By Bob Bruno
Many new and advanced drug (and vaccine) formulations that could effectively treat human and veterinary diseases may never make it beyond the laboratory. Three common problems exist with these drugs: a) limited bioavailability (the rate at which the active drug enters the systemic circulation, making it difficult for the body to adsorb), b) issues concerning the safe and efficient delivery of the drug into the circulatory system, and c) the toxicity level of the drug.
Drug formulations that attempt to overcome these limitations exist as liposomes, emulsions, or suspensions, the latter consisting of solid nonsoluble active pharmaceutical ingredients (APIs) suspended in a liquid. The size of the API particles determines the stability of the formulation. If the particles are too large or are nonuniform in size, they will no longer remain suspended in the liquid and will prematurely settle out, rendering the formulation unusable.
With the advent of innovative nanotechnology-based processing, it is becoming more of a reality that many of these drug formulations can now be created as stable nano-suspensions. These consist, ideally, of uniform nonsoluble particles that are measured as nanometer-sized entities where a nanometer (nm) is one billionth of a meter. Drugs consisting of nano-suspensions are of great interest to scientists not only because of their potential to solve stability problems, but because they can enhance bioavailability and provide a safe and efficient method of delivery. Additionally, nano-suspensions can be designed to enhance targeting and improve drug specificity to the disease region, thus minimizing toxicity and harmful side effects.
To date, a limited number of ‘nano drugs’ have made it to the market. They are produced by Élan Pharmaceutical’s proprietary NanoCrystal technology, which is a ‘top-down’ wet milling process combined with a variety of surface modifying agents (surfactants) for stabilization of the resulting nano-suspension. The first of these drugs to appear on the market was Rapamune, which is used to prevent the rejection of organ and bone marrow transplants by the body. Other nano drugs created with Elan’s process include Emend, TriCor, and Megace.
The top-down process cannot always produce enough energy to reduce the large API particles to uniform nano-size particles. As a result, this process does not offer a reliable pathway to the marketplace for the increasing number of new and advanced drug formulations with solid APIs.
A New ‘Bottom-Up’ Process
During the past several years, scientists at Microfluidics Corp. (www.mfics.com) have reported the progress of their self-funded Microfluidics Reactor Technology (MRT) program, which is a ‘bottom up’ approach and is depicted in the diagram in Fig. 1. MRT is a technology that delivers particles of the desired size and uniformity through the controlled crystallization of individual molecules.
To achieve this, the large, solid API particles are first dissolved in a solvent, usually other than water, forming a liquid solution referred to as Solution A. Solution A is then pressurized with a pump to form a continuous high velocity jet stream that is impinged directly onto an opposing high velocity jet stream of Solution B, which is usually water pressurized with a second identical pump. The opposing continuous jet streams impinge within a specially designed interaction chamber that creates an environment in which the dissolved API particles reprecipitate (or resolidify) as nano-crystals flowing in a continuous stream and becoming a very stable liquid nano-suspension.
As a bonus, this process also produces nano-suspensions of the highest purity possible, which is a great benefit in the production of sterile pharmaceutical drugs. Dr. Thomai Panagiotou, CTO at Microfluidics, states, “Much of the ongoing development work on MRT is now focused on process optimization for a wide range of candidate drugs. Also, we are in the process of developing and testing equipment that will enable pharmaceutical companies to scale up the MRT process and produce larger quantities of the nano drugs for clinical trials and eventually for production.”
MRT may be better defined as a ‘high throughput solvent/antisolvent crystallization’ technology. It is a continuous process having the potential to unlock numerous drugs and vaccines that could not otherwise be formulated or efficaciously administered, and to streamline the production process and dramatically lower capital equipment costs. The key to this advantage for MRT is the interaction chamber in which the precipitation/crystallization takes place. The short dwell time and high levels of energy dissipation within the high pressure environment of this chamber forces the two solutions to interact at the nano-scale level in a continuous fashion. “This is a good example of ‘process intensification’ [PI] that expedites the rate at which processes occur resulting in high throughput systems. This is of great importance for the eventual manufacturing of the drug,” states Dr. Robert J. Fisher of MIT, a consultant to Microfluidics on the MRT program.
In the laboratory, the coaxial MRT approach has proven to be successful in producing stable nano-suspensions with exceptionally small particle sizes for a number of candidate drugs, including two antibiotics, an antihistamine, an anticonvulsant, and a nonsteroidal anti-inflammatory formulation.
Controlled experiments were performed on each of the candidate drugs for comparison purposes by using a conventional ‘top-down’ particle reduction method. In these cases, micronization was used. In all cases, it was determined that after 25 passes no further particle size reduction occurred.
The conventional ‘Top-Down Micronization’ method was unable to achieve either smaller median particle sizes or the uniformity of the particles of those that were created by one pass with the MRT Coaxial Technology, regardless of the number of micronization processing cycles. It has been observed that the coaxial approach provided better crystalline structure of each particle than the control methods and, also, there were no detectable impurities in the resultant nano-suspension.
Nano-suspension Development Road Map
To efficiently make an evaluation of which drug formulations are candidates for MRT, Microfluidics has established a road map consisting of a three-step process. The first step is to basically conduct screening experiments to determine the optimum solvent and antisolvent to produce Solvent A and Solvent B respectively. As previously noted, Solvent B, the antisolvent, most often is water. Further analytical work must be conducted to consider other issues such as toxicity and compatibility for the particular application. The second step is to use MRT to produce nano-suspensions. The goal at this stage is to determine mainly the optimal processing parameters, such as the interaction chamber geometry, process pressure, supersaturation ratio, and the number of passes. The third and final step is to purify the resultant nano-suspension, if necessary, using methods such as centrifuging, filtering, rinsing, and lyophilizing.
Demonstrating the ability to create nano-suspensions that can overcome the issues of bioavailability and safety is a major first step. However, there still remain barriers to successfully introduce these drugs to the market. Due to the inherent complexity of some of the nano-systems, much work lies ahead for pharmaceutical companies in order to gain approval for large-scale manufacturing under the FDA’s current good manufacturing practices (cGMPs). Guidelines and appropriate quality control measures also need to be carefully addressed early on to avoid having them become major stumbling blocks.
For instance, certain nano-materials that are used in nano-suspensions, such as fullerenes, carbon nano-tubes, and quantum dots, have excellent properties, but their systemic distribution and clearance profiles, tissue and cellular interactions, and associated toxicity, especially upon chronic in vivo administration, have not been clearly addressed. Therefore regulatory agencies will require comprehensive preclinical dose-escalating toxicity studies in multiple animal species before they can approve the final product. None of this is new to the pharmaceutical industry, where there remains much optimism for the approval of many new and upcoming nano-drug products.
In his highly acclaimed book The Post American World, author Fareed Zakaria writes: “Look at the industries of the future. Nanotechnology — [the] applied science dealing with the control of matter at the atomic or molecular scale — is considered likely to lead to fundamental breakthroughs over the next 50 years.” With the advent of nanotechnology and the success of the MRT program, we may be seeing this prediction soon come true.
Professor Mansoor M. Amiji from Northeastern University in Boston, one of the leaders in nano-medicine, states that “Nano-medical solutions can have a profound impact in disease prevention, early disease diagnosis, and target-specific therapeutic strategies. Focus must be paid on the use of safe materials and manufacturing methods that allow for industrial scale-up and ease of manufacturing for clinical translation of nanotechnology concepts for benefit to patients.”