In the last few decades, a number of probabilistic models

for drug delivery have been developed. Of particular

interest are those that model controlled release systems

to provide targeted dose delivery. Controlled release

is achieved by using polymers with dierent dissolution

characteristics. We present here a model based

on Monte Carlo and Cellular Automata approaches, for

simulating drug release from coated microspheres in the

gastro-intestinal tract. Controlled release is obtained using ethylcellulose as the coating polymer. Modelling features, such as the drug and coating dissolution are nontrivial, since material is non-homogenously dispersed

and the dissolution exhibits complex behaviour. Important

underlying mechanisms of the process, such as

erosion, are described here

Barat, Ana

Bezbradica, Marija

Crane, Martin

Ruskin, Heather J.

In the last few decades, a number of probabilistic models\ud
for drug delivery have been developed. Of particular\ud
interest are those that model controlled release systems\ud
to provide targeted dose delivery. Controlled release\ud
is achieved by using polymers with dierent dissolution\ud
characteristics. We present here a model based\ud
on Monte Carlo and Cellular Automata approaches, for\ud
simulating drug release from coated microspheres in the\ud
gastro-intestinal tract. Controlled release is obtained using ethylcellulose as the coating polymer. Modelling features, such as the drug and coating dissolution are nontrivial, since material is non-homogenously dispersed\ud
and the dissolution exhibits complex behaviour. Important\ud
underlying mechanisms of the process, such as\ud
erosion, are described here

Name not available

PROBABILISTIC MODELS FOR DISSOLUTION OF ETHYLCELLULOSECOATED MICROSPHERESMarija Bezbradica, Ana Barat, Heather J. Ruskin, and Martin CraneCentre for Scientific Computing and Complex Systems Modelling, School of ComputingDublin City University, Irelandemail: mbezbradica@computing.dcu.ieKEYWORDSDiscrete Simulation, Monte Carlo, Cellular Automata,Microspheres, Drug DissolutionABSTRACTIn the last few decades, a number of probabilistic mod-els for drug delivery have been developed. Of particu-lar interest are those that model controlled release sys-tems to provide targeted dose delivery. Controlled re-lease is achieved by using polymers with different disso-lution characteristics. We present here a model basedon Monte Carlo and Cellular Automata approaches, forsimulating drug release from coated microspheres in thegastro-intestinal tract. Controlled release is obtained us-ing ethylcellulose as the coating polymer. Modelling fea-tures, such as the drug and coating dissolution are non-trivial, since material is non-homogenously dispersedand the dissolution exhibits complex behaviour. Im-portant underlying mechanisms of the process, such aserosion, are described here.INTRODUCTIONDrug delivery systems (DDS) are pharmaceutical sys-tems designed for transporting drugs into the body. Thecomputational modelling of DDS is a constantly devel-oping field, with the potential to become an integralpart of pharmaceutical research, as some modern drugformulations are very complex and the influence of sys-tem composition and variables on the release profiles isnot fully understood. In-silico modelling of DDS can,therefore, be of benefit in reducing the cost of experi-ments, (involving large amount of in vitro testing), aswell as length of time needed to introduce the drug tothe market. Controlled drug delivery systems are a typeof DDS, the primary objective of which is to deliver drugat the desired rate to a targeted site in the body. Con-trol is maintained by using polymers of different struc-tures. Consequently, polymer dissolution is one of themost important problems to solve in achieving this typeof release.Here, we present a probabilistic model based on MonteCarlo (MC) and Cellular Automata (CA) approaches,for simulating controlled release from coated micro-spheres. The work is rooted in an ongoing industrial col-laboration and aims to address the release problem forthe drug (cyclosporine) in targeting the gastro-intestinal(GI) tract. As one of a number of suitable coating mate-rials, we model the use of ethylcellulose (EC), a generallynon-invasive polymer with good film-forming capabili-ties. It is both an inert and hydrophobic polymer but,when maintained under high humidity, can absorb waterin large amounts (Geraghty 2004). In general, propertiesof ethylcellulose make it ideal for use in matrix agents,for prolonged release, or as a coating material.THEORYThe first step in modelling the dissolution is to deter-mine the in vitro dissolution rate under various externalconditions, as measured in the dissolution test appara-tus. Standard test methods for measuring those ratesare outlined in the pharmacopoeias (European Pharma-copoeia, United States Pharmacopoeia). Here, we usedthe paddle apparatus II, (USP II), which allows us tomimic metabolic conditions, such as change of temper-ature, type of solution (pH and dynamic flux of thesolution), by varying speed of the paddle, and monitorexperimentally their influence on the drug dissolutionrate.Theoretical models will vary according to the type andcomplexity of the system, and can be used to exploreexperimental in vitro data. Theories are generally di-vided into three broad groups: mechanistic, empiricaland probabilistic (Siepmann and Siepmann 2008). Thefirst two groups take the top-down approach, start fromknown parameters and use specific deterministic releaserate equations for each individual problem, (i.e. to rep-resent physical laws and empirical information). Themost important properties must be either known fromthe manufacturing process or be possible to calculate,which is not straightforward given the complex natureof the formulations. Conversely, for complex detail mod-elling, bottom-up theories, (incorporating stochastic as-sumptions), have the potential to yield better predic-tions while requiring less initial information. These sim-ulate release curves by observing the probabilistic be-haviour of individual particles and have the advantageof providing a simplified representation of the system,Figure 1: Simplified Internal Morphology of one 3DSphere Simulating Drug Dissolution through CoatingLayer (Ethylcellulose). Enlarged: Part of the Spherewith Definition of Model Cell TypesFigure 2: Simulation Stages: Initial Stage (left), Dur-ing Release, with Gelatine (centre), After all Gelatine isDissolved (right)(Barat et al. 2008b).Monte Carlo methods have numerous applications,ranging from fluid dynamics, space and traffic modellingand statistical physics, to financial analysis (Li et al.2007, Sopasakis 2004, Tezuka et al. 2005). In one of thefirst direct MC models of DDS, microstructural changesin bioerodible polymers were simulated (Go¨pferich andLanger 1993). MC is also often used as a frameworkfor Cellular Automata movement. In a CA system, adiscrete grid of individual cells is defined, where eachcell can have one of a number of defined states. Thebehaviour of each cell is governed by a set of rules thatdescribe the local state transitions over discrete timesteps, (Zygourakis 1990).Drug Dissolution PhenomenaImportant phenomena in polymeric drug delivery sys-tems include: (i) diffusion: the motion of molecules froma region of higher to one of lower concentration i.e. flux.In the modelling of DDS, diffusion is often described byFick’s laws, (Crank 1975). In one dimension, Fick’s firstFigure 3: Release Profiles as a Function of the Degra-dation Rate Lambda (λ)law can be represented as:J = −D δcδx(1)where J is the diffusion flux, D is the diffusion coefficientand c is the concentration; (ii) degradation: the processwhereby chain scission occurs causing polymer chains tobecome oligomers and monomers, facilitating easy re-lease. Degradation is the first step of erosion (Go¨pferich1996); (iii) erosion: the loss of material from a polymerdue to degradation. It determines the release rate of thedrug (Siepmann and Go¨pferich 2001). When a polymererodes it leaves space for the drug to be released from thecompact, or for water penetration. Two types of erosionare defined (Langer and Peppas 1983): Surface erosion isa homogeneous process and represents the stage duringwhich the size of the compact decreases while the shaperemains constant; the compact loses material only fromits surface; Bulk erosion is a heterogeneous process withmaterial being lost from the whole compact, althoughthe size remains constant.MODEL FEATURESIn a previous project (Barat et al. 2008a), (Barat et al.2008b), microspheres filled with polylactic-co-glycolicacid (PLGA) polymer were modelled. In these, drugis homogeneously dispersed throughout the sphere andcontained within a polymer. Understanding the phe-nomena occurring in polymeric spheres was achievedthrough dimensional (3D) stochastic Cellular Automataand agent-based modelling. The rationale for introduc-ing the agent-basis is simplification of the interactionof system elements using specifically designed entities(agents), which have simple properties and character-istics. The influence of a number of parameters defin-ing release curves was investigated, including porosity,drug loading, sphere size and type of neighbourhood,(Von Neumann or Moore). Some of the earlier resultsare illustrated (Figure 3), which show how the sphereporosity growth dynamics affect the release rate.Current WorkThe modelled device now consists of a drug, non-homogenously dispersed in a coated sphere, where thecoating predominantly controls the rate of drug release.The aim of the model is to determine how different prop-erties of the device, such as coating thickness or size ofthe sphere, affect the release rates. Monte Carlo andCellular Automata methods are used to describe thesystem in terms of a 3D grid of cells, with erosion anddiffusion as the main release mechanisms. This discreteapproach is preferred over a continuous one, (used inmechanistic theories), due to straightforward mimick-ing of the real system which is discrete by nature. Eachcell can have one of several possible states, described inthe (Table 1). The state transitions are influenced bythe states of all the cells in the Von Neumann neigh-bourhood for a 3D matrix (i.e. 26 neighbouring cells).In its initial state, the drug is taken to be randomlydispersed in the form of ”packets” inside a gelatinoussphere, coated by a polymer layer. Diffusion of the druginside the sphere is represented as a random walk of drugpackets, influenced by concentration differences betweenneighbouring cells. The highest probability for move-ment will be in the direction of the largest concentrationgradient, based on the Fick’s first law.Behaviour of coating layer cells is based on work,(Go¨pferich and Langer 1993), where scission of the poly-mer chains and formation of pores follows the Erlangdistribution:e(t) = λteλt, t ≥ 0 (2)The rate of the pore formation is characterised by λwhich defines the lifetime, t, of an individual EC cell:t =1λln(U) (3)where U takes randomly distributed values between 0and 1. When the cell lifetime is reached, the cell isconsidered to be eroded, and forms a channel throughwhich the drug packet can diffuse. This occurs at arate slower than the diffusion rate inside the coating,(solvent cells), reflecting the influence of permeabilityof the membrane (Laaksonen et al. 2009). The releaserate is measured by counting the number of packets thatreach the buffer zone, which is assumed to have perfectsink conditions.RESULTS AND EXPLANATIONSThe simulation was developed in C++ with OpenGLused for graphical representation. The matrix size wasFigure 4: Release Profiles as a Function of the Simula-tion Time IntervalFigure 5: Simulated Release Profiles Against Experi-mental Release Profiles. Experimental Data Providedby Sigmoid Pharma Ltd.Figure 6: Release Profiles as a Function of the CoatingDegradation Rate LambdaCell type Behaviour descriptionBuffer Drug is released when it reaches bufferzone. Cell type acts as a perfect sink.Ethyl-celluloseDrug-free coating layer. Assigned life-time based on the λ (degradation rate)parameter. Forms an EC channel cellupon complete erosion.EC-channelGelatine and drug can diffuse throughEC channel cells.Gelatine Fixed lifetime. During diffusionthrough solvent cells, facilitates move-ment of drug ”packets”.Solvent Gelatine erodes into the solvent. Drugcan diffuse through the latter.DrugpacketDrug, initially dispersed in gelatinecells. Each cell can hold a maximum(saturation) amount of drug ”packets”.Table 1: Set of Cell Types and Rules of Behaviour.200 x 200 x 200, with cell size being 10µm. The averag-ing of the values for 24 repeated runs showed a negligiblevariation in results for a given set of same parameters.Model parameters, the effects of which on drug releaserates were studied in this work were: the size of the mi-crosphere, the erosion rates of gelatine and ethylcelluloseand the effect of coating thickness. The initial valueswere set according to the available in vitro data and un-less otherwise stated, the erosion rates of gelatine andethylcellulose are 90 minutes and 2 days, respectively.The sphere was taken to be 1.43 mm in diameter, andto contain 5% of EC coating. Drug loading is kept con-stant for all simulations at 10.8% of the mass.The first step in modelling was to determine the mostappropriate time interval in which cell states should beupdated. This essential parameter directly determinesthe diffusion and has order of magnitude in seconds,(from Fick’s first law and dimensional analysis). Sim-ulations were then performed for intervals between 5seconds and 1 minute, (Figure 4). By comparing resultsagainst experimental data, (Figure 5), a time interval of5 seconds was chosen for all subsequent simulations.The effect of porosity in the coating layer was investi-gated by varying lifetime of EC cells, (i.e. varying λ), toobtain different release behaviours for different lifetimesof EC chains, (Figure 6). The slower release rate of thedrug is due to decreased porosity, i.e. slower channelformation occurring in the coating.Weight gain of the coating thickness is also one of theprimary factors influencing drug formulation and perfor-mance. Here, we vary the coating levels from 4% - 8%,(Figure 7). The produced release curves qualitativelyreproduce reduction in diffusion rate, but the impactof adjusting the weight gain is somewhat smaller thanexperienced in vitro. This is expected, to some extent,as perfect sink conditions are modelled in this case. InFigure 7: Release Profiles as a Function of CoatingWeight GainFigure 8: Release Profiles as a Function of Gelatine Life-timereality, concentration of ethylcellulose in the boundarylayer inhibits movement of drug packets and some localsaturation occurs. This phenomenon must be taken intoaccount in future model extensions.As can be seen, (Figure 8), the lifetime of the gelatinecarrier can be considered to be negligible in terms ofinfluence on final release rate. However, gelatine is animportant controller of the drug release in the initialstages, as it influences the ”burst effect” by acceleratingdrug transfer through EC channels. The size distribu-tion of microspheres determines the actual mean andvariance of release rate, (Figure 9). This feature sug-gests refinement of initial parameters is necessary, (e.g.coating thickness or drug loading), as these are directlydependent on the size of the sphere. Increasing micro-sphere size mostly slows down drug release due bothto the capability of the device to hold more drug andthe fact that larger spheres have heavier and thus lesspermeable coatings.Figure 9: Release Profiles as a Function of Sphere Di-ameterFUTURE WORKAlthough simulated results do not reflect quantitativein vitro data precisely, (Figure 5), results obtained arepromising. These show that the model predicts qual-itatively similar behaviour compared to that seen forexperimental release curves. Results also show that thebehaviour of EC cannot be modelled using erosion only,but that other phenomena, such as swelling, which in-fluence volume increase due to the increased hydrationof the broken polymer chains, have to be taken into ac-count (Atyabi et al. 2004). A future focus will thusbe incorporation, into the model, of the swelling effect,caused by adding additives to the coating structure.Additionally, the model will be augmented to includethe effect of different polymer coatings and different me-dia surrounding the drug (biphasic release) in order tosimulate different stages of the GI tract environment.The deduction of unknown parameters from the exper-imental release curves using reverse engineering and in-verse Monte Carlo methods is a long-term aim. Nev-ertheless, the approach to date enables comparison ofa set of simulated and experimental release curves al-lowing us to determine key parameters and their valuesfor this novel formulation and to reproduce qualitativebehaviour. This enables us to compare a large set ofsimulated release curves with real ones in order to esti-mate best fit parameter values.ACKNOWLEDGEMENTSAuthors acknowledge the financial support from the IrishResearch Council for Science, Engineering and Technology(IRCSET), grant number P07669.REFERENCESAtyabi F.; Vahabzadeh R.; and Dinarvand R., 2004.Preparation of Ethylcellulose Coated Gelatin Microspheresas a Multiparticulate Colonic Delivery System for 5-Aminosalicilic Acid. Iranian Journal of PharmaceuticalResearch, 2, 81–86.Barat A.; Crane M.; and Ruskin H., 2008a. Quantita-tive multi-agent models for simulating protein release fromPLGA bioerodible nano- and microspheres. Journal ofPharmaceutical and Biomedical Analysis, 48, 361 – 368.Barat A.; Ruskin H.; and Crane M., 2008b. 3D Multi-agentmodels for protein release from PLGA spherical particleswith complex inner morphologies. Theory in Biosciences,127, –.Crank J., 1975. Mathematics of Diffusion. Clarendon: Ox-ford.Geraghty M., 2004. Investigation of ibuprofen release fromethylcellulose matrix compacts. Ph.D. thesis, University ofDublin, Trinity College.Go¨pferich A., 1996. Mechanisms of polymer degradation anderosion. Biomaterials, 17, 103 – 114.Go¨pferich A. and Langer R., 1993. Modeling of PolymerErosion. Macromolecules, 26, 4105–4112.Laaksonen T.; Laaksonen H.; Hirvonen J.; and Murtoma¨kiL., 2009. Cellular automata model for drug release frombinary matrix and reservoir polymeric devices. Biomate-rials, 30, 1978 – 1987.Langer R. and Peppas N., 1983. Chemical and PhysicalStructure of Polymers as Carriers for Controlled Releaseof Bioactive Agents: A Review. Journal of Macromolecu-lar Science, 23, 61 – 126.Li D.; Hohne D.; Bortz D.; Bull J.; and Younger J., 2007.Modeling bacterial clearance from the bloodstream usingcomputational fluid dynamics and Monte Carlo simula-tion. Journal of Critical Care, 22, 344 – 344.Siepmann J. and Go¨pferich A., 2001. Mathematical modelingof bioerodible, polymeric drug delivery systems. AdvancedDrug Delivery Reviews, 48, 229 – 247.Siepmann J. and Siepmann F., 2008. Mathematical modelingof drug delivery. International Journal of Pharmaceutics,364, no. 2, 328 – 343.Sopasakis A., 2004. Stochastic noise approach to traffic flowmodeling. Physica A: Statistical Mechanics and its Appli-cations, 342, 741 – 754.Tezuka S.; Murata H.; Tanaka S.; and Yumae S., 2005.Monte Carlo grid for financial risk management. FutureGeneration Computer Systems, 21, 811 – 821.Zygourakis K., 1990. Development and temporal evolutionof erosion fronts in bioerodible controlled release devices.Chemical Engineering Science, 45, 2359 – 2366.WEB REFERENCESEuropean Pharmacopoeia, http://www.edqm.euUnited States Pharmacopoeia, http://www.usp.org

Probabilistic models for dissolution of ethylcellulose coated microspheres

DCU Online Research Access Service

In the last few decades, a number of probabilistic models
for drug delivery have been developed. Of particular
interest are those that model controlled release systems
to provide targeted dose delivery. Controlled release
is achieved by using polymers with dierent dissolution
characteristics. We present here a model based
on Monte Carlo and Cellular Automata approaches, for
simulating drug release from coated microspheres in the
gastro-intestinal tract. Controlled release is obtained using ethylcellulose as the coating polymer. Modelling features, such as the drug and coating dissolution are nontrivial, since material is non-homogenously dispersed
and the dissolution exhibits complex behaviour. Important
underlying mechanisms of the process, such as
erosion, are described here

Irish Universities

In the last few decades, a number of probabilistic models for drug delivery have been developed. Of particular interest are those that model controlled release systems to provide targeted dose delivery. Controlled release is achieved by using polymers with different dissolution characteristics. We present here a model based on Monte Carlo and Cellular Automata approaches, for simulating drug release from coated microspheres in the gastro-intestinal tract. Controlled release is obtained using ethylcellulose as the coating polymer. Modelling features, such as the drug and coating dissolution are non-trivial, since material is non-homogenously dispersed and the dissolution exhibits complex behaviour. Important underlying mechanisms of the process, such as erosion, are described here

Probabilistic models for dissolution of ethylcellulose coated microsphere

http://doras.dcu.ie/17638/1/FLUID_02_MBezbradica_-_final_manuscript.pdf

Probabilistic models for dissolution of ethylcellulose coated microspheres

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Irish Universities

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