Medical Device Link.

DESIGN

For many years now, pharmaceutical companies have been expending huge resources in developing newer and more effective drugs to treat the growing number of diseases and ailments. Those companies well appreciate that if the drug cannot be delivered effectively to the intended target area in the body, then they do not really have a saleable product.

The drug to be delivered can be in liquid, solid or aerosolised powder form. Many methods are employed to deliver the drug to the target area in the body. These include intravenous, oral digestion, intranasal, transdermal, buccal/mouth cavity, subcutaneous, topical and implantable means.The target areas can be varied such as intramuscular or dermal tissue layers, depending on the clinical need.

The success or failure of the drug can, on occasions, depend highly on the design and effectiveness of the drug delivery device. Filter materials and filtration are playing a greater role in making delivery devices more effective.

The need for filtration

Nearly all drug delivery systems share the same common objectives, which are to enhance ease of use, compliance and the delivery profile of medications. Precise administration, coupled with dosage reproducibility of liquid formulations to the required area such as the subcutaneous space, which is remote from pain receptors, contribute to patient comfort. These types of administration help to address patients’ needle phobia. In spite of safety procedures and protective personal clothing, personnel and the localised atmosphere can be exposed to dangerous substances when using traditional needles and spikes in the preparation and administration of chemotherapeutic drugs.¹ Furthermore, difficulty in puncturing vial and bag septum coupled with low aspiration flow rates can slow down the procedure and lead to frustrated medical staff. Filtration and venting plays a crucial role in meeting these challenges.

Ensuring drug sterility

Table I: (click to enlarge) Filtration characteristics.

Liquid drugs for medically supervised administration are usually delivered in vials sealed with crimped rubber septum. Using a needle or cannula attached to a syringe system, the drug is aspirated from the vial in readiness for subsequent transfer and administration. This seemingly simple aspiration process can present many challenges. When aspirating the drug from a vial, the volume of drug removed must be replaced with sterile air. Hydrophobic filters (see Table I) are manufactured from materials such as polytetrafluoroethylene, polypropylene or acrylic copolymer that have had phobicity treatment and will repel the drug in question. A filter made from one of these materials with an absolute pore size of 0.2 µm will ensure that sterile air can replace the aspirated drug from the vial. This reduces the risk of compromising drug sterility and equalises vial pressure, thus eliminating aerosolisation of the drug.

Proper venting design

The ability to simultaneously repel the drug on the vial side and prevent egress of the drug from the vial is derived from the choice of filter media and the application of special coatings to provide the correct degree of phobicity. Depending on the drug constituents, the phobicity of the filter membrane may need to be altered to include oleophobicity properties (see Table I), for example, oleophobic media need to be used where hydrophobic membranes fail to vent drugs and solutions containing multivitamins, fats and oils.

Figure 1: (click to enlarge) Typical vent and overmoulded media atttachment.

To determine the required membrane, the constituents of the drug must be understood to enable venting materials to be selected that have the inherent phobicity characteristics. The materials will be tested initially on the drug placebo before on the drug to confirm acceptance. These repel characteristics will need to be present at the relatively high positive and negative vacuum pressures experienced when using a syringe in conjunction with a glass vial. Pressures of 3-bar to 1-bar vacuum would not be unusual, depending on the size of syringe being used, because large pressures can build up as a drug is being aspirated or injected back into the vial to achieve the exact dosage requirement in the syringe. This will help reduce the hand force required on the syringe plunger to withdraw the drug as pressure equalisation takes place. This has important device design criteria in that the membrane must be properly bonded to the venting element using insert and overmoulding (Figure 1).

Correctly sized media

Hydrophilic filtration is usually employed to remove liquid-borne contaminants. These filtration media (see Table I) will not have any drug repellent characteristics and suitable materials include acrylic copolymers, polysulphone, nylon and cellulose acetate. The drug supplied in a vial can be expected to be sterile and free of contaminants. However, when using a cannula to puncture the septum on the vial to access the drug, it is not uncommon for “coring” to occur, whereby the “core” of the septum is removed by the cannula and lodges initially within the cannula bore. As the drug is then injected from the syringe system through the cannula, fragments of the septum can be expelled into the drug. By employing a hydrophilic filter membrane, these contaminants will be retained on the filter surface and the drug will be allowed to pass through. To prevent any possibility of bacteria ingress to the drug, the filter media will need to have an appropriate pore size and 0.2 µm is a generally accepted standard to remove harmful bacteria. Obviously contaminants larger than 0.2 µm such as fragments of the cored septum will also be removed.

Dose-volume reproducibility

Figure 2 : Typical woven mesh weave pattern.

The filter media surface area and contaminant-loading capacity are important considerations in helping to optimise the performance of the drug delivery system. Although nonwoven membrane-based filter materials play a dominant role in drug delivery systems, woven mesh materials can also be important. As the name suggests, these filter materials are woven using threads of monofilament material such as nylon, polyester and polypropylene. The weave pattern and resulting pore size are usually regular and controllable (Figure 2). They are normally used when pore sizes of 5 µm and larger are required, for example, in dry-powder inhalers for the treatment of asthma. During each actuation of the delivery dispenser, a predetermined dose is transferred to the patient in powder form. The filter mesh material, which could be up to 30 µm in pore size, can be positioned between the granular drug and the patient side in the powder expulsion channel. This filter sieve breaks up the granular material. This helps to provide improved dispersion of the drug, thus improving the effectiveness of the treatment. Precision in the weave pattern and accuracy in the method of attachment of the filter mesh to the surrounding housing in the delivery system are important to ensure dose-volume reproducibility. The mesh material can be attached to the filter-housing using insert and overmoulding techniques or by welding or heatstaking. Whatever method is employed, it is essential that the drug is delivered through the mesh as intended. Minute amounts of the drug being trapped in the mesh and surrounding frame will result in poor dose reproducibility.

Combined hydrophobic and hydrophilic filtration

Some drugs, particularly those for the treatment of eye disorders, are dispensed in drop form onto the surface of the eye by the patient several times per day. The quantity and uniformity of the dose are challenges for the delivery system and patient alike. The drops are intended to free-fall onto the eye surface and distribute appropriately for effective treatment. Too little drug can lead to ineffective treatment and too much drug can cause serious side effects and could interfere with treatment of the targeted condition.

These drugs are usually contained in flexible plastic vials with suitable sized dropper tips. Finger pressure on the delivery vial forces the drops out onto the eye surface. When the pressure is removed, the elastic recovery of the vial creates an internal temporary vacuum in the vial, which causes air and small amounts of the drug at the dropper tip to be drawn back into the container. The drug at the dropper tip may become contaminated with bacteria present in the eye on contact or from the ambient atmosphere. Because this potentially contaminated drug is drawn back into the container and subsequently dispensed onto the eye, it could cause infection. Some drug manufacturers introduce antibacterial agents, which are effective in suppressing the growth of bacterial contaminants in the vial. However, these can cause eye irritants and in some cases allergic reactions. These problems can also be present in other drugs such as those for treatment of nasal and ear disorders.

Figure 3: (click to enlarge) Combined hydrophilic and hydrophobic filtration.

The use of microporous filter membranes in combination with the delivery container can overcome these disadvantages. This can be accomplished by constructing the delivery container with two communicating channels, one for the egress of the drug in droplet form and one for the ingress of air to replace the displaced volume in the container. The channel directed at the droplet tip for drug egress will contain a hydrophilic (liquophilic) membrane with a pore size no greater than 0.2 µm. This will ensure that only sterile droplets of drug are dispensed. The separate channel for the ingress of air will contain a microporous hydrophobic
(liquophobic) filter membrane, which will not allow passage of the drug. By having the filter membrane suitably sized, only sterile air will be allowed into the drug container (Figure 3).

This design of droplet container presents challenges for the filter designer. The membrane must be attached to the plastic housing or frame to ensure the passage of air or drug through the membrane rather than around it, which would result in an undesirable bypass. Difficulties can be encountered in working with such a small device. For example, the area of the hydrophobic membrane for venting can be less than 25-mm². Insert and overmoulding of the membrane performed insitu using carefully designed mould tooling will help prevent any possibility of a bypass

Continuing the combined effort

Balancing and optimising the filtration factors that go into meeting the challenges of a successful delivery system can be a complex and daunting task. However, successful products are realisable when the effects are understood and variables are brought carefully together to address each need, not only in meeting the actual requirements of the patient and clinician, but also the requirements of manufacture, assembly, test, and sterilisation in volume production.

The future of getting the drug to the target area for the effective treatment of the many ailments that afflict mankind is by having the drug companies, device developers and the filtration companies working together to provide the most optimised product
for use.

Brendan Hogan is Vice President of Engineering and Quality at Filtertek BV, Industrial Estate, Newcastle West, Co. Limerick, Ireland, tel. +353 69 62666, e-mail: bhogan@filtertek.ie, www.filtertek.com.