VIEWS & REVIEWS
Developing drug delivery systems for patient benefits -Helen CommanderAn appropriate drug delivery system is an important step in the drug development process. Designing and developing an effective strategy to meet this challenge can be a complicated and time-consuming process fraught with many difficulties. Senior personnel in this field met to discuss problems. current achievements and suggestions for the future at the mc UK conference on Drug Delivery Systems - Strategies and Technologies [London, UK; January 1998].
Strict regulatory controls ensure that the drug development process is a long and arduous process. Time obviously means money in the pharmaceutical industry and one way companies have attempted to streamline the process is by working on new ways to deliver old drugs.
A new spin on NCFs New and effective drug delivery strategies may breathe life back into some of the new chemical entities (NCEs) that have previously failed to meet the grade required for further clinical development because of poor pharmacokinetic profiles, according to Dr Keith Horspool, Manager of the Pharmaceutical Research Group, Zeneca, UK. However, it is not just a case of trying to make the most of such NCEs; drug delivery strategies may also be used in association with novel drugs. However, a drug delivery system will not make a 'bad' drug 'good', pointed out Dr Mike Dey, Director of Inhalation Industrialisation at Rh6ne-Poulenc Rorer, Dagenham, UK. Drug delivery is a less risky business than novel drug development, but does have the disadvantage of a possibly lower financial return. Therefore, cost versus performance is an important issue.
Special skills needed A drug delivery system is a technical approach to getting a drug to a patient, and some devices can be quite complex. Therefore, the skills needed for their development are not those associated with pharmaceutical R&D companies. For example, expertise in rubber, plastic and adhesives may be required. However, according to Dr Horspool, there is no need for one company to have all the skills in-house; established companies exist outside the pharmaceutical industry that have expertise in materials, processing and equipment development. By relying on external experts, however, it is essential that pharmaceutical companies do have the skills required for managing the relationship with the external company.
Protein delivery difficult The successful delivery of proteins to humans has posed many probiems in ihe pasi. These molecules ai't; often large, easily inactivated, prone to aggregation and expensive. Nevertheless, many companies are trying to address these issues. The most important issues to address if developing a protein-based drug are bioavailability and reproducibility of dosing, said Dr Jill Ogden from Andaris, UK. Her company is concentrating on dry powder inhaler technology using a proprietary spray drying process, she added. However, proteins can be 1173-B32~127-OOO31S01 .W' Adlelm.m.tlonlll Um"-d 1.... All rights ~
administered via many different routes (e.g. parenteral, nasal, oral, pulmonary, topical, buccal or trans dermal) and in different formulations (e.g. depot sustained-release injections). Significant progress has already been made in delivering proteins to humans. Currently, there are about 36 recombinant protein drugs that have been approved by the US FDA, including becaplermin ['Regranex'], a topical gel formulation of recombinant human platelet-derived growth factor, which has been approved for the treatment of diabetic foot ulcers. * However, many of the recently approved drugs are available as injectable formulations and may require long-term dosing. Therefore, there is still room in the market place for a protein drug delivery strategy that is patient friendly, non-invasive, has high bioavailability and good reproducibility and is economical.
Try it orally Oral delivery of proteins is the main focus of activity for Cortecs, UK, according to the company's president Dr Michael Flynn. A successful product would have some, if not all, of the qualities mentioned above. However, there are many obstacles to achieving this. One of the first that Cortecs came across was that preclinical studies in rats do not necessarily translate to humans; a protein delivered effectively to rats will not necessarily be active in humans. This problem has been overcome to some extent by using pigs in preclinical evaluation studies. This system is a better predictor of the drug's action in humans.
Calcitonin on the way One of the first proteins that Cortecs chose to develop was calcitonin, said Dr Flynn. Primarily, this was because precise dosing of calcitonin is not critical. Their product, 'Macritonin', has been doing well in clinical trials, based on measuring markers for bone destruction, and is awaiting registration in 5 European countries for the treatment of osteoporosis, he added. Other clinical trials with this product are ongoing and bone mineral density measurements are being conducted in these studies. Insulin, unlike calcitonin, has a narrc'.\' t..'lerapeutic window and is therefore a more challenging protein to develop into an oral formulation. Cortecs began developing their oral insulin ['Macrulin'} some time ago, said Dr Flynn. Initially, it took longer than expected to design and develop an insulin capsule formulation, but trials are now underway in patients with diabetes mellitus. Oral delivery of proteins has
*Seelnphamw 1119: 26, 10 Jan 1998; tnJ631806
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VIEWS & REVIEWS been a 'long. hard road', according to Dr Flynn, but he believes that it will become a reality.
Gene genie The delivery of therapeutic genes to humans has, in the past, been seen simply in terms of the vector used. However, new approaches need to be considered, according to Dr Phyllis Gardner, Vice President of Research, Alza, US. Researchers are now thinking about using delivery systems for vector/gene constructs. For example, Alza is working on the oral administration of vector/gene constructs in mice. This revolutionary thinking may have the potential to enhance the efficiency of gene therapy. How successful this approach will be in humans remains to be seen. Other delivery systems in development include a strategy for aerosolising the therapeutic gene for direct lung delivery in patients with cystic fibrosis. With advances in this area, targeting and containment of genes will become important issues in future gene delivery strategies, according to Dr Gardner. One example of a successful and commercially available drug delivery strategy is the use of liposomes. This is not a new approach and, in fact, liposome research began back in the 1960s. However, it wasn't until the 1990s that a product reached the market. Why did it take so long? One of the main problems was that of rapid removal of liposomes from the body, according to Dr Frank Martin, Vice President and Chief Scientist of Sequus, US. This problem was overcome using Sequus' proprietary Stealth technology. Now, several liposomal formulations utilise this technology and are available on the market. Liposomes are also being used to deliver DNA. However, this research is in its infancy. Problems associated with this strategy include having to condense the DNA to a size which can be wrapped in liposomes.
A balanced approach Other drug delivery approaches discussed at the conference included transdermal patches and metered dose inhalers. For all approaches, it was stressed that not every drug would suit each, or even any, of the drug delivery methods. It is important to remember to assess what benefit the drug delivery technology will give to the patient, said Dr Ian Tansey, Senior Technical Manager, 3M Health Care, UK. 800631883
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