POLYOX Water-Soluble Resins NF
`
`in Pharmaceutical Applications
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`An Introduction to POLYOX
`Water-Soluble Resins
`
`POLYO:x'hl Water-Soluble Resins, NF Grade are nonionic
`poly (ethylene oxide) polymers that meet all the specifications
`of the United States Pharmacopoeia-National Formulmy.
`They are white, free-flowing hydrophilic powders supplied in
`a wide variety of molecular weight grades, ranging from one
`hundred thousand to seven million daltons or amu.
`They are essentially tasteless, colorless, nonionic, and non-
`caloric. This unusual combination of properties makes them
`useful in a surprisingly broad array of pharmaceutical formu-
`lations. They have a long history of successful applications in
`uses such as con11'olled release solid dose matrix systems,
`transdetmal dmg delivery systems, and mucosal bioadhesives.
`Extremely Fast Hydration and Gel Formation
`POLYOX Resins are among the fastest-hydrating water-
`soluble polymers used in pharmaceutical systems. They very
`quickly form hydro gels that initiate and regulate release of
`active ingredients. Systems using POLY OX Resins are often
`superior to others in approaching zero order release models.
`
`Unusually Wide Range
`of Molecular Weights
`With molecular weights ranging from 100,000 to 7,000,000,
`POLYOX Water-Soluble Resins offer exceptional formulating
`latitude. You can select from many different options to help
`control dosage size, matrix release profiles, and production
`methods while maintaining consistent flow properties and
`tablet performance.
`Compliance With FDA and Other
`Regulatory Requirements
`POLYOX Water-Soluble Resins, NF Grade comply with the
`USP polyethylene oxide NF monograph.
`These products meet the requirements of the Food Chemicals
`Codex, the International CodexAlimentatius, and the U.S.
`National Formulary (NF). These products have also been
`approved in dmg products sold in all major European countries.
`Approval for use in Japan is under way and anticipated. The
`NF product family is listed in Table 1.
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`More Technical Assets to Help
`You Succeed Quickly
`With an expanded technical staff and assets of The Dow
`Chemical Company, we can offer an unusually broad and
`synergistic body of excipient knowledge. Our strong team of
`technical individuals in several global locations is actively
`engaged in product development, technology development,
`and pharmaceutical applications support. So when you need
`help with technical issues involving excipient behavior,
`product selection, and fommlation optimization, we can
`respond in surprisingly powerful ways.
`
`Table 1- POLYOX Water-Soluble Resins
`For Pharmaceutical Applications
`
`POL VOX Water-Soluble
`Resins, NF Grade
`
`Approximate
`Molecular Weight
`
`Viscosity Range at 25°C, cP
`5% Solution
`2% Solution
`
`1% Solution
`
`Brookfield Viscometer,
`Model RVF,
`Spindle No./Speed, rpm
`
`WSR N-10 NF
`WSR N-80 NF
`WSR N-750 NF
`WSR-205 NF
`WSR-1105 NF
`
`WSR N-12K NF
`WSR N-60K NF
`
`WSR-301 NF
`WSR Coagulant NF
`WSR-303 NF
`
`100,000
`200,000
`300,000
`600,000
`900,000
`
`1,000,000
`2,000,000
`
`4,000,000
`5,000,000
`7,000,000
`
`30-50
`55-90
`600-1,200
`4,500 - 8,800
`8,800- 17,600
`
`1/501' 1
`1/501'1
`1/10
`2/2
`2/2
`
`1/10
`3/10
`
`2/2
`2/2
`2/2
`
`400-800
`2,000 - 4,000
`
`1 ,650 - 5,500
`5,500- 7,500
`7,500-10,000
`
`The physical property data listed are considered to be typical properties, not specifications.
`C11Model RVT.
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`An Ideal Choice for
`Controlled Release Systems
`
`A hydrophilic matrix tablet is a simple-to-formulate, yet
`effective sustained-release chug-delivery system in which a
`bio-active is unifmmly distributed within a polymer matrix.
`The chug release mechanism is controlled by several variables
`in a dynamic process. Upon wetting of the tablet, the polymer
`on the tablet surface hych-ates to form a gel layer. The chug
`diffuses from this surface gel layer, which expands with time
`into the interior of the tablet, allowing diffusion of the chug
`from the tablet core.
`POLYOX Water-Soluble Resins are very hydrophilic polymers.
`They hych·ate rapidly to form a gel layer on the tablet surface
`for the release of actives. Because POLYOX Resins are non-
`ionic, no interaction between chug and polyn1ers is to be
`expected. The data presented here show how molecular
`weight and concentration ofPOLYOX Resins affect the
`release rate of a model water-soluble and water-insoluble
`chug in a matrix system.
`Experimental Procedure
`Tablet fmmulations (Table 2) were dry-blended in a double
`planetary mixer. Tablets were pressed with a single punch
`Carver Laboratmy Press in a one-half inch diameter die with
`a compression force of one metric ton. Drug release data were
`obtained from uncoated tablets in a USP-specified dissolution
`apparatus, which was equipped with baskets. The dissolution
`medium was simulated gastric fluid (without pepsin) at 37°C.
`Rotation speed of the baskets was kept at 50 rpm. All data
`presented here represent an average of a minimum of three
`determinations. UV/visible spectroscopy was used to deter-
`mine the concentration of the actives in the dissolution media.
`
`Results
`Molecular Weight
`Figure I shows the effect of molecular weights ofPOLYOX
`Water-Soluble Resins on the release rate. Increasing the
`molecular weight while maintaining a constant polymer
`concentration can ch-astically reduce the release mtes. The
`increased molecular weight leads to an increase in gel strength,
`which tends to decrease the diffusion of the chug; however,
`there is a maximum molecular weight beyond which no further
`change in release rate is affected. As can be seen, an increase
`in molecular weight from 5,000,000 to 7,000,000 does not
`appreciably alter the release mte for the water-soluble active,
`caffeine.
`
`Figure 1 -Effect of Molecular Weight of POLYOX
`Water-Soluble Resins on In Vitro Release Rate of
`Caffeine From a Matrix Tablet
`
`H,__+.~-1----::.6'"+-----l---l -
`-
`-
`
`WSR-11 05 NF
`WSR Coagulant NF
`WSR-303 NF
`
`2
`
`3
`
`4
`Time (hrs.)
`
`5
`
`6
`
`7
`
`8
`
`Table 2 -Tablet Formulations
`
`Weight Percent, Based on 500-mg Tablet
`
`Ingredients
`
`Caffeine
`
`Riboflavin
`
`POLYOX Water-Soluble Resin NF
`
`Lactose
`
`Magnesium Stearate
`
`A
`10
`
`20
`69
`
`B
`20
`
`20
`59
`
`c
`30
`
`20
`49
`
`D
`20
`
`10
`69
`
`E
`20
`
`60
`19
`
`F
`
`5
`10
`84
`
`G
`
`20
`20
`59
`
`~
`
`'
`
`~
`
`'
`
`~ ~
`
`~ ~ -~~~·:.~ ~ ~
`
`4
`• ; v~~-~~~~.=~ .:..~ -~~~.~
`
`• ~ -~· ~·
`
`'• : ·~ ·~ • ' - - :t ~' ·~:: ~· ~= ~ '.·~I ~·~, J:' .·'
`
`• ~
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`Polymer Concentration
`Figure 2 illustrates the effect of polymer concentration on
`release rate. Increasing polymer concentration increases the
`gel viscosity on the surface of the tablets, which will retard
`the diffusion of the drug fi"om the gel layer. Increasing the
`concentration from 20 to 60 percent of a relatively low
`molecular weight POLYOX Water-Soluble Resin results
`in a drug release profile very similar to that obtained fi·om
`20 percent of a high molecular weight POLYOX Resin.
`However, this concentration effect is seen only for low
`molecular weight polymer. Figure 3 shows caffeine release
`fi·om matrix tablets produced from POLYOX WSR-303 NF
`(7 ,000,000 molecular weight). When polymer concentration
`was changed from 1 0 to 60 percent in the formulation, no
`drastic changes in the release rate was obse1ved. At a very low
`polymer concentration, the initial drug release is larger, but
`the rate of release is ve1y similar to that obtained for higher
`polymer concentrations.
`
`Figure 2 - Effect of Polymer Concentration and
`Molecular Weight on In Vitro Release Rate of Caffeine
`From a Matrix Tablet With POLYOX WSR-1105 NF
`
`100
`
`80
`
`"C
`
`Q) "' "'
`~ 60
`Q)
`00:
`Q) c
`;@ 40
`"' u
`
`20
`
`/
`
`/
`
`I
`I
`I' v
`/
`
`-v I"""
`
`~~
`~
`-
`-
`-
`
`20% WSR-1105 NF
`20% WSR-303 NF
`60% WSR-1105 NF
`
`-
`
`0
`
`2
`
`3
`
`5
`4
`Time (hrs.)
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Figure 3 - Effect of Polymer Concentration on In Vitro
`Release Rate of Caffeine From a Matrix Tablet With
`POLYOX WSR-303 NF
`100.----.---,,---.----.----.----.----.----,
`
`20 1------l"'~"'--1-----+-----l---J -
`-
`
`20% WSR-303 NF
`60% WSR-303 NF
`
`0
`
`2
`
`3
`
`4
`Time (hrs.)
`
`8
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`Drug Loading
`Figure 4 summarizes matrix tablet release data obtained by
`changing the drug concentration of caffeine in POLYOX
`Water-Soluble Resins. Since diffusion is the primary kinetic
`factor in the release of water-soluble actives from matrix
`tablets, data were plotted using a Higuchi plot fmmat to
`illustrate this point better. As can be seen, the lines are almost
`parallel, showing that very little change in the release rate
`takes place when the caffeine concentration is increased from
`50 to 150 mg in 500-mg tablets.
`
`Drug Solubility
`Release of insoluble actives from hydrophilic matrix systems
`occurs through a diffusion-erosion mechanism. POLYOX
`Water-Soluble Resins swell greatly when hydrated, and the
`resulting gel layer does not erode readily. The polymer,
`therefore, is an ideal vehicle for insoluble drugs in matrix
`tablets. Figure 5 illustrates how drug-delivery profiles of
`water-insoluble actives can be manipulated with polymer and
`drug concentration in POLYOX Resin matrix tablets.
`
`Figure 4 - Effect of Drug Loading on In Vitro Release
`Rate of Caffeine From a Matrix Tablet With POL YOX
`WSR Coagulant NF
`
`Figure 5- In Vitro Release Rate of Water-
`Insoluble Actives From a POLYOX Water-Soluble
`Resin Matrix Tablet
`
`100.-----------.------------.----------~
`
`5omg
`-
`20~----~~~---r------+-_, - 100mg
`-
`150mg
`
`0
`
`1.5
`YTime (hrs.)
`
`2
`
`2.5
`
`3
`
`Time (hrs.)
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`Figure 7 - Effect of pH on Release of
`Theophylline From Matrix Tablets Using
`POL YOX Water-Soluble Resins
`
`-~ - -
`
`~
`
`~ ~
`l# I""
`
`100
`
`90
`
`80
`~ 70
`
`"' <ll &! 60
`
`<ll
`,§50
`~
`g. 40
`<ll
`.s::
`~ 30
`
`20
`
`10
`
`/
`~
`Cli"'
`~
`~
`
`-
`-
`-
`
`pH=1.1
`pH=4
`pH=6
`
`2
`
`3
`
`4
`
`6
`5
`Time (hrs.)
`
`7
`
`8
`
`9
`
`10
`
`pH
`When used in oral applications, POLYOX WSR systems do
`not show a strong pH response due to their nonionic nature.
`The data in Figure 7 show release profiles collected at different
`pH values for a theophylline matrix system. As expected, the
`release rate does not vary as a function of pH.
`
`Conclusions
`POLYOX Water-Soluble Resins NF are highly versatile
`water-soluble polymers. Upon exposure to water or gastric
`juices, they hydrate and swell rapidly to form hydrogels
`with properties ideally suited for a controlled drug-delivery
`vehicle. Their utility is not limited to the hydrophilic ma1:tix
`system that is the subject of this discussion. POLYOX
`Water-Soluble Resins NF have been successfully used in
`other drug-delivety systems, such as osmotic pumps. The
`polymers are available in a wide range of molecular weights,
`which enables the formulator to readily custom design to
`individual specifications.
`
`Figure 6 - Particle Size Effect on Riboflavin
`Release From Matrix Tablets Using POLYOX
`Water-Soluble Resins
`
`70 1----f----j
`
`60 1----f----j
`
`Mesh Size
`>60
`-
`60-100
`-
`100-200
`-
`al
`200-325
`-
`~ 50 1----f----j
`~
`L--,__<_3,2_5_~
`~40~-~-~--+-~~~~~~~q_-~--1
`·~
`'6
`~ 30
`
`3
`
`4
`
`6
`5
`Time (hrs.)
`
`7
`
`8
`
`9
`
`10
`
`Particle Size
`Particle size can play a role in matrix tablet performance
`by influencing the initial rate of hydration and gel layer
`formation. The data in Figure 6 were generated by selectively
`separating a standard POLYOX WSR sample into 5 different
`particle size fractions. Tablets were produced from each
`fraction and drug release rates were measured. The data
`indicate some variation in release rate as a function of particle
`size with the smaller particles producing slower initial release
`rates. Interestingly, extreme drug dumping is not seen even
`when using the very large particle size fraction due to the
`rapid swelling characteristics ofPOLYOX WSR.
`
`-
`
`-
`
`-~
`
`-
`
`-
`
`.
`
`c
`
`-
`
`...
`
`•
`
`7
`
`. -
`-
`
`~
`
`'
`
`•
`
`-
`
`-
`.
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`Water Granulation With POLYOX
`Water-Soluble Resins NF
`
`As environmental and manufacturing concems limit the use of
`organic solvents as granulating liquids, water is increasingly
`preferred as a granulating solvent The following study explores
`the performance ofPOLYOX Water-Soluble Resins in water
`granulation. This work indicates that POLYOX Resins can
`offer several important features in water granulation, including:
`• Ability to be water granulated in a high shear unit.
`• In addition to acting as a hydrophilic ma1rix or swelling
`agent, ability to also act as binders during granulation,
`eliminating the need for special binders.
`• Readily release water druing drying, leading to short
`drying times.
`Experimental Parameters
`
`Granulator
`High Shear Granulator equipped with chopper and impeller
`Chopper Speed .................... 3045 rpm
`Impeller Speed ...................... 450 rpm
`Fluid Bed Dryer
`Inlet Temperature .................. 60°C
`Outlet Temperature ............. .40°C
`Air Volume ............................ 280 CFM
`Drying Time .......................... l5 - 45 minutes
`Processing Variables
`Water Concentration
`Water Addition Rate
`Polymer Molecular Weight
`Responses
`Mean Particle Size
`Granule Friability
`Granule Morphology
`
`Results
`The initial set of experiments was carried out using I 00%
`POLYOX Water-Soluble Resin. This enabled evaluation of the
`polymer under vmi ous process conditions and is relevant to
`fonnulations containing high polymer and low dtug loadings.
`Figure 8 shows the median pmticle size developed as a fi.mction
`of water addition rate and concentration. The data indicate
`that particle size is inversely related to the water addition rate.
`Because no wet mashing was used in this study, rapid water
`addition limits the time for pmticle growth, leading to a
`smaller median particle size. The median pmticle size was
`found to be directly related to the final water concentration
`used in the granulation. Ten percent water was found to be
`sufficient for many granulations.
`In Figme 8 the pmple data points represent 200,000 moleculm·
`weight polymer while the blue data points represent 4,000,000
`molecular weight polymer. The polymer moleculm· weight
`did not have a significant impact on particle growth, as seen
`for the runs consisting of 10% water and an addition rate of
`60mL/min.
`
`Figure 8 - Median Particle Size
`
`115
`
`32
`
`680 -
`1730 -
`
`580 -680
`
`1870 -
`
`Note: Median particle sizes
`are listed values
`MW = 4,000,000 amu
`MW = 200,000 amu
`
`200
`
`I
`5
`
`•
`1720
`
`I
`10
`
`15
`% Water Added
`
`20
`
`25
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`Figure 9 - SEM Micrograph of Granule, 800x
`
`The granules could be &ied in the fluid bed to less than one
`percent moisture in about 15 minutes. Because no binder was
`added to the granulating liquid, additional work was petformed
`to test the susceptibility of the &ied granules to attrition.
`Because aggressive fluidization is known to cause attrition
`of friable granules, granules dried to less than one percent
`moisture were mixed in the fluid bed for an additional45
`minutes. No significant attrition was detected, indicating the
`product will withstand normal handling.
`
`Examination of the final granules by SEM indicates that the
`agglomeration leads to polymer bridging between particles
`as seen in Figure 9. The high molecular weight ofPOLYOX
`Resins would be expected to provide good granule strength.
`
`In order to compare granulation prepared via water and
`ethanol routes, a set of equivalent granulations was produced
`by these two approaches. The release profiles for the two
`tableted products are presented in Figure 10. Drug release
`from the water granulation is very similar to that seen for the
`ethanol granulation.
`
`Figure 1 0 - Riboflavin Release Profile: Water Versus
`Ethanol Granulation
`
`80
`
`20
`
`0
`
`-
`-
`
`Vector H20 Granulation
`Lab Ethanol Granulation
`
`4
`
`8
`6
`Time (hrs.)
`
`10
`
`12
`
`14
`
`Conclusions
`• POLYOX Water-Soluble Resins can be granulated using
`100%water.
`• The average particle size is dependent on the rate of water
`addition.
`• POLYOX Resins are effective binders.
`• Drug release :fi·om a water granulation is vety similar to that
`of an alcohol granulation.
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`POLYOX Water-Soluble Resins NF Provide Excellent
`Binding, Bioadhesion, and Melt Extrusion Properties
`
`Beyond their role in controlled release matrix systems,
`POLYOX Water-Soluble Resins pe1fom1 other valuable
`functions in pharmaceuticals. Often, a single POLYOX Resin
`can contribute several important properties in a single system.
`
`Direct Compression Tablet Binding
`POLYOX Resins pelform well as binders in economical direct
`compression systems. They often provide better flow and com-
`paction properties than other binders. And their lub1icity also
`assists tableting operations. This provides a system where a
`single excipient can provide both binding and rate-controlling
`properties.
`
`Mucosal Bioadhesives
`POLYOX Water-Soluble Resins offer a number of important
`properties for mucoadhesion-water solubility, hydrophilicity,
`high molecular weight, hydrogen bonding functionality, and
`good biocompatibility. These resins have a long linear chain
`structure which allows them to form a strong interpenetrating
`network with mucus. Data indicate that molecular weights of
`4,000,000 and higher have the highest level of adhesion.
`
`Using POL VOX Water-Soluble Resins NF in
`Controlled-Release Dosages by Melt Extrusion
`POLY OX Water-Soluble Resins are thennoplastic polymers
`with a low melting point of- 68°C. They can be used in melt
`extrusion processes to prepare pharmaceutical dosage forms.
`During a melt extrusion process, a mixture ofPOLYOX
`Resin, mugs, and optional fillers or plasticizers is fed into an
`extruder. The POLY OX Resin and other low melting point
`components are melted inside the extruder, and the molten
`mixture is extruded through a die mounted at the front of the
`device. The extrudate can be further processed into familiar
`shapes of tablets, caplets, or pellets.
`
`I
`
`10
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`A twin screw extruder allows low temperature extrusion
`of both low and high molecular weight POLY OX Resins.
`A small amount of vitamin E is often added to the mixture
`as an antioxidant to stabilize the solid dosage fom1. Various
`plasticizers such as water and glycerin can be added to reduce
`the melt viscosity. Solid and liquid ingredients can be added
`separately to the exttuder and mixed in situ during the
`extrusion process.
`As an example of a pharmaceutical solid dosage form produced
`by a melt exttusion process, three different grades ofPOLYOX
`Resin with high, medium, and low molecular weights were
`used to prepare tablets containing riboflavin. The POLYOX
`Resin powder was pre-mixed with riboflavin and vitamin E in
`a blender. The mixture was then fed into a twin screw exttuder
`fitted with a rod die. By using different grades of POLY OX
`Resin and adding different amounts of microcrystalline
`cellulose, the tablets cut fi:om extruded rods achieved
`sustained-release profiles ranging from 3 h to 24 h by in vitro
`dissolution tests using USP Method II at 37°C and 100 rpm in
`900 mL distilled water (Figure 11).
`
`Figure 11 -Release Profiles of Riboflavin at 3rc
`in Distilled Water From Tablets (250 mg) Cut From
`Extruded Rod Containing 15% by Weight Riboflavin
`Dispersed in Three Different Grades of POLYOX
`Resin or a Mixture of POLYOX Resin/Microcrystalline
`Cellulose ( 1:1)
`
`100
`
`'2 80
`(/) "' Q)
`Qj
`0:: 60
`c
`·~
`
`"" 0
`~ 40
`
`-
`-
`-
`-
`-
`-
`
`sample1
`sample2
`sample3
`sample4
`sample5
`sample6
`
`960 1 080 1200
`
`Sample 1: POLYOX WSR N-750 NF/microcrystalline cellulose= 1:1
`Sample 2: POLYOX WSR N-750 NF
`Sample 3: POLYOX WSR N-12K NF/microcrystalline cellulose= 1:1
`Sample 4: POLYOX WSR N-12K NF
`Sample 5: POLYOX WSR-301 NF/microcrystalline cellulose= 1:1
`Sample 6: POL YOX WSR-301 NF
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`

`

`For more information, complete literature, and product samples,
`you can reach a Dow representative at the following numbers:
`From the United States and Canada:
`call 1-800-447-4369
`fax 1-989-832-1465
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`
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`
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`
`Notice: No freedom from any patent owned by Seller or others is to be inferred. Because use conditions and applicable laws may differ
`from one location to another and may change with time, Customer is responsible for determining whether products and the information in this
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`GIVEN; ALL IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE ARE EXPRESSLY EXCLUDED.
`
`Published August 2004
`
`Printed in U.S.A.
`
`*Trademark of The Dow Chemical Company
`
`Form No. 326-00013-0804 AMS
`
`KASHIV1046
`IPR of Patent No. 9,492,393
`
`