Erosion-based drug delivery

Anders Vagno Pedersen, director of r&d, and Pernille Hoyrup Hemmingsen, formulation manager, r&d at Egalet review a drug delivery system that has benefits for chemically unstable drugs and that can also extend product shelf-life

Traditionally, the most popular form of drug delivery has been oral ingestion of pills or capsules. Virtually all of these are initially marketed in "immediate-release preparations" that disintegrate within the first five or 10 minutes after the patient swallows them. Usually these types of tablets or capsules are taken between once and three times daily, as dosing any more frequently than this proves to be impractical and leads to a decline in patient compliance. Although many drugs can be administered in this way, problems arise with instant-release preparations for drugs with short half-lives or small therapeutic windows. For these drugs, even with three-times daily dosing, the required plasma concentration of drug cannot be maintained. These types of drugs, in particular, can benefit enormously from controlled- and sustained-release drug delivery.

A controlled- or sustained-release delivery system does not disintegrate soon after ingestion, but remains intact and delivers the drug in a controlled manner to a greater length of the gastrointestinal tract. This type of drug delivery is not new as it has been in existence for over 30 years, but the challenge is to be able to reproducibly achieve therapeutic plasma concentrations of drugs over a sustained period via the gastrointestinal tract, regardless of the lifestyle of the patient.

The majority of commercially available controlled-release drug delivery systems rely almost exclusively on aqueous diffusion through a matrix or through a membrane to cause drug release. This causes a problem for delivery of poorly water-soluble drugs, and apart from the Oros tablet (ALZA Corporation), which uses osmosis to drive drugs from a solid unit, there are few drug delivery devices meeting this market opportunity.¹

The Egalet technology is relatively new, but offers some distinct advantages over more conventional controlled-release dose forms.^2,3 The primary advantage is its ability to deliver water-insoluble compounds in a controlled manner. This can be achieved because drug release from the Egalet dosage forms involves the processes of erosion rather than diffusion. An added advantage is that active compounds entrapped in the Egalet matrix are also protected from oxygen and humidity, therefore, the technology appears suited for chemically unstable substances and thus may increase in shelf-life.

The Egalet Constant-Release system consists of two components: a matrix consisting primarily of suited polymers, such as polyethylene oxide (PEO), together with other excipients and a coat. The drug is distributed evenly throughout the matrix, which is eroded by gastrointestinal fluids and gut movements as it travels through the gut (Figure 1).

The drug-release mechanism is predominantly surface erosion, effected through water diffusion, polymer hydration, disentanglement and dissolution. The matrix is designed to erode when in contact with available water but, at the same time, it is desirable that water does not diffuse into the matrix until the point of release, thus avoiding hydrolysis and diffusion and reducing the effects of luminal enzymatic activity. A balance is required where the erosion is as fast as the diffusion of water into the matrix. The diffusion of water into the edges of the matrix producing only a hydrating/dissolving thin layer and leaving a dry core even after 4 hours can be distinctly shown by Nuclear Magnetic Resonance (NMR) imaging studies (Figure 2).⁴

To ensure a gradual release of the active substances, the matrix has to be eroded in a heterogeneous manner, the opposite of homogeneous erosion or erosion occurring simultaneously throughout the matrix. The rate of drug release from an Egalet unit can be altered by adjusting the composition of the polymer-matrix. A possible explanation for this effect is that when molten polymer cools and solidifies, it produces a structure that is partly crystalline and partly amorphous, leading to inhomogeneous water penetration. A similar effect can be obtained if PEG-monosterate and PEG are melted together and then cooled. The PEG/PEG parts will align, whereas the monosterate groups will tend to be left on the surface of the particles, rendering the fissures hydrophobic and impassable to water. This results in heterogeneous erosion because the erosion proceeds layer by layer. This matrix gives a zero-order release profile of drugs in vitro independent of pH but somewhat dependent upon rate of agitation. Figure 3 shows the in vitro release of caffeine from an Egalet dose form demonstrating zero-order kinetics.

Most conventional controlled-release dose forms use a polymer that hydrates and it is only after the hydration of the outer layer is complete that the drug can diffuse out (Figure 4). Erodible barriers allow surface hydration of the unit, which then releases drug as the tablet disintegrates.

Figure 4 Demonstrates how hydration of the outer layers of the matrix and dissolution add a time-lag before drug release from conventional matrix preparations. This almost inevitably results in a lag before drug release occurs. Another disadvantage of these systems is that the surface area is constantly being reduced as the tablet erodes, therefore drug release is not linear. The advantage of the Egalet dose form is that the surface area available for erosion does not change with time and hence delivery can be more precisely controlled.

The proof for a controlled-release system is how well the in vitro data correlates with the in vivo data, and several clinical studies using the Egalet Constant-Release system have been conducted. One such study has been performed using the Egalet Constant-Release system containing caffeine and samarium oxide in a scintigraphic study.⁵ The samarium oxide was included in the dose form as it can be activated to ¹⁵³Sm₂O₃ upon irradiation, which is visible to the gamma camera. The effect of the irradiation on the in vitro release characteristics of caffeine can be seen in Figure 3. The activated dose forms were dosed to 6 healthy volunteers and an example is shown in Figure 5.

The in vivo release consisted of three linear phases with constant slopes (Figure 6). The rate of drug release was reduced when the Egalet unit crossed from the small intestine into the colon and again when it moved from the transverse colon to the descending colon. It is likely that this reflects both the reduction in motility and water associated with these regions, which will affect the rate of both erosion and dissolution of the drug.

Injection moulding

One issue with controlled-release technologies is that it can be a lengthy and costly process to tailor the dose form to match the required in vivo release profile of the drug. Often, only a few different designs are tried in vitro, and only the most promising one or two are selected from their in vitro release data to be tested in humans. The Egalet unit manufacturing process consists of a conventional two-component, injection moulding process, similar to the process used in the plastics industry. The premixed powders (usually in the form of extruded granulates), which are used to form the active matrix are fed into the mould. A reciprocating injection-moulding process allows sequential moulding of the shell and the core contents within the dies. This design provides an efficient manufacturing process coupled with high accuracy in dimensions, weight, and content. It also allows for flexibility in dosage form design at minimum cost. Egalet has signed a manufacturing agreement with SP Medical in Denmark for clinical supplies of its products in pain management and cardiovascular disease.

The concept of erosion technology for sustained-release appears to have a number of advantages over more conventional delivery systems. In summary, these advantages include the ability to deliver poorly water-soluble drugs; zero-order release (the rate of which is dependent on gastrointestinal motility and water availability); and easily tailor dosage form manufacture to obtain the desired release profile by altering size, width, and matrix composition.