PharmaSol's Lipid Nanoparticles
incorporation of lipophilic drugs (carrier: nanostructured lipid carriers - NLC®)
incorporation of hydrophilic drugs (lipid drug conjugate nanoparticles - LDC®)
enhancement of oral bioavailability exploiting the effect of nanoparticles and the effect of lipids on drug absorption
protection of chemically sensitive compounds in the gut and simultaneously absorption enhancement of highly
site-specific delivery of drugs via i.v. injection route
dermal application: enhancement of drug penetration into the skin, localisation in certain skin layers
Lipophilic compounds are incorporated into nanostructured lipid carriers so that the lipid nanoparticles
possess a matrix with a controlled structure for optimising drug incorporation and modifying drug
release. The drug is dissolved in a blend of melted lipid, containing both solid lipid and liquid lipid (oil). The
drug-containing lipid melt is dispersed in a hot surfactant solution by stirring and the obtained pre-emulsion is
passed through a high pressure homogeniser. The obtained hot lipid nanoemulsion is cooled, the lipid crystallises
and forms lipid nanoparticles with a solid matrix. The aqueous suspensions can be transformed to dry oral dosage
forms (tablets, pellets, capsules). The suspensions themselves can also be injected intravenously. After the addition
of a viscosity enhancer, dermal formulations are obtained.
Hydrophilic drugs are incorporated into lipid nanoparticles by transferring the soluble hydrophilic drugs
to insoluble lipid-drug conjugates (e.g. by salt formation with fatty acid). These conjugates melt between
50-100°C, and particles can be produced using the same method as described above for NLC. These particles can be
applied to enhance oral bioavailability. After i.v. injection of molecular solutions, the molecules distribute
themselves in the body according to their partitioning coefficient. However, targeting is possible by converting the
soluble molecules into insoluble LDC nanoparticles. Depending on the surface properties, they localise in
macrophage-rich tissues (liver, spleen) or alternatively can be directed to the brain or the bone marrow (PharmaSol┤s Pathfinder® technology).
Advantages over competing technologies:
Despite about 40 years of intensive research, the polymeric nanoparticles never made it to the pharmaceutical market. Possible reasons
include the lack of accepted status of excipients used and the lack of cost-effective regulatorily accepted production methods.
The lipid nanoparticles do not have these problems.
Liposome-based products are on the market, however, there are still problems with the physical stability of liposomes and
no "cheap" liposomes are available. In contrast, lipid nanoparticles can be produced as physically
stable aqueous or non-aqueous suspensions and excipients are typically of low cost.
SLN are considered to be the first generation of the lipid nanoparticles and are in principle an appealing
carrier system. NLC and LDC nanoparticles are the second generation, also developed by R. H. Müller.
Advantages of these nanoparticles are increased drug loading, improved drug incorporation and suspensions of
higher solid content can be produced (e.g. 30-50% solid).
Large scale production/costs:
Large scale production is easily achieved because high pressure homogenisation is a technology applied in
the pharmaceutical industry for the production of parenteral emulsions. Batch sizes can be 1 ton of dispersion or
more. Even larger batch sizes can be produced when homogenising in the food industry. The equipment is off the shelf
equipment and of relatively low cost. The excipients used for nanoparticle production are also low cost
substances and generally have excipent regulatory status.
For an overview of patents and patent applications please click "Intellectual property".
For a short overview please read :
Further Information regarding this topic can be obtained by reading:
Müller, R. H., Mäder, K., Gohla, S., Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art,
Eur. J. Pharm. Biopharm. 50, 161-177, 2000
Olbrich, C., Ge▀ner, A., Kayser, O., Müller, R. H., Lipid-drug conjugate (LDC) nanoparticles as novel carrier
system for the hydrophilic antitrypanosomal drug Diminazenediaceturate, Journal of Drug Targeting 10 (5), 387-396, 2002
Müller, R. H., Radtke, M., Wissing, S. A., Solid lipid nanoparticles (SLN) and nanostructured lipid carriers
(NLC) in cosmetic and dermatological preparations, ADDR Reviews 54 Suppl. 1, S131-S155, 2002
Müller, R. H., Radtke, M., Wissing, S. A., Nanostructured lipid matrices for improved microencapsulation of drugs,
Int. J. Pharm. 242, 121-128, 2002
Olbrich, C., Kayser, O., Müller, R. H., Preparation of the hydrophilic drug diminazene diaceturate as lipid drug conjugate
(LDC) nanoparticles, Intern. Symp. Control. Rel. Bioact. Mater. 28, 1285-1286, 2001
Müller, R. H., Radtke, M., Wissing, S. A., Nanostructured lipid carriers (NLC) - the next generation,
4th World Meeting ADRITELF/APV/APGI, Florence, 673-674, 2002
Radtke, M., Müller, R. H., Semisold NLC«-dispersions for the topical administration of cyclosporine A,
4th World Meeting ADRITELF/APV/APGI, Florence, 1165-1166, 2002
Olbrich, C., Müller, R. H., Lipid-drug conjugate (LDC) nanoparticles for incorporation of
hydrophilic drugs into lipid particles, 4th World Meeting ADRITELF/APV/APGI, Florence, 675-676, 2002
Radomska, A., Müller, R. H., The chemical and physical stability of the lipid matrices of solid lipid
nanoparticles, 4th World Meeting ADRITELF/APV/APGI, Florence, 683-684, 2002
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