Liposomal drug delivery systems

Liposomal drug delivery systems

Hardik Mody, Project Assistant, IIT Bombay, Powai writes about solid lipid nanoparticles as an alternative to the present drug carrier system

The author is a Project Assistant, Department of Biosciences and Bioengineering, Centre for Research in Nanotechnology and Science, IIT Mumbai, Powai. He can be contacted at hardik_2504@yahoo.co.in

Over the past few years, extensive research has been carried out with respect to the drug carrier systems and their potential applications in the delivery of drugs. There are various types of drug carrier systems which have been subjected to vigorous investigations, including microparticles, micellar systems, emulsions, liposomes and nanoparticles. Emulsions have been used in clinics successfully over the years for various purposes like parenteral nutrition (for example, several drugs including diazepam), however, there were certain limitations of emulsion formulations. Drug release from these formulations was much quicker than required. Apart from this, solubility problems of drugs, physical instability of the formulation were other drawbacks which led to the limited marketed products based on emulsions. The faster drug release of emulsions was overcome with the help of liposomes, which are concentric phospholipid bilayer systems which can be used for drug delivery, and longer release times were achieved with the help of liposomal delivery systems. However, the total number of marketed preparations of liposomes is still limited due to various problems associated with liposomes, including metabolism in vivo and physical properties of liposomes. Apart from this, non-availability of cheap liposome is also one of the drawbacks.

SLNs versus polymeric nanoparticles

Defined as the creation and application of materials which are in nanometer range, nanotechnology has had a significant impact on the drug delivery science. Due to their large surface area to volume ratio and small size, nanoparticles can permeate the membrane barriers and reach the target areas. They have been utilised in various forms for various purposes. However, polymeric nanoparticulate systems have several disadvantages like cytotoxicity of polymers. These polymeric nanoparticles can be internalised by cells and can lead to cytotoxicity. For example, 0.5 percent PLA/GA nanoparticles lead to death of cell cultures on incubation. Even after extensive research has been carried out in this field, this system has not been found applicable to a great extent. Also, it lacks availability of large scale production techniques. The above mentioned problems associated with polymeric nanoparticles could be overcome by replacing the polymer with solid lipid.

Solid lipid nanoparticles (SLNs) are a class of nanoparticles. While polymeric nanoparticles are made from synthetic or natural polymers, SLNs are made by utilisation of lipids or lipid blends. They are comparable with emulsions where the oil in emulsion and solid lipid in SLNs are analogous which are dispersed in an aqueous outer phase. They have diameters in the size range approximately between 80-1000nm. Various techniques are utilised as an aid to enhance their stabilisation such as increasing the viscosity of the outer phase and addition of stabilisers like lecithin, polaxamer 188. These SLN aqueous dispersions then can be included in the dosage form like tablets.

SLNs avoid problems of the above mentioned systems, but at the same time enjoy benefits of the particulate drug delivery. Large scale production of SLNs can be achieved with various techniques like hot and cold homogenisation technique, production via microemulsion. These SLN are composed of solid matrix, which is normally well tolerated as compared to cytotoxicity seen with polymeric nanoparticles. SLNs also have advantages of a typical solid matrix system providing flexibility in controlling the release profile of drugs, protection to the incorporated active ingredients and slower degradation in vivo allowing prolonged drug release periods. Besides these, SLNs allow hydrophobic as well as hydrophilic drugs to be incorporated for drug targeting.

Drugs delivered

Various drugs have been incorporated in SLNs, including aciclovir, azidothymidine palmitate, betamethasone valerate, campothecin, cortisone, cyclosporin, diazepam, doxorubicin, deoxycorticosterone, paclitaxel, retinol, timolol, tetracaine, oxazepam, pednisolone to name a few. Loading capacity of a drug in SLN is expressed in percentage related to lipid phase. For various drugs, loading capacity has been established, for example, for cyclosporine, capacity of 20-25 percent has been reported. Drug solubility in the melted lipid and miscibility of drug melt are the most important factors determining the loading capacity of a drug. The drug should be highly soluble in the lipid melt; the drug solubility in the lipid melt can be achieved with the aid of solubilisers. Polymeric form of lipids is also an important parameter with respect to drug incorporation. There are alpha and beta polymeric forms of lipid nanoparticles of which beta form is more stable. Thus, an optimal SLN carrier system can be designed when a certain fraction of lipid nanoparticles in alpha form can be created and preserved during storage. By trigger mechanism, alpha form converts into beta forms, thus increasing formation of more stable form, more perfect lattice, thereby promoting drug expulsion. Thus, by means of this consequently controlled drug release is obtained.

Initially, lipid nanoparticles faced a major problem of burst release. However, a prolonged release was obtained in case of incorporation of prednisolone which showed in vitro drug release up to five to six weeks. The in vitro prednisolone release profile from SLNs made from lipids like cholesterol and campritol was explained through partitioning phenomena. The drug partitions between the melted lipid phase and aqueous surfactant phase during production by hot homogenisation technique. With increasing temperature and surfactant concentration, the amount of drug partitioning in the aqueous solution increases. After the nanoemulsion formation, cooling of nanoemulsion is carried out. At this step, as temperature decreases, the solubility of drug in the aqueous phase decreases considerably and the drug re-partitions into the lipid phase. This results into formation of a solid lipid core including the drug at the recrystallisation temperature of the lipid. Further decrease in temperature leads to the formation of a crystallised core while the drug concentrates into the still liquid lipid outer shell of SLN and on the surface of particles. The drug incorporated into the crystallised core is released into a prolonged way while the drug in the outer liquid shell would be utilised as a burst release. Thereby, by manipulating the temperature conditions and surfactant concentration, the extent of burst release and prolonged release could be extended. Thus, higher temperatures and increased surfactant concentration increases partitioning of drug in the aqueous phase and increases burst. On the other hand, production at room temperature or low temperature with no surfactants minimises burst release. The patent rights for SLN production by high pressure homogenisation technique has been acquainted by Syepharma IN 1999. Thus, SLNs have made their way into the pharmaceutical world. However, extensive research still needs to be carried out With respect to the burst release profile and characterisation of SLNs. SLN based formulations would find a place in clinic and pharmaceutical industry in the future.

References:

1. Muller, H., K. Mader and S. Gohla, 2000. Solid Lipid Nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur. J. Pharm. Biopharm., 50: 161-177. 2. zur Mühlen, A., C. Schwarz and W. Mehnert,1998. Solid Lipid Nanoparticles (SLN) for controlled drug delivery-Drug release and release mechanism. Eur. J. Pharm. Biopharm.,45: 149-155. 3. AL-Haj, N. and A. Rasedee, 2008. Solid lipid nanoparticles preparation and characterization. Int.J. Pharmacol., 4: 1-4.

4. Wissing, S.A. and R.H. Müller, 2002. Solid lipid nanoparticles as carrier for sunscreens: In vitro release and in vivo skin penetration. J. Control Release, 81: 225-233.

The author is a Project Assistant, Department of Biosciences and Bioengineering, Centre for Research in Nanotechnology and Science, IIT Mumbai, Powai. He can be contacted at hardik_2504@yahoo.co.in