1.5 An overview of contemporary pharmaceutical technology
In essence, we can regard the vast majority of drug-loaded fibres as solid polymer/drug composite systems. The simplest way to generate such composites is to use film casting, a technique in which a co-dissolving solution of drug and polymer is prepared and the solvent allowed to evaporate to give a film. This is attractive in its simplicity, but suffers from a number of drawbacks in that the process is inherently rather slow (and thus inefficient from an industrial viewpoint) and as a result segregation between drug and polymer can arise. Consequently, researchers have developed a number of alternative methods to accelerate and control the drying process and generate drug/polymer composites from solutions.
At the present time, although drug-loaded nanofibres hold great promise as dosage forms, there are no marketed products based on this technology. It therefore behoves us to consider briefly the most common contemporary pharmaceutical technologies used to prepare polymer/drug composites.
1.5.1 Hot melt extrusion
Hot melt extrusion (HME) has been known as a polymer-processing technique since the early 1930s, and was first explored in the pharmaceutical industry in the 1970s. However, only in the past 20 years or so has it gained significant attention in the drug delivery field. HME has several advantages over traditional pharmaceutical manufacturing processes, including solvent-free processing, rapid fabrication of the final product and the ability to produce formulations able to achieve a wide range of drug delivery patterns.4 The technique involves heating a mixture of a polymer and API (plus potentially other excipients too) to a point at which it can flow (this could be such that the polymer is heated to above its melting point, Tm, or it may just be heated above its glass transition temperature, Tg). The resultant blend is forced through an aperture under pressure, which both shapes the material and allows intimate mixing between the components. This results in an extended strand of polymer/API blend. Because the extrusion process is continuous it is amenable to scaling up, and the extruded strand can be used as is or undergo secondary processing to give pellets or tablets.
Depending on the polymer used, systems can be prepared which allow for extended release, targeted release, or very rapid release of a poorly soluble active (particularly in the form of an ASD). A number of marketed products are based on HME materials.5 For instance, Zoladex is an implant based on poly(lactic-co-glycolic acid) produced by AstraZeneca through HME. It contains goserelin acetate as the API, and this is released over up to 90 days for the treatment of prostate cancer. Tablet formulations available include Kaletra (Abbott), a PVP/poly(vinylalcohol)-based system which releases lopinavir and ritonavir over 6 h for the treatment of human immunodeficiency virus (HIV).
1.5.2 Spray drying
Spray drying is another route widely used to prepare polymer/drug composites. A co-dissolving solution of polymer and API (plus any other excipients desired) is first prepared, and then ejected through an atomiser which generates fine droplets from the bulk solution. The droplets pass into a drying chamber and warm air (or an inert gas) is blown over them. This causes rapid solvent evaporation and results in spherical particles which are recovered in a cyclone unit. The droplets formed during spray drying typically have sizes ranging from less than 10 μm to upwards of 100 μm, which translates to a dry-particle diameter range of 0.5–50 μm.6 Spray drying is therefore very useful for producing materials for pulmonary administration, where a particle size of 2–5 µm is required for effective delivery to the lung.
Typically, the drug is amorphously distributed in the polymer matrix. By careful control of the inlet temperature, the air flow rate, the humidity of the drying chamber, the type of atomiser and the solution parameters (solvent system, concentration, etc.) it is possible to achieve near-monodispersity in the particle size distribution.7 Spray-dried excipients are widely used in tablet production, and several marketed medicines also rely on particles produced in this manner. These include Zortress (Novartis; used to prevent organ rejection), Kalydeco (Vertex Pharmaceuticals; indicated for the treatment of cystic fibrosis) and Intelence (Janssen Therapeutics; employed to treat HIV infections).
1.5.3 Freeze drying
Freeze drying (or lyophilisation) is also frequently employed in the pharmaceutical setting. It involves the preparation of a (typically aqueous) solution of drug and polymer, freezing this, and then reducing the pressure such that the water is sublimed to yield a solid drug/excipient composite. The technique is easily scalable, but is rather high-cost and the drying time can be prolonged. Freeze drying is particularly widely used in the preparation of biopharmaceuticals, where maintaining the three-dimensional structure of the active ingredient is both vital and challenging. Medicines such as Synagis (MedImmune; a humanised monoclonal antibody treatment for respiratory syncytial virus) are prepared in this manner, as are some very fast-dissolving formulations such as Nurofen Meltlets (an ibuprofen-containing medicine manufactured by Reckitt Benckiser).
1.5.4 Nanofibre manufacturing
The most common route used to prepare drug-loaded nanofibres is known as electrospinning. This is an electrohydrodynamic (EHD) process in which electrostatic forces are employed to reduce a bulk liquid material down to nanometre dimensions. The details of the process will be discussed in Chapters 2–5, but the basic principles are as follows:
In the most common process, monoaxial solution electrospinning, a co-dissolving solution of a filament-forming polymer and functional component (API) is prepared in a relatively volatile solvent.
This is then extruded at a controlled flow rate through a narrow-bore blunt-end metal needle (the spinneret) pointing towards a metal collector, which is usually located at a distance of 10–20 cm.
A high potential difference (commonly 5–25 kV) is applied between the spinneret and the collector, with the former typically being positively charged and the latter grounded.
The potential difference causes the polymer solution at the spinneret to stretch rapidly while travelling towards the collector, and generates continuous fibres with diameters typically of the order of nm or µm.
A wide range of modifications can be made to the process to control the morphology and properties of the fibres, and Chapters 3–5 will be devoted to a detailed consideration of these. There also exist other fibre production technologies such as solution blowing, island-sea spinning, melt blowing, centrifugal spinning and electro-centrifugal spinning, which will be discussed in Chapter 6. Several of the processes, including electrospinning, solution blowing and centrifugal spinning, potentially have a number of advantages over more traditional pharmaceutical manufacturing technologies because heat is not required to facilitate solvent evaporation. This can be beneficial in cost terms and allows for easier processing of drugs which are heat-labile. The EHD process is also very rapid, with the solvent evaporating in well under 1 s, which can ameliorate some of the issues encountered with freeze drying (see section 1.5.3).
There are, however, a number of challenges which must be overcome. Electrospinning is known to be scalable, but because it often relies on volatile solvents there are a number of health and safety issues which must be addressed to implement it on an industrial scale. Many of the solvents which work best for electrospinning could have undesirable side effects in humans, and thus great care must be taken to ensure that all the solvent has evaporated during the process. Further, for clinical applications it is vital to ensure that there are very high levels of batch-to-batch consistency, and robust quality control measures must be implemented. We will address some of these challenges in Chapter 7.