More than skin-deep

Using new drug delivery methods to administer long-term treatments can have benefits for both patients and manufacturers. Jean-Francois Grenier talked to Hilary Ayshford about Schering Oy's Delvivo technology

Patient non-compliance is one of the main reasons why drugs fail to treat effectively the disease for which they were prescribed. This is particularly the case for chronic conditions where efficacy may depend on a long-term regime of regular doses being taken at specific intervals to maintain stability and prevent the recurrence or flare-up of symptoms. For example, the compliance rate in the US for antihypertensive drugs is only 53%,¹ in part because the condition is asymptomatic and patients are not prompted by symptoms to take their medication.

It is estimated that in the US alone 50% of prescriptions are taken incorrectly, resulting in some 125,000 deaths each year. Non-compliance causes huge costs to society and healthcare systems, and medication misuse contributes an estimated US$76bn (€68.7bn) a year to healthcare costs in the US alone.²

life-style factors

Poor compliance can result from several factors, including lack of motivation, life-style and/or the patient's understanding of the treatment, not to mention simple forgetfulness. Side effects are another factor. These can, in some cases, be due to fluctuations in plasma level during courses of orally or otherwise frequently administered medication, while in other cases the GI tract may also be irritated, resulting in heartburn, nausea and other gastrointestinal problems.

Implants, using polymer-based drug delivery technology, offer a method of administering a therapy in a controlled way that requires no action by the patient for a period of up to five years, but which can be halted at any time should side-effects develop or there is no further need for the medication.

One of the pioneers of this technology is Schering Oy, the Finnish pharmaceutical company that has been a subsidiary of the Schering Group since 1996. For more than 20 years it has been employing polymer-based drug delivery in fertility control products: Mirena, a hormone-releasing intrauterine system (IUS); and Norplant and Jadelle, subdermal contraceptive implants. These contraceptive devices are used by some 9m women worldwide.

The delivery method, which is suitable for use in an implant, IUS or intravaginal ring (IVR), centres on Schering Oy's Delvivo release technology. The implant remains in place for the duration of the treatment, releasing the active ingredient into the surrounding tissue and circulation. However, it can be removed at any time.

pharmacological benefits

The technology offers a range of pharmacological benefits, explained Schering Oy president Dr Jean-Francois Grenier. First, because the drug supply is continuous and controlled throughout the treatment period the serum levels remain stable within the therapeutic window. Second, the bioavailability of certain drugs is greater than if they were administered orally, which frequently allows the daily dose to be reduced and the risk of side-effects to be minimised. This increased bioavailability could potentially reduce the attrition rates for new clinical entities (nces) by increasing the chances of drugs unsuitable for orally administration making it to market.

A further advantage of Delvivo for pharmaceutical companies is that it can provide a cost-effective means of extending the life cycle of existing products by offering the opportunity to apply for a new patent for a drug and thus extending its brand life by up to 20 years. It also offers manufacturers the chance to differentiate their products from those of their competitors, at the same time as increasing compliance, efficacy and consumer acceptance. Delvivo offers a high level of protection, said Grenier, combining the IP relating to the molecule, the drug delivery technology and the high level of expertise needed to manufacture it.

At the heart of the product is a core consisting of active ingredient mixed with siloxane polymers (PDMS ; poly(dimethylsiloxanes)), which acts as a reservoir of the active pharmaceutical ingredient. For a drug to utilise Delvivo technology, the minimum and maximum dosage is 1-2µg/day and 2-5mg/day respectively. The API is mixed homogeneously with the PDMS in a ratio that is set according to the desired treatment time and dosage requirements. The resulting matrix is then processed into a round rod.

controlled diffusion

To produce the implant the core is then mounted inside a PDMS polymer membrane (fig. 1). Conventional PDMS are suitable for releasing only a limited number of drug molecules while maintaining serum levels within the therapeutic window. However, Delvivo technology enables the release rate to be manipulated by mixing modifiers with the conventional PDMS of the membrane to alter the hydrophilic and hydrophobic properties of the conventional PDMS (fig. 2). This controls the solubility and thus the diffusion properties of the active.

The modifiers are accelerating and decelerating PDMS derivatives. Accelerating derivatives are added if the release rate needs to be increased to achieve the serum level required, and decelerating derivatives are added to slow the release rate of the active substance through the membrane. The release rate is fine-tuned by other factors such as release membrane thickness. In this way implants can be produced that release drugs over long periods of time ; from six months to five years ; while maintaining serum levels within the therapeutic window.

The modified PDMS is processed into a continuous, thin-walled tube with the desired release properties. The resultant membrane covered rod is end-capped to avoid bursting. Delvivo products are non-biodegradable, solid and crosslinked; they contain no gel that might leak out into surrounding tissue and are also elastic, which minimises breakage or crumbling.

Until now, Delvivo technology has been used exclusively with products from the Schering portfolio, but Schering Oy is now making it available to other pharmaceutical and biotechnology companies for use with both nces and products currently on the market, said Grenier. Potential partners will be able to take advantage not only of Schering Oy's proven track record and expertise with polymer technology and product development, but also the full service chain that can be tailored to the partner's needs from pre-evaluation, r&d, pilot scale and full scale manufacturing right through to marketing.

Delvivo technology can be adapted for use with a number of drugs across several therapeutic areas, with the overall development process from initial studies to launch taking at least five years. As well as being applicable for implant drug delivery, Delvivo technology can also be applied to intra-uterine and intravaginal drug delivery.

The suitability of a molecule depends on several factors: its melting point has to be high enough to withstand the processing temperatures needed to crosslink the polymer, and the daily dose has to be sufficiently low to allow a sensible duration of treatment (between six and 60 months). The technical compatibility of the drug molecule and the polymer will be checked in the first feasibility tests.

Therapy areas that could benefit from the technology are those where long-term stable treatment is required and where compliance can be an issue; for example, some cardiovascular indications such as hyperlipidemia, some CNS indications and osteoporosis.

One area with great potential, Grenier believes, is antihypertensives, where an implant would free patients from having to remember to take daily tablets for up to five years. He also sees possibilities in other chronic conditions, such as epilepsy and schizophrenia. Looking further ahead, other areas currently being evaluated are implants for insertion into the nasal submucosa for treatment of rhinitis, for example during the hayfever season, and implants for the inner ear for treatment of MeniEres disease.

Schering Oy is currently undertaking a screening programme to assess the potential compatibility of larger molecules, especially those within five years of patent expiry, and then approaching the manufacturer with a view to developing them using the Delvivo platform. Discussions are ongoing with several potential partners and a letter of intent with one was likely to be signed within 'a matter of months'.