More than 40 per cent of the drugs coming from high-throughput screening are poorly soluble in water. Obviously poorly water-soluble drugs show many problems in formulating them in conventional dosage forms. One of the critical problems associated with poorly soluble drugs is too low bioavailability and or erratic absorption.
The problem is even more complex for drugs such as itraconazole and carbamazepine (belonging to BCS Class II) as classified by BCS System as they are poorly soluble in both aqueous and organic media, and for those drugs having a log P value of 2. The performance of these drugs is dissolution rate-limited (for Class II and III drugs) and is affected by the fed/fasted state of the patient. Dissolution rates of sparingly soluble drugs are related to the shape as well as the particle size. Therefore decrease in particle size results in an increase in dissolution rate.
There are number of formulation approaches to resolve the problems of low solubility and low bioavailability. The approaches include micronization, solublization using co-solvents, use of permeation enhancers, oily solutions, surfactant dispersions, salt formation and precipitation techniques. Other techniques like liposomes, emulsions, microemulsions, solid-dispersions and inclusion complexes using Cyclodextrins show reasonable success but they lack in universal applicability to all drugs. These techniques are not applicable to the drugs, which are not soluble in both aqueous and organic medias. Hence there is need of some different and simple approach to tackle the formulation problems to improve their efficacy and to optimize the therapy with respect to pharmacoeconomics.
Nanotechnology can be used to resolve the problems associated with these conventional approaches for solubility and bioavailability enhancement. Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10-9 meters. The drug microparticles/micronized drug powder is transferred to drug nanoparticles by techniques like Bottom Up Technology (precipitation) and Top Down Technologyor disintegration methods. Nano is a Greek word, which means 'dwarf'. Nano means it is the factor of 10-9 or one billionth.
Methods of preparation
Mainly there are two methods for preparation of nanosuspensions. The conventional methods of precipitation (hydrosols) are called 'Bottom Up Technology'. In Bottom Up Technology the drug is dissolved in a solvent, which is then added to non-solvent to precipitate the crystals. The basic advantage of precipitation technique is the use of simple and low cost equipments. The basic challenge of this technique is that during the precipitation procedure the growing of the drug crystals needs to be controlled by addition of surfactant to avoid formation of micro particles. The limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and this solvent needs to be miscible with non-solvent. Moreover, precipitation technique is not applicable to drugs, which are simultaneously poorly soluble in aqueous and non-aqueous media.
The 'Top Down Technologies' are the disintegration methods and are preferred over the precipitation methods. The 'Top Down Technologies' include: Media milling (nanocrystals), high-pressure homogenization in water (dissocubes), high- pressure homogenization in non-aqueous media (nanopure) and combination of precipitation and high-pressure homogenization (nanoedege). Few other techniques used for preparing nanosuspensions are emulsion as templates, micro emulsion as templates etc.
Characterization of nanosuspensions
The various essential parameters to be characterized for nanosusepnsions includes:
■Size and size distribution
■Particle charge (zeta potential)
■Crystalline status
■Dissolution velocity and saturation solubility.
For surface-modified nanosuspensions, a number of additional parameters have to be investigated to obtain a complete picture, especially with relevance for the in-vivo behavior:
■Adhesion properties (in case of mucoadhesive particles)
■Surface hydrophilicity/hydrophobicity
■Interaction with body proteins.
Nanosuspension technology applications
Nanosuspensions can play a critical role as an enabling technology for poorly water-soluble and/or poorly permeable molecules having significant in vitro activity. Such molecules pose problems at any or both of the following during new drug development activities:
■Formulation of an intravenously injectable product for preclinical in vivo evaluation of the new molecule to measure its toxicity and other pharmacokinetic characteristics.
■Poor absorption of the drug candidate from the GIT resulting into poor bioavailability during preclinical as well as clinical development studies.
Pure drug nanosuspensions can provide solutions to both of these problems. A pure drug nanosuspension contains pure drug particles suspended in an aqueous media. As the particle size (usually below 400 nm) is way below the minimum particle size that can be administered intravenously (ie, 5 µm), a nanosuspension can be administered intravenously to conduct exploratory study with the candidate drug molecules.
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
Drugs with poor solubility and low bioavailability are called 'brick dust' candidates once abandoned from formulation development work can be overcome by using novel approach called nanosuspensions technology. The transformation of any drug to drug nanoparticles leading to an increase in saturation solubility, dissolution velocity, and providing the general feature of an increased adhesiveness to surfaces is one of the most important achievement. A fusion of the novel nanosuspension technology with the traditional dosage forms, e.g. incorporating drug nanoparticles into pellets or tablets for oral delivery is also a note worthy advantage.
(Kamal Dua is with Dept.of Pharmaceutical Technology, Faculty of Medicine & Health, International Medical University, Malaysia. VK.Sharma, UVS Sara, Kavita Pabreja are with DJ College of Pharmacy, Niwari Road, Modinagar-201204, UP, India)