BBI Contributing Writer

This is an exciting time for the drug delivery sector of the pharmaceutical industry. After years of tugging at the coat-tails of mainstream companies, peddling their wares like traders in a Moroccan souk, companies focused on drug delivery systems (DDS) are now taking their place alongside those very industry leaders as major players in the pharmaceutical marketplace. It's a heady situation to be in – and a mite perilous, too. To understand why, one needs to look at the current status of drug delivery technology, the contribution it can make to major brands and to the practice of medicine, the present size and growth of the market, and the nature of the industry.

Technology improving efficacy, safety

In a sense, drug delivery systems have always been with us, because any manipulation of a drug substance intended to facilitate its administration – for example, tableting, or incorporating it into an injection solution or topical ointment – may be called a delivery system. But by DDS nowadays we mean additional technology designed to improve the efficacy and/or safety of the drug, or to make its administration more convenient. The first DDS technology in this sense was probably the enteric-coated tablet, followed by the sustained-release multiparticulate forms (pellets in a hard gelatin capsule, usually) introduced in the 1960s.

Today's DDS repertoire consists mainly of oral, transdermal, inhalation and parenteral (injection) technologies. The oral route is still the preferred means of administering drugs because of its convenience which, in the case of elderly patients and asymptomatic conditions, can aid compliance with prescribed dosage schedules. Transdermal (skin patch) delivery has established itself for some types of drug administration (angina prevention, smoking cessation, hormone replacement therapy) and its uses are being broadened to other types of drugs; many drugs are easily absorbed at mucous surfaces, and this is being exploited in developing oral, nasal, vaginal and rectal mucosal delivery systems.

Current research in DDS technology is mainly focused on developing solutions for administration of large molecules, such as protein and peptides, and devising methods of targeting drugs to specific disease sites. Additionally, one of the most important reasons for the present buoyancy of this sector is the fact that DDS companies have been handed a major challenge for the near-term future: to develop a practical means of administering gene therapy. This form of therapy may be nothing less than a quantum shift in the practice of medicine but its development is stymied by the lack of appropriate delivery systems.

Most current development work in the field of oral DDS is focused on two areas: increasingly sophisticated sustained-release mechanisms, and achieving systemic absorption of large molecules such as peptides when given by the oral route.

Apart from the major drug delivery companies such as Alza (Menlo Park, California) and Elan (Dublin, Ireland), which are constantly engaged in development work in this area, some smaller companies focus on specific goals in oral delivery systems. Companies aiming for improved absorption efficiency and control in sustained-release oral systems include Core Technologies Moorfield, Scotland) and Fuisz Technologies (Vienna, Virginia) and recently acquired by Biovail (Mississauga, Ontario). Their technologies are basically more sophisticated approaches to long-established oral absorption methodologies such as multiparticulate delayed-release systems.

There were high expectations during the 1990s that it would be possible to use the oral route to get protein and pepticide drugs efficiently into the bloodstream, using carriers such as liposomes. Results of research projects did not bear out these expectations, and the focus of attention for large-molecule delivery has shifted to mucosal systems, and to refining parenteral delivery.

The mucous membrane should be an effective route for drug delivery, superior to the skin in some respects since it does not present as formidable a barrier to drug ingress as the stratum corneum. Several companies are involved in mucosal DDS research alongside other DDS approaches. For example, Watson Laboratories (formerly TheraTech; Salt Lake City, Utah), which has developed a number of transdermal formulations, has also been working on a special tablet to deliver glucagon-like insulinotropic peptide (GLP-1) through the oral mucosa as an alternative to injection in the treatment of Type II diabetes. Noven Pharmaceuticals (Miami, Florida) also is researching transoral drug delivery technology for insulin and other proteins. Acambis (Gaithersburg, Maryland), formerly the Peptide Therapeutics Group, specializes in vaccine development and has a proprietary mucosal DDS, offering an alternative to vaccine injections. 3M (Minneapolis, Minnesota), whose experience in adhesive technology has been put to use in the transdermal field, has similarly built on its adhesive expertise in the development of a proprietary mucosal tablet formulation named Cydot, which claims up to 24-hour delivery with good patient acceptability.

The main thrust of research in the parenteral field is towards delivering biopharmaceuticals (large-molecular entities) to specific targets in the body, and to protecting them from degradation by the immune system. Two technologies are in the forefront: liposomes and monoclonal antibodies.

Liposomes can move around in the circulation without provoking an immune response because their exterior structure is non-immunogenic. Sequus Pharmaceuticals (Menlo Park, California), now part of Alza, which in turn has recently been acquired by Johnson & Johnson (New Brunswick, New Jersey), has developed a proprietary technology to make liposomes even more "invisible" to the host's defence system by covering the surface of the liposome with a hydrophilic polymer such as polyethylene glycol (PEG). The technology is patented as Stealth. Other companies active in liposome research include The Liposome Co. (Princeton, New Jersey), recently acquired by Elan, and Nexstar Pharmaceuticals (Boulder, Colorado), acquired by Gilead Sciences (Foster City, California) in 1999.

Monoclonal antibodies (MAbs) are being used as targeting agents to deliver drugs to specific therapeutic sites. For example, a cytotoxic drug can be attached to a MAb that binds selectively to an antigen present on a particular type of cancer cell. In this way a concentration of cytotoxic drug can be built up around malignant tissue, while drug levels elsewhere in the body remain low.

Gene therapy a special case

Genetic defects are known to be the sole cause of many diseases, and they play a part in the causation and development of several others. Gene therapy is a major new field in the medical treatment and prevention of disease, based on replacement of defective genes or correction of inappropriate gene action. The major practical problem is delivering the corrective gene to the interior of the cells where its action is required. Genes are large molecules, which are recognized as foreign by the immune system, and consequently destroyed.

Current research into vehicles for gene delivery is focused on two technologies: liposomes and viral vectors. Liposomes work well to shield the genes from immune destruction but penetration of the genes into target cells is relatively inefficient. Specially modified viruses have been used with greater success to deliver genes into cells, but immune reaction remains a problem and although these viruses are stripped of their pathogenicity, reactions do sometimes occur. This whole field is still at an experimental stage, but the potential rewards, in human and commercial terms, are very great, and considerable research activity is ongoing both in academic research foundations and on the part of companies such as GeneMedicine (The Woodlands, Texas), Genzyme (Cambridge, Massachusetts), RPR Gencell and Therexsys (Keele, United Kingdom).

The DDS contribution

To the question "Why bother to develop drug delivery systems?" there are two categories of response, which may be labeled as clinical and commercial.

Clinically, drug administration may present problems related to the route of administration, and/or to the drug. Oral administration of drugs can be relatively unpredictable; the rate and extent of drug absorption from conventional formulations is affected by many factors including fluctuating pH in the stomach and small intestine, the presence or absence of food, esophageal transit and gastric emptying rates, posture, diurnal rhythms, drug interactions and gastrointestinal or other pathology. The nature of the g.i. environment also limits the types of drugs that may be administered in this way. Insulin and calcitonin are examples of large-molecule drugs which cannot be administered orally, at least in conventional form, because they are either destroyed in the stomach or are not easily absorbed through the stomach wall due to their size. Some drugs are also gastrotoxic, causing damage to the mucosal lining of the stomach. This is common when the drugs are self-administered in high concentrations.

Parenteral administration is necessary for drugs which are degraded if given orally. However, all injection routes have their problems. The effect of an i.v. dose is usually short-lived, and this route is not suitable for drugs which are required to exert a continuous therapeutic action. With subcutaneous and intramuscular administration, absorption and transport of the drug can be unpredictable. Intramuscular injection may cause muscle necrosis and pain. Although this route has traditionally been used for self-administration of insulin by diabetic patients, it is far from ideal.

Inhalation is favored for administering drugs which act in the lungs, but the the conventional metered-dose inhaler (MDI) has significant drawbacks, notably the difficulty many patients (especially children) have in achieving correct inhalation technique.

Drug-associated problems with conventional delivery formulations may include instability during storage, low aqueous solubility, rapid rates of drug metabolism in vivo, unfavorable pharmacokinetics (e.g. rapid clearance), dose-limiting toxicities and poor distribution to target tissues.

Novel delivery systems can confer important advantages on well-established products, products with previously limited potential and products in development. Major pharmaceutical companies increasingly are relying on DDS technology to bolster their portfolios for a number of reasons. Introduction of a DDS formulation can be used to extend the patent life of a product or to gain market share through product differentiation. Either way, DDS technology can play an integral role in product life-cycle management, and far-sighted company executives are including the DDS dimension at an early stage of marketing strategy planning.

Improved delivery systems can also be used to facilitate the inclusion of products on the formularies of managed care organizations, and to provide a second chance for products previously abandoned in clinical trials due to unfavorable side effects or lack of efficacy.

An increasingly cogent rationale for the inclusion of the DDS dimension into a company's overall product development strategy is the escalating cost of NCE development and the lengthening time from laboratory to market for novel drugs. DDS line-extensions of existing products, or of in-licensed or generic compounds, can be brought to market far more quickly, and at perhaps one-tenth the cost, of an NCE.

The DDS market opportunity

It is estimated that the value of the total world market for all DDS products was $35 billion for the calendar year 2000. The annual market growth rate has recently been around 15% – faster than for pharmaceuticals overall This vigorous rate of market increase is the result of several factors including innovation in drug delivery technologies, a wider range of therapeutic applications for DDS, the increasing reliance on DDS in life-cycle management, and increasing use of DDS formulations by generics manufacturers for product differentiation and advantage. Other growth drivers are also expected to become important in the longer term, including successful DDS solutions for gene therapy and new targeting systems for anticancer therapies.

Taking all these factors into account, the global value of the DDS market is expected to be in the region of $40 billion for the year 2001 and $75 billion by 2005. This represents annual growth rates around 15% in the early part of the period, later rising to 20%. Some analysts foresee even more vigorous growth for this sector.

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