DEVELOPMENT OF SOLID LIPID NANOPARTICLES (SLN) CONTAINING LINALOOL FOR TOPICAL DELIVERYS. Cavalheiro Filho1; S. Silva1; F.J. Veiga1,2; E.B. Souto1,2; S. Doktorovovà1;

1 Department of Pharmaceutic Technology, Faculty of Pharmacy, Coimbra University, Azinhaga de Santa Comba 3000-548, Coimbra, Portugal2 Center for Neuroscience and Cell Biology, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal

email: ebsouto@ff.uc.pt

INTRODUCTION & AIMS:

Linalool is small terpenic compound whose inhibitory effect on the growth of melanoma cells has promising results in in vitro studies even at concentrations as low as

0.56 μM1. Our goal was to develop a stable formulation for the delivery of linalool for topical administration, starting from raw GRAS materials.

Materials:

In an initial approach we tested the solubility of linalool in 14 different lipids

(Stearic Acid, Dynasan 118, Dynasan 116, Imwitor 491, Imwitor 900K, Koliwax

GMS II, Witepsol E85, Compitol 888 ATO, Gelucire 50/13, Gelucire 44/14,

Cetomil, Ketostearic Acid, Precirol ATO 5, Dynasan P60 (F)), which were chosen

based on our solubility prediction calculations (Tab. 1) and data from literature.

For our final formulation we used Imwitor 900K (BASF) as our lipid-carrier and

Cetomil (Fabriquimica SA) as our surfactant. All screening and final formulations

were prepared by high-shear homogenization using an Ultra-Turrax.

Lipid Screening:

Lipids were weighted, mixed with linalool and put in the oven at a temperature

rounding 80ºC. After melting, solubility was evaluated based on phase-

separation visible to the naked eye. A two-phase screening test was run to

evaluate linalool’s solubility at 1% and 10%.

SLN Production:

Our screening and final formulations were prepared by high-shear

homogenization (Ultra-Turrax). Lipids were heated until melting and, after

adding linalool, the oil fase was added to a 2,5% surfactant solution.

Homogenization was done under heating at a speed of 24000 RPM for 5

minutes.

We seem to have found a good, safe and inexpensive lipid-carrier for linalool - Imwitor 900K (Glyceryl Monostearate) – and we are currently working to find a suitable

tensioactive for our formulation. Even though further work is necessary to attain a more stable formulation, we were already able to produce different solid lipid

nanoparticles (SLN) by high-shear homogenization, using Cetomil (Fabriquímica SA) at 2,5% as our surfactant with linalool at 20%. A mean particle size of 417,0 ±

3,15nm and polydispersity index of 0,29 ± 0,088 were obtained for this formulation. We seem to be heading in the right direction and we believe we will soon be able to

produce a stable formulation with innovative ingredients for the delivery of an innovative drug.

Linalool showed limited solubility in most lipids tested. Based on our observations,

we chose to use lipids nº5 and nº6 (Imwitor 900K and Koliwax GMS II) as our

carriers for our first screening formulations. Linalool showed good solubility in these

lipids even at concentrations as high as 10%. Observation of mixtures nº 5 and nº6

under optical microscope revealed an even smooth surface, with no signs of

crystallization or precipitation.

Ackowledgements:

SD is recipient of postdoctoral scholarship from FCT under ref. BPD/101650/2014

CONCLUSIONS

MATERIALS & METHODS RESULTS

Tab. 2: Lipid Screening results for linalool at 10%.

Fig. 2: Particle size distribution by intensity of our final formulation. A mean particle size of 417,0 ±

3,15nm and polydispersity index of 0,29 ± 0,088 were obtained.

References:

[1] Cerchiaraa T., Strafaceb S. V., Brunellic E., Tripepic S., Galluccib M.C. and Chidichimo G., Natural

Products Communications, Vol. 10 No. 4: 547-549, 2015.

NºLipid Weight

(g)

Drug Weight

(g)Drug %

Solubility (naked eye)

Liquid phase Solid phase

Stearic acid 1 0,9903g 0,0985g 9,046657 Yes X

Dynasan 118 2 0,9943g 0,1194g 10,72102 Yes X

Dynasan 116 3 0,9912g 0,1023g 9,355281 Yes X

Imwitor 491 4 0,9926g 0,1172g 10,56046 Yes X

Imwitor 900K 5 0,9900g 0,108g 9,836066 Yes Yes

Koliwax GMS II 6 0,9907g 0,1019g 9,326377 Yes Yes

Witepsol E85 7 0,9864g 0,1014g 9,321566 X X

Compitol 888 ATO 8 0,9932g 0,1045g 9,519905 Yes X

Gelucire 50/13 9 0,9922g 0,1041g 9,495576 X X

Gelucire 44/14 10 1,0031g 0,1003g 9,090085 Yes X

Cetamil 11 0,9887g 0,1037g 9,49286 X X

Ketostearic acid 12 0,9986g 0,0999g 9,094219 Yes Yes

Precirol ATO 5 13 0,9852g 0,1106g 10,09308 Yes X

Dynasan P60 (F) 14 1,0023g 0,1056g 9,531546 X X

Chemical name Present in δd δp δh δtotal SQRT(Δδtotal)

Stearic acid Stearic acid 16,924 1,349 5,667 17,898 5,597

Glyceryl tristearate Dynasan 118 16,385 0,869 4,636 17,051 6,386

Glyceryl tripalmitate Dynasan 116 16,388 0,967 4,890 17,129 6,119

Glyceryl distearate Imwitor 900K, Kolliphor Wax II 16,659 1,284 7,147 18,173 4,130

Glyceryl monostearate Imwitor 491, 900K, Kolliphor Wax II 16,362 2,281 11,164 19,939 1,279

Glyceryl tribehenate

Compritol 888 ATO

16,382 0,722 4,227 16,934 6,813

Glyceryl dibehenate 16,610 1,071 6,529 17,879 4,704

Glyceryl monobehenate 16,362 1,942 10,299 19,431 1,389

Glyceryl dipalmitate Precirol ATO 5 16,692 1,425 7,530 18,367 3,787

Linalool Linalool 15,849 2,820 10,621 29,286

Tab. 1: Prediction of solubility of linalool in various lipids using Hansen Soubility Parameters.

Fig. 1: SLN production method.