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STUDY OF SOLID LIPID MICROPARTICLES AS SUSTAINED RELEASE DELIVERY SYSTEM FOR PULMONARY ADMINISTRATION
Sverine Jaspart, Pascal Bertholet, Luc Delattre, Brigitte Evrard Laboratory of Pharmaceutical Technology, University of Lige, Belgium E-mail: sjaspart@ulg.ac.be Keywords: SOLID LIPID MICROPARTICLES, SUSTAINED RELEASE, PULMONARY ADMINISTRATION, EXPERIMENTAL DESIGN. INTRODUCTION Up to now sustained release formulations for pulmonary delivery have still not been marketed in spite of the increasing interest in this research field. The control of the drug delivery in the respiratory tract may be achievable by employing suitable carriers, possessing appropriate drug release characteristics. In this purpose liposomes have been the most studied carriers. They proved to be able to provide a sustained release to the incorporated active substances but they present some disadvantages, i.e a high production cost, a relative unstability during storage and during nebulisation that can lead to disruption and loss of entrapped substance (1). Polymeric microspheres have also been successfully tested as sustained release drug delivery system (2) but their safety still remains uncertain (3). That is the reason why we decided to focus on Solid Lipid Microparticles (SLMs), a carrier that has not been up to now much studied especially for pulmonary administration. However SLMs present several advantages: they can be considered as physiologically compatible, physicochemically stable and allowing a large-scale production at a relative low production cost. The aim of this work was to produce a drug carrier able to provide a sustained release to a 2mimetic agent and thereby to prolong its duration of action. The active substance we chose to work with is salbutamol acetonide (SA), a derivative of salbutamol that have been synthetised in order to get a more lipophilic substance and thereby to allow a more effective incorporation of this drug into SLMs. This paper describes SLMs production technique, SLMs optimisation and an in vitro drug release study. EXPERIMENTAL METHODS SLMs loaded with salbutamol acetonide were prepared by hot emulsion technique followed by a high shear homogenization using Ultra-Turrax T25 at 8000 rpm. The SLMs suspension obtained after cooling at room temperature are lyophilized in order to get dried SLMs. SLMs geometrical diameter was determined using laser diffractometry, by means of a Mastersizer 2000 (Malvern Instruments, United Kingdom). Some production parameters were studied in order to get a suitable SLMs size. In this way, the percentage of particles (calculated in volume) whose geometrical diameter lies between 0.5 and 6 m (corresponding to the suitable size for pulmonary administration) was optimized with the help of the methodology of experimental design using the software MODDE 6.0. In that purpose two experimental designs were carried out, the first one using 2.5% of dispersed (lipidic) phase Compritol 888 ATO (Gatteffoss, France) and salbutamol acetonide and the second one using 5% of the same dispersed phase. The surfactant concentration (Lutrol F68, BASF, Germany) was studied from 0.1 to 0.5% (w/wtotal), the initial drug loading from 1 to 25% (w/wdispersed phase) according to the upper limit of salbutamol acetonide in the dispersed lipidic phase. The mixing duration was studied varying from 1 to 10 minutes. The encapsulation efficiency (E.E) of SA in SLMs was determined by a validated method of liquid-liquid extraction (CHCl3/ diluted HCl pH1) followed by a HPLC assay in which the degradation product of SA at acidic pH, ie salbutamol, can be quantified. The SA equivalent is then calculated. The in vitro drug release was studied using the rotating basket method described in the 5th edition of the European Pharmacopoeia with the help of a Sotax AT7 dissolution apparatus coupled with an autosampler Sotax C615. The drug release study was carried out at 150 rpm in PBS pH 7.4 at 37C. RESULTS AND DISCUSSION The analysis of the experimental design showed that the parameter SA concentration does not influence the response. The optimised parameter and the theoretical corresponding responses are summarized in Table1. Lutrol F68 ((%) w/ wtotal) 0.1 0.1 0.1 0.1 Mixing duration (min.) 10 10 10 10 SA ((%) w/wdispersed phase) 11.5 5.5 20.2 16.5 SLMs in range of size 0.5-6 m (%) 45.31 45.00 44.73 44.53

Table 1: Optimization of manufacturing parameters by experimental design. Seeing that SA concentration does not influence the response and that drug loading is likely to influence drug release profiles we chose for further studies SLMs

15th International Symposium on MICROENCAPSULATION, Parma (Italy), September 18-21, 2005

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containing 5-10-15 and 20% of SA. SLMs suspensions were produced in triplicate for each theoretical optimal manufacturing mathod determined by the software. The obtained results were compared with the theoretical ones and are presented in Table2. Lutrol Mixing SLMs in Theoretical SA F68 durarange of response ((%) ((%) tion w/wdispersed size 0.5-6 calculated w/ m (%) (min.) by the phase) wtotal) SD (n=3) software (%) 0.1 10 5 44.520.61 44.90 0.1 0.1 0.1 10 10 10 10 15 20 43.211.42 44.471.61 43.590.87 45.30 45.25 44.76

pulmonary administration. It has also been proved in vitro that SLMs can reasonably be considered as a suitable carrier to provide a sustained release to the incorporated active substance. The release rate has been proved to be slower for SLMs with low drug loadings. ACKNOLEDGEMENTS The authors would like to acknowledge the Walloon Region (Belgium) for its the financial support to this research work. REFERENCES 1. FINLAY WH, WONG JP: Regional lung deposition of nebulized liposome-encapsulated ciprofloxacin. Int. J. Pharm. (1998) 167(1-2): 121-127. 2. EL-BASEIR MM, KELLAWAY IW: Poly (L-lactic acid) microspheres for pulmonary drug delivery: release kinetics and aerosolization studies. Int. J. Pharm. (1998): 135-145. 3. COURRIER HM, BUTZ N, VANDAMME TF: Pulmonary drug delivery systems: Recent developments and prospects. Critical Reviews In Therapeutic Drug Carrier Systems (2002) 19 (4-5): 425-498.

Table 2: Comparison between theoretical and experimental percentages of SLMs whose geometrical diameter lies between 0.5 and 6 m. Table 2 shows that experimental responses are well correlated with the theoretical ones. The SA encapsulation efficiencies were respectively 87.30 % 0.44, 88.27 % 4.65, 87.08 % 1.74 and 89.26 % 3.03 (n=3) for SLMs containing 5-10-15 and 20% SA. The drug release profiles are presented in Figure 1. This figure shows that dissolution of pure SA is complete after 2 hours and that the release rate is the slower for SLMs with 5% SA. Then the drug release rate increases with the drug loading but is in every case lower than the dissolution rate of pure SA.

Salbutamol Acetonide release (%)

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75 SA SLMs SLMs SLMs SLMs

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25 0 0 4 8 Time (h)

5% SA 10% SA 15% SA 20% SA

12

16

Figure 1: SA dissolution profile of pure SA compared with SA release profiles of SLMs containing 5-10-1520% SA. CONCLUSION We can conclude that the methodology of experimental design can be used to optimize SLMs manufacturing parameters in order to reach a suitable particle size for

15th International Symposium on MICROENCAPSULATION, Parma (Italy), September 18-21, 2005

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