Nanosuspension drug delivery: Technology and application

Poorly soluble and low bioavailablity drugs so called ‘brick dust’ candidates once abandoned from formulation development work can be rescued with nanosuspension technology says Kirupakar B R

A large proportion of new chemical entities coming from drug discovery are water insoluble, and therefore poorly bioavailable, leading to hurdles in formulation development efforts. Attempt to increase solubilisation by complexation techniques (using cyclodextrin) which uses high quantity of complexing execipients is not suitable when high drug dosing is crucial as in injection and ophthalmic preparations. Conventional method to solubilise using co-solvents will cause toxicity problem.

The criteria for selection of various techniques to enhance solubility

Nanosuspension technology offers novel solution for these poorly soluble drugs. Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilised by surfactants. Nanosuspensions differ from nanoparticles, which are polymeric colloidal carriers of the drug and solid lipid nanoparticles , which are lipidic carrier of drug.

Nanosuspension technology is applied to drugs that are insoluble in both water and oils. The drugs which have high crystal energy i.e. high melting point, reduces the solubility of drug substances. Nanosuspension technology is used for these drugs without the necessary to solubilise them. By this technology the drug is maintained in required crystalline state with reduced particle size and this cause increased dissolution rate and therefore improved bioavailability. Nanosuspension provides chemically and physically stable product.

Nanosuspension are formed by building particles as in precipitation or breaking as in milling .In both case new surface area is formed .Therefore has more free energy and system tends to agglomerate which is prevented by addition of surfactants. Surfactants causes high energy barrier and prevents particles coming together.

Nanosuspension techniques

Homogenisation: The suspension is forced under pressure through a valve that has nano aperture. This causes bubbles of water to form which collapses as they come out of valves. This mechanism cracks the particles.

Wetmilling: Active drug in the presence of surfactant is defragmented by milling.

Other technique involves the spraying of a drug solution in a volatile organic solvent into a heated aqueous solution. Rapid solvent evaporation produces drug precipitation in the presence of surfactants.

Characterisation technique

To study particle growth, field emission low voltage scanning electron is used to image individual particles and atomic force spectroscopy is used for visualisation of particle shape. With near infrared sedimentation rate studies and online monitoring of particle size can be done and with differential scanning calorimetry and X ray diffraction polymorph stability can be studied. Particle size distribution in response to accelerated ageing and shipping can be studied by free thawcycling, mechanical agitation and centrifugation. Syringibility of injection nanosuspension should be studied. Biological tests like sterility and pyrogenicity should be studied.

Solid state stability:Crystal structure analysis between the raw material and suspension particles before and after homogenisation remains same, confirming no change have occurred. Unstable formulation can be lyophilised and this nanosuspension can be reconstituted without any significant change in particle size. No substantial change occurs even after steam sterilisation and thermal cycling. Stability of formulation can be increased upto two years at room temperature.

Diagrammatic representation of nanosuspension technology

Small scale processing: Time is crucial in product development and often a new drug s only available in extremely limited quantity. Experiment can be designed with help of computational tools and formulation process time can be reduced. Process strategy and surfactant choice depends on rate of crystallisation and solubility of nascent crystal relative to rate of particle breakdown in homogeniser.

Application: Oral nanosuspensions have been specifically used to increase the rate and extend of absorbtion of drugs. Evidence for enhanced onset of action, reduction of fed/fasted ratio and enhanced dose proportionality and reduced gastric irritancy have been found. To target lungs, aerosols has smaller drug particles, but they show statistical inhomogeneity in partitioning of drug particles among carrier droplets.

Nanosuspension provides solution to this by increasing number of particles per droplets and as a result leads to increased onset of action and bioavailability. Nanosuspension helps in administration of huge drug concentration of poorly water soluble drugs to brain with decreased systemic effects. Thus nanosuspension has application to various route of administration like parenteral, oral topical, pulmonary and targeted drug delivery system.

Conclusion

The poorly soluble and low bioavailable drug so called “brick dust”candidate once abandoned from formulation development can be rescued by formulating into nanosuspension. Nanosuspension technology offers solution not only to solubility of drug but also alters the pharmacokinetic of drug and thus improves drug safety and efficacy. It is clear that an era will emerge when soluble drug will be intentionally made to insoluble complex to take advantage of Nanosuspension technology.

The writer is a senior research pharmacist with Zydus Pharmaceuticals, Bangalore.
E-mail: kirupapharmacy@rediffmail.com