Medical Device Link.

MATERIALS

Demands from the regulators

Increasingly, health care companies are developing products that combine an active or functional coating with a medical device to treat unmet medical needs. Drug eluting stents (DES) are a high profile example of how the performance of a device can be improved via the addition of a functionally active coating. Other combination products include bioactive vascular prosthetic coatings and antimicrobial coatings such as Ceragenix’s (Denver, Colorado, USA, www.ceragenix.com) developmental coated endotracheal tubes.¹

Although there are many potential benefits of the combination product approach it must be realised that there are also significant technical and regulatory challenges. In 2004, the United States Food and Drug Administration (FDA) called for increased research into specific areas related to health care in the Critical Path Opportunities List publication (www.fda.gov/oc/initiatives/criticalpath). One of the identified areas was improved technologies for assessing and characterising combination products. The FDA stated that, “combination products can present significant challenges in characterisation, manufacturing and quality assessment. For example, existing analytical techniques are often not designed to assess the micro quantities of drug found in some combination products such as drug eluting stents. New techniques and standards are needed so individual companies do not have to reinvent new paradigms and testing tools for each new product.”

Table I: Formulation and analytical challenges in active medical device coatings. (click image to enlarge)

Already the FDA recommends that device manufacturers describe in detail parameters such as the thickness of individual coating layers, coating uniformity, cohesive and adhesive properties and the overall coating integrity and durability when tested under clinically relevant conditions.² In addition to mechanical character-isation it is likely that regulators will also request data on the main physico–chemical attributes of a coating. Table I shows a summary of some of the coating attributes that need to be addressed through a combination of formulation and analytical science.

Understand performance attributes

A common feature for all active device coatings is that they are likely to be complex in form, function and method of production. For example, device coatings are typically

• multiple component systems with controlled release rates of an active ingredient
• mixtures of polymeric carriers with low or high molecular weight actives
• multiple coatings with different individual functionalities and/or functional regions on a single device
• multilayer structures sometimes applied using different coating principles.

The purpose of the active coating is to help achieve the product’s requirements and deliver benefit to the end user. These product requirements should be developed by multiple stakeholders and prioritise the main features and attributes of the product. Typically, these will include patient and end-user requirements as well as strategic, commercial and technical requirements. For products with a pharmaceutical active many of these technical requirements relate to pharmacokinetic properties (site of action, speed of onset and duration of action), but they will also address requirements such as shelf life. To achieve the requirements necessitates careful selection of the right active and right carrier vehicle. Consideration must be given to the ability of the selected carrier(s) to control drug elution, its biocompatibility, its interaction with the mode of action of the device, its compatibility with the device delivery mechanism and its compatibility with the coating technology. The ability of the device coating to meet these requirements will be significantly affected by the physical state of the coating.

Analyse the drug and the coating

There are three main components of a functional device coating: the active substance, the coating vehicle and the device. To demonstrate the safety and efficacy of the product all three elements and the interrelation-ships between them must be understood. This is best approached in a stepwise fashion: understand the individual components, evaluate the subsystems and then test and investigate the finished product.

The first step is characterisation of the solid state form of the active prior to its formulation into a coating. Drug molecules show different physical properties depending on their crystalline form and may exist as different polymorphs, solvates and hydrates and as amorphous solids. Understanding the solid state form of the active helps to ensure that³

• the target active substance form can be consistently manufactured
• the effect of pharmaceutical manipulations such as milling and spray drying are understood
• the effect of storage conditions on the product can be predicted.

Once the solid state form of the active alone is understood the next step is to determine the solid state properties when formulated for application onto the device. In almost all cases application of an active onto a device will require the addition of a carrier vehicle, generally a polymer or combination of polymers. Although solid state analysis of the isolated active is relatively straight forward, similar analysis of the active dispersed in a polymer carrier can be particularly challenging given the low active concentrations of some coatings.⁴

Investment in analysing the effects of this step is important because there is a high likelihood that there will be a change in the physical form. Indeed, the purpose of the coating step may be to intentionally modify the physical form of the active with the aim of tailoring performance characteristics. For example, formulation scientists routinely use dispersed drug/polymer oral dose formulations to alter the pharmacokinetics of the drugs through manipulation of the drug dissolution rate. Typically, these dispersed systems are used to enhance the bioavailability of compounds that have poor water solubility, a process that is optimally achieved via molecular dispersion of the drug in a highly water soluble carrier.⁵

Table II: Classification of solid dispersions, where A = amorphous and C = crystalline. (click image to enlarge)

The process technology used to coat medical devices can also influence the physical characteristics of the active in the coating. Coating technologies such as spray coating and hot melt film technology tend to favour the formation of metastable crystalline and amorphous solid state forms dispersed throughout the polymer vehicle because of the rapid rate that the active is brought out of solution or cooled from a molten state. This effect is clearly observed for Rapamycin/poly-lactic-co-glycolic acid stents prepared by spray coating from chloroform.⁶ Preventing the change of the active to a metastable form during coating may not be possible, therefore, being able to determine the change in solid state form will be fundamental to controlling the coating performance.

It is also possible to control the dispersion of the active in the polymer by selecting polymer carriers with the appropriate degree of miscibility. Solubility parameters can be used to understand the likelihood of components being miscible and should be used in initial formulation studies.^7,8 Small differences in solubility parameters between components (<2 (MPa)1/2) are likely to produce a single phase dispersion whereas larger differences indicate the likelihood of immiscible systems. These calculations can be easily reinforced by simple thermal experiments using milligram quantities of material.⁷ The extent of miscibility will effect active release rates, physical and chemical stability and mechanical properties.

Figure 1: Change in the surface appearance of a drug/polymer dispersion when crystalline (left amorphous, right partially crystalline). (click image to enlarge)

Before considering additional approaches to characterising active/polymer coatings, it is important to understand more about the physical state(s) that can exist. Dispersions of drug and polymer can be described based on the number of solid phases and the solid state nature of those phases (Table II). The solid states of the phases are classified as crystalline or amorphous, but between either end of this range mixed systems can occur. Amorphous materials lack the long range three-dimensional (3D) packing order seen in crystalline materials. Because of this, the amorphous form is more soluble, but also less stable being prone to recrystallise. Therefore, the amorphous state can potentially be used to improve the dissolution performance of the active, but may be chemically and physically more reactive leading to dramatic performance changes over time. Crystallisation of the amorphous state in dispersion can affect critical properties of the coating and lead, for example, to the loss of the smooth and featureless surface required to improve biocompatibility by preventing clotting and particulate generation (Figure 1). Detecting change (recrystallisation) in an amorphous material is relatively straightforward using a wide range of solid state analytical techniques such as polarised light microscopy or X-ray powder diffraction.

One of the major reasons to monitor solid dispersion and physical changes is their potential effect on drug elution performance. The Noyes Whitney equation is commonly used to describe drug elution:

Where dm/dt = dissolution rate, k is the dissolution rate constant, A is the surface area of the dissolving solid, Cs is the concentration of the drug in the saturated diffusing layer and C is the concentration of the drug in the dissolution medium at time, t.

It can be seen from the equation that the surface area (A) of the active has a direct effect on the elution rate. In particular, compounds that have poor water solubility show particle size (surface area) limited dissolution. This will mean that any particle growth in a crystalline coating or crystallisation of an amorphous coating will change the surface area and therefore change the release properties of the active. In addition, a change in solid state form can alter the solubility (Cs) of the active because the metastable forms of the active tend to be more soluble in water. These factors will be of particular concern for coatings with sustained release functionality. Therefore, it would be prudent to determine any changes in particle size, solid state form or homogeneity
after stability testing and after in vitro or in vivo elution testing.

Glass transition temperature

Figure 2 : Tg analysis (shown as inflection) of a drug/polymer solids dispersion using Temparature Modulated Differential Scanning Calorimetry (MTDSC). Also shown in the figure is the effect of increased water content on lowering the Tg. (click image to enlarge)

For an amorphous active or polymer the glass transition temperature (T_g) influences its physical stability (tendency to recrystallise) and its mechanical properties such as elasticity, hardness and Young’s modulus. Therefore, knowing the T_g helps identify potential stability issues for storage of an amorphous formulation, identify approaches to conditioning the coating to crystallise active post application and may also help determine coating durability. The T_g can be analysed relatively easily by using thermal analysis (Figure 2).

The effect of plasticisers on the T_g of the polymer must be also understood as shown in Figure 2 for water on an amorphous drug/polymer dispersion. If a crystalline dispersion is desired then a combination of elevated temperature and the adventitious plasticising effect of a volatile solvent can be used to crystallise any amorphous fraction post coating. If an amorphous product is the target then rapid and complete removal of processing solvents post coating is likely to be critical because even extremely low levels of residual solvent (<1% weight/weight) can have a significant effect on its tendency to recrystallise.

Phase analysis and active distribution

Traditionally, active content in the coating has been measured by conventional liquid chromatographic techniques following an extraction method. This analysis can be more challenging for coatings with low drug loading and for biological actives because the sensitivity and repeatability performance of bio-analytical methods tends to be decreased compared with small molecule analysis. In both these cases, newer chemical imaging technologies may be useful for proving the presence or quantity of active material.

Phase analysis is an approach that is greatly aided by advances in chemical imaging. Phase analysis can help describe the distribution and homogeneity of the coating and explain changes in performance. For example, a glass solution will exhibit as a single phase with no drug or polymer rich domains. Certain coatings may contain drug rich layers, especially at the surface to facilitate a burst release of drug immediately following implantation of the device. Phase analysis may also help provide explanations for the release pattern of the active, for example, by determining the porosity of the device before and after elution studies.⁹

Advances in chemical imaging technologies have significantly improved the characterisation of low loadings of drug within a carrier matrix and allow detailed phase analysis. Spectroscopic techniques in combination with microscopic analysis such as confocal Raman microscopy can provide semiquantitative distribution information in three dimensions. Quantitative analysis is possible with techniques such as secondary ion mass spectroscopy.⁴ The selection of the right chemical imaging technology depends on a number of factors including,

• the component distribution information required: 3D, surface depth profiling and solid state analysis
• how the components and device matrix can be uniquely identified and therefore, discriminated
• particle size and domain size
• required sensitivity
• coating composition.

Some of the above characteristics are summarised for a number of chemical imaging technologies in Table III.

Table III: Examples of chemical imaging technologies and their application. (click image to enlarge)

Analysis of distribution should be repeated during in vitro elution studies because this can demonstrate how a drug can concentrate at, or be preferentially dissolved from, certain locations in the coating forming drug rich or poor areas that may or may not cause changes in elution rate. This type of analysis may also provide important information on drug release mechanisms and the integrity and durability of the polymer carrier.

Understanding the science

Part I of this article has attempted to demonstrate that a knowledge of coating science is important in coating formulation and early development of the coating. Understanding the physical characteristics of the coating is a critical step in developing a coating formulation that will consistently meet the product requirements, allow the relationship between physico–chemical and mechanical characteristics and coating performance to be undestood, and meet increasing regulatory challenges. Part II addresses testing and verification of the finished coating on the device.

Angus Forster, Thomas Neudeck and Stephen Blatcher are all Principal Consultants in PA’s Technology and Healthcare Group at PA Consulting Group, Cambridge Technology Centre, Melbourn SG8 6DP, UK, tel. +44 1763 267 492 e-mail: innovation@paconsulting.com www.paconsulting.com