Hindawi Publishing Corporation
`Journal of Drug Delivery
`Volume 2014Article ID 620464
`11 pages
`155/2014/620464
`
`http//dic.doi.org/10.l
`
`Research Article
`Development of Risperidone PLGA Microspheres
`
`Hindawi
`
`EXHIBIT
`
`WIT
`
`DATE
`DAWN HILLIER RMR CRR
`
`Susan DSouza Jabar
`
`Faraj2 Stefano Giovagnoli3 and Patrick
`
`DeLuca4
`
`Inc. Marl boiougli MA 01752 USA
`Sunovion Pharmaceuticals
`2Fresenius Kabi USA Skokie IL 60077 USA
`Department of Chemistry and Technology of Drugs Universitd degli Studi di Perugia Via del Liceo
`University of Kentucky College of Pharmacy Lexington KY 40536 USA
`
`06123 Perugia Italy
`
`Correspondence
`
`should he addressed to Susan DSouza dr ssdsouza@yahoo.com
`
`Received
`
`May 2013 Accepted 20 Dctober 2013 Published 28 January 2014
`
`Academic Editor Sophia Antimissaris
`
`the Creative Commons Attribution License
`2014 Susan DSouza et al This is an open access article distributed under
`Copyright
`in any medium provided the original work is properly cited
`use distribution and reproduction
`which permits unrestricted
`
`The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone with an
`Two PLGA copolymers 50 50 and 7525 were
`eventual goal of avoiding combination
`therapy for the treatment of schizophrenia
`The microspheres were characterized by several
`four microsphere formulations of Risperidone
`used to prepare
`in vitro techniques
`rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst
`In viva studies in male Sprague-Dawley
`followed by sustained release of the active moiety Additionally formulations prepared with 50 50 PLGA had
`shorter duration of
`action and lower cumulative AUC levels than the 7525 PLGA microspheres
`simulation of multiple dosing at weekly or 15 day
`by the second dose Overall the clinical
`formulations with steady state being achieved
`regimen revealed pulsatile behavior
`for all
`will eliminate the need for combination
`therapy and reduce time to achieve
`oral
`steady state
`use of Pormulations
`or
`the suitability of using PLGA copolymers of
`smaller washout period upon cessation of therapy Results of this study prove
`with
`in vivo behavior and enhance
`varying composition and molecular weight
`to develop sustained release formulations that can tailor
`pharmacological
`effectiveness of the drug
`
`Background
`
`The treatment
`
`using oral conventional
`of schizophrenia
`antipsychotics dates back to the mid-1950s Administration of
`antipsychotic drugs via the oral route offered several advan
`tages in terms of ease of administration noninvasiveness of
`is common knowl
`therapy and portability of medication It
`number
`formulations possess
`edge that
`injectable depot
`of advantages
`over oral dosage forms such as avoidance
`first-pass metabolism and the certainty of delivery of
`Therefore
`by the 1960s the first
`agent
`therapeutic
`injectable depot conventional antipsychotic was introduced
`The sustained release properties of the injectable depot
`strides in the treatment of schizophrenia
`led to significant
`reduced relapse rates in comparison to the oral dosage
`as it
`form reduction in the number of days of hospitalization
`for patients on injectable antipsychotics over those on oral
`medication was also documented by researchers
`Despite
`being an injectable
`it was noted that patients preferred
`
`of
`
`the
`
`injectable depot antipsychotics over oral agents Additionally
`the use of
`the treatment
`injectable depot preparations for
`as it ensured
`of schizophrenia was considered beneficial
`to treatment over an extended duration leading to
`adherence
`Compliance with treatment
`improved health outcomes
`regimens sharply increased when patients were switched
`better mechanism
`to depot agents allowing physicians
`to therapy Further the injectable
`to detect noncompliance
`depot allowed better control
`over drug management and
`more predictable and consistent plasma drug concentrations
`when compared with oral formulations
`In general
`inject
`able depots were well tolerated and more clinically efficacious
`than oral preparations
`The second generation antipsychotics or atypical antipsy
`chotics were introduced in the 1980s and led to significant
`improvements in the treatment of schizophrenia Atypicals
`effective for the positive symptoms of schizophrenia demon
`strated lack of negative symptoms leading to greater efficacy
`and reduced side effects Indeed atypical antipsychotics have
`
`ALKERMES Exh. 2020
`Luye v. Alkermes
`IPR2016-1096
`
`

`

`substantially
`
`better adveise
`
`is effective
`
`tardive
`
`reluctance
`
`in
`
`low incidence
`
`effect profile than first gen
`to movement disorders
`eration antipsychotics with respect
`Notably concerns with
`akathisia and tardive dyskinesia
`symptoms EPS and
`the risk of
`extrapyramidal
`dyskinesia with older antipsychotics
`led to
`accepting injectable depots of first generation antipsychotics
`and
`preference for oral atypical antipsychotics
`novel benzisoxazole type atypical antipsy
`Risperidone
`chotic
`in the treatment of positive as well as
`negative symptoms of schizophrenia and has
`In vivo Risperidone
`of extrapyramidal
`side effects
`is extensively metabolized by cytochrome P450 2D6 subject
`to genetic polymorphism to form its main metabolite 9-
`hydroxyrisperidone via hydroxylation and
`dealkylation
`18
`Hydroxyrisperidone displays similar
`pathways
`pharmacological activity to the parent compound
`thus the
`summation of both species Clin
`active moiety in vivo is
`ically the efficacy of Risperidone has been well established
`and is effective
`against positive and negathe symptoms of
`20 Risperidone is an antagonist of the
`schizophrenia
`5HT2A receptor compared with the D2 receptor which allows
`lower
`symptoms and
`for
`greater efficacy against negative
`rate of EPS which makes it
`suitable candidate for treatment
`of schizophrenia
`Two decades of clinical usage have clearly established that
`atypical antipsychotics like Risperidone offer several benefits
`concerns with movement disorders and
`including reduced
`and mood
`symptoms than
`However
`these benefits
`first generation antipsychotics
`diminish greatly in patients who suffer from severe psychi
`atric ailments primarilydue to non adherence
`to oral therapy
`reports have documented the reduced effectiveness
`Several
`of oral Risperidone therapy in young and old schizophrenic
`Daily dosing of oral Risperidone is non ideal
`patients
`to treatment and often ineffective
`due to patient
`resistance
`given that efficacy depends on constant adherence
`to therapy
`has
`that adherence
`to daily medication
`Despite the fact
`been better
`patients dosed with atypi
`in schizophrenic
`cal antipsychotics than conventional antipsychotiLs Dolder
`et al
`recorded that poor compliance issues persisted in
`schizophrenic patients
`
`greater efficacy
`
`for negative
`
`critical
`
`factor
`
`is
`
`long term
`in achieving
`beneficial
`mechanism wherein
`outcomes
`the
`in establishing
`schizophrenic patients demonstrate adherence
`to treatment
`intake of medication or partial dosing is
`cycles Infrequent
`far more common than complete non-adherence to therapy
`and
`challenge
`to patients
`posing
`caregivers
`significant
`large Robinson et al reported
`five fold increase
`society at
`in the risk of relapse with patients who partially adhered to
`treatment
`Incidence of relapse in schizophrenic patients
`large economic and personal cost Relapsed patients
`suffer from reversal of gains achieved during therapy loss of
`function demoralization loss of confidence danger to self or
`loss in productivity and
`others and loss of job leading to
`opportunity Further rehospitalization
`of
`relapsed patients
`huge economic burden on existing healthcare system
`places
`in the US
`Continuous delivery of the atypical antipsychotic is an
`to therapy with minimal
`effective way to ensure adherence
`
`carries
`
`Journal of Drug Delivery
`
`its efficaciousness
`
`to the first geneiation
`antipsychotics
`relapse Analogous
`formulations of Risperidone were developed
`injectable depot
`and marketed Studies on long acting Risperidone revealed
`and
`in the treatment of schizophrenia
`27 Extended treatment with
`schizoaffective disorder
`long acting Risperidone also reduced movement disorders
`relative to baseline in patients clinically stable on
`variety of
`
`for
`
`antipsychotic drugs
`major drawback of the currently marketed
`However
`long acting Risperidone administered every 15 days neces
`sitates an additional supplementation with oral Risperidone
`three weeks after administration of
`for
`the injectable for
`mulation While challenges
`related to patient compliance
`continue to persist with oral therapy oral supplementation is
`necessary due to the delayed response profile obtained with
`the injectable preparation where drug release occurs approxi
`mately weeks after administration Published literature cites
`7-week
`in vivo levels peak 4-5 weeks after dosing for
`that
`duration of action
`Co-administration of oral Risperi
`done while necessary
`in an inpatient or outpatient setting is
`inconvenient
`and poses major compliance issues in patients
`with psychotic disorders Additionally costs incurred with
`31
`co-administration therapy of Risperidone are high
`Thus the latency in drug release is major shortcoming of the
`long acting Risperidone depot preparation Therefore there is
`non oral controlled delivery dosage form
`strong need for
`for this drug
`Over the years several polymers have been evaluated
`development of controlled release injectable formulations
`Of
`these polymers one class of polymers
`has achieved
`significant commercial success in the pharmaceutical market
`The polylactide PLA and polylactide-co-glycolide PLGA
`biocompatible and
`class of polymers
`are biodegradable
`nontoxic and have
`In vivo they are
`long history of use
`hydrolyzed into metabolic products that are easily eliminated
`from the body Initially approved for surgical use in humans
`by the US Food and Drug Administration they have since
`been used to formulate
`wide range of therapeutic
`agents
`34
`few commercially
`formulations using
`available
`PLA or PLGA polymers include Lupron Depot Somatuline
`LA and Trelstar Depot
`These polymers have been shown
`to be efficacious
`in the delivery of biologically active agents
`and also improve patient compliance by eliminating the need
`for frequent administration
`PLGA polymers are well suited for controlled delivery
`they exhibit good
`of drugs via the parenteral
`route as
`mechanical properties and demonstrate predictable degra
`dation kinetics Notably polymeric microspheres prepared
`using PLGA have been
`sustained
`successful
`in ensuring
`release of therapeutic agents for various drugs
`examples in literature discuss their effectiveness
`in providing
`in vivo for long periods of time
`targeted drug levels
`40 For this reason they are popular
`as delivery vehicles
`for drugs where sustained release is desired for extended
`intervals ranging from few weeks to several months
`42 These polymers are also used in marketed injectable
`formulations as carriers to deliver antipsychotic drugs and are
`noted to provide benefits over conventional oral therapy
`striking benefit of using PLGA polymers to deliver atypical
`
`Several
`
`

`

`Journal of Drug Delivery
`
`includes
`
`reduction
`
`in dosing frequency
`antipsychotics
`in adherence
`leading to measurable increase
`to treatment
`45 In
`regimens in
`schizophrenic patient population
`the success of PT.GA polymers as delivery systems is
`general
`due to the fact
`that polymer properties are well understood
`and can be customized to afford sustained drug release For
`instance selection of copolymers of various lactide glycolide
`with variable molecular weights is an effective way to control
`polymer degradation rate and drug release By changing the
`composition of lactide or glycolide in the copolymer wide
`can be obtained An increase
`range of degradation rates
`in the more hydrophobic
`slower
`lactide moiety ensures
`degradation rate of the PLGA polymer leading to extended
`duration of drug release
`Similarly utilization of
`higher molecular weight copolymer
`increases
`degradation
`times leading to prolonged drug release Additional prop
`erties that can be varied include polymer crystallinity and
`glass transition temperature These physical and chemical
`properties have been well studied and characterized leading
`to predictable degradation kinetics of the PLGA polymer in
`vitro and/or
`in vivo
`Upon in vivo administration of PLGA based injectable
`interacts with the polymer and hydrolysis of
`depot water
`the ester bonds commences As the polymer degrades its
`and the number of hydrophilic
`hydrophobicity decreases
`hydroxyl and carboxylic
`end groups in the matrix
`increases An accumulation of hydrophilic acidic end groups
`the amount of water
`has
`twofold effect
`
`acid
`
`it
`
`increases
`
`into the polymer and
`incursion
`initiates autocatalysis
`of the polymer matrix
`Therefore polymer degradation
`and consequently drug release from PLGA is very complex
`and dynamic process This is of particular significance as it
`provides the researcher
`sound approach to
`scientifically
`select an appropriate polymer specific to
`therapeutic need
`or treatment
`regimen
`When plotted as
`function of time drug release from
`PLGA matrix occurs in three phases
`The first phase
`of release is known as initial burst and occurs
`
`result
`
`as
`
`drug or drug that
`
`is
`
`of detachment of surface
`associated
`easily dissociated from accessible
`pores in the polymeric
`microspheres Depending on the surface area arid porosity
`high or low initial burst may be observed The second phase of
`release that is diffusional release is
`of initial
`consequence
`release or
`polymer hydration and is followed by erosional
`the final phase of drug release Once the polymer is hydrated
`polymer autocatalysis ensues causing bulk hydrolysis that
`is complete polprier degradation and erosion mass loss
`Previous reports have also documented that properties of the
`formulation have an impact on drug release kinetics
`Therefore depending on the properties of the polymer and
`the microsphere dosage form the rate and extent of each
`of these phases
`can be altered to customize drug release
`profiles Hence in this study two PLGA copolymers having
`varying molecular weights and lactide glycolide ratios as
`well as drug loading were evaluated with an aim to obtain
`Risperidone PLGA microspheres
`having varying duration
`of action Results
`and discussions related to the findings
`the study demonstrate the suitability of
`this approach
`
`of
`
`in developing sustained release formulations where in vivo
`behavior can be customized to meet patient needs
`
`Materials and Methods
`
`2.1 viaterials Risperidone was purchased from Cipla Ltd
`India and PLGA 50 50 45 and 74 kDa and 75
`25 54 and
`Ingelheim Ingelheim Germany
`65 kDa from Boehringer
`and Alkermes Cambridge MA All other chemicals were
`
`obtained commercially
`
`as analytical grade reagents
`
`2.2 Preparation of Microspheres The four formulations eval
`uated were
`
`45 kDa PLGA 50 50 lactide glycolide Formulation
`
`74 kDa PLGA 50 50 lactide glycolide Formulation
`
`54 kDa PLGA 75
`
`25 lactide glycolide Formulation
`
`65 kDa PLGA 75
`
`25 lactide glycolide Formulation
`
`Briefly
`
`sol
`
`in
`
`Briefly four Risperidone PLGA Formulations
`and
`microspheres formulations were prepared by
`vent extraction/evaporation method
`solution
`of drug and polymer 1020% polymer concentration
`continuous
`dichloromethane was injected into an aqueous
`250 and 350 parts of polymer
`ratio between
`Silverson L4R
`aqueous phase under stirring with
`mixer Silverson machines MA USA at 5000 rpm Subse
`quently the solvents were removed by stirring after which
`the microspheres were recovered by filtration suspended
`suitable vehicle filled into vials and freeze-dried The
`in
`microspheres were characterized as described in Section 2.3
`
`phase
`
`at
`
`phase
`
`2.3 Characterization of Microspheres
`
`2.3.1 Particle Size Particle size distribution of the micro-
`
`spheres prior to vialing was determined using
`tion technique Malvern 2600c Particle Sizer Malvern UK
`The particles were suspended in 0.05% Tween 80 and counted
`laser sensor
`The
`size was
`using
`average particle
`in microns ym
`expressed as volume mean diameter
`
`laser diffrac
`
`The
`
`2.3.2 Surlace
`
`Ivlorphology
`
`surface morphology was
`examined by scanning electron microscopy SEM Hitachi
`S800 Japan at an appropriate magnification after palla
`sample on an alu
`coating of
`the microsphere
`dium/gold
`minum stub
`
`to
`
`2.3.3 Bulk Density Bulk density of the microspheres was
`weighed amount of micro
`determined
`by transferring
`graduated cylinder The cylinder was subse
`spheres
`quently tapped 50 times from vertical distance of approx
`imately 0.5 inches and the occupied volume recorded The
`the volume occupied
`tapping process was repeated
`until
`
`

`

`TABLE
`
`Propcrtics of Rispcridonc PLGA mlLrosphercs
`
`Journal of Drug Delivery
`
`45kDa
`
`5050
`
`25
`
`0.76
`
`24.6
`
`20
`
`74kDa
`
`5050
`
`34
`
`067
`
`18.9
`
`20
`
`54kDa
`
`7525
`
`34
`
`0.65
`
`17.1
`
`40
`
`65kDa
`
`7525
`
`33
`
`0.68
`
`21.9
`
`40
`
`Formulation
`
`MW
`PLGAtype
`
`Drug load
`
`Bulk denaity glee
`Mean particle size pm
`Dose of Risperidone mg/kg
`
`final volume was
`remained unchanged
`The
`by particles
`recorded as bulk volume
`and the tapped bulk density
`as M/Vb where
`was the weight of
`g/cc was calculated
`microspheres employed
`
`in the micro-
`content
`2.3.4 Drug Content Risperidone
`reverse phase HPLC method using
`spheres was analyzed by
`Nucleosil C-18 column Phenomenex Torrance CA at
`flow rate of mL/min The mobile phase consisted of 30%
`v/v acetonitrile and 01% v/v trifluoroacetic
`acid in water
`as the weight of drug in
`Drug content
`was expressed
`i00
`microspheres/weight of microspheres
`
`with Institutional
`
`2.3.5 In Vivo Studies In accordance
`Guidelines and an in-house developed and an approved pro
`four groups of male Sprague Dawley rats Harlan Inc
`tocol
`Indianapolis IN weighing approximately 300gm were used
`in the in vivo study Group received Formulation
`Group
`received Formulation
`received Formulation
`and
`
`Group
`received Formulation
`
`at
`
`Group
`Briefly vials containing freeze dried microspheres along
`with diluent were reconstituted with WFI water for
`injec
`tion and injected subcutaneously at the base of the rat neck
`Blood was
`dose of 20 or 40mg/kg Risperidone Table
`sampled from the rat
`tail vein at predetermined
`intervals
`after which the samples were centrifuged in Microtainer tubes
`Becton Dickinson Co Franklin Lakes NJ and serum was
`collected Serum samples for each of Group Formulation
`and
`Formulation
`Group Formulation
`Group
`were frozen and stored at 20C
`Formulation
`Group
`until analysis Subsequently serum levels were assessed at
`Medtox Labs USA using
`validated analytical method
`
`3.1.1 Morphology of Risperidone Microspheres The scanning
`revealed
`shape with
`electron micrographs
`spherical
`smooth surface and homogeneous particle size distribution
`that would be appropriate for subcutaneous admin
`Figure
`istration to rats Additionally the microspheres could not be
`the interior of all four formulations
`fractured suggesting that
`was not hollow When viewed at
`the same magnification
`size of Formulation
`
`appeared
`while the particle size
`
`than Formulation
`
`area allows for
`
`faster dissolution
`
`size of
`
`the
`
`commercial
`
`Figure
`the particle
`marginally larger than Formulation
`of Formulation
`was slightly smaller
`confirms these observations as the mean
`glance at Table
`particle sizes for Formulations AD were 24.6 18.9 17.1 and
`21.9 ym respectively For dosage
`forms like drug loaded
`microspheres measurement of particle size is important as
`impacts initial burst
`smaller particle
`release
`area to volume ratio to the
`size confers
`dosage form It
`larger surface
`incursion and consequently
`rapid water
`of drug molecules that are associated with the outer surface
`or accessible pores Hence an initial burst
`is expected with
`smaller sized microspheres
`From literature the particle
`long acting Risperidone microsphere formulation has been
`25 and 150
`reported to be between
`significantly
`Hence the SEM
`and
`than Formulations
`the release profiles from
`indicated that
`results in Figure
`the four formulations would be vastly different
`from the
`marketed preparation For instance an initial burst of drug
`the formulations Given that the
`release was expected for all
`particle sizes for Formulations AD are quite similar overall
`the extent ofinitial burst was expected to be broadly similar
`
`it
`
`higher
`
`surface
`
`follows that
`
`larger
`
`Results and Discussion
`
`formulations
`Properties of the four
`3.1 Polymer Selection
`and
`used in this study are shown in Table
`Formulations
`were prepared with 50 50 PLGA at molecular weights 45
`and 74 kDa respectively while Formulations
`and
`were
`manufactured from 54 and 65 kDa PLGA having
`25
`75
`lactide glycolide ratio Based on the molecular weight and
`and were expected to have
`copolymer ratio Formulations
`and
`shorter duration of action while Formulations
`would provide more prolonged in vivo drug release profile
`due to
`25 copolymer
`higher lactide content
`in the 75
`
`for PLGA micro
`3.1.2 Bulk Density Bulk density values
`sphere formulations are routinely measured as they provide
`information on the porous network in these dosage forms
`to porosity and
`change
`Density is inversely proportional
`indicates inefficient packing due to the
`in this parameter
`of nonspherical microspheres or the formation
`presence
`between bulk
`of hollow microspheres
`relationship
`density surface area and onset of mass loss has also been
`reported by Mehta et al
`Hence
`low bulk density
`is indicative of highly porous microspheres
`since porosity
`correlates well with polymer hydration and thereby degra
`dation bulk density values are an indicator of drug release
`53
`
`rates
`
`

`

`Journal of Drug Delivery
`
`Fonnulation
`
`Formulation
`
`FIGURE
`
`SEMs of Risperidone PLGA microspheres
`
`summarizes the results of bulk deosity measure
`Table
`ments Values for all
`the formulations ranged from 0.65 to
`The high bulk density values were indicative of
`0.76 g/cc
`low degree of internal porosity with similar pore volumes
`for Formulations AD Given that particle sizes for all
`four
`formulations are similar and bulk density is high both
`to contribute equally to the initial
`parameters were expected
`release from the microspheres
`burst
`
`3.1.3 Drug Con tenf Drug content
`is an important property
`of the microsphere dosage form as it provides information
`related to the amount of drug available for release
`from
`form Results of drug content
`as determined
`the dosage
`by HPLC are presented in Table
`For
`the purposes of
`the current
`study high drug loadings were
`targeted in
`to mimic the loading level of 38.1% in the marketed
`part
`Risperidone depot formulation
`Therefore Formulations
`loadings between 25 and 34% Table
`
`were prepared at
`These values suggest
`
`high drug polymer ratio for the four
`
`value higher
`
`formulations at
`
`than the drug solubility in
`the polymer This situation avors the initial burst release phe
`nomenon Hence
`high value of initial burst was expected
`for all four formulations
`
`Based on the morphology particle size and drug con
`tent data the formulations
`were
`to behave
`expected
`in
`the following manner
`High initial burst was expected
`and
`from all
`the formulations and
`Formulations
`manufactured using 5050 PLGA were expected to exhibit
`shorter duration of action than Formulations
`and
`where
`
`the duration of action was expected to be prolonged
`
`3.2 In Vivo Results
`
`3.2.1 Serum Levels of Risperidone and Its Metabolite for
`Formulations
`and
`In vivo Risperidone is exten
`liver by CYP2D6 to
`active metabolite
`pharmacologically
`hydroxyrisperidone
`Serum levels of Risperidone and its metabolite for each
`
`sively metabolized in the
`
`foi
`
`

`

`Journal of Drug Delivery
`
`250
`
`200
`
`150
`
`as
`
`100
`
`50
`
`10
`
`15
`
`10
`
`15
`
`Time days
`
`Time days
`
`250
`
`200
`
`150
`
`as
`
`100
`
`50
`
`250
`
`200
`
`150
`
`Os
`
`100
`
`50
`
`250
`
`200
`
`j150
`
`100
`
`50
`
`15
`
`30
`
`45
`
`15
`
`30
`
`45
`
`Time days
`
`Time days
`
`Risperidone
`
`9-hydroxyrisperidone
`
`Active moiety
`
`Risperidone
`
`9-hydroxyrisperidone
`-a Active moiety
`
`FIGURE
`
`In vivo release of Risperidone and 9-hydroxyrisperidone from microsphere Formulations
`
`and
`
`formulation after administration of
`single subcutaneous
`dose are shown in Figures 2a to 2d including the levels
`the sum of Risperidone and
`of active moiety which is
`metabolite levels
`
`and
`administered to
`20mg/kg dose in
`Formulations
`rats showed an initial burst around 100 ng/mL of Risperidone
`The high initial burst
`followed by
`trough in levels by day
`combination of the small particle size and
`was attributed to
`
`high loading levels for both formulations These results are
`in excellent agreement with previous studies that discuss the
`role ofparticle size and high drug loading on burst release
`54 By day
`levels rose slightly to release drug in sustained
`manner with levels being depleted slowly through day 15
`active metabolite
`In vivo profile of the pharmacologically
`hydroxyrisperidone mimicked those of the parent molecule
`albeit at slightly lower levels
`
`

`

`Journal of Drug Delivery
`
`at
`
`An initial burst was also observed with Formulations
`and
`administered
`dose
`in rats The
`40mg/kg
`which was
`highest burst was observed with Formulation
`25 PLGA and
`prepared with the lower molecular weight 75
`had the smallest particle size lowest bulk density value and
`maximum drug loading albeit
`the differences in these values
`are not significant Asidc from the initial burst the profiles
`and
`of Formulations
`were similar After an initial burst
`sharp drop occurred and the drug levels through day 22
`steady manner while progressing to
`remained in
`decline
`up to day 45 for both formulations In manner similar to that
`and
`observed with Formulations
`the metabolite levels
`
`and
`
`depict similar in
`
`attributable
`
`to surface
`
`were lower than Risperidone
`In summary Formulations
`vivo behavior
`is characterized by
`high initial burst
`that
`associated drug Once initial burst
`was complete depletion of circulating levels of drug led to
`trough that was followed by
`slow sustained release of drug
`from the PGLA matrix until values diminished In contrast
`mean plasma levels of Risperidone and its active metabolite
`9-hydroxyrisperidone show
`weeks after
`latency of nearly
`administration of
`single injection of Risperdal Consta in
`No initial burst is observed rather levels are low
`and almost
`till approximately
`21 days after dosing after
`which levels rise to peak at weeks 4-5 and last until week
`slow decline in levels This necessitates
`leading to
`the intake
`of supplemental oral dosage forms for the first
`the treatment
`regimen making non-adherence to therapy
`
`patients
`
`flat
`
`three weeks of
`
`serious issue
`The initial burst phenomenon
`is an excellent platform
`bolus dose This type of effect
`is desirable
`for delivering
`in certain therapeutic regimens especially those involving
`long term therapy For instance burst
`release of Leuprolide
`Luteinizing Hormone Releasing Hormone LHRH analog
`from PLGA microspheres has been documented in literature
`42 Leuprolide
`LHRH super-agonist
`reports
`causes
`spike in testosterone levels when administered after which
`testosterone levels drop to below chemical castration levels
`Long acting injectables
`containing
`initial burst phenomenon
`impacts
`as
`significantly
`pharmacodynamic
`in vivo Similarly for long acting
`effects
`injectable dosage forms of Risperidone
`an initial burst
`desirable Ramifications of
`lack of initial burst
`dosage form are that
`the schizophrenic patient will
`ineffective therapy similar to the observed with the currently
`marketed formulation thus necessitating the need for supple
`mental Risperidone
`
`Leuprolide exhibit
`
`it
`
`the
`
`the
`
`is
`
`from the
`
`receive
`
`3.2.2 Cumulative AUC Results of cumulative area under the
`curve AUC for
`the active moiety were calculated by the
`trapezoidal method
`are shown in Table
`
`AUCt1t2
`
`C1 C2
`
`xt2 ti
`
`In
`
`denotes
`
`represents time in hours while
`serum concentration of Risperidone ng/mL
`Results from AUC calculations indicate that
`the cumu
`lative AUC values
`for Formulations
`15 days
`
`through
`
`TABLa
`
`AUC for Riiperidone PLGA mic.sospheres
`
`Formulation
`
`Dose
`Cumulative AUC
`ng mL/day
`
`20 mg/kg
`
`20 mg/kg
`
`40 mg/kg
`
`40 mg/kg
`
`1110
`
`1159
`
`1821
`
`1522
`
`and
`were remarkably similar 1110 and 1159 ng mL/day
`respectively Both formulations administered at 20 mg/kg
`dose were prepared using the fast degrading 50 50 PLGA
`had
`small particle size and high loading but
`copolymer
`10 kDa in molecular weight
`difference of
`In vivo they
`exhibited similar burst levels followed by brief trough with
`noticeable levels through 15 days Though the formulations
`high initial burst more than 98% of the cumu
`exhibited
`lative AUC was contributed by drug encapsulated
`in the
`polymer matrix with initial
`burst amounting to mere 1.4
`1.8% of the total profile
`Cumulative AUC levels for Formulations
`at 40 mg/kg
`Values of 1821 and
`are presented in Table
`1522 ng mL/day were obtained for Formulations
`respectively As expected values are higher
`than those
`and
`With Formulation
`observed with Formulations
`initial burst contributed nearly 2% to the cumulative AUC
`the value was smaller 1%
`whereas with Formulation
`Once again these data suggest
`that most of the in vivo activity
`was due to drug incorporated in the polymer matrix that was
`available for release in sustained fashion
`
`and
`
`dosed
`
`and
`
`the marketed formulation does not exhibit
`
`In contrast
`initial burst and supplementation with oral therapy is needed
`to achieve pharmacologically effective
`levels of the drug
`in the polymer matrix was
`suggesting that drug encapsulated
`solely responsible for in vivo activity
`The following observations were noted upon analyzing
`the cumulative AUC values of Formulations
`
`The contribution
`of initial burst
`towards the total
`AUC for all formulations was minor equal to or less
`than 2%
`
`in the PLGA polymer was
`Risperidone encapsulated
`responsible for over 98% of the cumulative AUC in
`vivo
`
`The cumulative AUC obtained with Formulations
`and
`than that
`was nearly 1.51.7 times greater
`and
`observed with Formulations
`These results
`
`choice of
`that proper
`copolymer
`suggest
`molecular weight will enable customization
`of drug
`release profiles from microsphere
`dosage forms of
`
`and
`
`Risperidone
`
`3.2.3 Selection of Dosing Regimen The objective of the cur
`and evaluate PLGA microspheres
`rent study was to develop
`of Risperidone that offered initial and maintenance levels of
`the drug for extended intervals To predict
`the in vivo profile
`of Risperidone PLGA microspheres for
`prolonged duration
`doses for all four formulations were
`plasma levels through
`simulated using the superposition principle Simulations of
`
`

`

`Journal of Drug Delivery
`
`biD
`
`5.
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`14
`
`21
`
`28
`
`Time days
`
`.- Formulation
`Formulation
`
`FIGuRE
`and
`
`Simulation of multiple dosing regimen for Formulations
`doses
`administered weekly total
`
`15
`
`30
`
`45
`
`60
`
`Time days
`
`Formulation
`
`Formulation
`
`FIGURE
`and
`
`Simulation of multiple dosing regimen for Formulations
`doses
`administered
`every 15 days tuul
`
`medical professional
`
`dosing regimen for
`simulation
`
`that
`
`used previously
`multiple dosing have been
`as they have
`excellent clinical utility due to the fact
`they allow the
`to determine selection of an appropriate
`formulation
`In addition
`given
`also provide information on the
`experiments
`in vivo drug levels over an extended duration of
`expected
`treatment Such types of studies are popular as they minimize
`the unnecessary usage of human and/or animal subjects
`in
`studies and also offer
`actual multiple dose pharmacokinetic
`time and cost
`
`to
`
`clinician Further the multiple
`savings
`dosing simulations also provide data on the steady state
`concentration that are expected
`dosing of
`upon repeated
`given formulation Typically simulation experiments require
`that concentration time data generated from single dose be
`extrapolated to multiple dosing scenario using the principle
`and
`of superposition Based on this principle Formulations
`would be dosed
`with
`short duration of action Figure
`and
`intervals from Formulations
`at different
`
`Once
`
`istration of
`
`the peaks
`then fall
`
`and
`week dosing for Formulations
`Figure
`shows active moiety levels between
`100 and 260 ng/mL with
`after the admin
`an initial
`spike in drug levels observed
`the first dose As dosing continues
`occur
`immediately after each administration but
`the peak and trough
`quickly to 100 ng/mL only to repeat
`doses administered In general
`the
`profiles throughout
`peak values of 280 ng/mL were obtained after dose
`steady
`state with trough values of tOO ng/mL Thus Formulations
`andB exhibited
`pulsatile profile after simulations of multiple
`dosing As expected from Figure
`the similarity in behavior
`was attributed to the small particle size high drug load and
`high bulk density of the two formulations prepared using
`5050 PLGA
`For Formulations
`
`t5-day dosing regimen was
`and
`Once again
`attempted Figure
`pulsatile release profile
`is observed primarily due to the initial burst observed with
`both formulations From an initial peak active moiety value
`of -.250 ng/mL for Formulation
`and nearly 110 ng/mL for
`
`Formulation
`values reach 290 ng/mL for Formulation
`The in vivo profiles of
`and 190 ng/mL for Formulation
`the