Oral transmucosal administration

The skin is biologically intended to be a barrier. Evading this barrier is not easy, because drugs must traverse dead epithelium and live dermis the former is hydrophobic, while lipophilic drugs tends to form a reservoir in the latter. As in oral transmucosal administration, potent drugs, with modest requirements for mass absorbed and reasonable lipophilicity, are the best candidates for transdermal delivery. Fentanyl, nicotine, and scopolamine are good examples. 

F. Bektas, C. Eken and V. Sayrac, Opioid toxicity as a result of oral/ transmucosal administration of transdermal fentanyl patch, Eur. J. Emerg. Med., 2009, 16, 344-345. 

Dosages and routes of administration For acute (postoperative) pain and for anesthesia, fentanyl is given by the intravenous route. For pre-medication in anesthesia and for break-through pain the compound can also been given as an oral-transmucosal formulation (Ashburn and Streisand, 1994). A transdermal patch has been developed for chronic pain treatment (Jeal and Benfield, 1997 O Siordin, 1998). The intravenous doses for premedication are 50-100 pg, oral-transmucosal systems contain 200-400 pg and patch formulations have a delivery rate of 25-100 pg/h. 

The trends in parenteral, oral, rectal, transdermal, pulmonary and transmucosal administration will be described with the aid of products that are already on the market or are under development. 

An oral transmucosal formulation of etomidate, which is absorbed over 15 minutes, has been studied in 10 healthy adults at four doses 12.5, 25, 50, and 100 mg (25). Dose-related drowsiness and light sleep occurred 10-20 minutes after administration. Peak serum concentrations and clinical effects were noted at about 20 minutes, with no clinical effect noticeable by 60 minutes. There was no vomiting and only four patients had transient nausea. Two patients had brief episodes of involuntary tremor with the 100 mg dose. Of note was the increasingly unpleasant taste with increasing dose and the apparent reduction in absorption with higher doses. 

The more novel routes of administration of opioids, including oral, nasal, rectal, transdermal, spinal, and by patient-controlled methods, have been outlined (SEDA-17, 78). Oral transmucosal fentanyl administration, avoiding first-pass metabolism, produces analgesia and sedation in both adults and children undergoing short, painful outpatient procedures. The quality of analgesia is good, and the adverse effects are those typical of the opioids. 

In the field of bioresorbable polymers, dendrimers are usually not included. In contrast, polymerosomes, polymeric micelles, and polymeric NPs find a large number of applications as bioresorbable systems, mainly in dmg delivery. It is an extremely vast field of research that covers the development and use of innovative systems for the administration of pharmaceutically active ingredients. In this case there are numerous administration routes for dehvering the active ingredients loaded in these systems, such as oral, transmucosal, pulmonary, and intravenous. The preferable route is oral (noninvasive dehvery), although very often it is not feasible, as with anticancer compounds for which the intravenous route (invasive delivery) is preferred (Fig. 12.1) [1]. 

The nitrates are available in various forms (eg, sublingual, transmucosal, translingual spray, and inhalation). Some adverse reactions are a result of the metiiod of administration. For example, sublingual nitroglycerin may cause a local burning or tingling in the oral cavity. However, die patient must be aware that an absence of this effect does not indicate a decrease in the drug s potency. Contact dermatitis may occur from use of die transdermal delivery system. 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

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. 

If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, the fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation has been shown to be efficacious, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines have been shown to enhance the analgesic actions of the opioids and thus may be very useful adjuncts in the patient with chronic pain. 

Nitroglycerin (NTC) is distinguished by a high membrane penetrability and very low stability. It is the drug of choice in the treatment of angina pectoris attacks. For this purpose, it is administered as a spray, or in sublingual or buccal tablets for transmucosal delivery. The onset of action is between 1 and 3 minutes. Due to a nearly complete presystemic elimination, it is poorly suited for oral administration. Transdermal delivery (nitroglycerin patch) also avoids presystemic elimination. 

One of the key pieces to development of a successful drug product is the ability to deliver the drug to the site of action with minimal discomfort or inconvenience to the patient. For small molecule therapeutics, there is a wide range of options available for drug administration. Delivery via injection (IV, IM, and SC), oral, nasal, ocular, transmucosal (buccal, vaginal, and rectal), and transdermal routes is possible with small molecule drugs. However, the size of proteins and the complexity of their structures severely limit the routes of administration available to proteins. 

Metabolic pathways fentanyl buccal tablets have an absolute bioavailability of 65% following oral administration, compared to an absolute bioavailability of 50% following oral administration of fentanyl oralet. The difference is mainly due to the fact that 50% of the total dose administered of fentanyl buccal tablet is absorbed transmucosally vs. 25% of fentanyl oralet. The remaining half of the total dose of fentanyl buccal tablets and 75% of the total dose of fentanyl oralet is swallowed and undergoes more prolonged absorption from the gastrointestinal tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Therefore, a unit... 

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