(12) United States Patent
`Odidi et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,607,751 B1
`Aug. 19, 2003
`
`USOO6607751B1
`
`(54) CONTROLLED RELEASE DELIVERY
`DEVICE FOR PHARMACEUTICAL AGENTS
`INCORPORATING MICROBIAL
`POLYSACCHARIDE GUM
`
`(75) Inventors: Isa Odidi, Mississauga (CA); Amina
`Odldl, Mlsslssauga (CA)
`
`.
`_
`.
`.
`(73) Assignee. Intelhpharamaceutrcs C0rp.,
`Mississauga (CA)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) App1_ NO; 09/169,409
`
`(22) Filed:
`
`Oct. 9, 1998
`
`Related US. Application Data
`(60) Provisional application No. 60/061,501, ?led on Oct. 10,
`1997'
`(51) Int. Cl.7 .......................... .. A61K 9/22; A61K 9/24;
`A61K 9/10; A61K 9/ 16; A61K 47/36
`(52) US. Cl. ..................... .. 424/488; 424/485; 424/468;
`424/472; 424/499; 514/961
`(58) Field of Search ............................... .. 424/464, 485,
`424/488> 494> 472> 451> 457> 468; 514/960>
`962’ 961
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,916,899 A 11/1975 Theeuwes et al. ........ .. 128/260
`4,016,880 A
`4/1977 Theeuwes et al. ........ .. 128/260
`4,160,452 A
`7/1979 Theeuwes ................. .. 128/260
`4,200,098 A
`4/1980 Ayer et al. ................ .. 128/260
`4,756,911 A * 7/1988 Drost et al.
`4 832 958 A * 5/1989 Baudier et aL
`5,240,712 A * 8/1993 Smith et al.
`
`5,415,871 A * 5/1995 Pankhania et al.
`5,472,711 A * 12/1995 Baichwal
`
`* cited by examiner
`
`Primary Examiner—EdWard J. Webman
`(74) Attorney, Agent, or Firm—Foley Hoag LLP
`
`(57)
`
`ABSTRACT
`
`The present invention provides a controlled release device
`for sustained or pulsatile delivery of pharmaceutically active
`substances for a predetermined period of time. This inven
`tion further provides such device in Which sustained or
`pulsatile delivery is obtained by the unique blend and
`intimate mixture of pharmaceutically active substances With
`a microbial polysaccharide and uncrosslinked linear poly
`mer and Optionally a Crosslinked polymer and/Or lipophillic
`polymer and/or lipophillic polymer and/or saturated polyg
`lycolyZed glyceride. The invention also provides for the
`manufacture of such devices and pharmaceutical composi
`tions containing the same.
`
`3,845,770 A 11/1974 Theeuwes et al. ........ .. 128/260
`
`20 Claims, N0 Drawings
`
`Exhibit 1017
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`US 6,607,751 B1
`
`1
`CONTROLLED RELEASE DELIVERY
`DEVICE FOR PHARMACEUTICAL AGENTS
`INCORPORATING MICROBIAL
`POLYSACCHARIDE GUM
`
`This application claims the bene?t of Provisional appli
`cation Ser. No. 60/061,501, ?led Oct. 10, 1997.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a controlled release
`device Which provides sustained or pulsatile delivery of
`pharmaceutically active substances for a predetermined
`period of time. This invention further relates to such device
`in Which sustained or pulsatile delivery is obtained by the
`unique blend and intimate mixture of pharmaceutically
`active substances With a microbial polysaccharide and
`uncrosslinked linear polymer and optionally a crosslinked
`polymer and/or lipophillic polymer and/or saturated polyg
`lycolyZed glyceride. The invention also relates to a process
`for the manufacture of such devices and pharmaceutical
`compositions containing the same.
`
`BACKGROUND OF THE INVENTION
`
`The prior art teaches many systems for the delivery of
`pharmaceutically bene?cial agents. One such system oper
`ates by means of an osmotic pumping mechanism. HoWever,
`it suffers from being very complex and is complicated to
`manufacture. A second type of pharmaceutical delivery
`system utiliZes hydrogels either from a group consisting of
`uncrosslinked linear polymers or from a group consisting of
`crosslinked polymers. In devices using uncrosslinked
`polymers, viscosity is the rate controlling factor for drug
`release kinetics. In these systems a gelatinous layer is
`formed on the surface upon hydration. The thickness and
`durability of this gelatinous layer depends upon the
`concentration, as Well as the molecular Weight and viscosity
`of the polymer in the device. At higher concentrations the
`linear polymer chains entangle to a greater degree leading to
`virtual crosslinking and a stronger gel layer. Drug release is
`by the dissolution of polymer and erosion of the gel layer
`and hence the rate of erosion is What controls the release
`rate. Although viscosity is an important consideration in
`controlled drug release from hydrogel matrices, it is viscos
`ity under loW shear conditions that control diffusion through
`the matrix.
`Several US. Patents are directed to the various pharma
`ceutical delivery systems as mentioned above, see for
`example US. Pat. Nos. 3,845,770, 3,916,899, 4,016,880,
`4,160,452 and 4,200,098. While these systems do provide
`for the delivery of a selected pharmaceutical agent, none of
`these provide a controlled or pulsatile delivery of the phar
`maceutical agent in Which drug release is modulated by
`combining a microbial polysaccharide and uncrosslinked
`polymer. Furthermore, none of the prior art teaches a device
`comprising a microbial polysaccharide and uncrosslinked
`polymer and optionally a crosslinked polymer and/or lipo
`phillic polymer and/or saturated polyglycolyZed glyceride.
`There Was therefore a need to develop a novel controlled
`release pharmaceutical delivery device Which could be made
`in a cost efficient manner and provide for either sustained or
`pulsatile delivery of the selected pharmaceutical incorpo
`rated therein.
`
`SUMMARY OF THE INVENTION
`
`It is an object of the present invention to provide a novel
`controlled pharmaceutical release device capable of deliv
`
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`2
`ering in a controlled, continuous or pulsatile manner thera
`peutically effective amounts of pharmaceutically active
`agent for a predetermined period of time in mammals,
`especially human beings.
`According to an object of the present invention is a
`controlled pharmaceutical release device for use With a
`selected pharmaceutical to provide continuous or pulsatile
`therapeutically effective amounts of the pharmaceutical, the
`device comprising;
`about 1 to 60% by Weight microbial polysaccharide; and
`about 1 to 60% by Weight uncrosslinked linear polymer.
`The device may optionally comprise about 1 to 50% by
`Weight crosslinked polymer, about 1 to 50% by Weight
`lipophillic polymer and/or 1 to 50% by Weight saturated
`polyglycolyZed glyceride.
`According to another object of the present invention is a
`pharmaceutical composition Which provides controlled
`release of the pharmaceutical contained therein, said com
`position comprising;
`about 1 to 60% by Weight microbial polysaccharide;
`about 1 to 60% by Weight uncrosslinked linear polymer;
`and
`about 1 to 80% by Weight pharmaceutical active.
`The composition may optionally comprise about 1 to 50%
`by Weight crosslinked polymer, about 1 to 50% by Weight
`lipophillic polymer and/or 1 to 50% by Weight saturated
`polyglycolyZed glyceride. According to yet a further object
`of the present invention is a method for making a controlled
`release formulation of pharmaceutically active agents, said
`method comprising:
`blending about 1 to 80% by Weight pharmaceutical active
`With about 1 to 60% by Weight microbial polysaccha
`ride and about 1 to 60% by Weight uncrosslinked linear
`polymer to form a homogeneous blend;
`granulating said homogeneous blend and kneading to
`form Wet granules;
`drying the Wet granules to a loss on drying of about
`<5%;
`siZe reducing the dried granules to provide a granule siZe
`of about <1400 microns;
`blending the dried granules With about 0.5 to 10%
`lubricant; and
`compressing the lubricated granules into tablets.
`Preferably, the pharmaceutically active agent is intimately
`mixed With a microbial polysaccharide and uncrosslinked
`linear polymer and further Wet granulated, dried, sieved,
`lubricated and pressed into tablets.
`Optionally, to the mixture of pharmaceutical active,
`microbial polysaccharide and uncrosslinked linear polymer
`may be added about 1 to 50% by Weight crosslinked
`polymer, about 1 to 50% by Weight lipophillic polymer
`and/or 1 to 50% by Weight saturated polyglycolyZed glyc
`eride.
`In a further aspect of this invention there is provided a
`method for delivering soluble or poorly soluble pharmaceu
`tically active agents by deliberate and expert manipulation
`of the composition and ratios of a microbial polysaccharide,
`preferably xanthan gum, and uncrosslinked linear polymer,
`preferably hydroxypropylmethyl cellulose polymers,
`present in the device. The composition and ratios of the
`optional crosslinked polymer, preferably Carbopol 971P,
`and/or lipophillic polymer, preferably glyceryl behenate,
`and/or saturated polyglycolyZed glyceride, preferably gelu
`cire 44/14, may also be manipulated to vary the type of
`release provided.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`The novel controlled delivery device of the present inven
`tion provides the controlled release of a selected pharma
`
`000002
`
`

`

`US 6,607,751 B1
`
`3
`ceutically active agent in a sustained or a pulsatile manner.
`In one embodiment, the device is formulated as a compo
`sition comprising pharmaceutically active agents in a sus
`tained release matrix tablet. In another embodiment, a
`method is provided for making the controlled release phar
`maceutical delivery device.
`The present invention is simple in fabrication, permitting
`ef?cient and reproducible mass production by conventional
`techniques.
`The device comprises a mixture of about 1 to 60% by
`Weight uncrosslinked linear polymers and about 1 to 60% by
`Weight microbial polysaccharides to Which about 1 to 80%
`by Weight selected pharmaceutical active is added. Suitable
`pharmaceuticals for use in the device include but are not
`restricted to diltiaZem, glipiZide, buspirone, tramadol,
`gabapentin, verapamil, etodolac, naproxen, diclofenac,
`COX2 inhibitors, budesonide, venlafaxine, metoprolol,
`carbidopa, levodopa, carbamaZepine, ibuprofen, morphine,
`pseudoephedrine, paracetamol, cisapride, pilocarpine,
`methylphenidine, nifedipine, nicardipine, felodipine,
`captopril, terfenadine, pentoxifylline, feno?brate, aciclovir,
`Zidovudine, moclobemide, potasium chloride, lamotrigine,
`citalopram, cladribine, loratadine, pancrelipase, lithium
`carbonate, orphenadrine, ketoprofen, procainamide, ferrous
`sulfate risperidone, clonaZepam, nefaZodone, lovastatin,
`simvastatin, pravachol, ketorolac, hydromorphone,
`ticlopidine, seligiline, alpraZolam, divalproex and pheny
`toin.
`Uncrosslinked linear polymers suitable for use in the
`present invention are cellulose ethers preferably hydrox
`ypropylmethyl cellulose (HPMC). Suitable microbial
`polysaccharides for use in the invention include xanthan
`gum.
`The device may optionally comprise about 1 to 50% by
`Weight crosslinked polymer, preferably Carbopol 971P,
`about 1 to 50% by Weight lipophillic polymer, preferably
`glyceryl behenate, glyceryl palmitostearate or glyceryl, and/
`or 1 to 50% by Weight saturated polyglycolyZed glyceride,
`preferably gelucire 44/14.
`The device may optionally include about 0.5 to 10% by
`Weight lubricants such as for example magnesium stearate
`and/or talc as Well as about 0.5 to 10% by Weight granulating
`or tabletting aids such as silicone dioxide, microcrystalline
`cellulose, calcium phosphate, sodium laurel sulphate, cal
`cium sulphate and silici?ed microcrystalline cellulose.
`The device can be fabricated With any suitable pharma
`ceutical active as a tablet, a ?lm coated tablet or a capsule
`for easy ingestion.
`It Was unexpectedly found that controlled delivery
`devices comprising xanthan gum and uncrosslinked linear
`polymers together in an intimate mixture With a pharma
`ceutically active agent perform ef?cient and optimal con
`trolled release of the pharmaceutical active than if either
`polymer Were to be used alone. It Was also found that such
`delivery devices When additionally comprising crosslinked
`polymers and/or lipophillic polymers and/or saturated
`polyglycolyZed glyceride also provides ef?cient controlled
`release of the pharmaceutical active contained therein.
`Uncrosslinked linear polymers such as hydroxypropylm
`ethyl cellulose (HPMC) tend to become more neWtonian at
`loW shear and the viscosity becomes independent of shear
`rate. Xanthan gum on the other hand displays a pseudoplas
`tic nature in Which there is a linear dependence of viscosity
`as a function of the shear rate. At loW shear rates xanthan
`gum has higher viscosity compared to hydroxypropylmethyl
`cellulose (these differences are larger at even loWer shear
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`4
`rates) While the opposite is the case at higher shear rates.
`During transit in the gastrointestinal tract (GIT) a matrix
`controlled delivery device encounters regions of turbulence
`and non turbulence. It is hypothesiZed that regions of non
`turbulence present loWer shear rates to the matrix tablets,
`conditions for Which xanthan gum demonstrates higher
`viscosity than HPMC While regions of turbulence present
`higher shear rates to the matrix tablet, conditions for Which
`HPMC demonstrate a higher viscosity than xanthan gum.
`Since matrix devices rely on the development of a viscous
`layer around the tablet to control diffusion of the drug from
`the surface and interior of the tablet, the use of xanthan gum
`alone in a matrix tablet Will presumably be more ef?cient in
`regions of non turbulence While HPMC matrices Will be
`more ef?cient in regions of turbulence. HoWever, since these
`tablets encounter both environmental conditions, a con
`trolled delivery device comprising of both xanthan gum and
`HPMC together in intimate mixture With the pharmaceuti
`cally active agent(s) Will provide optimum controlled per
`formance.
`According to one embodiment of the present invention is
`the preferred form of the sustained release device Which is
`presented as a matrix tablet that is prepared using the
`folloWing steps:
`Step 1. Intimately blending a pharmaceutically active agent
`(s) (about 1—80% by Weight) With about 1—60% by Weight
`of xanthan gum and about 1—60% by Weight of hydrox
`ypropylmethyl cellulose (preferably MethocelTM pre
`mium grade type K100M CR or K4M CR) in a planetary
`or high shear mixer.
`Step 2. Granulating the homogeneous blend from step 1 With
`a granulating solution (preferably isopropyl alcohol) in a
`planetary or high shear mixer. It is preferable to knead the
`Wet mass for about 1—3 minutes after Wet granulation.
`Step 3. Drying the Wet granules in a ?uid bed dryer or tray
`dryer to a loss on drying (LOD) of about <5%. Preferably
`they are dried in a tray dryer at about >40° C. to an LOD
`of about <2%.
`Step 4. SiZe reduction of the dried granules from step 3 is
`done in a mill, preferably a Cone mill, such that granule
`siZe is about <1400 microns.
`Step 5. Intimately blending the milled granules With about
`0.5—10% by Weight of magnesium stearate and/or about
`0.5 to 10% by Weight talc in a V-blender.
`Step 6. The lubricated granules from step 5 are compressed
`into tablets using a rotary tablet press. The resulting
`tablets have a hardness of about >5 Strong Cobb units and
`a friability of about <1%.
`Step 7. Optional Other granulating or tabletting aids such as
`silicone dioxide, microcrystalline cellulose and calcium
`phosphate can be added into step 5.
`Step 8. Optional The tablet produced in step 6 can be ?lm
`coated With a suitable coating. Such coatings are Well
`knoWn in the art of pharmaceuticals. One skilled in the art
`Would readily comprehend the type of ?lm coating mate
`rials and quantity that may be used in the present inven
`tion.
`Depending upon the conditions under Which the materials
`are processed and the depending on the relative proportions
`of the several components, one obtains a product of unique
`sustained release characteristics. The sustained release char
`acteristic of the composition can be predetermined and
`varied by adjusting the makeup of the composition Within
`the aforesaid limits. The duration, uniformity and continuity
`of release of the pharmaceutically active agent(s) can be
`suitably controlled by varying the relative amount of the
`xanthan gum and HPMC.
`
`000003
`
`

`

`US 6,607,751 B1
`
`5
`Pulsatile delivery is achieved by making a unit dose such
`as a capsule containing a plurality of tablets or population of
`granules Which release the active agent at different rates or
`at different time intervals so that, for example, if one tablet
`or population of granules starts releasing ?rst and reaches a
`peak, another can start and peak as the previous one is
`declining. This results in pulsatile delivery.
`For a sustained release effect one population or a uniform
`matrix is used Which releases the pharmaceutical active
`gradually. A desired rate is obtained by manipulating quan
`tities in the composition.
`When the delivery device of this invention is administered
`to the gastrointestinal tract by oral route it comes into
`contact With an aqueous environment and hydrates forming
`a gelatinous layer. During transit in the gastrointestinal tract
`it encounters regions of non turbulence and turbulence
`Which presents loWer shear rates and higher shear rates
`respectively. Matrix devices rely on the development of a
`viscous layer around the tablet to control diffusion of the
`drug from the surface and interior of the tablet. On a
`comparative basis xanthan gum gives higher viscosity at
`loWer shear rates and HPMC give higher viscosity at higher
`shear rates. Therefore, the use of either xanthan gum or
`HPMC alone in a matrix tablet Will not give an optimum
`performance When compared to matrix tablets comprising of
`both xanthan gum and HPMC together in intimate mixture
`With the pharmaceutically active agent(s). The present
`invention consist of a controlled delivery device capable of
`optimum performance in the GIT in Which the active agent
`is in intimate mixture With both xanthan gum and HPMC
`and optionally crosslinked polymer and/or lipophillic poly
`mer and/or saturated polyglycolyZed glyceride in a matrix.
`
`EXAMPLES
`
`The examples are described for the purposes of illustra
`tion and are not intended to limit the scope of the invention.
`Methods of synthetic chemistry, pharmacy and pharma
`cology referred to but not explicitly described in this dis
`closure and examples are reported in the scienti?c literature
`and are Well knoWn to those skilled in the art.
`
`Example 1
`
`DiltiaZem Hydrochloride ER Tablets
`
`% composition
`
`Diltiazem hydrochloride
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Talc
`Magnesium stearate
`
`3O
`3O
`38
`1
`1
`
`DiltiaZem hydrochloride Was blended With xanthan gum and
`hydroxypropylmethyl cellulose in a high shear mixer until a
`homogeneous mixture Was obtained. The mixture Was
`granulated With isopropyl alcohol and dried in ?uid bed
`dryer to a loss on drying of about <2.0%. The dried granules
`Were passed through a sieve #14 mesh. The milled granules
`Were blended With talc and magnesium stearate for 5 min
`utes in a V-blender. Finally, the treated granules Were
`pressed into tablets using a rotary tablet press.
`
`6
`Example 2
`
`DiltiaZem Hydrochloride ER Tablets
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`% composition
`
`Diltiazem hydrochloride
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Talc
`Magnesium stearate
`
`3O
`10
`25
`33
`1
`1
`
`DiltiaZem hydrochloride Was blended With microcrystalline
`cellulose, xanthan gum and hydroxypropylmethyl cellulose
`in a high shear mixer until a homogeneous mixture Was
`obtained. The mixture Was granulated With isopropyl alco
`hol and dried in ?uid bed dryer to a loss on drying of about
`<2.0%. The dried granules Were passed through a sieve #14
`mesh. The milled granules Were blended With talc and
`magnesium stearate for 5 minutes in a V-blender. Finally, the
`treated granules Were pressed into tablets using a rotary
`tablet press.
`
`Example 3
`
`GlipiZide ER Tablet
`
`% composition
`
`Glipizide
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Silicone dioxide
`Talc
`Magnesium stearate
`
`4
`20
`4O
`33
`1
`1
`1
`
`GlipiZide Was blended With silicone dioxide, microcrystal
`line cellulose, xanthan gum and hydroxypropylmethyl cel
`lulose in a high shear mixer until a homogeneous mixture
`Was obtained. The mixture Was granulated With isopropyl
`alcohol and dried in ?uid bed dryer to a loss on drying of
`about <2.0%. The dried granules Were passed through a
`sieve #14 mesh. The milled granules Were blended With talc
`and magnesium stearate for 5 minutes in a V-blender.
`Finally, the treated granules Were pressed into tablets using
`a rotary tablet press.
`
`Example 4
`
`GlipiZide ER Tablet
`
`% composition
`
`Glipizide
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K4M CR
`Silicone dioxide
`Talc
`Magnesium stearate
`
`4
`20
`4O
`33
`1
`1
`1
`
`65
`
`GlipiZide Was blended With silicone dioxide, microcrystal
`line cellulose, xanthan gum and hydroxypropylmethyl cel
`lulose in a high shear mixer until a homogeneous mixture
`Was obtained. The mixture Was granulated With isopropyl
`
`000004
`
`

`

`US 6,607,751 B1
`
`7
`alcohol and dried in ?uid bed dryer to a loss on drying of
`about <2.0%. The dried granules Were passed through a
`sieve #14 mesh. The milled granules Were blended With talc
`and magnesium stearate for 5 minutes in a V-blender.
`Finally, the treated granules Were pressed into tablets using
`a rotary tablet press.
`
`Example 5
`
`Naproxyn Sodium ER Tablets
`
`% composition
`
`Naproxyn sodium
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Carbopol 971P NF
`Talc
`Magnesium stearate
`
`55
`10
`1O
`18
`5
`1
`1
`
`Naproxyn sodium Was blended With microcrystalline
`cellulose, xanthan gum and hydroxypropylmethyl cellulose
`in a high shear mixer until a homogeneous mixture Was
`obtained. This mixture Was granulated With isopropyl alco
`hol and dried in ?uid bed dryer to a loss on drying of about
`<2.0%. The dried granules Were then passed through a sieve
`#14 mesh. The milled granules Were blended With Carbopol
`971P for 10 minutes, then With talc and magnesium stearate
`for 5 minutes in a V-blender. Finally, the treated granules
`Were pressed into tablets using a rotary tablet press.
`
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`Example 6
`
`Naproxyn Sodium ER Tablets
`
`% composition
`
`45
`
`Naproxyn sodium
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Gelucire 44/14
`Talc
`Magnesium stearate
`
`55
`10
`1O
`14
`9
`1
`1
`
`Naproxyn sodium Was blended With microcrystalline
`cellulose, xanthan gum and hydroxypropylmethyl cellulose
`in a high shear mixer until a homogeneous mixture Was
`obtained. This mixture Was granulated With Gelucire iso
`propyl alcohol solution and dried in a ?uid bed dryer to a
`loss on drying of about <2.0%. The dried granules Were then
`passed through a sieve #14 mesh. The milled granules Were
`blended With Carbopol 971P for 10 minutes, then With talc
`and magnesium stearate for 5 minutes in a V-blender.
`Finally, the treated granules Were pressed into tablets using
`a rotary tablet press.
`
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`
`65
`
`8
`Example 7
`Verapamil Hydrochloride ER Tablets
`
`% composition
`
`Verapamil Hydrochloride
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Compritol 888 ATO
`Talc
`Magnesium stearate
`
`5O
`14
`1O
`14
`1O
`1
`1
`
`Verapamil hydrochloride Was blended With microcrystalline
`cellulose, xanthan gum, hydroxypropylmethyl cellulose and
`Compritol in a high shear mixer until a homogeneous
`mixture Was obtained. This mixture Was granulated With
`isopropyl alcohol and dry in ?uid bed dryer to a loss on
`drying of about <2.0%. The dried granules Were then passed
`through a sieve #14 mesh. The milled granules Were blended
`With Carbopol 971P for 10 minutes, then With talc and
`magnesium stearate for 5 minutes in a V-blender. Finally, the
`treated granules Were pressed into tablets using a rotary
`tablet press.
`
`Example 8
`Citalopram Hydrobromide
`
`% composition
`
`Citalopram hydrobromide
`Lactose anhydrous
`Microcrystalline cellulose
`Xanthan gum
`Hydroxypropylmethyl cellulose K1OOM CR
`Carbopol 971P
`Gelucire 44/14
`Compritol 888 ATO
`Talc
`Magnesium stearate
`
`5
`3O
`14
`1O
`14
`5
`10
`1O
`1
`1
`
`Citalopram hydrobromide Was blended With microcrystal
`line cellulose, xanthan gum, hydroxypropylmethyl cellulose
`and Compritol in a high shear mixer until a homogeneous
`mixture Was obtained. This mixture Was granulated With
`Gelucire isopropyl alcohol solution and dry in ?uid bed
`dryer to a loss on drying of about <2.0%. The dried granules
`Were then passed through a sieve #14 mesh. The milled
`granules Were blended With Carbopol 971P for 10 minutes,
`then With talc and magnesium stearate for 5 minutes in a
`V-blender. Finally, the treated granules Were pressed into
`tablets using a rotary tablet press.
`Although preferred embodiments have been described
`herein in detail, it is understood by those skilled in the art
`that variations may be made thereto Without departing from
`the scope of the invention or the spirit of the appended
`claims.
`What We claim:
`1. A controlled release pharmaceutical device Which pro
`vides sustained or pulsatile delivery of pharmaceutically
`active substances for a predetermined period of time, the
`device comprising;
`about 25 to 60% by Weight microbial polysaccharide; and
`about 15 to 60% by Weight cellulose ether.
`2. The device of claim 1, Wherein said device additionally
`comprises about 1 to 80% by Weight pharmaceutical active.
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`000005
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`US 6,607,751 B1
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`9
`3. The device of claim 2, wherein said pharmaceutical
`active is selected from the group consisting of naproxen,
`COX2 inhibitors, budesonide, venlafaxine, metoprolol,
`carbidopa, levodopa, carbamaZepine, ibuprofen, morphine,
`pseudoephedrine, paracetamol, cisapride, pilocarpine,
`methylphenidine, nicardipine, felodipine, captopril,
`terfenadine, pentoxifylline, feno?brate, aciclovir,
`Zidovudine, moclobemide, potassium chloride, lamotrigine,
`citalopram, cladribine, loratadine, pancrelipase, lithium
`carbonate, orphenadrine, ketoprofen, procainamide, ferrous
`sulfate risperidone, clonaZepam, lovastatin, simvastatin,
`pravachol, ketorolac, hydromorphone, ticlopidine,
`seligiline, alpraZolam, divalproex and phenytoin.
`4. The device of claim 3, Wherein said device additionally
`comprises at least one agent selected from the group con
`sisting of about 1 to 50% by Weight crosslinked polymer;
`about 1 to 50% by Weight lipophillic polymer; about 1 to
`50% saturated polyglycolyZed glyceride and mixtures
`thereof.
`5. The device of claim 4, Wherein said device additionally
`comprises;
`about 0.5 to 10% by Weight lubricant.
`6. The device of claim 5, Wherein said lubricant comprises
`magnesium stearate or talc.
`7. The device of claim 1, Wherein said microbial polysac
`charide is xanthan gum.
`8. The device of claim 1, Wherein said cellulose ether is
`hydroxypropylmethyl cellulose.
`9. The device of claim 4, Wherein said device additionally
`comprises about 1 to 65% granulating or tabletting aids.
`10. The device of claim 9, Wherein said granulating or
`tableting aids are selected from the group consisting of
`silicon dioxide, microcrystalline cellulose, calcium
`phosphate, calcium sulphate, sodium laurel sulphate and
`silici?ed microcrystalline cellulose.
`11. The device of claim 4, Where said device is fabricated
`as a unit dose for pulsatile delivery of the pharmaceutical
`active or as a uniform matrix tablet for a sustained release of
`the pharmaceutical active.
`12. The device of claim 11, Wherein said device is
`formulated as a tablet having a hardness of about >5 Strong
`Cobb units and a friability of about <1%.
`13. A pharmaceutical composition comprising:
`over 25 to 60% by Weight microbial polysaccharide;
`about 15 to 60% by Weight cellulose ether; and
`about 1 to 80% by Weight pharmaceutical active.
`14. The composition of claim 13, Wherein said composi
`tion additionally comprises at least of the agents selected the
`group consisting of about 1 to 50% by Weight crosslinked
`polymer; about 1 to 50% by Weight lipophillic polymer;
`about 1 to 50% saturated polyglycolyZed glyceride and
`mixtures thereof.
`15. The composition of claim 14, Wherein said composi
`tion additionally comprises about 0.5 to 10% by Weight
`lubricant.
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`10
`16. The composition of claim 15, Wherein said composi
`tion additionally comprises about 1 to 65% granulating or
`tabletting aids.
`17. A pharmaceutical composition comprising;
`about 25 to 60% by Weight xanthan gum;
`about 15 to 60% by Weight cellulose ether;
`about 1 to 80% by Weight pharmaceutical active;
`at least one of the agents selected from the group con
`sisting of;
`about 1 to 50% by Weight crosslinked acrylic acid
`polymer; about 1 to 50% by Weight lipophillic poly
`mer selected from the group consisting of glyceryl
`behenate, glyceryl palmitostearate and glyceryl
`stearate; about 1 to 50% saturated polyglycolyZed
`glyceride
`about 0.5 to 10% by Weight lubricant selected from the
`group consisting of at least one of magnesium stear
`ate and talc; and
`about 1 to 65% by Weight granulating or tableting aids
`selected from the group consisting of silicone
`dioxide, microcrystalline cellulose, calcium
`phosphate, sodium laurel sulphate, calcium sulphate
`and silici?ed microcrystalline cellulose and mixtures
`thereof.
`18. The composition of claim 17, Wherein the pharma
`ceutical active is selected from the group consisting of
`COX2 inhibitors, budesonide, venlafaxine, metoprolol,
`carbidopa, levodopa, carbamaZepine, ibuprofen, morphine,
`pseudoephedrine, paracetamol, cisapride, pilocarpine,
`methylphenidine, nicardipine, felodipine, captopril,
`terfenadine, pentoxifylline, feno?brate, aciclovir,
`Zidovudine, moclobemide, potassium chloride, lamotrigine,
`citalopram, cladribine, loratadine, pancrelipase, lithium
`carbonate, orphenadrine, ketoprofen, procainamide, ferrous
`sulfate risperidone, clonaZepam, lovastatin, simvastatin,
`pravachol, ketorolac, hydromorphone, ticlopidine,
`seligiline, alpraZolam, divalproex and phenytoin.
`19. The controlled release pharmaceutical composition of
`claim 1, comprising about 4% by Weight glipiZide, about
`20% by Weight microcrystalline cellulose, about 40% by
`Weight xanthan gum, about 33% by Weight hydroxypropy
`lmethyl cellulose, about 1% by Weight silicone dioxide,
`about 1% by Weight talc and about 1% by Weight magne
`sium stearate.
`20. Acontrolled release pharmaceutical composition com
`prising about 55% by Weight naproxyn sodium, about 10%
`by Weight microcrystalline cellulose, about 10% by Weight
`xanthan gum, about 14% by Weight hydroxypropylmethyl
`cellulose, about 9% by Weight saturated polyglycolyZed
`glyceride, about 1% by Weight talc and about 1% by Weight
`magnesium stearate.
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`000006
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