Elastic Liposomes Bearing Meloxicam – Beta-Cyclodextrin for Transdermal Delivery

Summary by Sneha Subramanian – 22/06/2012

Current Drug Delivery, 2008, 5, 207-214 207

1567-2018/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

Sanjay K. Jain*, Yashwant Gupta, Anekant Jain and Sadia Amin

In this experiment, elastic liposomes are used for the delivery of Meloxicam-β-Cyclodextrin vie skin.

Meloxicam has anti-inflammatory activity which is used for the treatment of ostereostasis and rheumatoid arthritis. This drug is poorly soluble in water; hence, its absorption from GI track is prolonged. This leads to many side effects like ulceration and bleeding. Cyclodextrin has hydrophobic central cavity and hydrophilic outer surface. They form inclusion complex with the drug and improves stability, solubility and dissolution rate of the drug. Recently various vesicles are used for the effective delivery of drug via Transdermal route, they include liposomes and niosomeswhich have their own mechanism to deliver drug. These vesicles are obstructed by the layer of the skin called stratum corneum which is very thick. Hence, a specialised vesicle which is elastic is developed to overcome this problem. They vary from liposomes and niosomes by their characterisctic fluid membrane and can easily pass through the tough stratum corneum. They have the ability to sqeeze and bend, hence, can pass though small intracellular space.  Transdermal water gradient aids it in this movement of elastic liposomes. This work aims at he delivery of Meloxicam-β-Cyclodextrin complex along with the elastic vesicle to exploit the characteristics of both the carriers.

Meloxicam-β-Cyclodextrin complex was taken in the molar ratio 1:2. This complex was watted in water and was kneaded to paste. This method is called kneading method. This paste was stirred continuously till it peeled off the walls of the mortar. This preparation was then dried in rotary evaporator at 45° which was then sieved. The particles below 50-100µm was used for this experiment.

Solubility studies – This was carried out according to the method given by Higuchi and Connors. In this method excess amount of Meloxicam was transferred into 25ml of aqueous solution containing β –Cyclodextrin from 0-10M/L concentration. It is also shaken for 48hours at room temperature. After filtration, their spectrophotometric studies were carried out at 361nm to estimate the quantity of Meloxicam. Their mixtures were shaken till three consecutive samples estimated same amount of drug.

Differential scanning calorimetry – All samples were taken in 0.5-1mg size range and scanned in temperature 100-270°C/10°/min under nitrogen atmosphere.

X- ray powder Diffractometry (XRD) – was used for the interval of 10-60°/20. The conditions were taken as follows: voltage, 50 kV; current , 200mA; angular speed, 3°/min and angular step of 0.02°

FTIR studies – In this technique, the samples are vacuum drived for 12 hours before studies. The samples- Meloxicam, β-Cyclodextrin and Meloxicam-β-Cyclodextrin mixed with potassium bromine (100mg) and compressed with palate.

Elastic liposomes are prepared by conventional rotary evaporation sonication method. Here HSPC and span80 (85:15w/w) was taken in a clean dry round bottom flask. To this organic solvent- chloroform:methanol  (2:1 v/v) was used to dissolve the lipid phase. This organic solvent was removed rotary evaporation above phase transition temperature. This thin film was hydrated with PBS (pH 6.5) containing Meloxicam/ Meloxicam-β-Cyclodextrin complex by rotation at 60rpm for 1hour at 55°C. This was kept for annealing for 2 hours to form multilamellar vesicles (MLVs) and was then was sonicated using probe sonicator for 20mins at 40W. This sonicated vesicles were extruded between 100-200nm polycarbonate membranes. The final lipid drug concentration was 5% wv and 1%wv and similarly Rhodaminered loaded elastic liposomes were prepared.

Morphology was visualised using TEM at voltage of 100KV. For this a drop of sample was kept of the carbon-coated copper and to leave a thin film and before drying was negatively stained with 1% PTA. After the sample was stained and dried and was viewed under TEM. The size and size distribution was determined using DLS method-dynamic light scattering . All measures were conducted in triplicates

Unentrapped drugs were separated using minicolumn centrifuge method. The separated liposomes were separated using 0.1% triton X-100 and was analysed for drug content at 361nm.

These elastic vesicles were extruded through the polycarbonate filter of 50nm diameter with 200ml capacity barrel at 2.5 bar pressure for 10mins. Vesicular sizes were compared before and after extrusion and were repeated.

The in-vitro studies were carried out using dialysis membrane and Franz diffusion cell.

The maximum drug solubility was at 4mM/L concentration of Meloxicam-β-Cyclodextrin. The stability constant (Kc) of Meloxicam and Meloxicam-β-Cyclodextrin complex was calculated

The thermal behaviour of Meloxicam and Meloxicam-β-Cyclodextrin was studies using DSC to confirm the formation of solid complex. The thermogram of Meloxicam-β-Cyclodextrin shows an endothermic peak at 173.8°C while the DSC pattern showed a very diminished melting endotherm of Meloxicam which was shifted to 249°C suggesting a complex formation in 1:2 molar ratio and indicating that the drug has been engulfed in the Cyclodextrin cavity.

The X-ray pattern of Meloxicam and β-Cyclodextrin are shown in the above figure.The XRD of pure of Meloxicam and β-Cyclodextrin are intense and sharp. Thus, inclusion complex indicates their crystalline nature. The inclusion complex shows a completly different pattern which cannot be distinguished from the peak of of Meloxicam. This confirms the existence of new compound at 1:2 molar ratio.

TEM revealed that they are unilamellar and spherical in shape. Precipitation of dry crystals was observed in drug loaded liposomes. This was due to the lower stability of the complex of Meloxicam with native cyclodextrin, part of the drug, less strongly complexed with Cyclodextrin was recrystalized in the aqueous solution during the elastic liposome preparation.

It is observed that the size of drug loaded liposome and empty liposome are almost similar. Larger vesicles are obtained in the presence of Meloxicam-β-Cyclodextrin complex. Polydispersion index is less than 1 indicating narrow size distribution of both formulations. After the entrapment studies , high entrapment of Meloxicam was observed due to its small size as compared to Meloxicam-β-Cyclodextrin complex. This may be due to the lower stability of the complex of Meloxicam with mature cyclodextrin.

The combined effect of using both elastic liposomes and cyclodextrin for Transdermal delivery was studies in this experiment Anti-inflamatory drug Meloxicam was used as a sample drug. Use of cyclodextrin increased the drug’s dissolution property. This increase in water solubility increased its entrapment in the internal aqueous phase of elastic vesicle. This in turn improved the permeability of drug through the skin.

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