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Int J Pharm Bio Sci 2013 Apr; 4(2): (P) 21 - 33

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&esearch Article 'anotechnolo

International Jo*rnal o# Pharma an! Bio SciencesISS'

0+,-.2++

S/I IPI 'A'/PA&TIS (S') BAS 56&/7 8/&9ATI/'

8/& T/PIA I&6 /8 9I/'A

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INTRODUCTION

8uring the past several years, solid lipidnanoparticles (SLN) egan to act as a topicalcarrier not only for pharmaceutical molecules,ut also for cosmetic products. Solid lipid

nanoparticles have emerged as an alternativeto liposomes due to various advantages suchas improved physical staility, low costcompared to phospholipids and ease of scale"up and manufacturing1,'. 9ompared withconventional carriers such as cream, tinctureand emulsion, SLN comine their advantagessuch as controlled release, in vivo goodtoleration and protection of active compounds.#specially, SLN can favor drug penetration intothe s&ins-, , maintain a sustained release toavoid systemic asorption4, act as a :;

sunscreen system6

and reduce irritation5,

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0ermany) at 5 rpm for - min. The otainedpre"emulsion was homogenized at atemperature C9 to 1C9 higher than themelting point of the ul& lipid, using anhomogenizer /*; Micron La - and applying

a pressure of ar and homogenizationcycles. The otained dispersion was cooled inan ice ath in order to solidify the lipid matri%and to form SLN. #ach preparation wascarried out in triplicate.

Table I

Composition of various SLN formulations (! m"m#$ Particle size! Pol%dispersit% &nde'(P! eta potential and Drug entrapment parameters of different

SLN formulations o)tained immediatel% after production

Formulationcode

Composition arameters

MN !ynasan ""# olo$amer"%%

&ater article size(nm)

olydispersityInde$ (I)

' (m) !rug*ntrapment

SLN " 1

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DSC +nal%sis8S9 analyses were performed on pure Miconazole nitrate and 8ynsyan 114 y a Mettler Toledo8S9 5'' instrument (*er&in"#lmer 8S9"6). 1"' mg of solid lipid has een accurately weighted in- l aluminium pans. 8S9 scans have een recorded at a heating rate of 1 9 7min and was runover the range '" 9, using an empty pan as reference. @or the analysis of pure model drugs(5"1 mg) were carefully transferred and heated in crimped to the aluminum pans for accurateresults.

Preparation and Characterization of SLN,Based -%drogel@or the preparation of hydrogel, the gel"forming polymer 9aropol

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have een performed using a computere!uipped with the Te%ture #%pert softwsare.

&n Vitro Drug .eleaseThe in vitro drug release profile of MN"loadedSLN"earing hydrogel and mar&etedformulation were studied using a dialysis ag.

@ormulations were ta&en into a dialysis ag(molecular weight cut"off, 1' D8a, 3imedia,+ndia) and placed in a ea&er containing ' mlof mi%ture of methanol= *>S (p3 4.-) (=6).Then, the ea&er was placed over a magneticstirrer and the temperature of the assemlywas maintained at 6 E 19 throughout thestudy. Samples (1 ml) were withdrawn atdefinite time intervals and replaced with e!ualamounts of fresh uffer. The samples wereanalyzed for drug concentration y :;";+Sspectrophotometer at '6' nm.

' Vitro s0in permeation Studies#% vitro permeation of MN from SLN asedgel and mar&eted formulation (@lucos 0el,9osme *harma ltd, +ndia) were performedusing e%cised full thic&ness hairlessadominal s&in of rats (Male alino rats,Sprague 8awley2 1O1 g). The s&insamples were mounted on modified @ranzdiffusion cells (9rown 0lass 9o., NG) with asurface of .1- cm'and a receptor volume of

1 ml such that the dermal side of the s&inwas e%posed to the receptor fluidPmethanol=*>S (p3 4.-), i.e. =6Q ratio andthe stratum corneum remained in contact withthe content of donor compartment.@ormulations were placed in the donorcompartment enaling one to cover the entires&in surface evenly. The temperature wasmaintained at 6 E 19. Serial sampling (.ml) was performed at specified time intervals(1, ', , -, , 4, 6, 5, 1, 1', 15, '- h) yremoving the contents of the receptor

compartment and replacing it with the freshmedium. The samples were analyzed usingGasco :;";+S spectrophotometer at '6' nmand mean cumulative amount diffused R(mg7cm') at each sampling time points wascalculated. /t the end of '- h, the s&in wascut, homogenized, and e%tracted, first withmethanol and then filtered2 them ethanolice%tract was evaporated and the residue wasagain e%tracted with 8M@, filtered, diluted with

.1 N 39l and analyzedspectrophotometrically at '6' nm.

RESULTS AND DISCUSSION

Preparation and Characterization of SLN

@or the current study, SLNs were successfullyprepared and the composition of theformulations prepared is shown in Tale 1.9aliration curve (yI.'1%.1-,$'I.

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three different temperatures to challenge thesystems under stress conditions. +n all storagetemperatures, the systems remained in theircolloidal particle size range ( 1 m). Themean size was maintained lower than nm,with a *+ in the same magnitude as the valuesotained immediately after production (*+

.). /fter one month of storage, all lipidnanoparticles showed a negative charge attheir surface. /lso the p3 values did not varynotaly etween the variales investigated.The differences etween the evaluatedparameters were not significant, neither underdifferent storage temperatures nor with thepresence of drug molecules, meaning that thesystems SLN for topical delivery of antifungalswas physicochemically stale under stressconditions. No gel formation has eenoserved after one month of shelf life at threedifferent temperatures. *olo%amer 155 couldstailize the developed formulations evenunder stress conditions. Uields of productionotained were always relatively high and werein the range 5O

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3owever, the curve 9 e%hiite a wea& roade%otherm etween 169 and 1rownian motion to ring the

particles into contact so that they aggregate.

Table 0'eta potential and particle size parameters o- SLN.based semi.solids a-ter

one day and t1ree mont1s (23 days) o- storage at 45C6 +75C and 435C

Sizeparameters

8ge(!ays)

Temperature(5C)

SLN.based semi.solid-ormulations

F* (m;)

1 - "'.E.1

' "1.-E.-

- "'

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The rheological properties of caromer gels have een characterized in several studies ','1. Thefocus of the present investigation was the rheological ehavior of such gels when lipidnanoparticles are entrapped into their networ&. /ccording to this, analysis has een performed forSLN"ased formulations and @ig.' shows, respectively, the otained results recorded after onewee& of storage at -C9, 'C9 and at -C9.

Figure +Shear rate 31"s4 versus shear stress 3Pa4 of SLN,)ased semi,solid formulations o)tained

after one 5ee0 of storage at 6 different temperatures$ Data are means 7 s$d$! n 8 6

+n the range of shear rates studied in thiswor&, the shear stress was not proportional tothe shear rates in systems (SLN). Thecharacteristic concavity of the rheogramtoward the shear rate a%is indicates that alldeveloped formulations e%hiitedpseudoplastic flow. This pseudoplasticityresults from a colloidal networ& structure thataligns itself in the direction of shear, thereydecreasing the viscosity as the shear rate

increases. 8uring all e%periments, thetemperature has een accurately maintainedat 'E.1C9 using a thermostated water ath.+t is important that the temperature does notchange during the rheological determination toavoid otaining false positive results in the testfor thi%otropy. @rom @igs.' it can e statedthat all systems show thi%otropy, which maye defined as an isothermal and

comparatively slow recovery, on standing of amaterial, of a consistency lost throughshearing. +n comple% systems such as SLN"loaded hydrogel in which a loose networ&connects together the sample, thi%otropyproceeds from structural rea&down and re"aggregation. The ehaviour of SLN"asedsemi"solid systems was more dependent onthe storage temperature. The incorporation ofa!ueous SLN dispersions into 9aropol

hydrogel affects the te%ture of the developedformulations in terms of adhesiveness,consistency and gel strength. Theadhesiveness of freshly prepared pure9arapol

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lipid nanoparticles. SLN"ased formulationshave shown to e more adhesive. Thisoservation is in good agreement with theassumption that swelling is not interrupted ythe water insolule lipid nanoparticlesdispersed in the gel networ&. Theadhesiveness was also evaluated according to

the storage temperatures (-C9, 'C9 and-C9) of SLN"ased semi"solid formulations.@igure - shows the otained results after onewee& of storage. SLN"ased semi"solid

formulations stored at -C9 were moreadhesive than those stored at -C9. /sreported previously SLN"ased semi"solidformulations stored at 'C9 showed thehighest hysteresis loop, i.e. area of thi%otropy,in the flow curves. This means that underthese conditions the systems are more

sensitive to shear deformation, which might erelated to the lowest adhesive properties incomparison to the ones stored at higher(-C9) and lower (-C9) temperatures.

Figure 0+dhesiveness patterns of Car)apol 96:P gel o)tained on da% ;! in comparison to freshl%

prepared SLN, )ased semi,solid formulations$ Data are means 7 s$d$! n 8 6

Figure 4+dhesiveness patterns of SLN,)ased semi,solid formulations o)tained after one

5ee0 of storage at three different temperatures$ Data are means 7 s$d$! n 8 6

/ test for measuring the consistency of SLN"ased semi"solid formulations has eendeveloped y adapting a te%ture"profile

analyzer to pull the test sample placed on thease of the instrument upwards from mm to' mm and downwards from ' mm to mm.The force (N) needed to lift the sample proeto the pre"set distance has een recorded. /ta distance of ' mm, SLN"ased formulationsstored at 'C9 recorded a force of .455 N,emphasizes the higher consistency.9omparing those values with the consistency

of pure 9aropol hydrogel, i.e. without lipidnanoparticles (.6' N), it confirms that othconsistency and adhesiveness of hydrogel

decreases with the incorporation of lipidnanoparticles.0el strength analysis has eenperformed in the 9arapol

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penetration force was otained for the9arapol

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The e% vivo permeation of MN from MNSLN0el and Mar&eted gel was evaluated using@ranz diffusion cell. The mean cumulativeamount diffused R (mg7cm') at each samplingtime point was calculated2 high amount ofMiconazole nitrate release was facilitatedthrough adominal s&in of rats from mar&eted

gel (.456 mg7 cm') of Miconazole nitrate thanMNSLN 0el (.'4 mg7cm') (@igure -). MN"SLN gel produced significantly higherdeposition of Miconazole nitrate in s&in((JE.

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RE!ERENCES

1. Muller, $.3., Mader, D., 0ohla, S., Solidlipid nanoparticles (SLN) for controlleddrug deliveryXa review of the state ofthe art. #ur. G. *harm. >iopharm. ,

141O165, (').'. Muller, $.3., $adt&e, M., Aissing, S./.,Solid lipid nanoparticles (SLN) andnanostructured lipid carriers (NL9) incosmetic and dermatologicalpreparations. /dv. 8rug 8eliv. $ev. -,11OS1, ('').

. Sylvia, /., Muller, $.3., Aissing, S./.,9osmetic applications for solid lipidnanoparticles (SLN). +nt. G. *harm. '-,4O45, (').

-. Genning, ;., 0ysler, /., Schafer"Dorting,

M., 0ohla, S.3., ;itamin / loaded solidlipid nanoparticles for topical use=occlusive properties and drug targeting tothe upper s&in. #ur. G. *harm. >iopharm.-unHes, 3., Doch, M.3.G.,*hysicochemical characterisation of lipidnanoparticles and evaluation of their drugloading capacity and sustained releasepotential. G. 9ontrol. $elease -5, ''O'4, (1

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y differential scanning calorimetry. +nt G*harm2 -='1O'5, (').

'. Souto, #.>.,Aissing, S./., >arosa,9.M.,MYuller, $.3., 8evelopment of acontrolled release formulation ased onSLN and NL9 for topical clotrimazoledelivery. +nt. G. *harm. '65, 61O66,

('-).'1. Rueille"$oussel, 9., *oncet, M.,

Mesaros, S., 9lucas, /., >a&er, M.,Soloff, /., 9omparison of the cumulativeirritation potential of adapalene gel andcream with that of erythromycin7tretinoinsolution and gel and erythromycin7isotretinoin gel. 9lin. Therap. ', 'O'1', ('1).

''. Gain, S.D., 9hourasia, M.D., Masuriha,$., Soni, ;., Gain, /., Gain, N.D., 0upta,

U., Solid lipid nanoparticles earingfluriprofen for transdermal delivery.8rug 8eliv. 1'='6O1, (').

'. *uglia, 9., @ilosa, $., *eduto, /.,9aprariis, *., $izza, L., >onina, @., >lasi,*. #valuation of alternative strategies tooptimize &etorolac transdermal delivery.

//*S *harm Sci Tech. 6=#1O

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