Drug Administration and Delivery Systems
A route of administration is the path by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. Common examples include oral and intravenous administration. Routes can also be classified based on where the target of action is. Action may be topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered by routes other than the GI tract).Drug Administration and Delivery Systems
Routes of administration are usually classified by application location (or exposition). The route or course the active substance takes from application location to the location where it has its target effect is usually rather a matter of pharmacokinetics (concerning the processes of uptake, distribution, and elimination of drugs). Nevertheless, some routes, especially the transdermal or transmucosal routes are commonly referred to routes of administration. The location of the target effect of active substances is usually rather a matter of pharmacodynamics (concerning e.g. the physiological effects of drugs). Furthermore, there is also a classification of routes of administration that basically distinguishes whether the effect is local (in “topical” administration) or systemic (in “enteral” or “parenteral” administration).
- Drug delivery systems
- Nanobiotechnology
- Targeted drug delivery
- Controlled release
- Protein/peptide delivery Drug formulations
As governments tighten the screw on health care budgets, novel drug delivery systems have the potential to lessen the blow, according to a new report from Datamonitor.
The pharmaceutical industry is reaching a watershed in its long and successful history, says the report. No longer is the idea of pure research enough to justify the substantial profits made by pharmaceutical companies, and no longer is therapeutic benefit the sole driver behind clinical treatment.
As governments tighten their health care belts, the report continues, all levels of the health care industry, from pharmaceutical manufacturers to physicians, are being asked to provide value for money, and prove that they are doing so. In practice, these changes have led to a real reduction in the health care expenditure of the world’s developed countries, and to enforced price cuts or promises that prices will rise no faster than inflation. The buzzword, says Datamonitor, is pharmacoeconomics (see also page 17), measuring the economic effect of a drug as well as its clinical effect.
The US Food and Drug Administration has indicated that it will not allow “me-too” products to support a company in the 1990s, and this has forced companies to focus on the need to discover truly new therapeutic compounds. However, the research and development costs entailed in selecting a new compound for ground-breaking therapy are enormous, and not every player in the industry will be able to support this level of expenditure. Drug Administration and Delivery Systems
Datamonitor believes that the drug delivery industry offers a means of lessening “the blow delivered by the Hillary Clinton in the major governments.” Drug delivery systems have to be adjusted for each type of drug, but general principles can be applied to the initial stages of the formulation, and this is where drug delivery specialists can make their mark. With proprietary technology and experience, drug delivery specialists can provide reformulations for other companies or develop their own reformulations of existing or new drugs, at a cost far lower than developing an entirely new product.
This approach has already proved to be a formula for success. In the first section of Datamonitor’s report, opportunities in drug delivery systems, the basic structure of the industry and the potential strategies that a full-integrated pharmaceutical company could use to exploit the new technologies are assessed. The section also contains case studies looking at the difference drug delivery technology has made to existing markets.
For example, a delivery system developed by Alza has been applied to Pfizer’s Procardia XL/Adalat OROS (nifedipine), and turned the sustained-release formulation into a $1 billion-plus product in 1992, seeing off challenges from generic competition.
Perhaps surprisingly, the new formulation also gave Procardia XL a price advantage. In the UK, for example, licensee Bayer charges L11.76 for a 28-tab pack of 30mg tablets of Adalat OROS, which works out at a treatment cost of 42p/day. The standard form of the drug costs L1.63 for a 20-tab pack of 5mg tablets, working out at 50p/day. However, the standard daily-dose is 10mg three times daily, meaning that the standard form is actually three times as expensive as the sustained-release form.
The nearest competing generic form is a twice-daily formulation, and this works out more expensive than standard Adalat in the UK. Datamonitor notes that the price advantage that this gives to Bayer is enormous – if even generic companies cannot compete on price, there is no obstacle to continuing healthy Adalat OROS sales. Drug Administration and Delivery Systems
Nicotine and hormone replacement patches are another example of a delivery system which can transform a “mundane” compound. The use of technology to deliver therapeutic substances through the skin, which was previously thought to be an impenetrable barrier, has proved to be enormously popular for chronic administration of drugs.
Nicotine patches sold exceptionally well in their first year on the market (1992), but sales fell equally fast following disappointment with success rates, problems of using patches while smoking and concerns about marketing tactics. The patches were initially taken as a blockbuster development as consumer reaction was very good, but the need for behavioral modification as well as the purchase of the patches meant that success rates were as low as 25%. The second generation of nicotine patches, such as those under development at Cygnus, are expected to be more effective as they will target the heavier smoker, who will gain greater benefit from nicotine replacement.
Drug delivery systems can also improve the efficacy of drugs that have been discarded for present therapy. For example, a novel, liposomal formulation of the anticancer drug doxorubicin has vastly increased the efficacy of the drug in the treatment of lung and colon cancers due to the tendency of the new formulation to accumulate at the site of tumors, as well as significantly reducing the side effects profile. The drug delivery system has, in this case, allowed an existing drug, which is not subject to the prices which have to be charged for a new product, to increase its therapeutic index enormously.
Aside from increasing the efficacy and ease of administration of a treatment, drug delivery systems can extend the patent life of a drug. If a delivery system is covered by patents, then any new formulation of a drug in that delivery system will benefit from that protection, an example of this being Marion Merrell Dow’s Cardizem CD (diltiazem) cardiovascular drug.
However, even if the delivery system is off-patent, there is another, non-patent form of exclusivity that the manufacturers can benefit from. Any New Drug Application from the US Food and Drug Administration of a New Chemical Entity or a new dosage form/delivery system which is based, at least in part, upon the required submission of new clinical data is entitled to a non-patent regulatory exclusivity against abbreviated NDA approvals pending the expiration of the applicable exclusivity period, which is five years in the case of an NCE and three years for other approvals. Drug Administration and Delivery Systems
The reformulation of a drug into a new delivery form can therefore be used as a method of extending the high-revenue generating life of a product beyond the expiration of its patent, says Datamonitor.
At present, the stated aim of most of the drug delivery companies is to become fully-integrated pharmaceuticals companies in the medium- to long-term, notes the report. At present they are mostly royalty-intensive companies whose income depends partly upon the marketing efforts of other companies. Two of the largest companies in this area are Alza and Elan, and around 30% of their income comes from royalties. This means that the drug delivery company is a slightly uncertain investment, because it cannot know whether a partner will drop a product which contributes to its royalty stream.
The present market situation in the drug delivery industry is based around a form of R&D collaboration that has been called virtual integration. This allows companies to expand without necessarily increasing mass. The drug delivery companies with in-house technology and manufacturing are critically placed to take advantage of this phenomenon, as they can provide a cost-effective method of improving an existing drug or a NCE.
The Datamonitor report also discusses in some detail the scientific background behind the major new drug delivery technologies which are currently on the market or in development. An introduction reviews the factors which must be taken into consideration when selecting a drug delivery technology, as well as the advantages and disadvantages of controlled-release products. Five chapters then give a comprehensive review of each form of delivery in turn – oral delivery, transdermal delivery, liposomal delivery, respiratory delivery and a miscellaneous section. Drug Administration and Delivery Systems
Market Forecasts Datamonitor forecasts that some 10% of all drug sales will be for products using novel delivery forms by the turn of the century. On these estimates, somewhere near $30 billion of the total market in the year 2000 will flow not to the pharmaceutical giants, but in the forms of royalties or royalties to drug delivery companies (see table). Add this to the manufacturing revenues that these companies will earn on top of royalties, and these startup companies do not look so insignificant.
Those therapeutic categories where compliance with existing medication is currently a major problem, such as respiratory and cardiovascular drugs, will experience large growth. The success of once-a-day forms of cardiovascular drugs, such as Procardia XL and Cardizem CD, shows how effective a novel formulation can be in increasing sales of a drug, and this trend should continue.
A second trend is that formulations which increase efficacy will drive growth in the smaller therapeutic sectors. The cancer, endocrine and immunology categories are areas where the emergence of new or improved therapies will drive the market’s growth.
In 1993, cardiovascular drugs had the largest share ($2.9 billion) of the total drug delivery market, and this is expected to continue through to the year 2000, when sales of $7.7 billion are forecast. The second largest category in 1993 by therapeutic category was central nervous system agents ($1.1 billion), followed by endocrine agents ($345 million). By 2000, Datamonitor estimates that these two categories will have swapped positions, with the endocrine drug delivery market expanding to $5.8 billion, and the CNS market showing more modest growth to reach $2.52 billion. Other major sectors by 2000 will be cancer ($2.51 billion), immunology ($2.3 billion) and respiratory ($1.99 billion)Drug Administration and Delivery Systems