Alternative Delivery Routes

Another limitation of traditional adjuvants is the limited routes of administration, and to this end, efforts have been made to prepare polyphosphazene adjuvant formulations for mucosal delivery [25]. In recent work it was shown that PCEP combined with the influenza vaccine X 31 could be applied successfully via intranasal, oral and intrarectal routes [48], with intranasal application proving to be superior to the other routes tested. Moreover, a cooperative effect with enhancement of Thl-cell-mediated and Th2 humoral responses was observed, meaning mucosal delivery of PCEP adjuvants may prove to be an optimal route for protection against influenza viruses as well as with other vaccines. 

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Many therapeutic proteins must be delivered by injection as alternative delivery routes (e.g., oral) result in low bioavailability. This can be difficult,... 

Zanamivir (Relenza, 3.22) is used to fight the viruses that cause influenza A and influenza B (Figure 3.13). Because its oral bioavailability is low at only 2%, an alternative delivery route, inhalation, is required for zanamivir. As a possible demonstration of the public s general preference for oral drugs, oseltamivir (Tamiflu, 3.23), an oral influenza drug, far outsells the inhaled drug zanamivir. 

Particle design applied to pharmaceutical processing has the potential to improve the efficacy of current medications as well as to open the way to the use of alternative delivery routes. An example is the administration of drugs, such as insulin, that are subject to extensive gastrointestinal breakdown and thus cannot be administered orally. The alternative is parenteral administration, which has major side effects, especially in long-term or chronic conditions. 

The most important requirement is that the salt possesses sufficient solubility at physiologically compatible pH values to permit incorporation into the dosage form. Buffering the solution to an appropriate pH can often enhance solubility. Salts may also be prepared in situ in the formulation. This is particularly useful when the main route of administration utilizes the parent drug form. Where the aqueous solubility of the salt is not sufficiently high, co-solvents may need to be added to enhance solubility (e.g. propylene glycol is used as the vehicle in phe-nobarbitone sodium injection). Parenteral solutions based on co-solvent vehicles normally cannot be directly injected intravenously because there is the risk of precipitation at the injection site. Therefore, such products are diluted with isotonic saline or 5%w/v dextrose solution to produce a lower concentration that remains soluble and can be safely administered by infusion. Alternative delivery routes are by subcutaneous or intramuscular administration by which, in... 

Insulin is a hydrophobic peptide drug for diabetes. Diabetes mellitus is a serious pathologic condition responsible for major health care problems all around the world costing billions of dollars annually. In the United States, it represents the fourth leading cause of death. Diabetes also leads to severe complications such as kidney disease, retinopathy, neuropathy, leg or foot amputations and heart disease [2G. As a consequence of poor oral bioavailabiUty and current lack of alternative delivery routes, insulin is presently administered parentally. The subcutaneous route, requiring single or multiple daily injections, is the main stay of conventional insulin therapy [27]. 

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Parenteral administration is not perceived as a problem in the context of drugs which are administered infrequently, or as a once-off dose to a patient. However, in the case of products administered frequently/daily (e.g. insulin to diabetics), non-parenteral delivery routes would be preferred. Such routes would be more convenient, less invasive, less painful and generally would achieve better patient compliance. Alternative potential delivery routes include oral, nasal, transmucosal, transdermal or pulmonary routes. Although such routes have proven possible in the context of many drugs, routine administration of biopharmaceuticals by such means has proven to be technically challenging. Obstacles encountered include their high molecular mass, their susceptibility to enzymatic inactivation and their potential to aggregate. 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

The pharmacokinetics of intranasal lorazepam compared with oral administration have been evaluated in 11 volunteers in a randomized, crossover study (20). Lorazepam had favorable pharmacokinetics for intranasal administration compared with standard methods. Intranasal delivery could provide an alternative non-invasive delivery route for lorazepam. 

Alternate delivery systems are the focus of many laboratories throughout the world. The major routes selected are oral, pulmonary, intranasal, transdermal, vaginal, and others. Successful drug delivery discoveries are the result of interdisciplinary efforts of biochemists, chemists, engineers, physicists, pharmaceutical scientists, and clinical investigators. 

Topical delivery systems are intended to deliver the medicaments to body surface such as the skin or the mucus membrane. These systems minimize the problems associated with the conventional drug delivery systems. Hence, the delivery route may be used as an alternative... 

The oral route is undoubtedly the most widely investigated alternative administration route however, it presents major concerns in the delivery of macromolecular actives. The gastrointestinal route can promote degradation in the stomach due to the acidic gastric pH. The intestine has issues arising from the presence of proteolytic enzymes and insufficient permeation toward these actives, all of which result in limited bioavailability. Therefore, other routes of delivery have been investigated and the oral mucosal route presents a convenient alternative. 

Parenteral (injected) administration of drugs provides a solution to many problems associated with the oral delivery route. A drug injected into the blood circulation is considered to be completely bioavail-able thaefore, the quantity of the surfactants and otha inactive excipients in intravenous dosage forms are usually strictly limited. The most common alternative routes of parenteral drug administration are intramuscular or subcutaneous injections [2], Several otha injection routes are available to elicit rapid local reaction, such as intrathecal, intraarticular, and intracardiac. 

The pulmonary and transdermal routes are the least investigated of the alternative, nonparenteral delivery routes for insulin, and perhaps therefore they still hold some promise. The potential of pulmonary delivery for bolus therapy has been demonstrated as this route is feasible from a bioavailability standpoint, even without the addition of enhancers. However, long-term safety remains to be established. Inhalation of insulin may offer fairly reproducible absorption kinetics, but it is a major challenge from a device point of view to ensure reproducibility of the administered dose. 

Recent methods draw on natural mimicry to find best solutions by using swarms of either pseudo-ants or -bees to test a large number of possible alternatives to find the ones that work well. Ant colony methods are useful in other fields such as delivery route optimization (the traveling salesman problem), but in essence the natural systems are individually trying many options in parallel and reporting back to the other members of the colony about the success or otherwise of their attempts. In the natural world, this is encoded by a pheromone trail and in the computational world it is the upweighting of selection parameters [62,63]. 

A number of comparative researches exist in literatures, some of which have evaluated the utility of microemulsion and emulsion formulations against alternative delivery systems for antitumor agents. Furthermore, it has proven possible to formulate preparations suitable for most routes of administration. There is still, however, a considerable amount of fundamental work in order to figure out the physicochemical behavior of microemulsions that needs to be performed before they can live up to their potential as multipurpose drug delivery vehicles. 

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