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    Formulation optimization of itraconazole loaded PEGylated liposomes for parenteral administration by using design of experiments.pdf

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    Formulation optimization of itraconazole loaded PEGylated liposomes for parenteral administration by using design of experiments.pdf

    International Journal of Pharmaceutics 448 2013 189– 197Contents lists available at SciVerse ScienceDirectInternational Journal of Pharmaceuticsj o ur nal ho me page www.elsevier.com/locate/ijpharmFormulation optimization of itraconazole loadedfor parenteral administration by using designAnamarijaa,b,1 a,1abHeidelberg,aArticleReceivedReceivedAcceptedAvailable online 22 March 2013KeywordsPEGylatedItraconazoleDesignResponseSix-sigmato systematicallypreparedencapsulationto25processbe demonstrated that DoE plays an important role in optimization experiments leading to robust resultssupporting high quality. 2013 Elsevier B.V. All rights reserved.1.parenteralresultingmulationsoralferentsolublearemembranes.verydothelialtheseThetimetemogy,Germany.0378-5173/http//dx.doi.org/10.1016/j.ijpharm.2013.03.029IntroductionThe major challenge in formulation of poorly soluble drugs foradministration is to find an efficient preparation methodin a sufficiently high dose. Development of parenteral for-of such drugs is considerable limited in comparison toformulations. For decades many scientists have been using dif-carriers, such as liposomes, as delivery systems for poorlyor lipophilic drugs van Hoogevest et al., 2011. Liposomesvesicles containing an aqueous core surrounded by lipid bilayerThey are biocompatible and posses low toxicity butsoon after administration they are recognized by reticuloen-system RES Atyabi et al., 2009. The amelioration ofvesicles by surface PEGylation results in “stealth” liposomes.PEGylation modification enables extended blood circulationof the drug and diminishes the mononuclear phagocyte sys-uptake which is an advantage over the conventional liposomes∗Corresponding author at Institute of Pharmacy and Molecular Biotechnol-Ruprecht-Karls-University, Im Neuenheimer Feld 366, D-69120 Heidelberg,Tel. 49 06221 54 8336; fax 49 06221 54 5971.E-mail address gert.frickeruni-hd.de G. Fricker.1These authors contributed equally to this work.Immordino et al., 2006; Gubernator, 2011; Knop et al., 2010. Itra-conazole ITZ, an antifungal triazole drug, represents one of themost hydrophobic pharmaceutical agents and has been shown ashighly active against the isolates of Candida species, Aspergillusspecies, and dermatophytes Marichal and Vanden Bossche, 1995;Fromtling, 1988. Oral administration of ITZ showed very goodclinical results in treatment of different deep fungal infections,e.g. histoplasmosis and aspergillosis as well as in treatment ofsuperficial fungal infections such as dermatomycoses Fromtling,1988. Topical administration of cyclodextrin-based, emulsifiedwax cream containing 1 ITZ was shown to be effective in treat-ment of vaginal candidiasis where the clinical cure was reported inabout 77 of patients Francois et al., 2003. Parenteral administra-tion of ITZ is necessary in medication of patients, who are incapableof receiving oral therapy for instance if they are unable to swallowdue to health and physical conditions. Janssen Pharmaceutica com-mercialized the parenteral form of ITZ also known as SporanoxInjection. In this case the dissolution of ITZ is achieved by complex-ation with 2-hydroxypropyl-13-cyclodextrin HPCD Rhee et al.,2007. Some other groups have used nanosuspensions of ITZ as par-enteral formulation Kipp, 2004. Nanosizing technique such as wetmilling was shown to be effective in generation of ITZ nanocrystalsLiu et al., 2011. ITZ microemulsions as another type of parenteraladministration of ITZ was described by Rhee et al. 2007. Paradeike– see front matter 2013 Elsevier B.V. All rights reserved.Curic , Regina Reul , Jan MschwitzerAbbVie Deutschland GmbH moreover, it was important to consider only the most relevant fac-tors. Controllable factors considered as important for the procedurewere included in corresponding designs while the uncontrollablefactors were kept fixed in order to reduce redundant variability.3.3. Screening phaseFig.method 100–150 nm, PDI 0.15–0.35 during this work.To avoid false positive results two negative controls were run.liposomes, as negative control 1, and ITZ diluted in CHCl3lipids as a negative control 2, were additionally ana-Both, empty liposomes 62.5 mg/ml and ITZ diluted in31 mg/ml have undergone the complete formula-procedure film formation, sonication, filtration. Since the ITZ2. Ishikawa diagram with different factors which might have an influence on encapsulationcombined with sonication.Factors were varied using fractional factorial two-level resolu-tion IV design as described in Table 1. Lipid film was formed asdescribed above. The temperature used during the rehydration wasidentical with the temperature during the film formation. All exper-iments were randomized in order to avoid the systematic errors andto ensure the quality of results.efficiency [EE ] in the process of PEG-Lip formulation using the filmA.Curic et al. / International Journal of Pharmaceutics 448 2013 189– 197 193Fig. 3. Actual by predicted plot for the fractional factorial model.Table 2Sorted parameter estimates for screening design.Term Estimate Std error t ratio Prob |t|Temperature rotary40, 65−5.8375 0.0825 −70.76 0.0090*Itraconazole *sonication 4.0775 0.0825 49.42 0.0129*whichtodictionmeandenceat least one parameter is significantly different from zero Goupyand Creighton, 2007.All factors indicated an influence on EE Table 2. Since thisdesign was resolution IV design the main effects of these factorsmight be equal to three factor interactions. However, the chancethat three factors or more are interacting with each other simulta-neously is very low Goupy and Creighton, 2007. It has been shownthat the temperature, rehydration time and sonication device havesignificant effect on the EE. The ITZ percentage indicated interac-tions with sonication type or rehydration time. Since some twofactor interactions in resolution IV design were confounded withsome other two factor interactions it was not possible to distinguishwhich of them really posses the significance.Possible confounded interactions are shown belowITZ ∗ temperature rotary rehydration time min ∗ sonication typeITZ ∗ rehydration time min temperature rotary ∗ sonication typeITZ ∗ sonication type temperature rotary ∗ rehydration time minThe prediction profiler Fig. 4 is a tool of the JMPsoftwarewhich was used for the calculation of optimal factor settings. All fac-tors are assigned to a specific desirability value which was definedtypeRehydration min 10, 30 3.795 0.0825 46.00 0.0138*Sonication type −2.5625 0.0825 −31.06 0.0205*itraconazole*rehydration min−1.42 0.0825 −17.21 0.0369*itraconazole 3, 6 0.445 0.0825 5.39 0.1167*0.05.The EE was used as a single response for the model fitting,was run stepwise using standard least square fitting in orderremove insignificant effects.The actual by predicted plot Fig. 3 demonstrates that the pre-values were significant p 0.018 and random noise or rootsquare error RSME 0.2333 was small, which gives evi-that the chosen model had a good predictive capability andFig. 4. Prediction profiler withbetween the 0 and 1. Zero represented the lowest EE and the1 represented the highest EE . Since our goal was to maximizethe EE , all factors were calculated to reach the desirability of1. The main advantage of the prediction profiler is that the user isable to predict the values which were not actually examined as longas they are within the experimental space. The temperature dur-ing the film formation at 40◦C, the rehydration time of 30 min andthe sonotrode as a sonication device with decreased drug amountresulted in increased EE of approximately 25. In comparison tothe first experiment the EE was increased for approximately 12.A reduction of the temperature during the film formationimproved the EE. Regarding all lipid components used for thefilm formation, the temperature of 40◦C during the film formationis above the transition temperature Szoka and Papahadjopoulos,1980. In order to define the temperature effect on encapsulationoptimal factor settings.194 A.Curic et al. / International Journal of Pharmaceutics 448 2013 189– 197Fig. 5. Z-Avr and PDI values measured in 8 different conditions. In the runs 2, 4, 6and 8 the sonotrode was used for sonication.result the temperature during the film formation was increasedfor 25◦C. However, increasing temperature during the film forma-tion did not improve the encapsulation of ITZ. In contrary, furtherincrease in temperature resulted in lower EE.In contrast to the application of water bath sonication, the useof a sonotrode probe sonicator resulted in smaller liposomes inshorter time Fig. 5.Therefore, the sonotrode was applied for further experiments.All lipid components were kept in identical mass ratios to avoidthetiespresence3.4.werefactorialusedusedcentrationloadingbefullyranges.wereTable 3Full factorial design with EE results.Run name Lipid conc. mg/ml ITZ EE DoE1 6.3 1.6 25.44DoE2 6.3 12.2 13.27DoE3 6.3 24.5 7.82DoE4 12.5 1.6 24.04DoE5 12.5 12.2 6.13DoE6 12.5 24.5 1.82DoE7 25.0 1.6 40.16DoE8 25.0 12.2 0.29DoE9 25.0 24.5 0.18Table 4Response surface CCD extended by augmented foldover design with results.Run name Lipids mg/ml ITZ RSM EE Block 1AUGM EE Block 2DoE1 25 0.3 96.6 89.3DoE2 25 1.65 31.7 32.2DoE3 25 3 40.6 36.1DoE4 62.5 0.3 32.4 55.0DoE5 62.5 1.65 40.9 44.8DoE6 62.5 3 13.1 10.6DoE7 100 0.3 50 35.3DoE8 100 1.65 35.7 35.5DoE9 100 3 23 29.6be used if varying only lipid concentration and ITZ amount in ordereffects of single components on the physicochemical proper-of liposomes. For instance, it has been shown that cholesterolhas an effect on liposome size by using sonication methodLapinski et al., 2007.Optimization phaseFor the optimization of EE the lipid concentration and ITZ examined each at three different levels.First trial in optimization phase was carried out using the fulldesign. Table 3 outlines the factor and level combinationsfor this design.When using smaller amounts of ITZ the EE could be increasedTable 3. The EE could be increased when both of the factors wereat their extreme limits. The EE increased when the lipid con-was increased. ITZ should not exceed 5 of theoreticalif the encapsulation efficiency of approximately 30 shouldgained Fig. 6. The lipid concentration was analyzed more care-by using a response surface design in extended concentrationFurther, the ITZ percentage and lipid concentration mg/mltested again using central composite on face design CCDFig. 6. Contour plot a and histogram b with Table 4. In comparison to the full factorial design the factors wereanalyzed at low and high levels with center points. The surfaceof responses was investigated in order to find the optimum lipidconcentration with ITZ percentage settings. As shown in Fig. 7 theincrease in lipid concentration up to 100 mg/ml did not improve EEof ITZ as suggested in first optimization experiment. In this workthe different lipid concentrations were relevant for the EE but infurther studies not only the lipid concentrations but also differ-ent lipid types with different mixture ratios should be analyzed.Newly, it has been shown that using different components of thelipid mixture can have an influence on encapsulation efficiency ofwater soluble components Maherani et al., 2011.The exploration of the response surface diagram depicted inFig. 7 indicated that 25 mg/ml of lipids results in the highest EEwhich was proven after comparison of these results with the CCDresults. It seemed that an increase in lipid concentration does notnecessarily means higher capacity to encapsulate the drug. TheEE was plotted as a y-variable and lipid concentration withITZ as x-variables in one simple contour plot Fig. 8. It wasobserved that only limited range of the experimental space couldthe data achieved by full factorial design.A.Curic et al. / International Journal of Pharmaceutics 448 2013 189– 197 195Fig. 7. Response surface diagram with lipid concentration and ITZ percentage asvariable factors.to achieve higher EE. Increase in lipid concentration up to 25 mg/mlincreased the EE. However, increasing the lipid concentration abovethe 25 mg/ml does not follow the same tendency. Other scientistsvariedmization2009;designandescribed3.5.methodologyformingITZusingtions.bycanceprocess.Fig.faceTable 5Two-Way ANOVA for response surface and augmented design.Source of variation p value summary p value SignificantRSM vs AUGM ns 0.8919 NoDesign conditions***0.0002 Yesns not significant.***0.001.robustness. Both CCD and augmented design were separated byblocks in order to eliminate the variability between days.Block factor did not show significant influence on EE and thiswas confirmed by Two-Way ANOVA statistics Table 5, where thedifference between repeated designs was not significant. Thereforethe process was considered as reliable.The variance analysis was performed using GraphPad Prismand it showed that the difference between conditions or DoEruns was significant p 0.0002 but the difference between thefull factorial and repeated augmented design was not significantp 0.8919. This showed that almost all combination results wererepeatable Fig. 9.The ANOVA results demonstrated that the formulation pro-cedure for ITZ loaded PEGylated liposomes is a robust methodTable 5. Additionally, this work showed that the systematic exam-ination by using statistical approaches such as DoE allowed both,the increase in yield and the detection of factor interactions usingrelatively low number of experiments.lipid ratios or lipid type as controllable parameters in opti-designs to improve encapsulation efficiencies Patel et al.,Mohammed et al., 2004. More specifically, Patel et al. usedof experiments to show that the drug-lipid amount hasinfluence on encapsulation efficiency. However, there is littleabout the optimal lipid concentration as such.Verification phaseIn order to confirm the results achieved using response surfacethe experiments had to be repeated. Instead of per-the runs with only the final optimal factor settings 0.3 ofand 25 mg/ml of lipids the verification phase was performedan augmented design repeating the entire last phase condi-Here the existing data table of CCD Table 4 was expandedthe augmented design. This permitted an increase in the signifi-of the previous CCD model due to the iteration of the existingHereby, the results in all conditions could be tested on8. The contour plot containing the results from full factorial and response sur-CCD design.One of the conveniences in the DoE is the ability to optimizethe process on as many responses as desirable. However, it hasto be considered that not all responses have identical weightingfor the process. With higher EE reduced loss of the pharmaceuticalagent is ensured. However, in order to achieve an optima

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