Monodisperse Microspheres for Parenteral Drug Delivery

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PARENTERAL D E L I V E R Y Monodisperse Microspheres for Parenteral Drug Delivery By: Gert Veldhuis, PhD, Míriam Gironès, PhD, MSc and Debra Bingham INTRODUCTION Throughout the past few years,

Well-known examples are Lupron Depot (Abbott Laboratories), Trelstar Depot (Watson Pharmaceuticals), and Risperdal ConstaTM (Ortho-McNeilJanssen Pharmaceuticals).

performance and process efficiency. Many of these challenges are related to the lack of control over particle size and uniformity of conventional microsphere manufacturing methods.

We believe that a novel manufacturing process based on MicrosieveTM emulsification offers the best and most straightforward opportunity to overcome these challenges.

1 PARENTERAL D E L I V E R Y Monodisperse Microspheres for Parenteral Drug Delivery By: Gert Veldhuis, PhD, Míriam Gironès, PhD, MSc and Debra Bingham INTRODUCTION Throughout the past few years, several products based on drug-loaded biodegradable microspheres have reached the pharmaceutical marketplace. Well-known examples are Lupron Depot (Abbott Laboratories), Trelstar Depot (Watson Pharmaceuticals), and Risperdal ConstaTM (Ortho-McNeilJanssen Pharmaceuticals). These types of injectable depot formulations (IM or SC) can provide sustained and controlled delivery of the active over a period of weeks or months and thus significantly increase patients comfort and compliance. From the perspective of the pharmaceutical companies, microsphere-based depot formulations of existing compounds offer an attractive tool in life cycle management, but most importantly, offer significant value to patients. Although microsphere-based drug delivery is attractive from both the market and patient perspective, developers of microsphere formulations face many challenges in achieving the desired product performance and process efficiency. Many of these challenges are related to the lack of control over particle size and uniformity of conventional microsphere manufacturing methods. There are a number of techniques in development designed to overcome issues regarding size and uniformity. We believe that a novel manufacturing process based on MicrosieveTM emulsification offers the best and most straightforward opportunity to overcome these challenges. KEY FACTORS IN DESIGNING SUSTAINEDRELEASE MICROSPHERE FORMULATIONS The most important goal in designing a microsphere formulation for sustained drug delivery is to achieve a gradual release of the active at a constant rate over the desired period of time. Given a certain microsphere size, such a zero-order release profile is typically achieved by careful selection of the biodegradable polymer matrix material. Usually, this is a poly (D,L-lactic-co-glycolic) acid, PLGA, which is biodegradable, biocompatible, and equally important, has been used in many FDA-approved products. The properties of PLGA can be tailored to the purpose by changing the block ratios and the molecular weight, which have to be chosen such that the diffusion rate of the active and the degradation rate of the polymer match the desired release period. In addition, the polymer has to be selected such that the release rate reduction over time (typical for diffusion controlled release) is compensated by the degradationrelated release rate, which increases over time. An important parameter for robust drug formulation, and the focus of this paper, is the microsphere size. The chosen microsphere size is usually a compromise between two main considerations. 1. The smaller the microspheres, the better the syringability (Figure 1) and the smaller the needle gauge required, which translates into reduced patient discomfort. A 27-gauge needle has an inner diameter of 191 microns. Taking a fair safety margin of a factor 4, this suggests an upper limit for the FIGURE 1 PLGA microspheres (21 microns) in a 25-gauge needle (240 microns id), showing a high degree of monodispersity and optimal syringability.

particle size of about 50 microns for use with this needle gauge. 1 2. The larger the microspheres, the less risk that the particles will be cleared from the injection site by macrophages.

2,3 Therefore, 10 microns is generally considered to be a safe lower boundary in order to avoid particle uptake by macrophages.

2 particle size of about 50 microns for use with this needle gauge The larger the microspheres, the less risk that the particles will be cleared from the injection site by macrophages. It is known from literature that phagocytosis can occur up to microsphere sizes of 5 microns. 2,3 Therefore, 10 microns is generally considered to be a safe lower boundary in order to avoid particle uptake by macrophages. Considering the aforementioned, an average microsphere diameter of about 30 microns seems ideal for depot applications. In addition to the average microsphere size, the uniformity of the microsphere size is very important. A high fraction of particles much smaller than the average will significantly reduce the encapsulation efficiency of the active in the microspheres and will also cause an unwanted initial burst of active right after administration of the microsphere depot. 4 Conventional methods for producing microspheres, such as solvent evaporation/extraction by high-speed homogenizers, do not allow for total control of microsphere size and uniformity, are very difficult to scale-up, and often show poor batch-to-batch reproducibility. Moreover, obtaining an acceptable size and uniformity requires a lot of process development. Typically, very wide particle size distributions with standard deviations of the mean diameter of about 30% to 50% (Figure 2) are achieved. Obtaining narrower size distributions has to be achieved through expensive classification steps with high losses of active in the unwanted size ranges. Given the fact that current manufacturing processes are not capable of predictably producing uniform sized particles, and that size uniformity is important to quality outcome, a technology that can offer complete control over size distribution is of great value to the industry. TECHNOLOGIES FOR MONODISPERSE MICROSPHERE PRODUCTION Advances in microengineering and semiconductor technologies have allowed the development and production of precisely designed microfluidic structures for obtaining monodisperse droplets and microspheres. 4-7 One example is given by flow focusing devices in which a fluid is injected through a nozzle into a stream of another fluid, and droplets are detached by Rayleigh instability. Perfectly monodisperse particles can be obtained in the laboratory. However, scaling up this F I G U R E 2 technology for industrial purposes is extremely difficult, mainly due to the low production rate and the need for exact control over two different fluid streams (crucial to obtain a certain droplet size). Thousands of these relatively complex devices would have to be placed in parallel with all the exact same supply of two different fluid streams in order to produce volumes suitable for pharmaceutical applications. Another approach for obtaining uniform and monodisperse droplets and particles is offered by membrane emulsification. 8 In membrane emulsification, a fluid is forced through a porous membrane. The droplets emerging on the other side of the membrane surface are wiped off by the shear forces induced by a stream of another fluid across the membrane. The typical membranes used are similar to those used for filtration purposes, and processes can be easily scaled up. Control over droplet size and Particle size distribution of a microsphere formulation fabricated via Nanomi s Microsieve TM emulsification (A), with a narrow CV of 5%, and a conventional emulsification with homogenizers (B), with a CV of about 30%. The size limits for phagocytosis and optimal syringability for depot formulations are also displayed.

3 uniformity is better than for high-shear homogenizers but inferior to the control that can be achieved by single microfluidic devices. In the following section, a new technology that combines the scaling advantages of membrane emulsification with the size control advantages offered by microfluidics will be discussed. MICROSIEVE TM EMULSIFICATION: PRINCIPLES & KEY FEATURES In microsieve emulsification, a Nanomi proprietary technology, monodisperse droplets are generated by dispersing one fluid into a second, immiscible fluid through a precise microsieve (Figure 3). Microsieves are silicon-based membranes fabricated by proven precise semiconductor technology in a cleanroom environment. By means of photolithographic techniques, excellent uniformity of pore size and shape is F I G U R E 3 obtained in a highly reproducible way. Because every pore is the same, every droplet generated by the membrane is the same, resulting in highly uniform, reproducible, and size-controlled droplets or, after an appropriate solidification step, particles. A unique feature of the microsieve emulsification technology is the independence of the droplet size to the specific formulation, the size being solely determined by the membrane design. This, and the fact that no cross-flow is needed to produce droplets, differentiates this process from other membrane emulsification systems. Microsieve emulsification can be applied in the most common method of particle fabrication for drug delivery, solvent evaporation. Basically, the polymer and the active substance are dissolved in a volatile solvent and emulsified into an aqueous surfactant solution. The solvent is then eliminated by evaporation, resulting in the formation of solid particles. For Schematic representation of the microsieve TM emulsification process (A), where a fluid is emulsified through a silicon microsieve TM membrane with uniform pores (B). Image of a wafer containing microsieves TM (C) fabricated by semiconductor technology. encapsulation of hydrophilic molecules like peptides or proteins, the W/O/W emulsion method is used. Here, a primary W/O emulsion containing an aqueous solution of the active ingredient dispersed in the oil phase is emulsified with an aqueous surfactant solution, forming a W/O/W double emulsion. In addition to the solvent evaporation process, microsieve emulsification can be used in melt emulsification (eg, for making lipid microspheres) and is suitable for the production of O/W, W/O, W/O/W, S/W/O, and S/O/W emulsions. Compared to other conventional or membrane-based droplet and particle production methods, Nanomi s technology offers the following advantages: TOTAL CONTROL OF DROPLET/PARTICLE SIZE - no process or formulation optimization required to obtain the desired size and size distribution of the product (Figure 2, comparing size distributions achieved with high-speed homogenizers and microsieve emulsification). NO LOSS OF VALUABLE INGREDIENTS - all generated droplets and particles have the right size, thus no post-processing such as fractionation is required and no valuable ingredients are lost. ROBUST, REPRODUCIBLE & STABLE IN OPERATION - the process is insensitive to fluid flow and pressure conditions near the membrane surface and therefore performs very well in a relatively simple process configuration. STRAIGHTFORWARD SCALABILITY - if the process works for one pore, the

Due to the smaller droplet to pore diameter ratio compared to other methods, even relatively large nanoparticles can be encapsulated.

4 process can easily be scaled to any size by increasing the number of pores of the microsieve or by adding more microsieves to the process. HIGHLY EFFICIENT ENCAPSULATION - Because each droplet is formed individually at negligible imposed shear and pressure, actives can be incorporated in the particle very effectively. Due to the smaller droplet to pore diameter ratio compared to other methods, even relatively large nanoparticles can be encapsulated. MILD PROCESS CONDITIONS - the process operates at very low pressures and shear, and no heat is generated, which allows processing of sensitive actives, such as proteins and peptides. On the other hand, microsieves are very robust and can resist high temperatures, aggressive cleaning agents, and autoclaving. ASEPTIC PROCESSING UNDER GMP CONDITIONS - the process can be run in a continuous and closed configuration. MICROSIEVE EMULSIFICATION IN THE PRODUCTION OF MONODISPERSE MICROSPHERES FOR DRUG As mentioned previously, particle size is a crucial parameter that should be controlled when designing microsphere drug delivery systems. Therefore, Nanomi focuses its efforts in developing monosphere formulations with a specific size and tight size distribution (often with a coefficient of variation, CV, under 5%), which can be chosen for optimal product performance. Currently, droplets in the range of 2 to 100 microns and microspheres in the range 1 to 50 microns are routinely manufactured with tight size distributions at a scale in the multiple gram range. Very recently, the process has successfully been scaled up to 1 kg/day. Development is ongoing to drive the minimum particle size down to the nano range. In addition, development is in progress to integrate the process in a GMP-qualified fill and finish production line. Nanomi has validated the microsieve emulsification process for a large number of biodegradable and biocompatible polymers, such as PLGA, PCL, PLGA- PEG, PEG-PBT, PTMC, PEA, and PMMA. In addition, other materials such as lipids can also be processed into microspheres. Many combinations of (biodegradable and biocompatible) polymers and active compounds (water soluble/insoluble) have been processed by microsieve emulsification (Figure 4, which displays some examples of microspheres developed by Nanomi). Peptides, proteins, small molecules, antibodies, and other relevant molecules can be encapsulated with high efficiency and high loading. Recently developed PLGA microspheres (PURASORB PDLG 5004, PURAC F I G U R E 4 biomaterials) loaded with 10% progesterone demonstrated a perfect diffusion-controlled release without burst. This is in agreement with observations reported in literature for monodisperse microsphere formulations fabricated by another droplet-generating method. 4,9 Microsieve emulsification enables the production of cost-efficient monodisperse microsphere-based systems for parenteral, sustained released, drug delivery applications (IV, IM, SC, Intra-articular, embolization, etc). Although drug delivery is the main focus of attention, Nanomi also provides expertise in the production of emulsions and microspheres and nanospheres for diagnostics, molecular imaging, and research and analysis. SUMMARY In summary, the microsieve emulsification technology is highly suitable for the production of microspherebased drug delivery formulations. It can provide high predictability and reproducibility, robustness, scalability, size control and narrow size distributions. Moreover, other features like good syringability, no phagocytosis, high encapsulation efficiency and no burst can also be achieved. Monodisperse PLA microspheres (10 micron-diameter) without (A) and with (B) encapsulated fluorescent FITC-BSA. Monodisperse 9-micron Polycaprolactone (PCL) microspheres (C) and fluorescent red polymeric markers (D).

New controlled-release technologies like microsieve emulsification can extend the life cycle of proprietary drugs that run out of patent protection and allow for the delivery of new drugs, among

Moreover, Nanomi s patent-protected technology can improve the therapeutic properties and performance of existing products, but also enable new products and therapies, eg, in the field of radio- or

Optimizing drug suspension particle size as a means to reduce the frequency of intravitreal steroidal injections. Paper presented at the AAPS Annual meeting & Exposition in San Diego;2007. 2.

5 New controlled-release technologies like microsieve emulsification can extend the life cycle of proprietary drugs that run out of patent protection and allow for the delivery of new drugs, among others. Moreover, Nanomi s patent-protected technology can improve the therapeutic properties and performance of existing products, but also enable new products and therapies, eg, in the field of radio- or chemo-embolisation, in which extreme control over microsphere size and uniformity is a must to achieve a successful therapy. REFERENCES 1. Boyd B, Banz K, Rodger J, Carrol S. Optimizing drug suspension particle size as a means to reduce the frequency of intravitreal steroidal injections. Paper presented at the AAPS Annual meeting & Exposition in San Diego; Yamamoto N, Fukai F, Ohshima H, Terada H, Makino K. Dependence of the phagocytic update of polystyrene microspheres by differenciated HL60 upon the size and surface properties of the microspheres, Colloids Surf., B. 2002;25: Katare YK, Muthukumaran T, Panda AK. Influence of particle size, antigen load, dose and additional adjuvant on the immuneresponse from antigen loaded PLA microparticles. Int. J. Pharm. 2005:301: Kim K, Pack D. Microspheres for drug delivery. In: Ferrari M, ed. BIOMEMS and Biomedical Nanotechnology, Volume 1: Biological and Biomedical Nanotechnology Springer; Utada AS, Lorenceau E, Link DR, Kaplan PD, Stone HA, Weitz DA. Monodisperse double emulsions generated from a microcapillary device. Science. 2005;308: Xu S, Nie Z, Seo M, Lewis P, Kumacheva E, Stone HA, Garstecki P, Whitesides GM. Generation of monodisperse particles by using microfluidics: control over size, shape, and composition. Angew. CHem. Int. Ed. 2005;44: Garstecki P, Gitlin I, Diluzio W, Whitesides GM, Kumacheva E, Stone HA. Formation of monodisperse bubbles in a microfluidic flow-focusing device. App;/ Phys. Lett. 2004;85: Vladisavljevic GT, Williams RA. Recent developments in manufacturing emulsions and particulate products using membranes. Adv. Colloid Interface Sci ;113:1. 9. Berkland C, Pollauf E, Raman C, Silverman R, Kim K, Pack DW. Macromolecule release from monodisperse PLG microspheres: control of release rates and investigation of release mechanism. J. Pharm. Sci. 2007;96:1177. B I O G R A P H I E S Dr. Gert Veldhuis is Co- Founder and Managing Director at Nanomi. He earned his degree in Physics and his PhD in Micro Systems Technology (MST) (cum laude) at the University of Twente (The Netherlands). He authored many publications in international peer-reviewed journals and has several patents. Prior to founding Nanomi in 2004, Dr. Veldhuis was employed at Philips Research in Eindhoven and C2V in Enschede (The Netherlands), where he managed MST design activities. Dr. Míriam Gironès is Senior Development Engineer at Nanomi. She earned her MSc in Chemistry at the University of Girona (Spain) and her PhD in Chemical Technology at the University of Twente (The Netherlands), where she studied the fabrication and fouling behavior of microsieve TM membranes. Her research in this area has produced several publications in international peer-reviewed journals. Following a post-doctoral fellowship in Tissue Engineering and Biomaterials (University of Twente), she joined Nanomi s team in 2006 and has since then been involved in business development and the technical supervision of several R&D projects. Ms. Debra Bingham is a Partner of Valeo Partners, a Washington, DC-based firm that provides strategic consulting, business development, and M&A services to life science companies in the pharmaceutical, biotechnology, medical device, and drug delivery markets. Ms. Bingham brings clients over 14 years of specialized expertise in the pharmaceutical and drug delivery industries. Her clients include large multinational pharmaceutical and chemical companies as well as medium to small specialty pharma and drug delivery companies. She has worked directly with North American, European, and Japanese companies in the area of business development strategy and licensing. Her uniquely strong network in Japan, Europe, and North America has been an asset to her clients. Ms. Bingham s primary focus is directing companies in the areas of partnering, business strategy, and growth opportunity assessment.

Model based design of controlled release drug delivery systems

Model based design of controlled release drug delivery systems Aditya Pareek, Praduman Arora, Venkataramana Runkana Copyright 2012 Tata Consultancy Services Limited 1 Why we need controlled drug delivery?