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Michael J Rathbone of Griffith University, Australia and Padma V Devarajan of the Institute of Chemical Technology, Mumbai highlight the potential for crossover between human and veterinary controlled release systems

The area of controlled release science and technology is broad, covering human health, animal health and production, and consumer and diversified products. The basic difference between controlled release and immediate release products is schematically depicted in Figure 1. The prolongation of the effect of a compound through the retardation of its release from a carefully designed delivery system affords many advantages, including compliance to human patients, farm management benefits to the farmer, and consumer satisfaction to a shopper. Each area is regulated to different degrees (in some case none at all) and to different regulatory standards (which can be prohibitorily high for some companies), and each offers its own challenges and opportunities for innovation. However, every area is underpinned by the same science, and can make use of the same technology to produce products that offer value to the end user. This provides the opportunity for all areas to learn from one another. Microparticles, for example, are used in all three areas to deliver compounds of interest. However, many consumer and diversified products utilise microparticulate technology, and scientists in this area have contributed greatly to our understanding of the science and process development of this type of dosage form. Both human and veterinary formulation scientists would benefit greatly from interactions with their consumer and diversified product colleagues. Coating and taste modifying technologies are other examples where human or veterinary scientists can learn from those working in the consumer and diversified products area.

Despite this, in some instances the science results in quite different outcomes. Compare a human tablet destined to be swallowed and deliver its contents slowly along the gastrointestinal tract, to that of a rumen bolus that is forced down the throat of a cow, and is designed to resist regurgitation by the animal and be retained in the rumen for long periods while it very slowly delivers its contents. The former are designed to erode, dissolve or disintegrate during their passage through the human gastrointestinal tract, eventually disappearing to nothing (an eight- to 18-hour process). In contrast, the latter products can deliver their contents for up to six months and the retentive mechanism remains in the rumen for the life of the animal.

However, such differences in outcomes should not be interpreted to mean that learning outcomes cannot be shared. The rumen is physiologically and anatomically very different from the human stomach, but the innovative ideas between human and veterinary formulation scientists could mean the invention and development of a novel idea in one area that could enhance the drug delivery capabilities in another. Indeed, the Controlled Release Society actively encourages learning opportunities and the exchange of ideas between its human, veterinary and consumer and diversified products members.

It is beyond the scope of this article to provide an extensive list of the technologies that exist within the area of controlled release, and readers are referred to the excellent books that cover this subject (1-5). This article will briefly describe the landscape in which these technologies are used and provide some insight into the potential of controlled release science and technology.

THE DIFFERENT AREAS OF CONTROLLED RELEASE

Human health controlled release products can be classified according to many systems: mechanism of release (diffusion, erosion, osmotic and so on); route of delivery (for example transdermal, nasal, vaginal or rectal); technology type (such as patch, microparticle or nanoparticle), and so on (1-3). The focus is on developing delivery systems that cure or prevent disease, or at least reduce the suffering of the patient. The advantages of developing a controlled release product for human use includes increased compliance, increased convenience, reduced side effects and product lifecycle extension.

Animal health and production controlled release products can also be classified according to many systems, such as mechanism of release (diffusion, erosion, swelling and so on), route of delivery (intramammary, dermal, subcutaneous or rumen), technology type (for example pour-on, spot-on or rumen bolus), and animal type (companion animal, production animal or exotic animal) (4). For companion animals such as cats and dogs, the focus is the same as human delivery systems – to cure or prevent illness, or to ease discomfort. In contrast, for production animals the focus is on developing delivery systems that are of financial benefit to the owner. The advantages of developing a controlled release product for animal use is dependant upon the animal type that it is being developed for. For companion animals the main factors are increased owner compliance and convenience and less handling and stress for the animal itself. For production animals factors such as the reduction of handling (one-time per treatment), less stress (on both the animal and the farmer), reduction in cost of treatment, increased time saving due to reduced herding and handling are more important. Overall, controlled release products for production animals result in reduced cost for the farmer and increased farm management efficiencies and profits.

Consumer and diversified products focus on controlled release in non-pharmaceutical and non-drug areas (essentially anything that the human and animal areas do not cover) (5). Traditionally, this area has focused on food, nutrition, personal care, household, agricultural, pest control, and industrial and chemical applications. More recently, nutraceutical, cosmetic, cosmeceutical, textile, and other application areas have gained a growing interest. The advantages of developing a controlled release product for consumer and diversified product use are the added benefits impelled into the final product by controlled release technology. This takes many forms, dependant upon application, including the prolongation of effect, masking of taste, prolongation of colour or improved durability of coatings or coverings.

CONTROLLED RELEASE LANDSCAPE

The human health controlled release landscape is dominated by the presence of oral controlled release formulations. Controlled release technologies play a critical role in the product lifecycle management of branded pharmaceuticals through reformulation. The introduction of a controlled release product to a pharmaceutical company’s product line offers them the opportunity to expand a market by differentiating themselves from their competitors, or to defend an existing market of a compound by making the product more competitive. This latter approach is done to offset the impact of generic erosion, but to be successful still requires the controlled release formulation to offer a distinct advantage, for example by launching a once-a-day formulation into a therapeutic area where competing products are only available in multiple-times-per-day dosing regimes. Historically, pharmaceutical companies have developed controlled release formulations as their immediate release forerunners near patent expiration. This approach is not unique and companies do develop controlled release formulations earlier in the product lifecycle. The rationale to this approach is to launch multiple formulations in parallel, in order to expand the potential patient population and gain a significant share of the market. The downside of this approach is that the company will forgo the extension of the lifecycle as a means of generic defence. Either way, drug reformulation into a controlled release dosage form must be conducted prudently and occur in the right sequence and at the right time if the value of the product is to be fully recognised. Companies develop their new reformulations in-house; alternatively, there is the opportunity to buy-in controlled release technologies from companies that specialise in technology-focused research. This latter approach generally results in pharmaceutical product development that is more rapid, costs less and has a large part of the therapeutic risk removed.

Several forces drive the human controlled release area, including:

  • Patent expirations
  • Fierce generic competition
  • Use of controlled release technologies as a viable option to extend product lifecycles
  • The need for novel delivery systems to enable new biotechnology bioactives to reach the market
  • The need for product differentiation
  • The potential to license established delivery technologies
  • The need for patient-friendly technologies

The animal health and production controlled release landscape is divided into segments. These can vary dependent upon the purpose for which they are used, but segments can describe the country, therapeutic class or animal types. When considering geographic location, the US and Europe are the biggest markets; however, these are also the most difficult markets to register and manufacture for from a regulatory standpoint. Based on therapeutic segment, parasiticides, biologicals and anti-infectives occupy about a quarter of the market each. The parasiticide and anti-infective markets are highly competitive and cost sensitive. On the one hand, controlled release offers an opportunity for market differentiation, but the cost of manufacture is a critical consideration and one that often prevents a good idea for a controlled release delivery system becoming a commercial reality. By animal type segment, cattle and companion animals both occupy about one third of the market each. Using cattle offers many opportunities for controlled release due to their unique anatomy and physiology which, although it presents many challenges to the formulation scientist, also offers many opportunities for an innovative scientist to exploit. Products for cattle must be very cheap to purchase, as their main advantages lie in improved farmed management processes and profits; therefore a narrow cost to benefit ratio dictates their commercial success.

At first sight, the companion animal market offers high financial returns for a controlled release product. Generally, each owner will have only one or two pets per household and each will be considered as part of the family. Pets are manageable, docile, trained and trusting. Owners are willing to treat their animals if they fall sick (based on a compassionate decision) and they are willing to pay for such treatment to ease the suffering or prolong the life of their beloved pet. In addition the owner is willing to undertake the medication process (feeling of contributing to the life of the animal). The opportunity for controlled release products lies in the premise of therapy for the individual, and thus higher margins. Therefore there is more scope for product sophistication, time and energy devoted to R&D, use of more expensive excipients and utilisation of more expensive manufacturing processes – as a result delivery systems that are more sophisticated and relatively expensive can be developed for this segment of the market. However, the smaller size of the animal and the unique anatomy and physiology of small animals, for example, erratic and short gastrointestinal transit times, limit the opportunities for the development of a controlled release delivery system. The remainder of the animal market is split roughly equally between sheep, pigs and poultry. Although the size and anatomy of the sheep is conducive to controlled release products, they are a low value animal, and therefore the cost of manufacture prohibits the appearance of many potentially useful products for sheep. Pigs and poultry could benefit from controlled release technology, however, both are difficult animals to treat: poultry on an individual basis, and pigs because they are simply a notoriously difficult animal to administer drugs to in the commercial setting.

The consumer and diversified products landscape is wide-ranging, covering areas such as:

  • Skin medications
  • Cleaning agents
  • Pest control systems
  • Plant-targeted products
  • Marine products
  • Food flavouring and packaging
  • Chemical reaction initiators or control agents

The market is complex, and varies depending upon which segment the product is being developed for. Some market segments are driven by need; others by desire. Consumer preferences dictate the development of controlled release to this area and can be strongly influenced by marketing and advertising strategies. The cost of goods is not always a limiting factor. Product differentiation or improved performance can often be achieved through controlled release science and technology.

OPPORTUNITY FOR LONG-TERM DELIVERY

In the final section of this article we will briefly compare the opportunities for controlled release products in the human and animal arenas. One way to do this is to compare the different lengths of durations each route for drug delivery can achieve in both the human and in animals (see Figures 2 and 3). Most striking is the oral route where ruminant animals can retain appropriately developed delivery systems for years, providing a unique opportunity for very prolonged drug delivery. In contrast, the shape and design of current intravaginal delivery systems for animals presents safety issues during prolonged use (damage to vaginal tissues), whereas in contrast the design of human vaginal rings makes them less irritating and permits much longer delivery durations. These figures should be viewed as an opportunity to apply failed delivery systems from one area to the other. For example, an oral tablet delivery technology developed for the human field, whose dissolution rate is far too long in comparison to gastrointestinal transit time, could be successfully applied to the animal field where very prolonged delivery via the rumen is required. A tablet formulation with a slow rate of erosion could be just what the veterinary formulation scientist is looking for.

Another way is to look at existing delivery systems and postulate the opportunity for human to veterinary cross-over and vice versa.

Transdermal Patches (Human to Veterinary)

Nowadays the science, technology and processing capability of the transdermal patch is well advanced. Many onlookers question why such a technology is not seen in the animal arena. Usually this is down to one of two reasons. One is that there are limited opportunities to adhere the patch directly onto the surface of the bare skin of the animal (whether it is a companion animal or a production or farmed animal). This problem arises due to the presence of dense coverings of animal hair and wool over virtually the entire body of the animal. Shaving a dog or a cat may sound like an option; however, owner dissatisfaction with this precludes it from being viable, although there are some places on a farmed animal that one might consider as an opportunity. Pigs, for example, appear relatively hairless. In these cases, the high drug loading means that large patches would have to be used that would result in poor adherence due to patch folding and stretching. Even if such problems could be overcome it would be likely that the inquisitive nature of the pig would result in fellow pen-mates nibbling off the patch out of interest.

Spot-Ons and Pour-Ons (Veterinary to Human)

In the veterinary area certain transdermal formulations comprise of highly permeable solutions or suspensions. These are simply poured onto the back of farmed animals or dropped onto the back of the neck of companion animals. Such a simple approach seems like an opportunity for human cross-over. However, the effectiveness of such products relies upon either the physicochemical properties of the drug (spot-ons), or harsh solvents (pour-ons) that would be unacceptable for use in humans. Innovative thinking, however, could result in the successful development of a human product that uses a similar concept to the pouron approach.

Rumen Bolus (Veterinary to Human)

The rumen of the farmed animal (cattle and sheep) affords an anatomical feature that permits veterinary formulation scientists the opportunity for very longterm retention of a delivery system in these animals. Such designs are not appropriate to solve the current desire of human scientists to develop a long-term retentive drug delivery system for the human stomach, however, the inventiveness of veterinary scientists in this area should not be dismissed. Human scientists interested in this area should review the patent literature for ideas that never made it for rumen retention.

Oral Mucosal Delivery Systems (Human to Veterinary)

Human products developed for local or systemic delivery via the mucosal lining the oral cavity include films, patches, pastes and tablets. Such delivery systems offer potential solutions to the ongoing and difficult problem of dosing cats. The cat is well known as a difficult animal to dose. Adhesive films or pastes currently used in the human field could find use for cats by incorporating the drug into such systems, adhering them onto the gums and then allowing the cat to lick off the medication over time.

Parenteral Delivery Systems (Human to Veterinary and Veterinary to Human)

The one area where the immediate possibilities for cross-over opportunities is apparent is in the area of parenteral drug delivery. The dosage forms (solutions, suspensions or implants) utilise the same formulation components, design approach, and physicochemical principles, anatomical and physiological features of human and animal skin are similar, doses can be easily changed for patient weight by administering different volumes, and both patient groups can tolerate the administration method of an injection or incision. Microparticles are a good example of technology cross-over in the parenteral area. Injection of solutions, suspensions and advanced delivery technologies (nanoparticles, liposomes and so on) are more advanced in the human area, whereas implant technology is more utilised and advanced in the veterinary field. It is interesting to note that the first commercially available microparticulate parenteral dosage form was a veterinary product that is still manufactured in New Zealand.

CONCLUSION

The same issues that face the veterinary scientist also face the human formulation scientist. In terms of manufacturing and compliance, controlled release products, whether they are destined for the human or veterinary market, are subject to the same standards of manufacture; both must meet and comply with the same cGMP requirements. This means that both fields must address the same issues and can benefit from the learnings and teachings of the other. Currently, an important and challenging question exists concerning stability, efficacy and safety. Namely, how can the developer of a new controlled release product assure regulatory authorities that the product will be as safe and efficacious as it was on the first day of manufacture when it is inserted into the animal on the last day of expiry? This question is far reaching, as it may potentially result in financial implications that could influence the final decision in a development process – in other words, the cost to demonstrate this attribute of the product could be prohibitory. The solution, however, could easily arise from scientists working in either the human or veterinary side of the interesting field of controlled release science and technology.

Controlled release science and technology finds many potential applications and offers many advantages to the areas of human health, animal health and production, and consumer and diversified products. The same science is used in each of these areas leading to products that utilise the same technology, or result in completely different outcomes, dependent upon which area and application the product is being developed for. Either way, scientists in the controlled release area (human health, animal health and production, and consumer and diversified products) can benefit from each other’s findings.


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Michael J Rathbone is Associate Professor of Pharmaceutics, School of Pharmacy, Griffith University, Australia. Previously he was the Director of Research at InterAg where he spearheaded the company’s modified release drug delivery research and directed its national and global collaborative research activities. He obtained his undergraduate degree in Pharmacy at Leicester Polytechnic, UK, and his PhD in Pharmaceutics from the University of Aston, Birmingham, UK. His research interests are in the area of systemic drug delivery via mucosal sites, the development of modified release drug delivery systems and veterinary drug delivery.

Padma V Devarajan is Professor and Head of the Department of Pharmaceutical Sciences and Technology at the Institute of Chemical Technology, Mumbai, India. With over 20 years of experience in teaching and research, she has supervised over 75 students for the Masters and PhD degree. Her research interests include innovative controlled release systems, targeted drug delivery in cancer and infectious diseases, bioenhancement strategies, and mucosal delivery systems. Her research presentations have won awards at national and international conferences and she is a Fellow of the Maharashtra Academy of Sciences. She has contributed over 100 presentations and publications, and has filed 20 patents (eight granted and two licensed).

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