(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0037883 A1
`(43) Pub. Date:
`Feb. 26, 2004
`Zhou et al.
`
`US 2004OO37883A1
`
`(54) CONTROLLED RELEASE DOSAGE FORMS
`(76) Inventors: Fang Zhou, Centreville, VA (US); Paul
`Maes, Potoma, MD (US)
`
`Related U.S. Application Data
`(60) Provisional application No. 60/357,851, filed on Feb.
`21, 2002.
`
`Correspondence Address:
`Crowell & Moring, LLP
`P.O. Box 14300
`Washington, DC 20044-4300 (US)
`
`(21) Appl. No.:
`
`10/370,109
`
`(22) Filed:
`
`Feb. 21, 2003
`
`Publication Classification
`(51) Int. Cl. ................................................... A61K 9/24
`(52) U.S. Cl. .............................................................. 424/471
`(57)
`ABSTRACT
`The invention provides stable controlled release monolithic
`coating compositions for use in coating pharmaceutical oral
`dosage forms comprising a polyglycol having a melting
`point greater than 55 C. and an aqueous dispersion of a
`neutral ester copolymer lacking functional groups.
`
`KASHIV1048
`IPR of Patent No. 9,492,392
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`US 2004/0037883 A1
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`Feb. 26, 2004
`
`CONTROLLED RELEASE DOSAGE FORMS
`
`RELATED APPLICATIONS
`0001. This application claims priority from U.S. provi
`sional patent application No. 60/357,851 filed Feb. 21, 2002.
`
`FIELD OF THE INVENTION
`0002 This invention relates to a novel monolithic film
`coating for obtaining controlled release of drugs from oral
`dosage forms.
`
`BACKGROUND
`0003. The manner in which chemicals or drugs are
`administered has gained increasing attention in the past two
`decades. Normally, a chemical is administered in a high dose
`at a given time only to have to repeat that dose Several hours
`or days later. This is not economical and Sometimes results
`in damaging Side effects. As a consequence, increasing
`attention has been focused on methods of giving drugs
`continually for prolonged time periods and in a controlled
`fashion. Controlled or Sustained release dosage forms pro
`vide a therapeutic dose of the drug Soon after administration,
`and then gradually release the drug over an extended period
`of time. The primary method of accomplishing this con
`trolled release has been through incorporating the drugs
`within polymers or to Surround or encapsulate a core com
`prising the drug with a polymer coat. Depending on the type
`and amount of drug, as well as the type and amount of
`polymer and other pharmaceutically acceptable excipients
`the desired controlled release profile can be obtained.
`0004. The majority of polymers used to develop coatings
`for controlled release dosage forms are hydrophobic and can
`be applied either dry, from a Solution, or Suspension. AS
`most of these polymers are poorly Soluble in water, they are
`usually applied by dissolving the polymer in an organic
`Solvent and then Sprayed onto the drug core and evaporating
`off the Solvent. The use of organic Solvents, however, is
`considered problematic for Several reasons. The most obvi
`ous reason relates to the Safety hazards associated with the
`use of organic Solvents. Organic Solvents in general are
`highly flammable and carcinogenic. Further, organic Sol
`vents are expensive and the Storage, disposal and use of
`organic Solvents raise environmental concerns. Accordingly,
`it would be desirable to prepare aqueous Suspensions or
`Solutions of controlled release coatings comprising hydro
`phobic polymerS Suitable for coating a wide variety of drug
`COCS.
`0005 Eudragit(R) NE30D, which contains 30% solids, is
`one of the first acqueous polymeric dispersions used for
`coating pharmaceutical dosage forms. Eudragit(R) NE30D
`has many advantages over other polymers for use as a film
`former for obtaining a controlled release drug profile and is
`thus ideally Suited for controlled or Sustained release drug
`formulations. The polymer forms a soft, flexible film at room
`temperature without any plasticizer. Also, no reactions or
`absorptive effects are observed when the polymer comes in
`direct contact with a therapeutically active agent. It is
`prepared by emulsion polymerization and consists of neutral
`copolymers of ethyl acrylate-methyl methacylate esters that
`are insoluble over the entire physiological pH range but will
`Still Swell in water and give permeable membranes. The
`permeability is independent of pH and is thus suitable for the
`
`development of pH-independent modified-release oral dos
`age forms, provided that the Solubility of the drug is also
`pH-independent.
`0006. One of the most significant differences between
`aqueous polymeric Solutions and dispersions is the role
`water plays during film formation. In Solutions, water is a
`Solvent and drying is accompanied by an excessive increase
`in Viscosity, which in turn Suppresses the rate of evaporation.
`ExceSS energy is therefore required to drive off the water. In
`contrast, in polymeric dispersions Such as EudragitE)
`NE30D, water is only a dispersion medium and does not
`Solvate the polymerS. Consequently, leSS heat is needed to
`evaporate the water. Fast water evaporation coupled with the
`high Solids content of the dispersion significantly reduces
`processing time. These properties are especially critical
`when dealing with highly water-Soluble or moisture Sensi
`tive therapeutically active agents.
`0007. The pigment binding capacity of Eudragit(R)
`NE30D is very high, so that up to -2-3 parts by weight of
`additives can be incorporated into 1 part by weight of dry
`polymer without affecting the film properties. The polymer
`is also compatible with a wide variety of pharmaceutical
`excipients.
`0008 Plasticizers are generally added to coating formu
`lations to modify the physical properties i.e., the glass
`transition temperature (Tg) of the polymer to make it more
`uSable. The Tg is the temperature at which an amorphous
`polymer (or the amorphous regions in a partially crystalline
`polymer) changes from a hard and relatively brittle condi
`tion to a viscous or rubbery condition. Plasticizers function
`by decreasing the Tg of the polymer So that under ambient
`conditions the films are Softer, more pliable and often
`Stronger, and thus better able to resist mechanical StreSS.
`Eudragit(R) NE30D, however, has a low Tg and accordingly
`does not require the use of plasticizers. In fact, addition of
`plasticizers can be detrimental as it can increase the ViscoS
`ity of the Eudragit(R) NE30D formulation and negate one of
`the distinct advantages of the dispersion over the polymeric
`Solution. Incorporation of plasticizers into EudragitE)
`NE30D formulations can also increase the tackiness of the
`coat and complicate the coating process (Ghebre-Sellassie
`and Nesbit. Application of Eudragit E30D in Controlled
`Release Coatings in Aqueous Polymeric Coatings for Phar
`maceutical Forms, J. McGinity Ed., 1989, Marcel Dekker,
`Inc., pp 247-266).
`0009. Due to its low Tg, Eudragit(R) NE30D is sensitive to
`excessive drying conditions or exposure to high tempera
`tures. Ghebre-Sellassie and Nesbit (Application of Eudragit
`E30D in Controlled-Release Coatings in Aqueous Poly
`meric Coatings for Pharmaceutical Forms, J. McGinity Ed.,
`1989, Marcel Dekker, Inc., pp. 247-266) state that excessive
`drying of Eudragit(R) NE30D coats can be detrimental as
`Such conditions do not allow the coating formulation to
`Spread out evenly and promote particle deformation and
`coalescence. Also, during the coating process, the product
`temperature should be kept at around 26 C. If the product
`temperature is very high, the coating material becomes tacky
`owing to the low Tg of EudragitE NE30D, which leads to
`agglomeration of the coated product. Ghebre-Sellassie and
`Nesbit also emphasize that Eudragit(R) NE30D coated prod
`ucts should not be stored at temperatures above 40 C., as
`Stability tests conducted at elevated temperatures may not
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`correlate with the long-term behavior of Eudragit(R) NE30D
`coated products at room temperature.
`0.010 Attempts have been made in the prior art to design
`microporous aqueous polymer coatings Suitable for use on
`drug cores to obtain controlled or Sustained release profiles
`using the Eudragits, and in particular Eudragit(R) NE30D.
`U.S. Pat. No. 5,529,791 for example, teaches controlled
`release dosage forms of Diltiazem in which the Diltiazem
`drug core is Surrounded by a water-Soluble and/or disperS
`ible film forming polymer or copolymer constituting the
`microporous membrane. The polymers or copolymers taught
`include the polyacrylates and polymethacrylates of the
`Eudragit type, such as Eudragit NE30D, L30D, and RS30 D,
`ethylcelluloses, hydroxypropyl cellulose and hydroxypropy
`lmethylcellulose and their derivatives. In addition to the
`polymer or copolymer, the microporous membrane contains,
`preferably, talc and/or magnesium Stearate as a lubricant,
`polyvinylpyrrolidone as a plasticizer, titanium dioxide as a
`pigment, Tween 80 as an emulsifier, and Silicone oil as an
`antifoaming agent. Other plasticizers taught include triace
`tin, dibutylpthalate, dibutylsebacate, citric acid esters, poly
`ethyleneglycols, and polypropyleneglycols. The EudragitE)
`NE30D coated beads were cured for 16 hours at 50° C.
`(Example 3) or for 15 hours at 45° C., 5-10° C. beyond the
`recommended temperature for Eudragit(R) NE30D. Further,
`long-term Stabilization data was not presented for the coated
`products, and accordingly, it is not known what effect the
`elevated temperature had, if any, on the Stability of the
`controlled release dosage form of Diltiazem.
`0011 U.S. Pat. No. 5.286,493 is directed to stabilized
`controlled release formulations having an aqueous acrylic
`polymer coating. The 493 patent also teaches the use of
`controlled release coatings covering a Solid dosage form.
`The coating is derived from aqueous dispersions of an
`acrylic resin, which provides a Substantially stable release
`pattern of a drug from the dosage form. The acrylic resins
`taught are the ammonio methacrylate co-polymers as for
`example Eudragit(R) RL30D, RS30D and combinations
`thereof. The acrylic coatings include an effective amount of
`a suitable plasticizing agent. The stable Eudragit(R) RL30D
`and/or RS30D coated products are cured at temperatures
`above the Tg of the acrylic polymers. The 493 patent does
`not teach the use of Eudragit(R) NE30D.
`0012 U.S. Pat. No. 5,478,573 teaches delayed, sustained
`release propranolol pharmaceutical preparations purportedly
`achieved by Surrounding a water-Soluble drug core with a
`hydratable diffusion barrier which delays drug release by for
`about 2-10 hours. The hydratable diffusion barrier is said to
`comprise a film-forming polymer Such as acrylic resin or
`ethyl cellulose or mixtures thereof and an additive which
`controlls the rate of hydration and permeability of the
`diffusion barrier. The preferred insoluble film-forming poly
`mers are aqueous dispersions of fully esterified acrylic resins
`such as Eudragit(R) NE30D. The additives controlling the
`rate of hydration and permeability of the diffusion barrier are
`preferably Selected from the group consisting of fully esteri
`fied acryclic resins containing quaternary amine Side chains,
`anionic Surfactants, lubricants, plasticizers, inert water
`soluble materials and mixtures thereof. The 573 patent
`teaches that the drug beads coated with the aqueous poly
`meric dispersion are dried at 35 C. to 60° C. for 8 hours to
`5 days. No data is presented on the long-term stability of the
`products.
`
`0013 Another controlled release pharmaceutical dosage
`form using an aqueous acrylic polymer dispersion is taught
`in U.S. Pat. No. 5,871,776. The controlled release profile is
`obtained, however, using multiple layers of films. The
`outermost layer is comprised of the aqueous acrylic polymer
`dispersion. The preferred acrylic polymer is EudragitE)
`NE30D. The coatings may also contain other pharmaceuti
`cally acceptable excipients Such as fillers, anti-adherents,
`pharmaceutically acceptable pigments and lubricants/gl
`idants. The coated drug pellets are cured at a temperature in
`the range of from about 30° C. to about 50° C., preferably
`from about 35 C. to about 45 C. and most preferably about
`40° C. for a period of about 5 to about 10 days, an preferably
`about 7 days. The inventors surprisingly found that in
`contrast to the preferred Short curing times taught in the prior
`art, long curing times help stabilize the release of the drug
`from the coated pellets after long Storage periods.
`0014 International
`Patent
`Publication No. WO
`02/058677 describes a film coating composition comprising
`an aqueous acrylic polymer dispersion, a Surfactant, and
`Sodium Stearyl fumarate. The acrylic polymer dispersion is
`preferably Eudragit(R) NE30D. There does not appear to be
`any teaching as to the curing temperature and furthermore
`no data is presented with regard to long-term Stability of the
`coated product.
`0015. In summary, it would seem that although the prior
`art teaches the use of aqueous acrylic dispersion coatings of
`Eudragit(R) NE30D, in most part, the prior art does not seem
`to have overcome long term Stability problems of products
`coated with aqueous EudragitE NE30D dispersions. Where
`the products have been found to be stable, the length of
`curing is very long and this is inefficient to the manufactur
`ing process and also raises problems with Storage of Scale-up
`product. Accordingly, and given the advantages and Versa
`tility of EudragitE NE30D, it would desirable that a stable
`controlled or Sustained release coat be developed with Short
`curing times to enhance process times. It is therefore an
`object of this invention to develop Such a product.
`
`SUMMARY OF THE INVENTION
`0016. This invention is related to a novel monolithic
`Stable controlled release coating for use in coating oral
`pharmaceutical dosage forms.
`0017. In one aspect, the coating comprises an aqueous
`dispersion of a neutral ester copolymer without any func
`tional groups, a poly glycol having a melting point greater
`than 55 C., and one or more pharmaceutically acceptable
`excipients, wherein Said coating composition is coated onto
`Said oral pharmaceutical dosage forms and cured at a
`temperature at least equal to or greater than the melting point
`of the poly glycol.
`0018. In another aspect, the invention provides a con
`trolled release dosage form comprising a core, wherein the
`core comprises an effective amount of at least one thera
`peutically active agent, and one or more first pharmaceuti
`cally acceptable excipients, and a stable controlled release
`monolithic coating composition for coating Said core, Said
`coating comprising an aqueous dispersion of a neutral ester
`copolymer without any functional groups, a poly glycol
`having a melting point greater than 55 C., and one or more
`pharmaceutically acceptable excipients, wherein Said coat
`ing composition is coated onto Said oral pharmaceutical
`
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`dosage forms and cured at a temperature at least equal to or
`greater than the melting point of the poly glycol.
`0019. In one embodiment, the neutral ester copolymer
`without any functional groupS is Selected from the group
`consisting of Eudragit(R) NE30D and Eudragit(R) NE40D.
`Preferably, the neutral ester copolymer without any func
`tional groups is Eudragit(R) NE30D. The neutral ester
`copolymer without any functional groups is present in an
`amount from about 1% to about 35% by weight of the
`coating composition.
`0020. In one embodiment, the poly glycol is selected
`from the group consisting of polyethylene glycol 6000,
`polyethylene glycol 8000, polyethylene glycol 10000 and
`polyethylene glycol 20000. The poly glycol is present in an
`amount from about 0.1% to about 10% by weight of the coat
`composition. Preferably, the poly glycol is polyethylene
`glycol 8000.
`0021. The addition of pharmaceutically acceptable
`excipients to the coating composition is contemplated and
`can include anti-tacking agents, emulsifying agents, hydro
`philic agents, anti-foaming agents, flavourants, colorants,
`Sweeteners and any combination thereof. The preferred
`ant-tacking agent is talc, the preferred hydrophilic agent is
`hydroxypropyl methylcellulose, the preferred ant-foaming
`agent is Simethicone, the preferred emulsifying agent is
`polyoxyethylene Sorbitan mono-oleate, and the preferred
`colorant is titanium dioxide.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0022. The present invention is directed to novel aqueous
`dispersions of neutral ester copolymers without any func
`tional groups Suitable for use as coatings for controlled or
`Sustained release drug dosage forms. The coating formula
`tion is quite versatile in that it can be used to coat a variety
`of drug cores and can be easily manipulated to obtain the
`desired drug release profile. In another embodiment, the
`invention consists of a controlled release pharmaceutical
`composition, in one embodiment, a tablet, comprising at
`least one form of a therapeutically active agent, wherein the
`pharmaceutical composition comprises a core and a stable
`controlled release coating of the invention.
`0023
`I. Cores
`0024. The core comprises an effective amount of a thera
`peutically active agent and at least one pharmaceutically
`acceptable excipient, in one embodiment a lubricant, a
`binder and/or filler, and optionally a glidants as well as other
`pharmaceutically acceptable excipients.
`0.025 A wide variety of therapeutically active agents is
`contemplated. These include but are not limited to anti
`tuSSives, anti-histamines, decongestants, alkaloids, mineral
`Supplements, Vitamins, antacids, ion exchange resins, anti
`cholesterolemics, anti-lipid agents, anti-arrhythmics, anti
`pyretics, analgesics, appetite SuppreSSants, anti-depressants,
`expectorants, anti-anxiety agents, anti-ulcer agents, anti
`inflammatory Substances, coronary dilators, opioid agonists,
`cerebral dilators, peripheral vasodilators, antibiotics, anti
`Virals, psycho-tropics, anti-manics, Stimulants, gastrointes
`tinal agents, Sedatives, anti-diarrheal agents, anti-anginal
`drugs, vasodilators, anti-hypertensive drugs, vasoconstric
`tors, migraine treatments, anti-infectives, tranquilizers, anti
`
`psychotics, anti-tumor drugs, anticoagulants, antithrombic
`drugs, hypnotics, anti-emetics, anti-nauseants, anti-convul
`Sants, neuromuscular drugs, hyper- and hypoglycemic
`agents, thyroid and anti-thyroid agents, diuretics, anti-Spas
`modics, uterine relaxants, mineral and nutritionaqladditives,
`anti-obesity drugs, anabolic drugs, erythropoietic drugs,
`anti-asthmatics, cough SuppreSSants, mucolytics, H-antago
`nists, anti-uricemic drugs. Mixtures are operable depending
`on the type of drugs. The skilled artisan will know, based on
`his technical knowledge, which drug combinations are
`acceptable. The therapeutically active agent(s) are present in
`an amount from about 5% to about 99% by weight of the
`cores. The amount present is highly dependent on the
`agent(s), the desired controlled release profile, and the
`strength of the desired dosage form. Different forms of the
`therapeutically active agent are also contemplated. One form
`of the therapeutically active agent may be the individually
`optically active enantiomers of the therapeutically active
`agent. Pharmaceutically acceptable Salts, as for example
`pharmaceutically acceptable addition Salts, of the therapeu
`tically active agent(s) are also Suitable. Suitable pharmaceu
`tically acceptable addition Salts may be the hydrochloride
`Salt, the hydrobromide Salt, the hydroiodide Salt, the Sac
`charinate Salt etc.
`0026 Glidants improve the flowabilitye of the excipient
`powder by reducing intraparticulate friction. This is espe
`cially important during tablet production at high production
`Speeds and during direct compaction. Examples of glidants
`include but are not limited to Starch, talc, lactose, Stearates
`(Such as for example magnesium Stearate), dibasic calcium
`phosphate, magnesium carbonate, magnesium oxide, cal
`cium silicate, Cabosil"M, colloidal silica (Syloid"M) and
`Silicon dioxide aerogels. Glidants, if present, range in
`amounts from greater than about 0% to about 20%, with
`amounts of about 0.1% to about 5% being typical.
`0027 Lubricants ensure that tablet formation and ejec
`tion can occur with low friction between the Solid and the die
`wall. High friction during tabletting can cause a Series of
`problems, including inadequate tablet quality (capping or
`even fragmentation of tablets during ejection, and vertical
`Scratches on tablet edges) and may even stop production.
`Lubricants are thus included in almost all tablet formula
`tions. Such lubricants include but are not limited to adipic
`acid, magnesium Stearate, calcium Stearate, Zinc Stearate,
`hydrogenated vegetable oils, Sodium chloride, SteroteX,
`polyoxyethylene, glyceryl monoStearate, talc, polyethylene
`glycol, Sodium benzoate, Sodium lauryl Sulfate, magnesium
`lauryl Sulfate, Sodium Stearyl fumarate, light mineral oil and
`the like may be employed, with Sodium Stearyl fumarate
`being preferred. Waxy fatty acid esters, Such as glyceryl
`behenate, sold as “CompritolTM products, can be used.
`Other useful commercial lubricants include "Stear-O-
`WetTM” and “MyvatexTMTL”. Mixtures are operable. Lubri
`cants are used in amounts typically ranging from greater
`than about 0% to about 10%, with about 0.01% to about
`5.0% by weight of the tablet preferred.
`0028. It is well known in the art that besides reducing
`friction, lubricants may cause undesirable changes in the
`properties of a tablet. The presence of a lubricant in the
`excipient powder is thought to interfere in a deleterious way
`with the bonding between the particles during compaction
`and thus reduce tablet Strength. Because many lubricants are
`hydrophobic, tablet disintegration and dissolution are often
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`retarded by the addition of a lubricant. Such negative effects
`are Strongly related to the amount of lubricant present. Other
`considerations known in the art include the manner in which
`a lubricant is mixed, the total mixing time and the mixing
`intensity. In order to avoid these negative effects, hydro
`philic substances may be substituted for the hydrophobic
`lubricants. Examples include, but are not limited to, Surface
`active agents and polyethylene glycol. A combination of
`hydrophilic and hydrophobic Substances can also be used.
`0029 Anti-adherents reduce adhesion between the
`excipient powder mixture and the punch faces and thus
`prevent particles Sticking to the punches, a phenomenon
`know in the art as "Sticking” or “picking, and is affected by
`the moisture content of the powder. One example of anti
`adherent is microcrystalline cellulose. Many lubricants Such
`as magnesium Stearate have also antiadherent properties.
`However, other substances with limited ability to reduce
`friction can also act as antiadherents. Such Substances
`include for example talc and Starch. Mixtures are operable.
`Antiadherents, if present, range from about 0% to about 20%
`by weight of the tablet depending on the antiadherent being
`used.
`0030 Sorbents are substances that are capable of Sorbing
`Some quantities of fluids in an apparently dry State. Thus,
`oils or oil-drug Solutions can be incorporated into a powder
`mixture, which is granulated and compacted into tablets.
`Other examples of Sorbing Substances include microcrystal
`line cellulose and Silica.
`0031 Diluents or fillers are added to increase the bulk
`weight of the blend resulting in a practical size for com
`pression. The ideal diluent or filler should fulfill a series of
`requirements, Such as: be chemically inert, be non-hygro
`Scopic, be biocompatible, possess good biopharmaceutical
`properties (e.g. water Soluble or hydrophilic), good technical
`properties (such as compactibility and dilution capacity),
`have an acceptable taste and be cheap. AS a Single Substance
`cannot fulfill all these requirements, different Substances
`have gained use as diluents or fillers in tablets.
`0.032
`Lactose is a common filler in tablets. It possesses
`a Series of good filler properties, e.g. dissolves readily in
`water, has a pleasant taste, is non-hygroscopic and fairly
`non-reactive and shows good compactibility. Other Sugars or
`Sugar alcohols, Such as glucose, Sucrose, Sorbitol and man
`nitol, have been used as alternative fillers to lactose, prima
`rily in lozenges or chewable tablets because of their pleasant
`taste. Mannitol has a negative heat of Solution and imparts
`a cooling Sensation when Sucked or chewed.
`0033. Apart from Sugars, perhaps the most widely used
`fillers are celluloses in powder forms of different types.
`Celluloses are biocompatible, chemically inert, and have
`good tablet forming and disintegrating properties. They are
`therefore used also as dry binders and disintegrants in
`tablets. They are compatible with many drugs but, owing to
`their hygroscopicity, may be incompatible with drugs prone
`to hydrolyse in the Solid State. The most common type of
`cellulose powder used in tablet formulation is microcrystal
`line cellulose.
`0034. Another important example of a diluent or filler is
`dibasic and tribasic calcium phosphate, which is insoluble in
`water and non-hygroscopic but is hydrophilic, i.e. easily
`wetted by water. Other examples of diluents include but are
`
`not limited to di- and tri-basic Starch, calcium carbonate,
`calcium Sulfate, and modified Starches. Many diluents are
`marketed in “direct compression” form, which adds other
`desirable properties, Such as flow and binding. There are no
`typical ranges used for the diluents, as targeted dose and size
`of a tablet are variables that influence the amount of diluent
`that should be used.
`0035 Binders (also sometimes called adhesives) are
`added to ensure that tablets can be formed with the required
`mechanical Strength. Binders can be added in different ways:
`(1) As a dry powder, which is mixed with other ingredients
`before wet agglomeration; (2) As a Solution, which is used
`as agglomeration liquid during wet agglomeration. Such
`binders are often referred to as “solution binders”, and (3) As
`a dry powder, which is mixed with the other ingredients
`before compaction (Slugging or tabletting). Such binders are
`often referred to as “dry binders”. Common traditional
`Solution binders are Starch, Sucrose, and gelatin. More
`commonly used binders with improved adhesive properties,
`are polymerS Such as polyvinylpyrrolidone and cellulose
`derivates Such as for example hydropropyl methylcellulose.
`Examples of dry binders include microcrystalline cellulose
`and crosslinked polyvinylpyrrolidone. Other examples of
`binders include but are not limited to pregelatinized
`Starches, methylcellulose, Sodium carboxymethylcellulose,
`ethylcellulose, polyacrylamides, polyvinyloxoazolidone and
`polyvinylalcohols. Binders, if present, range in amounts
`from about greater than about 0% to about 25% depending
`on the binder used.
`0036. The manufacturing process of the core can be as
`follows. The at least one therapeutically active agent is first
`granulated with the at least one binder, in one embodiment
`a granulator, but not necessarily a fluidized bed granulator.
`The at least one binder is first dissolved or dispersed in a
`Suitable solvent, in one embodiment water. The Solution or
`Suspension of the at least one binder is then Sprayed onto the
`at least one therapeutically active agent in a granulator, in
`one embodiment a fluidized bed granulator. For example,
`fluidized bed granulators manufactured by Glatt (Germany)
`or Aeromatic (Switzerland) can be used for this operation.
`An alternative proceSS can be to use a conventional or high
`Shear mixer for granulation. If necessary, the at least one
`therapeutically active agent can be mixed with a filler, prior
`to the granulation Step. Granules once dried can be mixed
`with the other pharmaceutically acceptable excipients, espe
`cially with the at least one lubricant, but also with at least
`one glidant and any other pharmaceutically acceptable
`excipient Suitable to improve processing. The mixture of
`granules (in one embodiment with the at least one lubricant),
`and optionally at least one glidant is pressed into tablets.
`Alternatively, the at least one therapeutically active agent
`and the at least one lubricant can be mixed in a granulator,
`in one embodiment a fluidized bed granulator, and heated to
`the melting point of the at least one lubricant to form
`granules. This mixture can then be mixed with at least one
`Suitable filler and compressed into tablets. Also, it is possible
`to mix the at least one therapeutically active agent and the
`at least one lubricant (in one embodiment polyvinyl alcohol)
`in a granulator, in one embodiment a fluidized bed granu
`lator, and then to press the resulting granules into tablets.
`Tablets can be obtained by Standard techniques, in one
`embodiment on a (rotary) press (for example Manesty
`Betapress(R) fitted with suitable punches. The resulting
`tablets are hereinafter referred as tablet cores.
`
`KASHIV1048
`IPR of Patent No. 9,492,392
`
`

`

`US 2004/0037883 A1
`
`Feb. 26, 2004
`
`0037. The tablet cores are then coated with the semi
`permeable coating designed to achieve a controlled release
`of the at least one therapeutically active agent.
`II. Coating Formulation
`0038
`0.039
`Particularly useful neutral ester copolymers with
`out any functional groups constituting the coat of the inven
`tion described herein are Eudragit(R) NE30D, Eudragit(R)
`NE40D (Rohm America LLC). The preferred polymer is
`Eudragit NE30D and is present in an amount of from about
`1% to about 35% by weight of the coat depending on the
`therapeutically active agent used and the controlled release
`profile desired. Hydrophilic agents may also be included in
`the coat to promote wetting of the coat when in contact with
`gastrointestinal fluids. Such hydrophilic agents include
`hydrophilic water Soluble polymerS Such as hydroxypropyl
`methylcellulose (HPMC), hydroxypropyl cellulose (HPC)
`and combinations thereof. HPMC is the preferred hydro
`philic water Soluble polymer. If hydrophilic agents are to be
`included in the coat composition the agents should be
`present in an amount from about 0.1% to about 10% by
`weight of the coating composition, preferably from about
`0.1% to about 5% by weight of the coating composition and
`most preferably from about 0.1% to about 3% by weight of
`the coating composition.
`0040. The coat formulation also comprises a polygycol
`with a melting point of greater than 55 C. The poly glycol
`is Selected from the group consisting of polyethylene glycol
`6000, polyethylene glycol 8000, polyethylene glycol 10000,
`and polyethylene glycol 20000. The preferred poly glycol is
`polyethylene glycol 8000. The poly glycol is present in an
`amount of from about 0.1% to about 5% by weight of the
`coat. Other Suitable polyglycol derivatives having a melting
`point at least of 55 deg C. can be, but are not limited to,
`Poloxamer 188, Poloxamer 338, Poloxamer 407, Polyeth
`ylene Oxides, Polyoxyethylene Alkyl Ethers, and Polyoxy
`ethylene Stearates.
`0041. In addition to the copolymers and the poly glycol,
`the coating formulation comprises other pharmaceutically
`acceptable excipients. The excipients can include but are not
`limited to anti-tacking agents, emulsifying agents, antifoam
`ing agents, flavourants, colourants, etc. It is known in the art
`that depending on the intended main function, excipients can
`affect the properties of the coat in a Series of ways, and many
`Substances used in coat formulations can thus be described
`as multifunctional. A skilled worker will know, based on his
`technical knowledge, which pharmaceutically acceptable
`excipients are Suitable for the desired controlled release
`coating composition.
`0042. The tackiness of polymeric films is important for
`the coating of Solid dosage forms and for the Subsequent
`curing Step (post coating thermal treatment). During coating
`with either cellulosic or acrylic polymers, an unwanted, and
`Sometimes irreversible agglomeration of Several granules or
`beads or, in the worst case, of the complete batch, can occur,
`especially at higher product processing temperatures.
`Accordingly, the addition of anti-tacking agents to coating
`formulations is desirable. The anti-tacking agents which can
`be used include but are not limited to adipic a