED RELEASE
`PHARMACEUTICAL DOSAGE FORM
`
`[75]
`
`Inventors: Pramod M. Kotwal, Blue Bell, Pa.;
`Stephen A. Howard, Flemington, NJ.
`
`4241494
`‘H1993 Philippon ea a.l.
`5,229,135
`424.-'49?
`6J'l994 Neda etal.
`.... ..
`5,320,353
`
`424.-’497
`5,364,620 11.31994 Geoghegan .
`.............................. 42419194
`5,407,686
`4!1995 Patel el al.
`'
`
`[73] Assignee: Ortho Pharmaceutical Corporation.
`Rflfilfinr N-L
`
`Primary Eraminer—Melvyr1 I. Marquis
`Assistant Examir1er—Amy Hulina
`
`[2]] App}. No; 319,186
`
`[22]
`
`Filed:
`
`Oct. 6, 1994
`
`Related U-5- APP1i‘33l-i011 D313
`
`6
`[ 2]
`
`,
`_
`_
`glflvfiigutigéifi Sen N0‘ 211331’ Mar" 23’ 1994’ Pa‘ ND‘
`'
`’
`A611‘ 9544 A61K 9362
`Int‘ CL6
`(51)
`4241472; 4241458; 4243461;
`[523 U.S. C].
`4241462; 424‘!469; 424"'48S;
`[58] Field of Search ..................................... 4241490, 494,
`4
`4
`4
`4
`424l495, 497, 488.
`59» 72- 58’ 4662
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`This invention is directed to a multilayered controlled
`release pharmaceutical dosage form. More particularly the
`dosage form is adapted for water soluble drugs and com-
`prises a plurality of coated particles wherein each has
`multiple layers about a core containing a drug active
`whereby the drug containing core and at least one otherlayer
`of drug active is overcoated with a ountmned release balfier
`layer and preferably an outer layer of additional drug is
`adapted f°' "”m°d‘a‘“ relme ‘° ”“"f°’ably p'°‘"d° “M
`immediate releasing layer and at least two controlled releas-
`ing layers of a water soluble drug from the multijayered
`coated parliele.
`
`5,213,311
`
`5r1993 Frisbee et a1.
`
`.......................... 4241494
`
`13 Claims, 1 Drawing Sheet
`
`SINGLE vs DOUBLE LAYER BEADS
`MEDIUM 7.4 pH
`
`10::
`
`so
`
`so
`
`% DISSOLVED
`
`OF 300 MG
`TRAMADOL H0!
`
`40
`
`20
`
`0
`
`
`
`0
`
`5
`
`1o
`
`15
`
`20
`
`25
`
`TIME (HOURS}
`
`-1- 3:10-DOUBLE
`% SUFlELEASE-
`TYPE
`
`—EI— 12.5%-SINGLE
`
`—><— 14%—SINGLE
`
`Amerigen Ex. 1035, p. 1
`Amerigen Ex. 1035, p. 1
`
`

`
`U
`
`m.ma
`
`O)91.
`
`%
`
`
`
`
`
`P_._n_5sS_om_2.S.moqmmmm_><._m_._m:on_m>m_._wz_m_.mu_n_
`
`5on
`
`a92comn_Omom_>._owm_o4..
`
`
`w...,9._o_._._oo<2<mF
`
`2:
`
`8
`
`8
`
`
`
`
`
`.72Au,mn_>:_-D:7-m_m<m._m_.._:m35,M,m._oz_m-o\..E$m|m._oz_m.o$.m_|mTm_._m:oo-o:mIT%
`
`22....mmmomE2mo....Om
`Ammnoa
`
`Amerigen Ex. 1035, p. 2
`
`A
`
`BA
`
`

`
`5,474,786
`
`1
`MULTILAYERED CONTROLLED RELEASE
`PHARMACEUTICAL DOSAGE FORM
`
`This is a division of application Ser. No. 217,331. filed
`Mar. 23, 1994, US. Pat. No. 5,395,626, which is hereby
`incorporated by reference.
`
`FIELD OF THE INVENTION
`
`This invention is directed to a multilaycred controlled
`release pharmaceutical dosage form. More particularly. the
`dosage form is adapted for controlled release of water
`soluble drugs and comprises a plurality of rnultilayered
`coated particles, wherein each particle has multiple layers
`about a core containing a drug active. The drug containing
`core and at least one other layer of drug active is overcoatcd
`with a controlled release barrier layer and an outer layer of
`additional drug may be adapted for immediate release.
`
`BACKGROUND OF THE INVENTION
`
`20
`
`Controlled release pharmaceutical dosage forms are well
`known and provide distinct advantages for delivery of
`certain chemothcrapies. Controlled release dosage forms are
`particularly useful for drugs which act optimally at certain
`levels of plasma concentration over extended periods of
`Controlled release systems may also avoid the pres
`ence of ineffective or toxic levels of drugs which result from
`periodic administration of immediate release dosage forms
`which provide high initial levels of drug but may leave only
`ineffectively small amounts of drugs in the plasma near the
`end of the administration periods (i.e. cycles] prior to
`subsequent administration of drug. Controlled release dos-
`age forms are also desirable for providing continuous che-
`motherapy for chronic conditions or those with a long
`duration of therapy by providing drugs in a sustained
`released manner that only requires administration either
`once or twice daily instead of every four to six hours as may
`be indicated for a particular drug.
`The administration of highly water soluble drugs in a
`controlled release dosage form presents particular problems.
`The introduction of such highly water soluble drugs in
`controlled release dosage forms into a patient's digestive
`system has met with limited success due to the normally
`unpredictable leaching out of the very water soluble drug
`active into the digestive system when using conventional
`sustained release techniques. It is also challenging to pro-
`vide a substantially zero or constant rate of release for drugs
`that are highly water soluble for extended periods of time.
`It is therefore an object of the present invention to provide
`a multilayered controlled release pharmaceutical dosage
`form system, particularly for very water soluble drugs. This
`system provides desirable plasma levels of drugs with a
`substantially constant rate of release of the drugs from
`controlled release layers over a preselected period of time.
`
`SUMMARY OF THE INVENTION
`
`45
`
`To achieve the objects and objectives in accordance with
`the invention the present invention provides a multilayered
`controlled release pharmaceutical dosage form, preferably
`for water soluble drugs, comprising a plurality of coated
`‘particles each comprising: a drug active core which is
`sequentially overcoated with a first controlled release barrier
`layer; at least one additional layer containing drug active
`which is overcoated with an additional controlled release
`layer; and preferably an outer layer containing drug active
`which is intended for immediate release; whereby,
`the
`
`60
`
`65
`
`2
`amount of drug active in the controlled release barrier
`material utilized in each coating layer thereof is provided in
`amounts effective to achieve a desirable plasma level of drug
`active in a patient over a preselected time period. In par-
`ticularly preferred embodiments the time period is twelve or
`twenty-four hours (i.e. corresponding to once or twice daily
`administration).
`
`In preferred embodiments of the invention the multilay-
`ered controlled release pharmaceutical dosage form for
`water soluble drugs comprises a plurality of coated particles
`each comprising:
`a core comprising an inert material which is coated or
`granulated with a water soluble drug active;
`a first coating layer over the drug containing core com-
`prising a water soluble film forming polymer, prefer-
`ably the film fcrming mixture additionally comprises a
`plasticizer;
`a second coating layer over the first coating layer comw
`prising a film forming dispersion or solution which
`forms a controlled release layer over the coated drug
`core, preferably a water-based dispersion;
`a third coating layer comprising a water soluble film
`forming polymer and preferably a plasticizer;
`afourth coating layer comprising additional water soluble
`chug active;
`21. fifth coating layer comprising a water soluble film
`forming polymer and preferably a plastieizer;
`a sixth coating layer comprising a film forming dispersion
`or solution which forms a controlled release layer over
`the coated drug core, preferably a water-based disper-
`sion; and
`
`a final coating layer of a water soluble Iilm forming
`polymer and preferably a plasticizer.
`In preferred embodiments of the invention the water
`soluble film forming polymer is hydroxypropyl methylcel—
`lulose and the plasticizer is polyethylene glycol.
`Preferably the film forming polymer which forms the
`controlled release layer is provided as a water-based disper-
`sion and comprises ethyl cellulose. Preferably the dispersion
`additionally comprises at least one of dibutyl sebacate, oleic
`acid, and sodium lauryl sulfate.
`In preferred embodiments of the invention the water
`soluble drug active is selected front the group consisting of
`tramadol, pseudoephedtine and phenylpropanolarnine and
`salts thereof. More preferably the drug active is very water
`soluble and is tramadol I-ICI or pscudoephedrine I-lCl. Most
`preferably the drug active is tramadol HCl. The invention is
`also intended to cover substantially pure active cnamtiomers
`of these drug actives.
`In a particularly preferred embodiment of the invention
`the controlled release layers of the second and sixth coating
`layers are provided at levels to obtain a substantially con-
`stant release profile of the drug active over about a twenty-
`four hour period.
`In other embodiments the invention provides a method of
`achieving a desirable plasma level of a water soluble drug
`over a twenty-four hour period in a patient comprising the
`steps of:
`preparing a multilayered controlled release dosage form
`by sequentially overcoating a drug active containing
`core with a first controlled release barrier layer;
`providing at least one additional layer containing drug
`active over said first controlled release barrier layer
`which in turn is overcoated by an additional controlled
`release layer; and
`
`Amerigen Ex. 1035, p. 3
`Amerigen Ex. 1035, p. 3
`
`

`
`5,474,786
`
`3
`providing an outer layer containing drug active which is
`intended for immediate release; whereby. the amount of
`drug active and the controlled release barrier material
`utilized in each coating layer thereof is provided in an
`amount efiective to achieve a desirable plasma level of
`drug active in a patient over a twenty-four hour period.
`In preferred embodiments of the method of the invention
`the drug is tramadol HCI or pseudoephedrine HCl.
`in other preferred embodiments of the method of the
`invention the sequential coatings are all applied in aqueous
`systems.
`In particularly preferred embodiments of the method of
`the invention the multilaycrcd dosage form comprises at
`least one additional coating layer of a water soluble film
`forrning polymer interposed between one or more of the
`controlled release ! layers and the adjoining layer containing
`drug active to assure uniformity of the dosage form.
`In other embodiments of the invention two or more drug
`actives may be provided in one or more of the drug con-
`taining layers of the multilayered dosage forms.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 is a graph showing percent dissolved over time of
`single and double layer (controlled release layer) coated
`heads of the drug tramadol HCI.
`
`DETAILED DESCRIPTION OF THE:
`PREFERRED EMBODIMENTS OF THE
`INVENTION
`
`to preferred
`Reference will now be made in detail
`embodiments of the invention. Examples of the preferred
`embodiments are illustrated in the following example sec-
`tion.
`As used herein the term water soluble refers to those
`compounds and compositions which range from slightly
`soluble to very soluble in water. Actives which are moder-
`ately to highly water soluble are particularly preferred for
`use in this invention because the multilayeted approach
`taken herein provides barriers to premature leaching of
`water soluble actives which may, in clinical use, undesirably
`speed up the rate of release of such actives from conven-
`tional sustained release dosage forms. Examples of very or
`highly water soluble actives include tramadol HCI. pseu-
`doephedrine HCl and phcnylpropanolamine HCl.
`The multilayered controlled release pharmaceutical dos-
`age form of the invention is well suited for water soluble and
`very water soluble drugs. The plurality of coating layers
`including at least two controlled release layers and various
`sealing layers provide adosage form which permits effective
`and desirable controlled release of drug substance from a
`plurality of coated pellets in a dosage form by providing at
`least two difiusion barriers through which drug active is
`slowly released. The multilayered coated particles of the
`invention are particularly well suited for very water soluble
`drugs since the multicontrol release barrier approach of the
`present invention mitigates the possibility of premature
`leaching out of very water soluble drug active in aqueous
`systems such as the digestive tract. While the present
`invention can be used for non-water soluble drugs it
`is
`particularly advantageous when applied to more water
`soluble drugs which are more prone to leaching as described
`above. The rnultilayered dosage form may contain more than
`one drug active in any or all of the drug containing layers
`thereof.
`
`15
`
`2|}
`
`25
`
`30
`
`45
`
`St]
`
`60
`
`65
`
`4
`The drug active core of the multilayered controlled
`release pharmaceutical dosage form is generally a sugar
`sphere which is coated with a drug active. This core may
`however he a combination of a drug active and hinder which
`is granulated into a sphere or the core may be some other
`non—active substance besides sugar. Each time drug active is
`provided in a layer it is first overcoated with a water soluble
`film fonning polymer to inhibit the leaching of such drug
`active during processing into the next applied layer, e.g.
`controlled release layer. Such leaclting into the controlled
`release layer may have the effect of contaminating the
`controlled release layer to provide for inconsistent results
`from layer to layer andior hatch to batch of the drug dosage
`form because the presence of the leached active would
`provide for premature release of the active as well as
`opening up excess space in the controlled release layer for
`further premature diffusion of the drug active therefrom. The
`inclusion of such a protective layer over the drug active is
`particularly indicated in the present invention because of the
`aqueous nature of the preferred water based polymer con-
`trolled release layer which is to he provided over each drug
`containing core. Further, in cases where the drug is particu-
`larly water soluble, undesirable leaching is a probable result
`absent provision of a protective coating of a water soluble
`film forming polymer over the drug containing layer.
`It is preferred that the water soluble film forming polymer
`comprises a plasticizer to assure adequate flexibility of the
`film forming polymer layer. If the film forming polymer
`layer is comprised of a substance which inherently has
`adequate flexibility then a plasticizer may not be necessary.
`The water soluble film forrning polymer
`is preferably
`hydroxypropyl methylcellulose but may be other suitable
`polymers such as hydroxypropyl cellulose or povidone and
`more preferably additionally comprises polyethylene glycol
`and or propylene glycol as plaslicizcr. Preferably this poly-
`mer is in a liquid solution. Other water soluble polymers
`may he applied as would be known to those skilled in the art.
`The controlled release layer of the multilayered drug
`dosage fon'n of the invention is a diffusion layer through
`which drug is released in a controlled manner. It is particu-
`larly desirable that the controlled release diffusion layer be
`water based for ease of processing and environmental con-
`cerns. The use of a water based dispersion to form a
`controlled release layer indicates the use of a protective
`undercoating as described above to protect against prema-
`ture leaching of the underlying drug into the subsequently
`applied controlled release layer which may provide incon-
`sistent release patterns for the drug. While the present
`invention preferably provides for two controlled released
`layers; three or more controlled release layers are contem-
`plated and are a part of the present invention. The use of two
`or more controlled release layers and the underlying dnrg
`layers may also provide for customization of the multilay-
`ered drug pellets controlled release profile of one drug or for
`the release of a mixture of drug actives from the pellet.
`In preferred embodiments of the invention an immediate
`release layer of drug is provided on the outside core of the
`multilayered pellet to provide for the immediate introduction
`of an effective amount of drug active to a patient. An
`effective level of drug active is then maintained through the
`gradual
`release of additional drug active by diffusion
`through the controlled release layers of the drug while it
`remains in the digestive system.
`The controlled release layer may be a solution or disper-
`sion of a film forming polymer. Preferably, the controlled
`release layer is applied as a water based dispersion com-
`prising ethyl cellulose. More preferably. the dispersion addi-
`
`Amerigen Ex. 1035, p. 4
`Amerigen Ex. 1035, p. 4
`
`

`
`5
`
`5 ,474,786
`
`6
`
`-continued
`
`tionally comprises plasticizer ingredients such as dibutyl
`sebaeate and oleic acid. A particularly preferred water based
`controlled release dispersion is sold under the trademark
`SURELEASE and comprises ethyl cellulose, dibutyl seba-
`cate. oleic acid. arnmoniated water, and fused silica.
`'I'he multilayered controlled release pellets of the inven-
`tion are preferably provided in a hard gelatin capsule but
`may also be provided in any other suitable oral dosage form
`such as a matrix comprising such pellets agglomerated with
`an appropriate and compatible binder to form a unitary solid
`dosage form which will release the intact pellets in the
`digestive tract after swallowing.
`The film forming process of the invention can be carried
`out in conventional pans, preferably pans with one way air
`flow to provide more control over the pan environment.
`More preferably the coating is accomplished in a fluidized
`bed which is an air
`suspension technique known as
`“Wurster“ coating. Most preferably the pellets are coated in
`a rotor granulator with a top fluid bed which provides
`rotation of the pellets during coating to ensure a. more
`uniform coat of the pellets. Examples of a preferred coating
`apparatus of the invention is a GLA'I'1" GPCG-5 rotor
`granulator. Other coating materials and techniques can be
`applied such as those disclosed in The Theory and Practice
`of Indttsrrinl Pharmacy, Lachmart et al., 3:! edition, 1936.
`The invention will now be illustrated by examples. The
`examples are not intended to be limiting of the scope of the
`present invention but read in conjunction with the detailed
`and general description above, provide further understand-
`ing of the invention and outline a process for preparing the
`compositions of the inventions and methods of practicing
`the invention.
`
`EXAMPLES
`
`The following ingredients, processes and procedures for
`preparing the compositions of the present invention corre-
`spond to that described above. The procedure below
`describes with particularity the various formulation ingre-
`dients and procedures utilized. Any methods, starting mate-
`rials,
`reagents or eiteipients which are not particularly
`described will be generally known and available to those
`sldlled in the pharmaceutical formulation arts. All formula-
`tion percentages are provided in percent by weight by total
`weight of the composition.
`
`Example 1
`
`300 mg. tramadol sustained release capsules
`
`A. Composition: Unit Dose
`
`The theoretical quantitative composition (per unit dose)
`for tramadol HCl 300 mg sustained release capsules is
`provided below:
`
`Components
`
`Capsules‘
`
`'56 wcightfweight
`(theoretical)
`
`n:glCapsuJe
`(theoretical)
`
`-—
`
`—
`
`Total
`
`100.00%
`
`438.98 mg‘
`
`‘A rnixtI.u1: of hydroxypropyl rnelhylcellulose. [Jolyedlylene glycol and pro-
`pylene glycol.
`_
`Purified Water, US? is evaporated during processing.
`3A rrtixlure cf hydroitypropyl n-tetliylcellulose and polyethylene glycol.
`‘Solid content only of a 25% aqueous dispersion of a mixture of ethyl
`cellulose. dibutyt scbaeate, olcic acid. arrurionjated water and fumed silica.
`The water in the dis
`rsion is evaporated during processing.
`Swhilc. opaque. ltaniegelatin capsule, size 00.
`‘Each batch is assayed prior to filling and the capsule weight is adjusted as
`required to attain 300 mg Iranindol hydrochloride per capsule.
`
`The quantadvc batch composition for tramadol hydro-
`chloride 300 mg sustained release capsule is shown below
`[Theoretical batch quantity 25341 capsules):
`
`10
`
`Components
`
`Step 1: Preparation of Tramadol
`Hydrochloride Bends (bead Build-up #1)
`
`Tramadol Hydrochloride
`Opadry ® Clear Y3-33011
`Purified Water. USP
`Sugar Spheres. NF
`Total Weight Traroadol Hydrochloride
`Beads (Bead Build-up #1)
`Step 2: Clear & Sustained Release
`Bead Coating #1
`
`Trarrtadol Hydrochloride Beads
`(derived from Step 1)
`Opadry ® Clear YS-1-7006
`Purified Water, US!’
`Surelcase ® E-'3-‘F050
`Total Weight Clear Coated Sustained
`Release Beads
`Step 3: Tramadol Hydrochloride Beads
`{Build-up #2)
`
`30
`
`35
`
`40
`
`Sustained Release Beads (derived from Step 2)
`Tramadol Hydrochloride
`Opadry ® Clear YS-3-Tllll
`Purified Water. USP
`Total Weight Tra.n::tdol Hydrochloride
`Beads (Build-up #2)
`Step 4: Clear 8: Sustained Release Bead
`Casting no
`
`Tramadol Hydrochloride Beads
`(derived front Step 3)
`Opadry o Clear Y5-1-7006
`Purified Water, USP‘
`Surelease ® E-T-T050
`Total Weigh Tramadol Hydrochloride
`Sustained Release Beads
`Step 5: Capsule Filling
`
`Weight
`
`12.000
`DECO
`5.454
`4.000
`16.200 kg
`
`3.000
`
`0.360
`5.92%
`0.671
`9.032 kg
`
`8.000
`4.320
`0.072
`1.964
`12.392 kg
`
`10.000
`
`nzso
`6.450
`1.050
`11.300 kg
`
`Components
`'1'l'amadol HCI
`(OPADRY ® Clea:
`YS-3-7011)‘
`Purified Wmer. USPI
`Sugar Spheres. NP
`OPADRY ® Clear
`vs-1-70065
`SURELEASE ti) E—'if—T050“
`
`‘I: weightfweight
`(theoretical)
`68.34
`1.14
`
`mgJ'Capsule
`(theoretical)
`300
`5.01
`
`—
`12.5 -
`4.48
`
`13.54
`
`—
`54.3?
`19.66
`
`59.44
`
`B. Methods of Manufacturing and Packaging
`
`NOTE: The drug substance and excipients may be
`deagglorrterated. if needed, by milling or screening.
`
`Step 1: Preparation of Tramadol Hydrochloride Beads
`(Bead Build-up #1)
`
`65
`
`a. Preparation of Tramadol Hydrochloride Build-up Solution
`i. Atimix the batch quantity of Purified Water, USP and the
`
`Amerigen Ex. 1035, p. 5
`Amerigen Ex. 1035, p. 5
`
`

`
`7
`
`5,474,786
`
`batch quantity of Opadry® Clear YS-3-7011.
`ii. Add the batch quantity of tramadol hydrochloride and
`mix for approximately 1.5 hours.
`b. Preparation of Tramadol Hydrochloride Beads
`i. Load the bowl of a suitable bead ooater such as the Glatt
`GPCG 5 Rotor-Granulator with the batch quantity of
`sugar spheres, NF and heat until
`the bed reaches
`approximately 40° C.—60° C.
`ii. While maintaining the bed temperature at approxi-
`mately 4(}°~60° C.. spray the entire
`trarnado] hydroch1orideJ'Opadry® Clear YS—3 -7011 solu-
`tion prepared in Step l.a. onto the sugar spheres.
`iii. Remove the tramadol hydrochloride beads from the
`granulator and screen to remove any agglomeratcs and
`any line powder.
`
`Step 2: Clear and Sustained Release Bead Coating #1
`
`a. Preparation of Clear Coat #1
`Add 54.7% of the batch quantity of Purified Water, USP
`(3.240 kg) and the batch quantity of 0padry® Clear
`YS~l—';'00l5 (0.360 kg) and mix for approximately 1-2
`hours.
`b. Preparation of Sustained Release Dispersion #1
`Add 11.3% of the batch quantity of Purified Water, USP
`(0.672 kg) and 2.688 kg of Surelease® E-7-T050
`dispersion and mix for approximately 1-2 hours.
`at. Preparation of Coated Beads
`i. Transfer the batch quantity of the tramadol hydrochlo-
`ride beads prepared in Step 1. (8.0 kg) into a suitable
`head coater such as the Glatt GPCG 5 Rotor—Gra.nulator
`and heat until
`the bed reaches approximately 40°
`C.—60° C.
`
`5
`
`20
`
`30
`
`Maintain the bed temperature at the following condi-
`tions and spray:
`40° C.—-60° C. 88.9% of the 0padry® ClearYS-1 -1006
`solution prepared in Step 2.a.
`42° C.—50“ C. the batch quantity of the Surelease®
`E—'i’—7050 dispersion prepared in Step 2.b.
`40° C.—60° C. the remaining batch quantity {l l . 1%) of
`the 0padry® Clear YS-1-7006 solution prepared in
`Step 2.a.
`iii. Remove die tramadol sustained release beads derived
`in Step 2.c.ii. from the granulator and screen the beads
`to remove any agglomerates and any remaining fine
`powder.
`
`8
`granulator and screen the beads to remove any agglom-
`erates and any fine powder:
`
`Step 4: Clear and Sustained Release Bead Coating #2
`
`a. Preparation of Clear Coat
`Add 34.9% of the respective batch quantity of Purified
`Water, USP (2.250 kg) and the respective batch quan-
`tity of Opadry® Clear YS-1 -7006 (0.250 kg) and mix
`for approximately 1-2 hours.
`b. Preparation of Sustained Release Dispersion #2
`Add to a suitable stainless steel mixing tank 16.3% of the
`batch quantity of Purified Water, USP (1.050 kg} and
`4.200 kg of Surelease® E-'? -7050 dispersion and mix
`for approximately l—2 hours.
`_
`c. Preparation of Coated Beads
`i. Transfer the batch quantity of the trarnadol hydrochlo-
`ride beads prepared in Step 3. (10.0 1-:g}into a suitable
`granulator such as the Glatt GPCG 5 Rotor~Granulator
`and heat until
`the bed reaches approximately 40°
`C.—60° C.
`
`ii. Maintain the bed temperature at the following condi-
`tions and sprays:
`40° C.—60° C. 80% of the Opadry® Clear Y5-1 -7006
`solution prepared in Step 4.a.
`42° C.—50° C.
`the batch quantity of the Surelease®
`E-1-7050 dispersion prepared in Step 4.b.
`40° C.—60° C. the remaining batch quantity (20.0%) of
`the 0padry® Clear ‘(S-1-7006 solution prepared in
`Step 4.9..
`iii. Remove the tramadol sustained release beads derived
`in Step 4.c.ii. from the grarrulator and screen the beads
`to remove any agglonterates and any remaining fine
`powder.
`iv. Dry the beads in a 45° C.—55° C. dry heat oven for
`approximately 24 hours.
`
`Step 5: Capsule Filing
`
`21. Based on the in-process assay results, calculate the till
`weight of the tramadol hydrochloride sustained release
`beads.
`
`4-5
`
`the
`fill
`13. On a suitable filling machine or by hand,
`calculated amount of trarnadol hydrochloride sustained
`release heads into white, opaque, hard gelatin capsules
`(size 00).
`
`Step 3: Tramadol Hydrochloride Beads (Build-up #2)
`
`50
`
`55
`
`a. Preparation of the Tramadol Hydrochloride Build-up
`Solution
`
`i. Add the batch quantity of Purified Water, USP and the
`batch quantity of Opadry® Clear YS—3-7011.
`ii. Add the batch quantity of tramadol hydrochloride and
`mix for approximately 1-2 hours.
`b. Preparation of the Tramadol Hydrochloride Beads
`i. Load the bowl of a suitable bead coater such as the Glatt
`GPCG 5 Rotor-Granulator with the batch quantity of
`sustained release beads from Step 2. (8.0 kg) and heat
`until the bed reaches approximately 40° C.—60° C.
`ii. Spray on the entire trarnadol hydrochlon'de:'0padry®
`Clear YS-3-7011 solution prepared in Step 3.a. onto the
`heated sustained release beads, while maintaining the
`bed temperature at approximately 40° C-60“ C.
`iii. Remove the tramadol hydrochloride beads from the
`
`Example 2
`
`Preparation of Pseudophedrine sustained Release
`Capsules
`
`Follow the procedure of Example 1 but replace the
`tramadol HCl with pseudophedrine HCl and reduce all of the
`ingredients to two—thirds to produce 200 mg pseudophedrine
`sustained release capsules.
`The present invention provides for a heretofore unrealized
`consistent drug release pattern for very water soluble drugs
`such as tramadol HCl and pseudophedrine HCI from a
`sustained released pellet system. The advantages obtained
`by the multilayered pellets of the invention are indicated in
`the appended graph of FIG. 1 for comparing formulations
`for tramadol, The graph shows that the double layer head of
`the invention (i.e. two controlled release layers, Lo. 8% and
`10% controlled release layer amounts, by weight of the total
`weight of the beads) provides a more linear (i.e., more
`
`Amerigen Ex. 1035, p. 6
`Amerigen Ex. 1035, p. 6
`
`

`
`5,474,786
`
`9
`constant or uniform) release rate as compared to single
`layered beads with a single controlled release layer [i.e.,
`12.5% and 14% controlled release layer amounts by weight
`of the total weight of the beads).
`The scope of the present invention is not limited by the
`description, examples or suggested uses herein and modifi-
`cations can be made without departing from the spirit of the
`invention. The multilayered dosage forms of the invention
`may,
`for example, have other applications and uses in
`addition to those described herein, e.g. For vitamin supple-
`ments or for controlled delivery of diagnostic agents.
`Applications of the compositions and methods of the
`present invention for medical or pharmaceutical uses can be
`accomplished by any clinical, medical, and pharmaceutical
`methods and techniques as are presently or prospectively
`known to those skilled in the art. Thus it is intended that the
`invention cover any modifications and variations of this
`invention provided that they come within the scope of the
`appended claims and their equivalents.
`What is claimed is:
`I. A multilayered controlled release pharmaceutical dos-
`age form for water soluble drugs comprising a plurality of
`coated particles each comprising:
`a core comprising an inert material which is coated or
`granulated with a water soluble drug active;
`a first coating layer over the drug containing core com-
`prising a water soluble film forming polymer;
`a second coating layer over the first coating layer com-
`prising a dispersion of a film forming polymer which
`forms a controlled release layer over the coated drug
`core;
`
`a third coating layer comprising a water soluble film
`forming polymer;
`a fourth coating layer comprising additional water soluble
`drug active;
`a fifth coating layer comprising a film forming mixture of
`a water soluble film forming polymer;
`a sixth coating layer comprising a dispersion of a film
`forming polymer which forms a controlled release layer
`over the coated drug core; and
`
`25
`
`Ill}
`
`35
`
`10
`
`a final coating layer of a water soluble film fonning
`polymer.
`2. The multilayer dosage form of claim 1 wherein at least
`one of the coating layers of water soluble film forming
`polymer additionally comprises a plasticizcr.
`3. The multilayer dosage form of claim 1 additionally
`comprising an outer layer of water soluble drug active
`intended for substantially immediate release.
`4. The multilayer dosage form of claim I wherein the
`water soluble film forming polymer is selected from the
`group consisting of hydroxypropyl methylcellulose, hydro»
`ypropyl cellulose and povidone.
`5. The multilayered dosage form of claim 2 wherein the
`plasticiaer is polyethylene glycol.
`6. The multilayered dosage form of claim 1 wherein the
`dispersion of the film forming polymer which forms a
`controlled release layer is water based.
`7. The multilayered dosage form of claim 1 wherein the
`water soluble drug active is selected from the group con-
`sisting of tramadol, pseudoephedrinc, phenylpropanolamine
`and salts thereof.
`8. The multilayered dosage form of claim 1 wherein the
`drug active is very water soluble and is tramadol HCI or
`pseudoephcdrine HCl.
`9. The maltilaycred dosage form of claim 1 wherein the
`drug active is tramadol HCl.
`10. The multilayered dosage form of claim 6 wherein the
`film forming polymer is ethyl cellulose.
`11. The multilayered dosage form of claim 10 wherein the
`dispersion of the film forming polymer which forms a
`controlled release layer additionally comprises at least one
`of dibutyl sebacate or olcic acid.
`12. The rnultilayercd dosage form of claim I wherein the
`total amounts of drug active provided in each of the drug
`containing layers are sclccted to achieve a desirable plasma
`level of drug active over about a twenty-four hour period.
`13. The multilaycred dosage form of claim 1 wherein two
`or more different drug activities are provided in one or more
`drug layers.
`
`Amerigen Ex. 1035, p. 7
`Amerigen Ex. 1035, p. 7