Citation: Lakio S, Sandler N, “Nanoparticle Engineering: Revolutionising Oral Drug Development and Delivery”. ONdrugDelivery Magazine, Issue 109 (July 2020), pp 26-29
Satu Lakio and Niklas Sandler discuss the benefits of nanoparticle engineering technology as a means of improving the bioavailability and solubility of drug compounds.
It is an established fact that the failure rate of drugs entering Phase I trials is over 90%.1 This is a staggering figure, considering the huge expense and the many years of hard work across the drug discovery and development pipeline that lie behind every investigational drug. As healthcare systems around the world continue to be challenged to create more efficient and effective therapies, there is increasing interest in methods for improving this low success rate.
“It is apparent that technologies which can enhance drug solubility and bioavailability have great potential to improve efficiency within the drug development pipeline.”
A significant obstacle to the release of new medicines is the increasing complexity of drug molecules, which contributes to increased hydrophobicity and poorer water solubility. This is clear from the contrast between the solubility of drugs within the development pipeline and those that reach the market: 70–90% of pipeline drugs fall into the low solubility categories of the Biopharmaceutical Classification System (BCS). Meanwhile, fewer than 40% of drugs on the market fall under the same classification.2 With this in mind, it is apparent that technologies which can enhance drug solubility and bioavailability have great potential to improve efficiency within the drug development pipeline. Nanoparticle engineering – the process of shrinking down the size of drug particles – has emerged as a promising solution to this problem.
ENHANCING SOLUBILITY AND BIOAVAILABILITY
Poor solubility and bioavailability are major causes of attrition in the drug development pipeline. Solubility, defined as the ability of a solute to dissolve in a solvent and give a homogenous system, is an important parameter for drug developers.3 It is one of the factors influencing whether a drug can achieve the desired concentration in systemic circulation for optimal therapeutic effect. This characteristic is often linked to bioavailability, which refers to the extent and rate at which a drug enters systemic circulation in an unchanged form, thereby reaching its target area.4
A significant proportion of drugs delivered through the oral route are absorbed into the body through the gastrointestinal tract. Poor water solubility will result in decreased drug absorption through the intestinal wall, consequently reducing bioavailability. The trend for larger, more complex drug molecules that do not naturally fit Lipinski’s ‘Rule of Five’ exacerbates this issue, as molecules of this nature often exhibit poor aqueous bioavailability. Consequently, with 70–90% of new chemical entities displaying poor solubility or permeability, the race is on to create technological innovations that can address the issue and create a pathway for novel treatments to reach patients.2
NANOPARTICLE ENGINEERING AS A SOLUTION
Various nanoparticle engineering techniques have received attention for their ability to improve the solubility and bioavailability of drug compounds, thereby addressing a leading cause of drug development failure. Engineering APIs down to the nanoscale has a dramatic impact on specific surface area – a phenomenon directly correlated with dissolution behaviour. The relationship between surface area and solubility was developed from the Ostwald-Freundlich theoretical model, which is specific to nanoscale particles.5
where p= density of the solid, v= number of moles of ions formed from one mole of electrolyte, R= gas constant, T= temperature, M= molar mass, Sr= the solubility of particles of radius r, S∞= the solubility of the solid of a plane surface, λsl = interfacial tension.
Greater surface area enables more interaction between the solute and solvent, which leads to improved solubility. Indeed, reducing particle size below 100 nm increases surface area by 30- to 40-fold. Extrapolating this further, a particle size reduction of around 50–100 nm can increase the surface area by up to 1000-fold.
“Improving the bioavailability and solubility of drug compounds also confers another advantage lowering the dose required for therapeutic effect.”
Different nanoparticle engineering approaches that exploit this relationship can, in general terms, be split into ‘top down’ mechanical attrition-based approaches and ‘bottom up’ solution-to-particle formation processes. Nanomilling is a popular example of the former, and can successfully produce nanoparticles as small as 150 nm. By raising the surface free energy, however, nanomilling can introduce amorphous domains on crystalline particles, making it unsuitable for some sensitive APIs. Moreover, the need for surfactants to stabilise milled material in suspension can create challenges with respect to stability and shelf life down the line.
Spray-drying is an example of a bottom up, solution-to-particle process which has already been widely adopted within the pharmaceutical industry. This technique is particularly useful for creating API particles for respiratory delivery in the low micron range, and can be used to increase bioavailability by producing API particles in spray-dried amorphous solid dispersions. These dispersions are produced by spray-drying the API with a polymer, which acts to stop the API particles from interacting. One disadvantage of this is that the polymer can add a lot of weight to the resultant preformulated material, which can make it impossible to create some formulations at the intended dose and in the desired format. While these techniques have their merits, and are useful in certain situations, it is clear that there is a need for a technology that can reduce particle size to the low nanoscale range, in a controlled and uniform manner, without necessitating the use of surfactants. Nanoform’s propriety Controlled Expansion of Supercritical Solutions (CESS®) technology provides precisely this.
RECENT BREAKTHROUGHS IN NANOPARTICLE ENGINEERING TECHNOLOGY
Recent advances have led to the development of Nanoform’s proprietary CESS® nanoforming™ technology, which reduces the size of API particles while maintaining tight control of system thermodynamics and, consequently, surface properties. The technique involves dissolving and extracting API particles from supercritical carbon dioxide (scCO2). As the process does not require excipients, the need for extended compatibility studies is significantly reduced, accelerating the initiation of clinical trials. This patented technique is the only existing technology to successfully and uniformly reduce drug particle size down to 50 nm, and on occasion as small as 10 nm. This is a major breakthrough, as increasing surface area to this extent means that many novel drugs written off as nonviable can be revisited. By significantly improving dissolution rates, intrinsic solubility, and bioavailability, Nanoform’s technology has the potential to double the number of compounds reaching clinical trial.
Improving the bioavailability and solubility of drug compounds also confers another advantage: lowering the dose required for therapeutic effect. By reducing the quantity of API that needs to be administered, this feature helps to reduce manufacturing costs and limit waste, as well as reducing side-effects for patients. In addition, as the CESS® nanoforming™ process does not require the use of organic solvents and possesses a small manufacturing footprint, there is also a substantial environmental benefit associated with its use. As the industry works towards incorporating more sustainable practices, this feature is expected to become ever more important.
NANOFORMING™ IN ACTION
Figure 1: SEM images show that nanoformed™ piroxicam remains as individual primary particles in suspension and does not agglomerate.
The extraordinary capabilities of the CESS® nanoforming™ process were demonstrated in a study on piroxicam, a nonsteroidal anti-inflammatory drug. The research assessed the different pharmacokinetic behaviour between d50: 236 nm piroxicam particles produced using Nanoform’s CESS® technology, and d50: ~2 μm piroxicam particles.
Both the nanoformed™ d50: 236 nm piroxicam and d50: ~2 μm particles produced suspensions that were easily re-dispersible. Scanning electron microscope (SEM) images of the material showed that the piroxicam nanoparticles produced using Nanoform’s CESS® nanoforming™ process remained as individual primary particles in suspension, and did not agglomerate (Figure 1). In addition, it was observed that the nanoformed™ piroxicam showed improved dissolution in vitro compared with the micron-sized particles (Figure 2).
Figure 2: Nanoformed™ piroxicam shows improved in vitro dissolution compared with its micron-sized counterparts.
Interestingly, the nanoformed™ suspension had significantly increased piroxicam plasma concentrations over the micron-sized suspension form (Figure 3). The increase was most pronounced within the first 80 minutes. Up to 480 minutes, the AUC was 85–87% higher and Tmax was reached two- to six-fold faster in the nanoformed™ suspension group compared with the micron-sized suspension reference group. In addition, the Cmax was 55–89% higher in the nanoformed™ suspension group within the 480 minutes follow-up time. The results suggest a potential 54% reduction in the dose required for therapeutic effect, which could be even more pronounced with a smaller particle size. This exciting dose reduction capability is highly relevant for BSC II and possibly BSC IV compounds – categories into which 70–90% of all drug development pipeline drugs fall.2
Figure 3: Piroxicam plasma levels in rats after 20 mg/kg and 5 mg/kg PRX administration. Nanoformed™ piroxicam shows improved concentration relative to other dosage forms. Suspension and powder in capsule show similar release profiles.
“Building on the success of the initial studies on piroxicam, Nanoform has progressed to developing a compressed tablet formulation in preparation for human clinical trials.”
The results of the study also demonstrated that a 20 mg/kg oral dose of nanoformed™ piroxicam possessed superior pharmacokinetic properties compared with piroxicam microparticles, with a p-value of less than 0.01 at 80 minutes, faster Tmax, higher Cmax and larger AUC. When tested at 5 mg/kg, both the suspension and powder blend of nanoformed™ material in capsule performed similarly and to good effect. This provides strong evidence for the efficacy of both formulations, from which researchers can draw confidence for moving forward with human trials (Figure 3). Altogether, the superior properties of nanoformed™ piroxicam formulations demonstrated in the study highlight the immense potential of the technology, and lay the groundwork for human trials.
FUTURE OUTLOOK
Figure 4: Nanoform is developing a tablet formulation in preparation for human trials.
Building on the success of the initial studies on piroxicam, Nanoform has progressed to developing a compressed tablet formulation in preparation for human clinical trials (Figure 4). The tablet is easily manufactured using direct compression. With 85% of the most sold drugs in the US and Europe being orally administered, this drug delivery route remains one of the most common in the world.3 Armed with recent advances, Nanoform is now well positioned to access this route and begin dosing nanoformed™ piroxicam in humans in 2021.
It is clear that as a solution to the recurring problem of poor bioavailability and solubility of novel drugs in the discovery and development pipeline, the power of nanoparticle engineering technology promises to pave the way forward. By reducing the size of drug particles to increase their surface area in a controlled manner, and without the use of excipients, the latest CESS® technology in particular has shown its enormous potential for improving efficiency within the pharmaceutical industry. This exciting development has implications not only for new drug candidates, but also for previously developed therapies that were discarded due to problems with solubility and bioavailability.
REFERENCES
- Lowe, D, “The Latest on Drug Failure and Approval Rates”. In the Pipeline Blog, May 9, 2019.
- Kalepu S, Nekkanti V, “Insoluble drug delivery strategies: review of recent advances and business prospects”. Acta Pharm Sinica B, 2015 Vol 5 (5), pp 442–453.
- Savjani KT, Gajjar AK, Savjani JK, “Drug solubility: importance and enhancement techniques”. Int Scholarly Res Notices, 2012, Article ID 195727.
- Polin, RA et al, “Fetal and Neonatal Physiology” (Fifth Edition), Elsevier, 2017.
- Sun J et al, “Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals”. Int J Nanomedicine, 2012, Vol 7, pp 5733–5744.