Solid lipid nanoparticle - A great promise
Thursday, November 27, 2008 08:00 IST
Over the last twenty years, nanotechnology has practically made its imprint in all technical fields, including pharmaceutics. Industry estimates suggest that approximately 40 per cent of lipophilic drug candidates fail due to solubility and formulation stability issues, prompting significant research activity in advanced lipophile delivery technologies. Solid lipid nanoparticle technology represents a promising new approach for delivering these moieties.
Solid lipid nanoparticles (SLN), which are colloidal systems comprised of a solid lipid core stabilised by a surfactant interfacial region, were developed at the beginning of the 1990s as an alternative carrier system to emulsions, liposomes and polymeric nanoparticles. These systems generally are spherical in shape with a size range of 1 to 1000 nm. The core lipids can be fatty acids, acylglycerols, waxes and mixtures of the same. Biological membrane lipids such as phospholipids, sphingomyelins, bile salts such as sodium taurocholate, sterols like cholesterol and mixtures of the same are utilised as surfactant stabilisers. The second generation of these nanoparticles includes nanostructured lipid carriers (NLC), in which the solid lipid is partially replaced with liquid lipids.
Scalable solid lipid nanoparticle production processes include high-shear homogenisation, high pressure homogenisation and microemulsion dilution.
In recent years, much research has been devoted towards the development of such lipidic nanocarriers, which have wide applications in pharmaceutical and cosmetic industry. Pioneering research in these systems was executed more or less in parallel by Prof Rainer H Muller and Dr Jorg-Stefan Lucks and Dr Maria Gasco in the beginning of 1990s. The German group produced the SLN by high pressure homogenisation, with Prof Gasco using a microemulsion technique. This process took advantage of the micron sized droplets of these systems containing lipids and emulsifiers to avoid energy expenditure to convert them to submicronic stage. The priority dates of both patent applications were just close together (1992).
Also, Dr Kirsten Westesen at Braunschweig University, Germany, exploited the high pressure homogenisation technique to generate solid lipid nanoparticles. In yet another instance, Prof Michele Trotta generated the lipid carriers by the solvent-in-water emulsion-diffusion technique in which SLN of spherical shape were obtained by simple water dilution of the O/W emulsion.
In India, Institute of Chemical Technology, Mumbai, one of the premier institutes of the country, is actively involved in developing lipid nanoparticulate drug delivery systems. Studies have been executed to formulate lipidic nano systems such as solid lipid nanoparticles and nano structured lipid crystals of Artemether for I.V. administration (nanoject). The in vivo results in a murine model showed much higher efficiency than marketed I. M. formulations, indicating a possibility of significant dose reduction and thereby making the overall therapy cost effective.
Another study undertaken in this lab has proven the ability of these systems to protect photosensitive agents like Tretinoin used for the topical cure of acne/cancer (nanojel). Photostability studies of the nanocarrier solution against the plain drug solution proved that encapsulating into lipidic carriers could retain 65 per cent of the drug as against 5 per cent in the control solution when both were exposed to direct sunlight for a span of three hours. In addition, the researchers at Institute of Chemical Technology are exploring the potential of SLNs for the intracellular drug delivery of actives by topical/mucosal route. Besides, affinanotechnology as an approach was suggested to associate hydrophilic moiety Polymyxin B to lipidic core and it was found to potentiate the antimicrobial activity, while enhancing the wound healing action.
Also, Dr Mishra's research group at M S University Baroda India has exploited these systems for the development of novel carriers for psoriasis. The group has achieved promising results in the clinical trials conducted on a moderate number of patients. Prof Murthy of this University utilised the potential of these systems for targeting anti-cancer moieties to solid tumours through parenteral administration. To add to it, Dr Singh and her group at S N D T Women's University, Mumbai, India, investigated the potential of SLNs for encapsulating various natural antioxidants. The group has achieved significant results to establish the potential of SLNs in improvising skin hydration and thus prevent aging through controlled release and selective localisation of the actives in the skin with no associated irritation. Besides, Dr Vyas and his research fellows at Sagar University, Madhya Pradesh, India, are working towards the development of SLNs of Amphotericin B for the topical cure of Leishmaniasis.
Apart from academia, the lipidic nanocarriers have also been exploited commercially in the recent years. The first commercial product based on lipid nanoparticles that has made its way to the market is the one based on the 'nanopearls' technology introduced by Prof Rainer H. Müller, Berlin, Germany. Almost twenty cosmetic products based on this technology are available in the market since the first introduction by Dr. Rimpler, Germany, in 2004. On close heals were the products 'NanoRepair Q10 Creme' and 'NanoRepair Q10 Serum', which were introduced to the market during the cosmetic fair "Beauty" in Munich in October 2005. Both these products contain natural anti-oxidants like hibiscus and ginger extract loaded along with the co-enzyme Q10 into tiny NLCs, which stimulate the body's functions against oxidative stress and lead to temporary lifting of muscle contraction to support the restructuring of the skin, guarding it against premature aging.
Yet another area where the lipid nanoparticles have a dominant market share is as concentrates to be used as cosmetic excipients. The incorporation of sunscreens into nano lipid carrier molecules has increased their effectiveness, whilst reducing the possibility of undesired side effects. Moreover, many of the lipids themselves block the UV rays thus accounting for a two-fold protection when the molecular sunscreens are incorporated into these carriers.
The astonishing effects of these carriers also have a major impact on the pharmaceutical industry as well. Some of the drugs that have been incorporated in these carriers include Paclitaxel, isotretinoin, tobramycin and anti-tubercular drugs like pyrazinamide, rifampicin and isoniazid that have been encapsulated in SLNs for administration by different routes such as parenteral, dermatological, transdermal, oral, duodenal and ocular. In vivo studies in different animal models have yielded promising results, which provide a strong reason to believe that these systems could actually reign the pharmaceutical market in near future.
A criterion for the success of an academic delivery technology is its marketing and a continuous growth in the number of the technology based products after its market introduction. Entry into the pharmaceutical market is more stringent as compared to the cosmetic market because of several considerations like regulatory acceptance of the excipients, proven feasibility of large-scale production, sufficient drug loading to achieve therapeutic levels and improvements of therapeutic performance versus traditional forms, which may mean reaching organs not sufficiently targeted by other formulations, achieving sustained/controlled release and improving patient compliance (for example oral SLN administration instead of the parenteral route).
Despite the perceived advantages, the application of solid lipid nanoparticle technology has proved extremely difficult. Physical instability, characterised by particle growth, unpredictable gelation tendency, unexpected dynamics of polymorphic transitions and inherently low incorporation capacities due to the crystalline structure of the solid lipid and drug burst release have plagued the success of these systems. Yet another area, where these systems have faced a major drawback is their commercialisation, which has been impeded by the lack of large-scale and economically efficient production processes.
The success of commercialisation also relies on the availability of suitable sophisticated characterisation methods for the various components of these systems. Especially, the polymorphic transitions of the lipid particle matrix represent a challenge in physico-chemical characterisation and successful formulation development. It is imperative that further research be directed in this area for the development of high-loading, efficacious lipid carriers of commercial utility.
Such high value lipid carriers, whenever commercialised, would have a unique place amongst the modern pharmaceutical products. Enhanced therapy, with reduced untoward effects, could be achieved through the innovative reformulation of drugs. An improved production process to realise the full technological and economic potential of solid lipid nanoparticle technology could have a huge social impact in terms of preventing the chronic use of drugs by the consumers, who are at the receiving end.
(The authors are with Institute of Chemical Technology, Mumbai)