Multi-Particulate Dosage Form for Oral Controlled Release ...

Multi-Particulate Dosage Form for OralControlled Release: DevelopmentConsiderationsNavnit H. Shah, Ph.D.Hoffmann La-Roche, Inc.

Rationale for Oral CR MultiparticulateSystemsAttributes Multiparticulate Single UnitGastric Emptying Uniform Variable (some effect of unit size)Inter- and IntrasubjectVariabilityFood Effects(on release and PK)Safety concerns dueto dose dumpingLowMinimalMinimalHighSignificant effect on the integrity ofdosage form particularly forhydrophilic matrixSignificant (drugs with narrowtherapeutic index)Drug LoadingComplianceOften limited but improvedwith technology (e.g.extrusion)High (often beads incapsules)Less frequent intakeHigh drug loading possibleCould be a concern if unit size islarge.Release Modulation Customized profile possible Some what Difficult

Application of Multiparticulate DeliverySystems• Extended Release Dosage Forms• Controlled Release (zero order)• Controlled Release (first order)• Controlled Release for drugs with pHdependent solubility• Controlled Release for sparingly soluble drugs• Pulsatile Release / Bi or Multiphasic Release• Site specific Release (e.g. colonic)

Major Types of Multiparticulate Systems(based on Drug Release)• Diffusion Controlled Release via MembraneMembrane CoatedWater Soluble Drugs• Erodible Matrix ReleaseSparingly / Poorly Soluble Drugs

% ReleaseIn-vitro Release Patterns for drug releasefrom CR systems1009080706050Fickian diffusion - drugrelease via diffusion4030201000 2 4 6 8 10 12Time (hrs)Non- Fickian diffusion - drug releasevia diffusion and erosion100Zero order release -constant release rate% Fraction Released60504030201000 2 4 6 8 10 12Time (hr)% Fraction Released8060402000 2 4 6 8 10Time (hr)

Diffusion based Multiparticulate Systems

Diffusion Based Release Mechanism fromMembrane Coated Multi-particulate SystemMembrane DiffusionPore DiffusionDiffusion throughplasticized membraneOsmotic DiffusionOzturk et al., J of Controlled Release, 14 (1990) 203-213

Diffusion Controlled Multiparticulate SystemSeal Coat (Optional)Polymers withPlasticizerDrug + Binder+Other ExcipientsSugarSphereWater Soluble Polymer(Pore Former; Optional)Drug release is controlled via diffusionpermeating through the functional coat

Diffusion Controlled Multiparticulate SystemProcess OutlineDrug + Binder + FillerGranulationPlastic Wet MassDrug + Binder+ Additive(solid / liquid)Layering on Inert Core(non-pareils)Fickian diffusionthrough coatingmembraneExtrusionSpheronizationCoatingSR PolymerCoatingBase CoatPrimarily WaterSoluble Drugs thatestablish conc.gradientFILM DIFFUSIONPELLETS

Polymers & Plasticizers Used in Modifiedrelease Film coatingNatural Polymers• Shellac• Zein• Rosin estersSynthetic polymers• Ethyl cellulose• Cellulose acetate• Acrylic resins• Methyl Methacrelate• Silicone elastomers• Poly (vinyl chloride)• Poly (vinyl acetate)Commonly Used Plasticizers• Triacetin• Triethylcitrate• Tributylcitrate• DibutylSebecate• Diethylphthalate• Dibutylphthalate• PEG• PG• Acetylated monoglyceride

Commercially available Aqueous PolymericDispersionBrand Type component DispersiontypeEudragitL 30 DRS/RL30DNE 30DCopoly (MA-EA)Copoly (EA-MMA-TAMCl)Copoly (EA- MMA)LatexPseudo latexLatexAdditivesTween 80, SDSSorbic acid,No surfactantPNPAquacoat Ethyl cellulose Pseudo latex Cetyl alcohol, SDSSureleaseEthyl cellulose Pseudo latex DBS, oleic acid,ammonia, fumed silicaEC N-10F Ethyl cellulose PowderAquateric CAP Pseudo latex Pluronic F-68Myvacet 9-40Tween 80Coateric Poly (VAP) Powder Plasticizer, pigmentAquoat HPMC-AS PowderKollicoat SR 30D Polyvinyl acetate Povidone, SDS

Typical In Vitro Characterization• Dissolution at various pHs• Dissolution in 40% Alcohol in 0.1 N HCl (FDA recommended method)• Dissolution under stressed hydrodynamic conditions mimicking fedconditions• Texture Analysis• Dynamic DSC to determine glass transition of the functional coat• DMA to determine mechanical strength of the film• Potential aging of the film upon storage or curing• Scanning Electron Microscopy of the Film Surface Morphology(Top and Cross-sectional View)

% Dissolved% AbsorbedMembrane-Coated Multiparticulate SystemPaddle Method• Diffusion is the rate limiting step ofdissolution, typically not impacted byrotational speed• IVIVC development can be establishedunder fasting conditions• Mechanical strength of the film mustwithstand the hydrodynamic stressobserved under fed conditions to avoiddose dumping• Dissolution profiles should be minimallyaltered in the presence of alcohol to avoidalcohol induced dose dumping10080100 RPM 50 RPM60402000 2 4 6 8Time (hr)12010080rsq=0.9760402000 20 40 60 80 100 120% Dissolved

Impact of Substrate (Core) onDrug Release

Core (Substrate) variables and their potentialImpact on Film Coating AttributesVariableSubstrate size and sizedistributionSurface roughnessDensityFriabilityChemical Properties of thedrugSolubility of DrugMolecular weight of DrugNature of ExcipientsImpactBatch surface area, Quantity of coating tobe appliedUniformity of distribution of coatingDrug erosion during coating processInteraction with coating- effect ondiffusivity and partitioning effectDrug release rateAbility of Drug to penetrate throughmembraneAbility of core to absorb liquid duringcoating and dissolution test ( or after drugadministration), Osmotic effect

Aqueous Film-forming Binders : Layering on SugarSpheresEquipment: Glatt GPCG5Spray Rate: 30 g/minInlet: 58 CDrug 25.0%Polymer 4.0%PEG 4600 0.8%Talc 1.0%Water to 100%Courtesy: Aqualon

Effect of various Core (Substrate) variables onDissolutionEffect of Substrate SizeEffect of Substrate SurfaceRef: Porter, S. and Ghebre-Sellassie, I.(1994), “Key factors in the development of Modified-release pellets”, in Multiparticulate oraldrug delivery, Ghebre-Sellassie, I., USA: Marcel Dekker, Inc.

Effect of various Core (Substrate) variableson DissolutionEffect of Method of Preparation of SubstratePelletsMethod of Preparing PelletsSpheronization vs LayeringMethod of Layering PelletsSprinkling vs. SprayingShah et al., Pharmaceutical Technology October 1994

Effect of API properties on in vitro releaseusing different coating systemShah et al., Pharmaceutical Technology October 1994

Impact of Membrane (Coating)on Drug Release

Film Formation MechanismsAqueous dispersionparticles coalesce inthe presence of heatand plasticizerIn organic solution,Polymer chain relax andform coherent film upondryingAdapted from Siepman Et al, CRS 2003

Membrane (Coating) variables and their potentialimpact on membrane propertiesPolymer typeVariableMolecular weight of the PolymerPlasticizers (type and concentration)Soluble/Insoluble additivesConc. of solid contents in coatingliquidPhysicochemical properties ofSolvent/vehicleMethod of PreparationSeal CoatingImpactPermeability characteristics of membrane, Filmformation,Tg of membraneFilm mechanical strength and elasticityFilm flexibility, Tg of membrane, Coalescence oflatex membranePermeability of membrane, Film strength andelasticityCoating uniformity, Drying rateDrying rate, Porosity of membraneInteraction of coating ingredients, variability inmembrane performanceSmoothness of the surface of the pellets,Prevent drug interaction with the functional coating

Mechanical properties of film formingpolymersPolymer PlasticizersCelluloseAcetateEthyl CelluloseTensile StrengthSD (psi)Elongation(%)SDModulus ofElasticity SD(ksi)DBS 4845 175 7.8 1.0 176.7 1.3TEC 4387 116 4.9 0.3 224.4 4.8Triacetin 3418 110 3.5 0.3 217.2 2.8DBS 1076 115 1.9 0.3 67.3 5.4TEC 2189 110 3.0 0.1 110.0 3.8Triacetin 4201 135 6.3 0.4 180.4 3.8Drug Dev. Ind. Pharmacy, 21(8), 955-963(1995)

Effect of plasticizers on mechanical properties of filmforming polymersElongation (at break) withtriacetin and propyleneglycolInfluence of plasticizer onminimum film formingtemperature (mft)Courtesy: BASF

Effect of membrane coating properties on in vitrorelease using different coating system:pre-plasticized system vs. external plasticizationAquacoatSureleaseShah et al., Pharmaceutical Technology October 1994

Effect of Plasticizer and Molecular weightEffect on Drug ReleaseCourtesy: Aqualon

Effect of various Membrane (coating) variables onReleaseEffect of coating levelEffect of inclusion of water-solubleadditivesRef: Porter, S. and Ghebre-Sellassie, I.(1994), “Key factors in the development of Modified-release pellets”, in Multiparticulate oraldrug delivery, Ghebre-Sellassie, I., USA: Marcel Dekker, Inc.

Impact of Process on DrugRelease

Process variables and their potential impacton membrane (coat) propertiesEquipmentAspectsWurster Vs. RotorImpactSpray RateNozzle Size/Atomizing AirPressure/VolumeDrying Conditions• Air Volume• Inlet Air TemperatureFilm structure, processing time,uniformity of the filmPattern of spray zone, drop size, uniformity ofstructure of the film, friability of pelletsMost critical for batch reproducibility toachieve consistent membrane structure, drugrelease, and coalescence of the film (foraqueous polymeric dispersion)• Humidity** Highly recommended to control an inlet air humidity

Various Spray ProcessesCourtesy: Aqualon

Process variable and their effect on in vitro releaseEffect of Product temperatureinlettemperature+ air flow rateEffect of nozzle heightEffect of CuringEffect of Spray rateRef: Porter, S. and Ghebre-Sellassie, I.(1994), “Key factors in the development of Modified-release pellets”, inMultiparticulate oral drug delivery, Ghebre-Sellassie, I., USA: Marcel Dekker, Inc.

Effect of Scale Factor on drug release frommembrane coated pellets

Most Commonly Manufacturing ChallengesObserved• Porosity of the film related to:• Excessive spray drying of the organic solvent coating system(faster drug release)• Gradual evolution of entrapped organic solvent (slower drug release)• Incomplete coalescence of the coatings from aqueous polymericdispersions (faster drug release)• Gradual coalescence (curing) the coatings from aqueous polymericdispersions (slower drug release)• Stress cracks of the film induced by over vigorous during coating or dryingprocesses• Polymeric film characteristics could be different depending batch size (masseffects), coating efficiency, drying conditions• Level of the functional coat needs to be established in scale-up batch

Erodible Matrix Multiparticulates

Why Erodible Matrix ?• Film controlled diffusion requires concentrationgradients to be established• dC/dt = A.D {Cs-Co}/h• Poorly soluble drugs with low value of Cs do notestablish good concentration gradients• dC/dt = K (constant) - zero-order• dC/dt = Kt n- power law kinetics• Erodible matrix provides drug release inassociation with erosion of the polymer

Typical Composition of Erodible MatrixMultiparticulatesCore Particle• Drug• Erodible SR Matrix Polymer• Plasticizer• BinderDownstream Additives• Fillers• Colorants

Erodible Matrix Multiparticulates – Process OutlineDrug + Plasticizer + Binder+ SR Polymer / FillerGranulationPlastic Wet MassExtrusionSpheronizationERODING MATRIXPELLETS

Illustration of Eroding Matrix during drug releasematrix pelletEroding layerErosion Time = tRate of Erosion = dM / dtErosion Volume = dV / dt

Pellet size is reduced by 90% (pellet volume by99.9%) after 12 h indicating bulk erosion at a constantrate.Image Analysis of Erosion of Matrix Pellets duringDissolution at various time intervals0 hrs, 2.0 mm 2 hrs, 1.75 mm 4 hrs, 1.7 mm6 hrs, 1.5 mm 10 hrs, 0.8 mm 12 hrs, 0.2 mm

Drug Release from Erodible Matrix PelletsMatrix Erosion as a function of Bulk Erosion VolumeCorrelation of Matrix Erosion with DrugReleased(2 mm Pellets, 10% w/w Drug Load, Eudragitpolymers 25%L 100-55 & 75% S100, n =5+SE)Correlation of Drug Released with ErosionVolume(2 mm Pellets, 10% Drug Load, Eudragitpolymers 25% L 100-55 & 75% S 100)PERCENT DRUG RELEASED &MATRIX EROSION (%w/w)100806040Matrix Erosion, r 2 = 0.951y = 8.021 + 7.830 x20Drug Release, r 2 = 0.964y = 3.110 + 8.214 x00 2 4 6 8 10 12DRUG RELEASED (%)100806040200r 2 = 0.96Drug ReleasedErosion Volume Reduction00 2 4 6 8 1010080604020EROSION VOLUME REDUCTION (%)TIME (hours)TIME (hours)Matrix erosion rate is dependent upon reductionin bulk erosion volume during dissolution

Formulation factors that influence drugrelease from Erodible Matrix Pellets100DRUG RELEASE RATE (%/hour)50403020100.8 mm1.2 mm2.0 mm00 5 10 15 20 25RESIDENCE TIME (minutes)Pellet SizeDRUG RELEASED (%)806040200Eudragit L 100-55 : S 1001 : 1.51 : 3.00 2 4 6 8 10 12TIME (hours)Polymer RatiosDRUG RELEASED (%)1008060402000%w/w5%w/w10%w/w20%w/w30%w/w40%w/w0 4 8 12 16 20 24TIME (hours)DrugLoading• Larger the pellet, slower the release(surface area effect)• With higher drug loading or solubilizeddrug, release rate tends to be firstorderdue to conc. gradient• Higher SR polymer results in slowerrelease rate

Comparison of Erosion vs. Diffusion(Poorly soluble vs. Solubilized Drug Pellets)Dissolution of Nifedipine pellets V/sNifedipine:Pluronic F-68 pellets100n = 4+S.E2 h80Drug Released (%)604020Nifedipine:Pluronic SD Pellets1:11:0.5Nifedipine Pellets4 hD(V, 0.5) = 2.31 um00 4 8 12 16 20 24Time (hours)DiffusionErosionPellets of nifedipine pellets prepared without a solid dispersion exhibitdrug release by erosion. Solubilization by dispersion in Pluronic resultsin gradients that deviate from zero-order kinetics (additional diffusion

Comparison of Erodible Multiparticulate vs.Disintegrating Single UnitPlasma concentration of Nifedipine Matrix Erosion Pellets and SoftGelatin Capsules in DogsConc of Nifedipine in plasma (ug/mL)2.01.61.20.80.40.0Matrix Erosion Pellets (30 mg/day/dog)Soft Gel Capsules (30 mg/day/dog)0 2 4 6 8 10 12 14 16 18 20 22 24 26Time (hours)n = 4+S.E.Compared to gelatin capsules that show a typical immediate releaseprofile, the matrix pellets erode at a constant rate providing asteady-state conc. over almost 24 h period in dog

Specialized Delivery Systems – SomeTechnologies and Examples

Pulsatile ReleaseCombination of drug with organic acid or salt on iner core, top coated withpolymer• Variable lag times controlled by thickness of coating layer• Pulsatile release profiles controlled by the quantity and type of acid or saltSite-Specific ReleaseColon-Targeting Coating LayerDrug CoreSustained-Release Coating LayerColon-targeted, pH-triggered, and sustained-release oral drug delivery technology formulti-unit dosage forms, for both local and systemic therapies.A multi-layer coating protects drug in the GI tract and controls drug release in thecolon.

Pulsatile ReleaseAqueous solutionPulsed releaseEudrapulse ®Courtesy: DegussaIn-vitro dissolution profile of Etilefrine Plasma conc. – time profiles after oralformulation at pH 1.2dosing of two Etilefrine formulationsDiffucaps ®Courtesy: Eurand

• Reduced peak-trough fluctuationsthan IR tabletsFocalin ® XR (Dexmethylphenidate HCL XR capsules)Bi-modal Release SODAS ® Delivery System• Dexmethylphenidatehydrochloride extended-releasecapsules indicated for thetreatment of ADHD• Contains immediate release andenteric coated beads• Bimodal plasma concentrationtimeprofile– Two distinct peaks 4 hrsapart• Focalin XR is bioequivalent to twoIR tablet doses taken 4 hrs apart

Examples of Multiparticulate TechnologiesTECHNOLOGIES COMPANIES MECHANISM / PRINCIPLE OF RELEASEDiffucapsOrbexaEudrapulseEudracolEurandDeGussaSR and Pulsatile ReleaseFilm diffusion via polymer coatingSite-specific and pulsatile releasePULSYS Middlebrook Pulsatile ReleaseSODAS / CODAS Elan Sustained and/or Pulsatile ReleaseSDD Bend Research Spray-dried dispersion beads / EntericReleaseMulti-Burst URL Pharma Multiparticulate mini-tabletsSR and/or Pulsatile

Some Examples of MarketedMultiparticulatesDRUG BRAND COMPANIES RELEASEMixed salts of asingle entityamphetamineAdderall XR Shire, US QD /double pulse drug layered and SR polymercoated beadsMorphine sulfate Avinza King QD / IR+SR layered beads in capsuleCarbamazepine Carbatrol Shire, US BID / IR+SR+Enteric beads in capsuleEquetro ERValidusCarvedilol Coreg CR GSK QD / IR+SR polymer coated beads in capsuleDexmethylphenidate Focalin XR Novartis QD / Bi-modal pulsatile releaseIR+Enteric delayed release beads in capsuleMethylphenidate Metadate CD UCB Inc. QD /30%IR + 70% SR coated beadsPropranolol HCl Innopran XL GSK QD / Delayed release SR coated beads incapsuleMesalamine Pentasa Shire, US Controlled release beads in capsuled-amphetaminesulfateSpansule GSK QD/IR+SR coated beads in capsuleFluvoxamine maleate Luvox CR Jazz QD / polymer coated beads in capsuleCyclobenzaprine HCl Amrix Cephalon QD/ polymer coated beads in capsulePhysicians’ Desk Reference 2008

AcknowledgmentsDipen DesaiRaman IyerHarpreet SandhuKetan Mehta

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