universitÀ degli studi di parma centro ...universitÀ degli studi di parma centro...
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UNIVERSITÀ DEGLI STUDI DI PARMA CENTRO INTERDIPARTIMENTALE MISURE
Corso di perfezionamento in TECNICHE DI MICROSCOPIA A FORZA ATOMICA
L'utilizzo dell'AFM nello Sviluppo di Prodotti Farmaceutici (Seconda Parte)
Dott.ssa Francesca Buttini, Dipartimento Farmaceutico,Università degli Studi di Parma
Parma, 29 maggio 2009
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AFM and the pMDI
Can
Valve
Actuator
Solution/suspension Formulation
Orifice
Metering Chamber
• Portable • No contamination • Tamper proof • Protective (light, O2, H20) • Multidose • Reproducible delivered dose • Inexpensive • Mature technology • Easy to use (in theory)
• PRODUCT TECHNOLOGY: SOLUTION SUSPENSION
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Particulate drug interactions with valve components in suspension formulations for metered dose inhalers
Adoseofthepar-culateformula-onisinconstantcontactwiththecomponentsofthevalve(meteringchamber,stem,sealsandspring)un-lexhaus-onoftheunitoccurs.
pMDI device components used withpropellants (CFC or HFA) can result ininefficient device performance, due toadhesion of the suspended par-culate APImaterial to the interior of pMDI devicesurfaces.
Other consequences of device–propellantinterac-ons include adsorp-on, poorlubrica-onandelastomerswelling.
(J.James Int J Pharm 366(2009) 124-132)
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The AFM was used to characterise the adhesive interactions between three pulmonary active pharmaceutical ingredient (API) materials and the components of pressurised metered dose inhalers (pMDIs) obtained from two commercially available products (termed ‘Prod-1’ and ‘Prod-2’).
This is of potential interest, as a greater understanding of the interactions between specific APIs and surfaces may aid manufacturers in component selection during pMDI system development.
Theinterac-onbetweeneachAPIandeachpMDIcomponent was determined using AFM colloidprobetechnique.
The study inves-gated the rela-onship betweenthe surface chemistry of each API/pMDI valvematerial and their corresponding adhesiveinterac-ons.
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SEMimagesofvariousvalvecomponentsurfacesatmicrometrescales
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Surfaceroughnesswasnotasignificantfactorintheadhesiveinterac-onsbetweeneachAPIandthepMDIcomponentfromeithermanufacturer.
The results generally suggest that for eachAPI–pMDI interac-on, the polar component ofsurface energy has the greatest influence on each adhesive event observed within thisexperiment.
This study highlights that different materials can have different effects on the adhesiveinterac-onswithpar-culateAPIs.
More considera-on should be given to determining the surface polar energe-cs of pMDIcomponentsandAPIpar-culatesinordertominimiseAPIadhesion,andthusproducemoreeffec-veandefficientpMDIsystems.
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AnInSituDissolu7onStudyofAspirinCrystalPlanes(100)and(001)byAtomicForceMicroscopy
ArdeshirDaneshetal.‐Pharmaceu-calResearch,Vol.18,No.3,2001
Purpose.Toobserve in situandon individualaspirin crystal faces thecompara-veratesandprocessesofdissolu-onofthedominantfaces.
Thekine-csof thedissolu-on rateof twoaspirincrystalplanes (001)and (100) under 0.05M HCl are studied in situ at room temperatureusingAtomicForceMicroscopy.Thedissolu-onprocessofeachcrystalplanewasfollowedbyobservedchangesintopographicFeatures.
Theunderstandingof fundamental factorswhich influence crystal growthanddissolu-onhaveprovedimportant,par-cularlywithinthepharmaceu-calindustrywherethecharacterisa-onofsuchprocessesmayhelp devisemoredesirable recrystalliza-onprocedures (by controlling thecrystalsizeandhabitduringgrowth)andprovideaninsightintothedissolu-onbehaviorofdrugcrystalsbothinvitroandinvivo.
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AFM:Sampleprepara7onandAnalysis
• Aspirincrystalswereobtainedfromrecrystalliza-onofaspirinatroomtemperaturefromahotsolu-onof95percentethanol.Thecrystalswere immobilizedonAFMsamplestubsusinganepoxyresinbasedadhesive(Araldite,Bos-k,U.K.).Twokindof samples were prepared, one exposing crystal plane (001) and the otherrevealingplane(100)attheirsurface.
• Images were obtained using a ThermoMicroscopes Explorer AFM(ThermoMicroscopes, U.K.) u-lizing oxidized sharpened silicon nitride probes.Experiments involved the addi-on of a few drops of freshly prepared dissolu-onmedium onto the surface of a sample followed by con-nuous imaging. Theacquisi-onspeedoftheimageswasdeterminedbytherateofchangeoffeaturesintheimages.
• Since the volume of dissolu-on liquid (~ 1ml) is large in comparison to a singlecrystalofaspirin, it isassumedthat theconcentra-onofsolute in thedissolu-onmedium isnegligiblecomparedtotheconcentra-ondissolvingandthereforesinkcondi-onsapply.
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DataElabora7on:
• This assump-on is explainedusing theNoyes‐Whitneyequa-on,where the rateofdissolu-on is expressed as the rate of change of concentra-on of the dissolu-onmediumwithrespectto-me(dc/dt)=k(cs−c)
Where c is the concentra-on of dissolved solute at -me t, cs is the concentra-onof saturated solu-on of the solute in dissolu-on medium, and k is a constant. Intheseexperiments,evenwhenassumingthecompletedissolu-onofawhole350µgcrystal,cwouldbenogreaterthan0.35%ofc.
• Dissolu-onrateofacrystalplane(nms−1)=
Stepheight(nm)×Stepvelocity(nms−1)
Stepspacing(nm)
• Toallowadirectcomparisonbetweenthedissolu-onratesofthetwoplanesintermsofmassdissolving,theirintrinsicdissolu-onrates(G)werecalculatedusingthefollowingequa-on:
G=dm/dt
Awheredm/dt,isthechangeinmasswith-me(gs−1)andA,istheexposedarea(cm2)
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Surfaceofaspirincrystalplane(001)10µmX10µm:
a) 0s
b) 66s
c) 132s
d) 197s
e) 263s
f) 329s
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Surface of aspirin crystalplane(100)5µmX5µm:
a) 0
b) 89s
c) 178s
d) 267s
e) 356s
f) 444s
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Conclusions:
• AFM inves-ga-ons demonstrated the profile of dissolu-on for two aspirin planes(001)and(100).Theresults re‐vealedthatcrystalplane(001)dissolvesbyrecedingstepedges,andhasadissolu-onrateof0.45nms−1.
• Conversely, crystalplane (100)displays crystal terrace sinkingat anaverage rateof2.93nms−1.
• Calculatedintrinsicdissolu-onvalues(G)(gs−1cm−2)forcrystalplane(001)and(100)are1.35×10−7gs−1cm−2and8.36×10−7gs−1cm−2,respec-vely.
• These values indicate that the rate of flux of material from plane (100) isapproximately six 7mes greater than that from crystal plane (001), under 0.05MHCl.
• Theseobserva-onsdemonstratetheabilityofthetechniquetomonitorandmeasuretheprogressofprocessesatamicroscopic level fromasinglecrystal,whichcanbedirectly related to the reported varia-ons between their commercial prepara-ons.That AFM could play a significant role in the characteriza-on of growth anddissolu-onbehaviorofcrystallinepharmaceu-caldrugs.
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A
ED
B C
A. Principioalvodiscioltonellamatricedellananosfera
B. Principioalvodisperso(“intrappolato”)nellamatrice
C. P.A.incapsulatodallamembranadellananocapsula
D. P.A.adsorbitoallasuperficiedellananosfera
E. P.A.adsorbitoallasuperficiedellananocapsula
Nanopar7celle polimeriche, nanopar7celle solide lipidiche
(SLN),micellepolimerichesonoveooricolloidaliperildirezionamentosito‐specificoedilrilasciocontrollatodi
‐Farmaci
‐ Vaccini
‐ Oligonucleo-di
MODALITA’DIINCORPORAZIONEDELPRINCIPIOATTIVO
1nm<∅<1µm
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• Maggiore stabilità STRUTTURALE nei fluidi biologici (rispeoo ai liposomi) per la loronaturapolimerica
• Possibilitàdicontrollareilrilasciodifarmaconeltempo
• PROBLEMA:ilsistemaimmunitario!
Dopo somministrazione endovenosa vengono opsonizzate, cioè ricoperte da elemen-delplasma
‐fibronec-na
‐faooridelcomplemento
‐immunoglobuline
erimossedalsanguerapidamenteperchécaptatedapartedelRES.
La velocità dell’uptake dipende dalle caraoeris-che superficiali delle par-celle e dalledimensioni.
Somministrazioneedes7noinvivo
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Nanopar7celle:
Somministrazioneorale
• Vengonoassorbiteaoraverso
lamucosaintes-nale
• Dimensioniidealiperl’assorbimento:50‐100nm
‐partenellamucosa
‐parteneltessutolinfa-coassociatoall’intes-no(GALT)
‐7%diquelleda50nme4%diquelleda100nmvannonelfegato,milza,rene,midolloviasangue
‐>500nmnonraggiungonoilsangue
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I. Nanodiamond-Embedded Microfilm Devices for Localized Chemotherapeutic Elution
Robert Lam, Mark Chen, Erik Pierstorff, Houjin Huang, Eiji Osawa, and Dean Ho (AcNano Vol.2, No.10, 2008)
Hybrid parylene-ND-based films were constructed as a flexible, robust, and slow drug-release device intended for implants or as stand-alone devices for specific therapies such as antitumor patches.
This device configuration offers a platform on which several therapeutic drug delivery devices can be developed. Hybrid films were capable of releasing a continuous amount of drug for at least a month.
The modification of DOX-ND deposition amounts and the thickness of the permeable parylene layer, dosage amounts and thus, total release times can be calibrated. Since drug release is presumably driven by drug concentration gradients, the patches can be optimized to reduce elution rates should the local therapeutic concentration reach a defined threshold
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Nanodiamond-Embedded Microfilm Devices
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AFMMicrofilmCharacteriza7onAsylumMFP3DAFM(SantaBarbara,CA):imagesofthesamplesweretakentoiden-fythestructureandinterac-onbetweenproteins.Imagedimensionswere20µmX20µm.
Contactmodeimagingat linescanratesof0.3to0.5HzwereperformedinatroomtemperaturewithOlympusTR800PSA200µmlengthsiliconnitridecan-levers(Melville,NY).
Roughnessofna-veprayleneCrms6.245nm
RoughnessofoxidizedprayleneCviaoxygenplasmatreatementrms9.291nm
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(c)DOX‐NDsweredepositedonaplasmatreatedlayerofparyleneC.Theimagesportraynanoscalefeaturesthatformviaparylenecoa-ngof theDOX‐NDconjugates,possiblyduetothegeneral roughnessof theunderlyingparyleneorNDaggrega-on.(d)DOX‐NDswerecoveredwithanaddi-onalthinlayerofparyleneC.Generalstructureandconforma-onoftheunderlyingDOX‐NDswereunaffectedbythethinfilmofparyleneCdeposi-on.
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TopographyofeachsuccessivelayerduringprocessingbyAFM
1stlayer,oxidizedprayleneCbase2ndlayer,coatedDOX‐NDdeposi-ononoxidzedparyleneCbase
3rd layer, top elu-ng parylene C layerdepositeduponDOX‐NDconjugates
3‐dAFMrepresenta7onsofthe(a)1stlayer,oxidizedparyleneCbase;(b)2ndlayer,coatedDOX‐NDdeposi7ononoxi‐dizedparyleneCbase;(c)3rdlayer,topelu7ngparyleneClayerdepos‐iteduponDOX‐NDconjugates.
a b
c
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Conclusions
Of particular importance, the grainy texture of the top eluting parylene layer is shown to maintain the structure of the underlying DOX-ND conjugates while simultaneously providing a means for modulating therapeutic release, indicated through slow-release assessment trials.
Nanodiamonds (NDs) of 2-8 nm diameters physically bound with the chemotherapeutic agent doxorubicin hydrochloride (DOX) were embedded within a parylene C polymer microfilm through a facile and scalable process.
The microfilm architecture consists of DOX-ND conjugates sandwiched between a base and thin variable layer of parylene C which allows for modulation of release.
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II. Forma7onofself‐organizednanopar7clesbylecithin/chitosanionicinterac7on
F.Sonvico,A.Cagnani,A.Rossi,S.Mooa,M.T.DiBari,F.Cavatorta,M.J.Alonso,A.Deriu,P.Colombo.
Inthiswork,nanopar-clespreparedbydirect injec-onofsoybean lecithinalcoholicsolu-on into chitosanwater solu-on are studied. The nanopar-cleswere obtainedfrom the supramolecular selforganizing interac-on of nega-ve lipid material inpresenceoftheposi-velychargedpolysaccharide.
The aim of this study was to inves-gate the influence of several processingparameterson thephysico‐chemicalandstructuralproper-esof thenanopar-cles.Theabilityofthesenanostructurestoencapsulateamodellipophylicdrugwasalsoinves-gated.Progesteronewaschosenasmodeldrugduetoitspoorwatersolubilityandloworalbioavailability.
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• Atomic force microscopy (AFM) was used to study thesurfacemorphologyofthecolloidsproduced.Nanopar-clesuspensionwas tenfolddilutedwithdis-lledwaterandadropwasdepositedonamicathinlayerfixedonametallicmagne-csupport.
• Thedropwasdriedovernight.
• The AFM images were collected in air with a Nanoscope III (DigitalInstruments,SantaBarbara,USA)opera-ngintappingmode.
Results:Noaggrega-onofthesampleseemedtohaveoccurredduringthedryingof
the suspension. The comparisonof these resultswith thoseobtainedbythe samples produced with lecithin alone, evidenced dimensional andmorphologicaldifferences.
• In thecaseof lecithin samplesAFMpictures showedsmallerandalmostflat structures, as typically described for vescicles during AFM tappingmodedetermina-on; on the contrary, the lecithin/chitosannanosystemsexhibitedwelldefinedandprojec-ngroundshapes.
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Atomicforcemicroscopyimagesoflecithinvesicles(A)and
lecithin/chitosannanopar-cles(weightra-o20:1)(B).
A B
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Summary:• AFMversa-letoolforsub‐microninves-ga-on
• Severalfieldofapplica-on(preformula-on,oraldelivery,pulmonary,parenteral,transdermal)
• Qualita-veandinves-ga-veresults: Force‐Adhesion Topography Dissolu-onCrystalStudy
!!Donothaverushbutalotofpa-ence!!
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Dimostrazionepra-ca:topografiadellasuperficiedidue-pidilaoosio
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References:
• F.Bulni,P.Colombo,M.Wenger,P.Masquilida,C.Marrioo,S.A.Jones.Backtobasics:Thedevelopmentofasimple,homogenous,two‐componentdry‐powderinhalerformula-onforthedeliveryofbudesonideusingmisciblevinylpolymers.2008.JPharmSci;97(3):1257‐67.
• J.James,M.Davies,R.Toon,P.Jinks,C.J.Roberts.Par-culatedruginterac-onwithpolymericand elastomeric valve components in suspension formula-ons for metered dose inhalers.2009.IntJPharm;366:124‐132.
• R. Lam, M. Chen, E. Pierstorff, H. Huang, E. Osawa, and D. Ho. Nanodiamond‐EmbeddedMicrofilmDevicesforLocalizedChemotherapeu-cElu-on.2008.AcNano;2(10):2095‐2102.
• A. Danesh, S.D. Connell, M.C. Davies, C.J. Roberts, S.J.B. Tendler, P,M. Williams, and M.J.Wilkins.An Insitudissolu-onstudyofaspirincristalplanes(100)and(001)byatomicforcemicroscopy.2001.PharmRes;18(3):299‐303.
• F.Sonvico,A.Cagnani,A.Rossi,S.Mooa,M.T.DiBari,F.Cavatorta,M.J.Alonso,A.Deriu,P.Colombo. Forma-on of self‐organized nanopar-cles by lecithin/chitosan ionic interac-on.2006.IntJPharm;32:67‐73.